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Utskriftsdato (27.6.2017)

Breast cancer

illustration breast cancer femaleBreast cancer is by far the most common cancer in women. 

The disease is characterized by a varied course, from rapidly growing tumors with early distant metastasis, to slow growing tumors which may stay in the breasts without metastasizing. 25-30% of these cases are agressive.

The majority of breast tumors are carcinomas. Sarcomatoid tumors are rare, but must be kept in mind as they are treated differently from other breast carcinomas.

Breast cancer rarely occurs in men.The treatment is similar as for women.

Incidence

Approximately 12.4 % of women will be diagnosed with breast cancer at some point during their lifetime. The risk of breast cancer increases with age and breast cancer primarily occurs in women over the age of 50. The average age at diagnosis is 62 years.

In 2017, it is estimated to be 252,710 new cases of female breast cancer in the United States (16).

 

 

Age-specific incidence of breast cancer, 2009–2013.

Source: Cancer Registry of Norway

 

 

Incidence of breast cancer, 1954–2013.

Source: Cancer Registry of Norway

Etiology of Breast Cancer

There is still lack of knowledge of the direct etiology of breast cancer development.

Risk factors

  • Hereditary
  • Sex
  • Hormonal circumstances (early menarche, late first-time birth, nullparity, and late menopause)
  • Atypical hyperplasia
  • Ionizing radiation
  • Estrogen use before 35 years
  • Protacted post-menopausal estrogen therapy
  • Previous breast cancer
  • Obesity, particularly combined with tallness (high BMI, especially > 30)
  • Alcohol, even in moderate amounts

Not all risk factors are equally important.

Factors reducing the risk

  • First pregnancy < 20-25 years
  • Multiple pregnancies < 25 years
  • Breastfeeding (15)
  • Asian descent
  • Regular exercise

Hereditary breast cancer

It is estimated that 5-10% of breast cancer cases is due to inheritance in the close family (first degree relatives such as mother, daughter, sister or grandmother).

BRCA1 and BRCA2 belong to a class of genes known as tumor suppressors. In normal cells BRCA1 and BRCA2 contributes to ensure the stability of the cell's genetic material (DNA) and prevent uncontrolled cell growth. Mutations in these genes raises risk of both breast and ovarian cancer.

In families with hereditary breast and ovarian cancer a mutation in one of the BRCA genes is common. Most families with accumulation of breast cancer have not simultaneous ovarian cancer, and there is usually not BRCA gene mutations. The reason for the accumulation of breast cancer in these families is not known. It is assumed to be caused by mutations in (so far) unknown genes. Almost all people with gene mutations belong to families who have had these mutations for a very long time. A gene analysis (Decaplex assay) detects these gene mutations. This genetic test will detect at least 50% of those with BRCA gene mutations in Norway, perhaps as much as 75%.

In addition to the few frequent BRCA gene mutations, there are a number of rare BRCA gene mutations. A normal gene analysis for frequent gene mutations does not exclude hereditary cancer or BRCA gene mutations. About one-third of patients with familial breast cancer have detectable BRCA gene mutations if one examines both genes completely, while almost all families with accumulation of both breast and ovarian cancer have detectable BRCA gene mutations. There is a transition now from rapid testing to complete analysis of genes (using modern sequencing techniques).

It is estimated that about 2% of patients with breast cancer have BRCA gene mutations. 

Criterias for referral to clinical geneticist

  • Proven gene mutation in the breast cancer patient
  • Accumulation of cancer in the family
    • Two sisters or mother-daughter with breast cancer before 50 years
    • Multiple instances of breast cancer in the family
    • Both breast and ovarian cancer in the family

One should be aware of breast and ovarian cancer where kinship is through men.

Histology of Breast Cancer

Proliferative changes in the breast

Premalignant lesions are recognized microscopically by abnormal proliferative activity in the ductal system (ductal) or in the glands (lobular), Without signs that the epithelial cells penetrating the basal membrane. If  penetration of the basal membrane is noted, it is an infiltrating carcinoma and it should be treated accordingly. 

Normally, the glands have two cell layers. Three or more cell layers are a sign of abnormal proliferative activity.

The lesions can be classified according to proliferation, cellular atypia and tissue architecture as shown below: 

  • Lobular and ductal epithelial hyperplasia without atypia
  • Lobular and ductal epithelial hyperplasia with atypia
  • Lobular carcinoma in situ (LCIS)
  • Ductal carcinoma in situ (DCIS) grade 1-3 (van Nuys grading) (2)

There is a gradual transition between the different types; therefore the classification is subjective and inter-observer variation must be considered.

Columnar cell lesions and Flat epitelial atypia (FEA)

The interest for these lesions has increased because they are seen more frequently in screening samples. Lesions with columnar epithelial cell in the terminal ductolobular entities may be divided into the following 3 types:

  • columnar cell change
  • columnar cell hyperplasia
  • flat epitelial atypia  

Columnar cell change  (CCC) and columnar cell hyperplasia  (CCH)

Lesions with enlarged ducto-lobular units with columnar epithelial without atypia covered with columnar epithelium without atypia including 1-2 layers of columnar epithelium (CCC) or  > 2 layers of cells (CCH). These entities are described under different names in the literature as for instance columnar metaplasia and blunt adenosis.)

Flat epitelial atypia (FEA)

Lesions with enlarged terminal ducto-lobular units with one or more layers of cubical or columnar epithelium of low grade celluar atypia. (This type is in the literature also called  clinging carcinoma (monomorphic type), atypical columnar cell lesion, columnar cell change with atypia, columnar cell hyperplasia with atypia).

There is a very low risk of recurrence or progression to cancer when these lesions present as isolated lesions. Since FEA most frequently is seen combined with other lesions the prognosis is difficult to predict. The WHO working group (2011) consider that the risk for cancer development is lower for FEA than for ADH and ALH.

When FEA is found in needle biopsies more sections should be taken to look for associated lesions. The need for routinely resection of  lesions with FEA is not clear. WHO working group 2011 recommends individual evaluation and possibly performing a wire located biopsy to exclude a more advanced lesion.

Lobular carcinoma in situ (LCIS)

LCIS is characterized by the overfilling of the terminal-duct lobular units with atypical epithelial cells, which have not penetrated the basal membrane. The proliferating cells are most frequently negative for the immunohistochemical marker E-cadherin. Based on the morphological appearance LCIS is divided into : classical, pleomorphic and florid type with comedo necrosis.

a) Classic LCIS has high-grade nuclei and are practically always discovered incidentally in a mammary resection specimen or a biopsy performed for a different histological type. The absolute risk for cancer development is around 10% at 10 years, 20% at 20 years and at life-long observation close to 30%. Infiltrating carcinoma in patients with LCIS will most frequently be of the ductal type.

The risk for developing invasive cancer is quite high in the contralateral breast as well as in the biopsied breast. Unilateral ablation therefore only reduces the risk by half. In the absence of a particularly heavy genealogy it is agreed that adequate follow-up care after proven classig LCIS is a yearly control includin mammography.

b) Morphologically, pleomorphic LCIS shows tumor cells with marked nuclear atypia comparable to that seen in high grade DICS. However, in contrast to DCIS, pleomorphic LCIS lacks E-cadherin expression. Since the histological subtype is newly recognized, the risk for subsequent development of invasive carcinoma is not clear. The risk is considered to be higher than classic LCIS and probably not similar to DCIS. This should be taken into account in the patient management.

c) Florid LCIS with comedo necrosis is characterized by distension of terminal-duct lobular unit by cohesive tumor cells with low-grade nuclei, often with central necrosis and calcification. This tumor is often detected by mammography. Morphologically, it resembles low-grade DCIS and it is recommended to manage as DCIS. (Ad therapy: it is also referred to WHO classification where the starting point is treatment of b and c (for instance render 2 mm), but that care/reflection is taken by more aggresive therapy, such as ablation).

Ductal carcinoma in situ (DCIS)

DCIS, also known as intraductal carcinoma, should not be confused with invasive carcinoma of the ductal type. In DCIS the milk ducts are filled with carcinoma cells which do not infiltratet the basal membrane encircling the duct. The cells ar most often positive for E-cadherin.

Previously, DCIS was a rare condition and constituted only between 1.4 and 5.3% of all newly diagnosed breast cancer cases. After the use of screening mammography, suspicion of such changes  has become more frequent (5-10%). In areas with established breast cancer screening DCIS will constitute 25-30% of new cancer cases in the first screening round, in later screening the frequency will be 10-20%.

Lobular carcinoma in situ (LCIS).
Click to enlarge the image.
Ductal carcinoma in situ (DCIS). Click to enlarge the image.

The main problem with DCIS is that the risk for local recurrence in the breast after resection alone is much greater than with other pre-malignant lesions in breast tissue.

Risk for recurrence is dependent on multiple factors, and is greater for:

  • Palpable than for nonpalpable DCIS tumors (3)
  • DCIS grade 3 than for DCIS grade 1 and 2 (3,4)
  • Diffuse spreading than for microfocal
  • Younger women (5)

It has been shown that the risk for recurrence increases with the size of the lesion. It has though, been difficult achieve good data on this correlation because it can be difficult to estimate the excact dimensions of the lesion, due to often several consecutive resections as well as heterogeneous classification and treatment.

Most recurrences are local and in close proximity to the primary scar. It is agreed in the literature that the resection margins should be microscopically free but the length in millimeters of the margin is discussed. NBCG has recommended at least 2 mm from the microscopic DCIS to the resection margin. This is due to the uncertainty of the histopathological  estimation of the resection margin. With such short free resection margin the histopathological examination must be very careful.

Invasive Carcinomas

 

Ablation specimen with tumor. Click to enlarge the image.

Seventy to 80% of invasive breast carcinomas are histologically of the infiltrating ductal type. Ten to 20% are of the infiltrating lobular type while other types constitute the rest. Some of these types have better than average prognosis for example tubular carcinoma, medullary carcinoma, mucinous carcinoma, and adenoid cystic carcinoma. Other types (without particularly good prognosis) are papillary, secretory, and apocrine carcinoma. Paget’s disease of the nipple is almost always connected with an underlying ductal carcinoma.

The pathology group of NBCG has distributed well defined criteria for histological grading of breast carsinomas to all pathology laboratories in Norway. All invasive carsinomas shall be graded after the same criterias. DCIS are graded after Van Nuys grading. In addition Her2 examination should be performed (by means of immunohistochemistry and/or FISH/CISH/SISH) and immunohistochemical examination of Ki67 (quantified according to a defined schedule). The IHC kits are standardized for histological specimens but may also be used on cellblocks from cytological material.

In addition, Her2 analysis should be performed (with the help of immunohistochemistry and/or FISH/CISH).

Infiltrating ductal carcinoma grade I. Click to enlarge the image. Infiltrating ductal carcinoma grade III. Click to enlarge the image.

 

Infiltrating lobular carcinoma. Click to enlarge the image. Infiltrating mucinous carcinoma. Click to enlarge the image.

 

The pathological/anatomical investigation should include information about:

  • Tumor localization, (possibel multifocality)
  • Tumor dimensions (in millimeter) tumor area in case of diffuse growth (typical for lobular carsinoma). and one or several tumofoci should be stated.
  • Histological type 
  • Histological grading 
  • Tumor extension, localization, and grade of DCIS in an invasive carcinoma 
  • Tumor’s relation to resection margins (given in mm), also possibly to the skin and to the breast wall 
  • Number of lymph nodes with metastases and total number of  investigated lymph nodes 
  • Size of the largest proven lymph node metastasis 
  • Perinodal tumor infiltration, including description of whether this is macro- or only microscopical, and description of possible islands of tumorcells in the fat. Hormone receptor analysis based on immunohistochemistry or  -cytology 
  • HER2 status 
  • Ki67 status

Immunohistochemistry. Negative ER. Click to enlarge the image.

Immunohistochemistry. Positive ER. Click to enlarge the image.

 

HER2 immunohistochemistry. Score 1+ Negative. Weak brown staining around the cells. Click to enlarge the image. HER2 immunohistochemistry. Score 2+Non-conclusive. No membrane staining around all cells. Click to enlarge the image. HER2 immunohistochemistry. Score 3+ Positive. Strong brown staining around all cells. Click to enlarge the image.

Immunohistochemistry is performed to determine HER2 amplification in the tumor. The result is graded from 0–3+, where 0 and 1+ are clearly negative and 3 is clinically positive. For a score of 2+, and additional FISH test is performed to confirm HER2 amplification. 

 

Negative FISH. Positive FISH.

FISH test to determine HER2 amplification. An excess of red dots (picture to the right) indicates HER2 amplification in the tumor (positive FISH). A balance between red and green (picture to the left) dots indicates no HER2 amplification (negative FISH).

In addition other tumor markers exist (oncogenes, proliferation markers, ploidity examination) which can be examined on both histological and cytological tumor material to present some additional information for special patient groups. At present there is no general consensus for inclusion of these analyses in routine pathology in Norway. 

Sarcomatoid tumors

Sarcomatoid carcinomas

Sarcomatoid carcinomas are tumors with malignant epithelial and heterologic elements. These tumors constitute less than 1% of malignant tumors in breast cancer. Clinically, there are small differences from the regular carcinomas. Microscopically, there is a varying degree of epithelial differentiation, either in the form of DCIS and/or epithelial differentiation of the invasive component. Sometimes, the epithelial differentiation can only be identified by means of the immunohistochemical analyses with epithelial markers or electron microscopy. The sarcomatoid component appears most often as variations of a high-grade malignant sarcoma. The tumors metastasize most often hematogenously.

Phyllodes tumors

WHO defines a phyllodes tumor as "a more or less well-defined lesion consisting of connective tissue and epithelial elements, as in fibroadenomas, but with larger cell density and varying degrees of atypia in the stromal component." Phyllodes tumors consists of a broad spectrum of fibroepithelial lesions and are classified as benign, borderline, or malignant. A benign phyllodes tumor can be difficult to differentiate from a fibroadenoma. It is usually larger and the shear section has a furcate appearance. It is important to differentiate a phyllodes tumor from a fibroadenoma, as a phyllodes tumor has a pronounced tendency to relapse. In middle-aged and older patients, phyllodes tumors occur more often than fibroadenomas. The relapse tendency pertains to both the benign and the malignant phyllodes tumors. One must be aware that apparent benign phyllodes tumors can be heterogeneous, with malignant areas. A malignant relapse after previous removal of a benign phyllodes tumor can on rare occasions occur. A malignant phyllodes tumor can further dedifferentiate to a higher grade malignant sarcoma. Metastases occur hematogenously.

Metastatic Patterns of Breast Cancer

The mode of metastatic spread depends on anatomical, physiological and molecular and biolological peculiarities of the tumor.

The disease can spread (disseminate) both lymphatically and hematogenously. Most often tumorcells invade lymph vessels and spread to regional lymph nodes, primarily to the axillae.The lymph node involvement depends on the location of the primary tumor in the breast. Hematogenous dissemination leads to metastasis in the bone (40-75%), lung/pleura (2-15%) and liver (3-10%), but also in other organs, for example the brain or skin.

There are steadily more patients having breast cancer which is confined only to the breast at the time of diagnosis. More than 60% of all the patients have no lymph node metastasis, while approximately 25% have positive axillary lymph nodes. The remaining patients have a locally advanced disease, either in the form of a large tumor or growth into the skin and chest wall. A small portion of patients have spreading to other organs.

The number of patients having distant spread at the time of diagnosis has remained stable in the last years. It is important to distinguish between breast cancer patients with locoregional metastasis only (curable) and those with distant metastasis (incurable).

Staging of Breast Cancer

TNM Classification

The TNM system describes the anatomical extent of the disease at presentation. “T” refers to the extent of the primary tumor in and around the breast. “N” (node) refers to the absence or presence and extent of regional lymph node metastasis. “M” refers to the absence or presence of distant metastasis. 

The TNM classification differentiates between the clinical classification (TNM) and the pathological classification (pTNM).

The classification is the decisive factor for determining of adjuvant treatment and prognosis.

Primary Tumor (T)

  • TX – Classification is not possible due to lack of information.
  • T0 – Primary tumor not identified.
  • Tis – Carcinoma in situ. 
    • Tis DCIS – Ductal carcinoma in situ 
    • Tis LCIS - Lobular carcinoma in situ
  • T1 – Tumor ≤ 2 cm in the largest dimension
    • T1mic – Tumor ≤ 0.1 cm in the largest dimension
    • T1a – Tumor >0.1≤0.5 cm in the largest dimension
    • T1b – Tumor >0.5 ≤ 1 cm in the largest dimension
    • T1c – Tumor > 1≤ 2 cm in the largest dimension
  • T2 – Tumor > 2 ≤ 5 cm in the largest dimension 

/upload/mammae/bryst_t1_2.gif 

  • T3 – Tumor > 5 cm in the largest dimension
  • T4 – Tumor independent of size, growing into the skin or breast wall
    • T4a - Invasion of the breast wall (the rib, intercostal musculature, serratus anterior)
    • T4b – With edema, infiltration or ulceration of the skin of the breast including peau d’orange, or satellite skin tumors of the same breast
    • T4c – Both T4a and T4b
  • T4d – Inflammatory carcinoma 

/upload/mammae/bryst_t3_4.gif 

  Clinical lymph node status (N)

  •  NX – N-classification not possible due to lack of information
  •  N0 – No apparent regional lymph node metastases
  •  N1 – Movable ipsilateral axillary lymph node metastasis
  •  N2 – Ipsilateral axillary lymph node metastases fused to each other or other structures or clinically or radiological identifiable metastasis to ipsilateral mammary internal lymph nodes and absence of clinically apparent axillary lymph node metastasis 
    • N2a – Ipsilateral axillary lymph node metastases fused to each other or other structures
    • N2b – Clinical or radiological apparent metastases to ipsilateral internal mammary lymph nodes in the absence of clinically visible axillary lymph node metastases 
  • N3 – Ipsilateral spreading of infraclavicular lymph nodes or spreading to clinically or radiologicaly identifiable ipsilateral internal mammary lymph nodes and simultaneously clinically apparent axillary lymph node metastases; or ipsilateral spreading to supraclavicular lymph nodes with or without axillary or internal mammary lymph node metastases   
    • N3a – Clinically identifiable ipsilateral infraclavicular lymph node metastases and axillary lymph node metastases
    • N3b – Clinically or radiologically apparent ipsilateral internal mammary lymph nodes and simultaneous clinically axillary lymph node metastases 
    • N3c – Clinically identifiable ipsilateral supraclavicular lymph node metastases

Histological lymph node status (pN)

  • pNx – N - classification is not possible due to lack of information
  • pN0 – No histologically apparent regional lymph node metastasis, not performed immunohistochemical examination for visualization of tumor cell clusters < 0.2 mm
    •   pN0(i-) – no histologically apparent regional lymph node metastases, negative immunohistochemical analysis
    •   pN0(i+) – No apparent regional lymph node metastases, positive immunohistochemical analysis, but no tumor cell clusters > 0.2 mm
    •    pN0(mol-) – No apparent regional lymph node metastases, negative molecular examination (rt-pcr)
    •   pN0(mol+) – No apparent regional lymph node metastases, positive molecular examination (rt-pcr)
  • pN1(mi) – Micrometastasis > 0.2 ≤ 2.0 mm in the largest diameter
  • pN1 – Metastasis to 1-3 axillary lymph nodes and/or microscopically apparent spread to internal mammary lymph nodes after sentinel node examination (not clinically apparent) 
    • pN1a – Metastasis to 1-3 axillary lymph nodes
    • pN1b – Microscopically identifiable spread to internal mammary lymph nodes after sentinel node examination (not clinically visible)
    • pN1c – Metastasis to 1-3 axillary lymph nodes and microscopically apparent spread to internal mammary lymph nodes after sentinel node examination (not clinically identifiable)
/upload/mammae/bryst_pn1.gif

 

  • pN2 – Metastasis in four to nine axillary lymph nodes, or in clinically or radiologically apparent ipsilateral internal mammary lymph nodes in the absence of axillary lymph node metastasis
    • pN2a- Metastasis to 4-9 axillary lymph nodes (greatest metastasis > 2.0 mm)
    • pN2b – Metastasis to clinical or radiological identifiable ipsilateral internal mammary lymph nodes in the absence of axillary lymph node metastasis

/upload/mammae/bryst_pn2.gif 

  • pN3 – Metastasis in 10 or more axillary lymph nodes, or in infraclavicular lymph nodes, or in clinically identifiable ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph nodes, or in more than 4 axillary lymph nodes with clinically negative microscopic metastasis in internal mammary lymph nodes or in ipsilateral supraclavicular lymph nodes
    • pN3a – Metastasis in 10 or more axillary lymph nodes (at least one tumor deposit greater than 2.0 mm), or metastasis to the infraclavicular lymph nodes
    • pN3b – Metastasis in clinically or radiologically apparent ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph nodes, or metastasis to ≥ 4 axillary lymph nodes in the presence of microscopic disease detected by sentinel lymph nodes dissection but not clinically apparent
    • pN3c – Metastasis in ipsilateral supraclavicular lymph nodes

/upload/mammae/bryst_pn3.gif 

  Metastasis (M)

  • MX – M- assessment not possible due to lack of information
  • M0 – No apparent metastasis 
  • M1 – Metastasis

Staging

Staging is applied for the determination of adjuvant treatment.

The staging for breast cancer has previously not been conformal to the international practice.

The Norwegian has been based on the staging by the Norwegien Cancer Registry. For instance has patients with T2 tumors  been classified as Stage I, in contrast to international staging lassifying them as stage II. This difference is not satisfying. Therefore The Norwegian Breast Cancer Group (NBCG) has adopted the international practice (UICC).  According to the Iast TNM classification patients with supraclavicular lymph node metastases will be classified as N3 and not M1 (6,7). This means that these patients in the future will be classified as stage III.

In the overview below, the staging is categorized according to whether the breast cancer is considered primary operable or inoperable. 

Primary operable cancer
Stage I T1N0M0
Stage II T0-2N1M0
  T2N0M0
Primary inoperable cancer
Stage II T3N0M0
Stage III T0-2N2M0
  T3N1-2M0
  T4N0-2M0
  T0-4N3M0
Stage IV T1-4N0-3M1

 

Symptoms of Breast Cancer

In most cases, patients with early breast cancer have no symptoms and their disease is discovered through mammography screening.

The following symptoms may be caused by breast cancer:

  • A palpable mass in the breast
  • A palpable mass in the axilla
  • An ulcer of the skin of the breast
  • Skin or nipple inversion or a nipple pointing in abnormal direction
  • Skin discoloration where underlying abscess is not the most probable diagnosis
  • Eczema-like changes on or around areola
  • Skin thickening/peau d`orange of unknown etiology
  • Nipple discharge or blood-containing secretion

Breast cancer in young women is quite rare. Changes in breasts of women under 35 are often caused by hormones and vary with the menstrual cycle. These can disappear spontaneously, so it is recommended to observe for 1-2 months/menstruation cycles before an assessment is made.

Differential Diagnoses of Breast Cancer

  • Benign papilloma
  • Adenoma
  • Cyst
  • Fibroepithelial tumor
  • Myoepithelial or mesenchymal tumor
  • Fibrocystic changes
  • Irradiated scar
  • Fatty tissue necrosis

By means of X-ray/ultrasound examinations and cytological examination/histological biopsies, it is usually easy to distinguish a carcinoma from a benign differential diagnosis of tumor/lump/swelling in the breast.

Prognosis of Breast Cancer

The earlier female breast cancer is caught, the better chance a person has of surviving five years after being diagnosed. 61.4% are diagnosed at the local stage and the 5-year survival for localized female breast cancer is 98.8%. Overall, female breast cancer survival is good. However, women who are diagnosed at an advanced age may be more likely than younger women to die of the disease. The number of female breast cancer deaths is highest among women aged 55-64.

Female breast cancer is the fourth leading cause of cancer death in the United States. Death rates have been falling on average 1.8% each year over 2005-2014.

In the United States, the five-year relative survival for patients with breast cancer, during the diagnosis period 2006-2012, is 90,8% for females. (Rate per 100 000 person-years).

In 2014, there were an estimated 3,327,552 women living with female breast cancer in the United States. (1)

 

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References on Breast Cancer

  1. Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2014, National Cancer Institute. Bethesda, MD
  2. Silverstein MJ, Poller DN, Waisman JR, Gierson ED, Colburn WJ, Waisman JR et al. Prognostic classification of breast ductal carcinoma-in-situ. The Lancet 1995; 345: 1154-7
  3. Kerlikowske K, Molinaro A, Cha I, Ljung B-M, Ernster VL, Stewart K et al. Characteristics associated with recurrence among women with ductal carcinoma in situ treated by lumpectomy. J Natl Cancer Inst 2003; 95: 1692-702 
  4. MacDonald HR, Silverstein MJ, Mabry H, Moorthy B, Ye W, Epstein M et al. Local control in carcinoma in situ treated by excision alone. Incremental benefit of larger margins. Am J Surg 2005; 190: 521-25
  5. Schouten van der Velden AP, Peters PHM, Koot VCM, Hennipman A. Local recurrences after conservative treatment of ducatal carcinoma-in-situ of the breast without radiotherapy: The effect of age. Ann Surg Oncol 2006; 13(7): 990-98
  6. TNM Classification of Malignant Tumours, 6th Edition L. H. Sobin (Editor), Ch. Wittekind (Editor)
  7. Greene FL, Page DL, Fleming ID, Fritz A, Balch CM, Haller DG et al. AJCC Cancer Staging Manual, Sixth Edition. New York, NY, Springer-Verlag, 2002
  8. Nasjonalt handlingsprogram med retningslinjer for diagnostikk, behandling og oppfølging av bryst (2014), Helsedirektoratet (National guidelines for diagnostic, treatment and follow-up care of breast cancer, Norwegian Directorate of Health)
  9. Early Breast Cancer Trialist’s Collaboratory Group (EBCTCG) Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomized trials. Lancet 2005; 366: 2087-2106
  10. Vinh-Hung V, Verschragaegen C. For the breast conserving surgery project. Breast conserving surgery with or without radiotherapy: pooled analysis for risks for ipsilateral breast tumor recurrence and mortality. JNCI 2004; 96(2): 115-121
  11. Khatcheressian JL, Wolff AC, Smith TJ, Grunfeld E, Muss HB, Vogel VG et al.  American Society of Clinical Oncology. American Society of Clinical Oncology 2006 update of the breast cancer follow-up and management guidelines in the adjuvant setting. J Clin Oncol. 2006 Nov 1;24(31):5091-7. 
  12. Goldhirsch A, Glick JH, Gelber RD, Coates AS, Thurlimann B, Senn HJ; Panel members. Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol. 2005 Oct;16(10):1569-83.
  13. Delay E et al. Fat injection to the breast: technique, results, and indications based on 880 procedures over 10 years. Aesthet Surg J 2009;29:360-76
  14. Rigotti G et al. Determining the oncological risk of autologous lipoaspirate grafting for post-mastectomy breast reconstruction. Aesthetic Plast Surg 2010;34:475-80
  15. Horta, B.L., Bahl, R., Martines, J.C., & Victora, C.G. (2007). Evidence on the long-term effects of breastfeeding: Systematic reviews and meta-analyses (Report). Geneva: World Health Organization. Retrieved from: http://whqlibdoc.who.int/publications/2007/9789241595230_eng.pdf

 

 

Diagnostics of Breast Cancer

The triple diagnostics is the basis for a safe and rational breast work-up and consists of:
  • a clinical examination
  • image diagnostics
  • needle biopsy

Clinical Examination

Systematic inspection and palpation of the breasts, axilla, and infra- and supraclavicular fossa provide the basis for further diagnostics.  Palpatory findings are recorded with localization (four quadrants and retroareolar area), size in millimeters, consistency, and mobility in relation to surrounding structures.

Image Diagnostics

Clinical mammography is performed in women who have symptoms or signs in the breasts. Mammography is also used as screening to identify tumors in the pre-clinical phase.

Ultrasound examination (ultrasonography) is today a very important supplement to mammography.

Magnetic Resonance Imaging (MRI) is a great improvement in breast diagnostics due to the high sensitivity for invasive breast carcinoma. In most studies, the sensitivity is found to be around 95-97%. With ductal carcinoma in situ (DCIS), the sensitivity is however considerably lower. Mammography and ultrasound are the fundamental diagnostics, while MRI is only indicated in special cases.

Needle Biopsy

Fine needle aspiration cytology (FNAC) can be done where there is a clinically apparent/palpable lesion.

Non-palpable, mammographic and/or ultrasound apparent lesions can be punctured with a fine needle using ultrasound guidance or ultrasound-guided core biopsy.

Ultrasound guided core biopsy is used in addition to or alone, for the same indications as the fine needle biopsy.

A patient program for breast cancer

A "Patient program" for cancer shall provide predictability and security for patients and their families and is a national standardized process which is evidence based .

The general practitioner should do a clinical examination of the breast and axillae before referring to "Patient program". A private imaging institute should carry out a mammography and ultrasound examination with preferably ultrasound-guided core biopsy.

Criteria for referral to "Patient program"

Justified suspicion of breast cancer occurs when one or more symptoms exists:

  • Palpatory suspect tumor. A palpatory suspect tumor is usually fixed and not well-defined. It can be fixed to the surrounding tissue, skin or fascia
  • Newly occuring nipple inversion which is not possible to retract
  • New skin inversion
  • Wounds or eczema-like changes on or around the nipple or areola
  • Clinically suspicious lymph nodes in the armpit

Examination for invasive breast cancer

When the diagnosis is verified, it is important to identify whether it is an operable (T1-2NO-1M0) or inoperable (T3-4N0-3M0-1 or T1-2N2-3MO-1) tumor. This has implications for which examinations are appropriate and for the choice of treatment.

Operable

Blood tests and x-ray examination of lungs are not considered mandatory for screening examination of metastases if the patient does not belong to a high-risk group. These examinations will be performed according to the general medical evaluation.

If there is no anamnestic information, symptoms or signs rising suspicion of distant metastases, the preoperative examination will be limited to:

  • Mammography/ultrasound

Postoperative evaluation of high-risk groups with operable mammary cancer

These patients should be evaluated for metastases before adjuvant treatment if this does not significantly delay start of treatment.
The following groups are considered at high risk:

  • Lymph node positive HER2 positive patients
  • Lymph node positive trippel negative patients

Primary inoperable

In women with locally advanced disease or metastatic disease, it is necessary to perform additional examinations before treatment regimen is decided.

For primary inoperable cancer, the following examinations are performed:

  • blood tests (preoperative routine tests including ALP, gammaGT, and s-Ca++)
  • CT of thorax, abdomen and pelvis
  • ultrasound or CT of liver (if needed)
  • bone scintigraphy (supplemented with X-ray if needed) or MRI of the spine/pelvis
  • mammography (also for possible response evaluation of systemic treatment) and ultrasound of breast/axilla and possibly MRI of the breast
  • other examinations on individual indications

Each case should be discussed with an oncologist before implementation of treatment.

Cardiac examination

MUGA or ECHO examination of the heart should be performed in patients who are to be treated with FEC100 regimen (HER-2 positive and locally advanced), to disclose the tolerability.

PROSEDYRER

Mammography

General

Mammography can reveal a tumor in the preclinical phase before it is palpable.  The examination renders three-dimensional structures in two dimensions.

Mammography is highly sensitive for revealing tumors in women with normal tissue density or parenchyma atrophy. However, the tumor may in rare cases be missed due to uncharacteristic appearance and growth pattern.

In women with dense tissue structure (abundant fibroglandular tissue/fibroadenomatosis), the sensitivity is lower.

Even if multiple projections are used with good compression, over projection of normal tissue can cause diagnostic difficulties. Ultrasound examinations (ultrasonography) are today a very important supplement to mammography. In very young women, with a probably benign palpable tumor, ultrasound may replace mammography as a primary examination.

Indications

  • Symptoms due to malignant disease or an infectious condition
  • Increased breast cancer risk 
  • Woman selected through the mammography screening program
  • Follow-up

In young women, mammography should only be performed for strict indications, for example cancer suspicion or for hereditary cancer risk.

Goal

  • Diagnose breast cancer

Definitions

Clinical mammography

Patients are referred for clinical mammography with breast symptoms and for suspicious result at mammography screening. 

The examination is performed at a diagnostic center for breast cancer with a radiologist present.

The radiologist will decide based on the image diagnostics and/or the clinical profile if there is need for supplementary examinations (supplementary mammography, ultrasound, intervention, MRI).

Mammography screening

Systematic organized mammography examination of women to discover breast cancer at an early stage.

The Norwegian Mammography Programmme became nationwide from February 2004, and offered women between the ages 50-69 two-dimensional mammography of each breast every second year. This program is quality-controlled enforcing European guidelines for mammography screening.

Special conditions for mammography screening

  • Women with implants ( silicone prosthesis) are invited even if the diagnostics are less certain in case of prosthesis.
  • Women with hereditary cancer risk are entitled to mammography every year till 60 years of age according to the national procedures. The department of medical genetics will decide the claim for annual examination.
  • Women operated for breast cancer shall be followed up for 10 years according to the schedule of NBCG. Subsequent to mastectomy the patient may after 50 years of age participate in the Mammography program and be referred to clinical mammography biannualy. After 10 years all patients above 50 years of age should be offered participation in the Mammography program similarly to those without breast cancer. Patients, who after 10 years have not reached the age of screening, should continue with clinical mammography until they may participate in the Mammography program.
  • Ultrasound examination is not included in the mammography program even not for women with implants.

Preparation

Mammography does not require any special preparation of the patient.

Implementation

  • The examination is performed standing or sitting if necessary.
  • Under graded compression of the breast, X-ray images are taken in two planes. This is done bilaterally.
  • Compression may be uncomfortable.
  • If necessary, additional pictures are taken.

In women with silicone implants:

  • The breast is fixed, but with less compression.
  • Images are taken with a modified technique.
  • Clinical mammography is most often supplemented with ultrasound.

Examples of mammography images

  Horisontal plane. No pathology.

  Vertical plane. No pathology.

  Horisontal plane. Suspect lesion.

  Vertical plane. Suspect lesion.

Mammography may be supplemented with ultrasound to increase the diagnostic precision, especially with clinically palpable tumors and uncertain mammography findings. Ultrasound alone is not suitable for examination of the whole breast.

Follow-Up

The result of an examination is usually available within one week.

In some cases, the patient may need supplementary mammography, possibly also ultrasound.

After breast conservation treatment

  • Follow-up is performed yearly for the first 10 years.
  • Subsequently the patient may participate in the Norwegian Mammography program

Both breasts should be examined. Two images may be taken with enlargement over the scar(s) in one or two dimensions.

After ablation

  • Follow-up is performed yearly for the first 10 years after treatment.
  • Subsequently the patient may participate in the Norwegian Mammography program.

Hereditary breast cancer 

Women with known risk for hereditary breast cancer based on family history (no known gene defect) should be screened annually from age 30. From 60 years, they should be screened every other year.

With a known gene defect, MRI is recommended from 25 years. In addition to MRI,  mammography should be done. Ultrasound is performed if the MRI findings are ambiguous.

MammographyMammographyMammographyMammography
MammographyMammography

Ultrasound-guided Fine Needle Biopsy

General

Fine needle aspiration cytology (FNAC), also called fine needle biopsy, is performed on palpable lesions in the breast and in cases of inconclusive ultrasound findings. Under the guidance of palpation or ultrasound, the method is both simple and quick.

A positive cytology result confirming a breast cancer diagnosis can be sufficient for further treatment measures if there is agreement between cytology, radiology, and the clinical examination.

The method requires a close collaboration between cytologist, radiologist, and clinician. Therefore, the method is being frequently replaced, both in Norway and internationally, frequently by coarse needle core biopsy.

Indications

  • Diagnostics

 Goal

  • To conclude if a lesion, palpable or non-palpable, is benign or malignant.

Equipment

  • Ultrasound apparatus
  • Biopsy needle

Preparation

Testing with the help of a fine needle is not very painful and does not require local anesthesia.

Implementation

  • The actual lesion is localized by means of ultrasound.
  • One to two samples are usually taken.
  • The puncture area is compressed in case of bleeding.

Follow-up

  • The patient may go home after the procedure.
  • The result from the test(s) is usually available after 1-3 days.

Ultrasound-guided Core Biopsy

General

Ultrasound-guided core biopsy is utilized for diagnosing inconclusive findings in the breast, either as an independent method or as a supplementary examination after a fine needle biopsy. In most breast diagnostic centers, core biopsy is preferred as a diagnostic method before breast cancer surgery.

There is an indication for core biopsy if the cytology result does not provide a conclusive diagnosis, or if there is lack of agreement between cytology results, image diagnostics, or clinical examination.

Indications

  • Diagnostics
  • Special analysis of a known malignant lesion

Goal

  • To conclude whether a lesion, palpable or non-palpable, is benign or malignant.

Equipment

  • Ultrasound apparatus
  • Local anesthesia
  • Biopsy gun
  • Needles (14G and 16G)

Preparation

  • Local anesthesia is injected through a thin needle.
  • It is important that the patient is able to lie still during the examination. The patient must be informed that the biopsy gun gives a moderate crack when the sample is taken to prevent her from spontaneous movement.
  • Ultrasound-guided core biopsy may be performed regardless of anticoagulation treatment.

Implementation

The examination is performed aseptically.

  • The lesion is localized by means of ultrasound.
  • The breast is disinfected.
  • Local anesthesia is applied.
  • An incision is made for the puncture.
  • The biopsy needle is inserted onto the lesion during ultrasound guidance.
  • When the gun is “fired”, the needle thrusts 22 (or 15) mm forward, first the core needle then the external casing.
  • The biopsy remains in a notch in the core needle.
  • Usually 1-3 samples are taken.
  • The area of puncture is compressed after the biopsy is taken.
  • Patients on anticoagulation are observed up to 30 minutes after the procedure.
  • The incision is bandaged.

Follow-up

The patient can go home after the procedure.

The patient should:

  • Observe the puncture point for possible bleeding
  • Minimize physical activity and should not lift heavy objects or do sport activities the same day
  • Wait until the next day to shower

Pain reducing drugs such as paracetamol should be used as needed (no salicylate drugs).

Results are usually available in 4-7 days.

Stereotactic-guided Core Biopsy

General

Stereotactic-guided (X-ray guided) biopsy is indicated when ambiguous mammographic findings cannot be localized by ultrasound. This applies especially for calcium containing lesions. The examination can be done as a core biopsy (gun technique) or vacuum technique.

Cancer in situ is often manifested as calcium deposits in mammograms. The method is therefore vital for the diagnosis of this condition.

Indications

  • Diagnostic

Goal

  • To clarify whether a mammography lesion is benign or malignant, and if possible, to determine the diagnosis.

Equipment

  • Special examination table and X-ray equipment
  • Local anesthesia
  • Biopsy gun
  • Gun or vacuum apparatus with needles 14G or 10G

Preparation

If the patient is under anticoagulation treatment, biopsy gun is preferred rather than vacuum biopsy, in most cases.

Implementation

The procedure is performed aseptically.

  • The patient lies in the prone, lateral, or sitting position.
  • The breast is fixed.
  • The lesion is localized by means of X-ray images from two angles.
  • The stereotactic apparatus is mounted.
  • The breast is disinfected and local anesthetic is applied.
  • The biopsy equipment is prepared.
  • 5-6 biopsies are usually taken with slightly different positions of the needle.
  • For a calcium containing lesion, the biopsies are put on a piece of X-ray film and X-rayed to determine whether the samples are representative.
  • The area of puncture is compressed after the biopsy is taken.
  • Patients on anticoagulants are observed for 30 minutes after the procedure.  This is also done if the examination is done with a vacuum technique.
  • The incision is bandaged.

Follow-up

The patient can go home after the procedure.

The patient should:

  • Observe the incision for possible bleeding.
  • Minimize physical motion and avoid heavy lifting or sport activities the same day.
  • Wait until the following day to shower.

If pain medication is needed, paracetamol may be taken (no salicylate drugs).

The result of the test(s) is usually available after 4-7 days.

Treatment of Breast Cancer

The aim of the treatment differ between presence of localized disease only (in the breast and regional lymph nodes) and if verified metastatic disease.

In localized breast cancer, the goal is always curative. With metastases, there is currently no curative treatment. The goal is then to minimize symptoms and maintain the disease under control. There are a variety of treatment options which in turn can achieve good results.

Treatment of localized breast cancer is today often multimodal. Multiple treatment modalities are combined to give the best possible results and to give the patient the possibility of breast conservation. The tumor size and characteristics, possible lymph node spreading, and the age of the patient will dictate which treatment is appropriate.

The breast cancer disease is often classified into invasive breast cancer and premalignant changes. The treatment and follow-up of premalignant changes are partially in line with treatment for invasive breast cancer but differ by less use of radiation therapy and seldom use of systemic treatment.

The treatment of localized breast cancer also may vary, depending on whether it is a primary operable or primary inoperable condition. If the tumor is primary operable, the patient will be treated according to the standardized national recommendations for surgery, radiation treatment, and systemic treatment. With locally advanced stages (primary inoperable), the treatment is more individualized.

Surgery of Breast Cancer

The goal of surgical treatment is to achieve local control of the tumor before metastasis occurs. This includes the intention of preventing symptoms from local and regional tumor growth and to avoid locoregional recurrence, as well as recurrence after breast conservative treatment.

Surgical alternatives for the primary tumor are either ablation or breast conserving surgery (BCT). Axillary surgery implies sentinel node biopsy, with or without subsequent axillary dissection, or primary axillary dissection. Axillary dissection is defines as removal of axillary lymph nodes in levels 1 and 2.   

In patients with metastasis or patients with other severe morbidity, customized less extensive surgery may be performed, possibly in combination with systemic treatment to achieve maximal control of the disease.SNB may have lower detection rate in the elderly, but the method seems safe and is also recommended in the elderly.

For breast cancer in elderly, comorbidity or limited expected survival should be taken into consideration.

For breast cancer in pregnant patients, treatment must be adapted to the length of pregnancy. Surgery and general anesthesia are rarely problematic. It is also possible to perform sentinel node biopsy, but methylene blue should not be used. Close collaboration between surgeon, oncologist, gynecologist and pediatrician is necessary. Also the parents should participate in the decision making process. Adjuvant systemic treatment in the second and third trimester must be discussed in each individual case. Delivery of the baby prior to adjuvant treatment may also be relevant.

Breast cancer in men should, in principle, be treated identically as in women, but breast conservative treatment is not relevant.

Types of breast cancer surgery:

  • Diagnostic biopsy
  • Resection with or without oncoplastic surgery
  • Mastectomy with or without breast reconstruction
  • Sentinel lymph node biopsy (SLNB)
  • Axillary dissection

Hereditary breast cancer

Information about prophylactic bilateral mastectomy and reconstruction, must be given to women who have a known mutation in the BRCA1 gene. This treatment can reduce the risk of breast cancer by 90-98 % and is currently the safest way of avoiding death by breast cancer. Another option is mammography and breast MRI yearly. Norwegian studies show slightly reduced survival in woman with a BRCA1 mutation.

Patients with a known mutation in the BRCA 2 gene or with hereditary breast cancer without a known gene mutation should also be offered prophylactic bilateral mastectomy and reconstruction. The prognosis in these two groups is as good as in sporadic breast cancer.

Prophylactic bilateral mastectomy may also be discussed for lobular carcinoma in situ (LCIS).  With the efficient follow-up available today, this alternative is rarely indicated.

Premalignant changes

Ductal carcinoma in situ (DCIS)

Lymph node metastasis hardly ever occurs in DCIS, and direct axillary dissection should therefore not be performed. If mastectomy is planned, a sentinel node biopsy should be performed for DCIS grade 3. If sentinel node cannot be detected, axillary dissection should be avoided as the potential benefit is small in comparison to the probability of side effects such as lymphedema, neuralgia, and reduced mobility of the shoulder. If conservation surgery is performed for DCIS, SLNB should be renounced as this can be performed afterwards if final histological examination shows invasive carcinoma.

The low frequency of recurrence seen with small grade 1 DCIS lesions suggests that postoperative irradiation may be justifiably avoided. When breast-conserving surgery is chosen for patients with a tumor diameter of > 10 mm grade 1, or for DCIS grades 2 and 3 independent of size, radiation treatment is recommended. 

Treatment recommendations for premalignant tumors

Lesion


Surgery Surgical margins  Radiation treatment  Mammography Clinical follow-up#
Epithelial proliferation without atypia

Biopsy Tumor-free or involved  
No
 

Epithelial proliferation with atypia

Biopsy Tumor-free or involved No

Annually*

LCIS

Biopsy or bilateral mastectomy Tumor-free or involved No
Annually*

Pleomorfic LCIS or florid LCIS with comedonecrosis


Wide excision** Tumor-free** ***

Annually

Annually
DCIS, unifocal, grade 1,
≤10mm

Wide excision Tumor-free**  
No
 
Annually

Annually
DCIS, grade 1 (>10mm)
or grade 2-3, where the area can be removed in single resection

Wide excision**
Tumor-free**  
Yes, after wide excision
 
Annually

Annually
Multicentric DCIS

Mastectomy
SNB ****
Tumor-free  No  
Annually

Annually

# Clinical follow-up may take place in hospital (physisian or specialized registered nurse) or by a general practitioner

*Annual follow-up till 50 years of age. Then, mammography every second year, following the program of mammographic screening for breast cancer. For patients with a first degree relative with breast cancer, mammography is recommended annually till 60 years. After that control every second year, following the program of mammographic screening.

** If wide resection is performed, a resection margin of at least 2 mm is recommended 

*** This type of lesion is rare. There are no studies documenting the benefit from radiation therapy and there is no general basis for radiation treatment.

**** If sentinel node cannot be completed, it is recommended to avoid axillary dissection. 

Locally advanced breast cancer

Locally advanced breast cancer is defined as:

  • T3 primary tumor: > 5 cm in size, found clinically or by imaging, ultrasound or mammography
  • T4 primary tumor: invasion of skin, papilla, muscle, or inflammatory cancer
  • Clinically N2 conglomerate of lymph node metastases

If at the time of diagnosis, locally advanced breast cancer is detected, the patient should not have primary surgery. Staging should then be performed with regard to distant metastases, and the patient should be treated with primary systemic therapy after consultation and referral to a regional oncological center before local treatment is carried out (surgery and radiation).

Advanced (metastatic) breast cancer

Breast cancer in stage IV is treated on an individual basis. Surgery is usually limited, aiming to maintain local control of the disease with survival taken into consideration.

Reconstructions

Reconstruction after mastectomy aims at reshaping the volume and shape of the breast by means of prosthesis, autologous tissue or combinations of these. For symmetrical reasons the contralateral breast may have to be corrected as well. The reconstructions may be performed simultaneously with the mastectomy (primary) or later (secondary). Reconstructive surgery requires experience and special training. There is a continuous development of operative techniques and prostheses. Oncoplastic and other reconstructive surgery requires close cooperation between breast and plastic surgeons. All patients to have such surgery should be discussed in a multidisciplinary team including also radiologist, pathologist and oncologist.

Evaluation of  reconstruction techniques

The goal of the reconstruction is to obtain the best possible reconstruction with minimal surgical risk for the patient. Several factors are of importance:

  • The situation for the patient after the cancer treatment
  • The size of the skin- and volume defect
  • Previous radiation will rendeer some reconstruction techniques less suitable
  • The general condition of the patient
  • Does the patient have additional disease that make advanced reconstructions riskier?
  • The patients motivation and expectation of the reconstruction

According to these factors the surgeon must decide the reconstruction method for the individual patient. The surgical procedures can be roughly ranked by their advantages and disadvantages.Advantages and disadvantages in regard to reconstruction method of the breast

PROSEDYRER

Wire Localization for Breast Surgery

General

Wire localization is performed prior to surgery for non-palpable lesions. A wire is inserted, usually with the help of ultrasound, with the point of the needle in or close to the lesion. If the lesion is not visible on ultrasound, the wire can be inserted using stereotactic or off-hand technique. After excision, the specimen is X-rayed to verify removal of the lesion.

Except for a small puncture in the skin from the needle, there is little discomfort associated with this procedure.

Indications

  • Non-palpable lesions to be removed surgically

  Goal

  • Localize and mark non-palpable lesions.

Equipment

  • Needle and guide wire with hook
  • Dedicated wire localization equipment 

Preparation

  • No preparations for the marking procedure
  • Local anesthesia is not required
  • Normal preoperative preparations for subsequent surgery

Implementation

  • The point of the needle is inserted through the lesion with the needle in or right behind the lesion.
  • The guide wire with hook is inserted into the breast tissue through the needle. 
  • Mammograms are taken after the marking to check the positioning of the wire.

There is little pain associated with the procedure, with the exception of the pinprick in the skin.

Follow-up

During surgery the surgical biopsy is X-rayed to check that the biopsy is representative.

Histological examination of the specimen

  • The specimen is fixed in formalin for 1 day before sectioning. The control X-ray accompanies the specimen. 
  • The specimen is examined and described macroscopically.
  • The specimen is cut into thin, parallel slices (maximum 5 mm). The slices are placed on a slide and are examined by X-ray if necessary.
  • The radiologist states in which slices the lesion is located.
  • Sections are prepared for histological examination from the relevant slices.
Wire localization for breast surgeryWire localization for breast surgery

Breast Conservative Treatment

General

Breast conservative treatment (BCT) is applied for early stage breast cancer and is always followed by postoperative radiation.
The resection must be complete and the procedure should be planned to achieve a tumor-free margin of a minimum of 5 mm to the sides.  

Reresection, however, is not necessary unless there is tumor in the resection margins ("ink not on tumor"). There is therefore no specific requirement for the width of the free resection margin. If it is uncertain whether the resection margins are free of tumor, a reoperation, reresection or mastectomy must be performed. If there is a need for multiple reresections, mastectomy should be considered as there is evidence for an association between repeated resections and local recurrence. 

For infiltrating cancer with no sign of metastasis to lymph nodes preoperatively, sentinel lymph node biopsy is performed (sentinel node diagnostics).

Several studies have shown that younger women treated with BCT have an enhanced risk of ipsilateral breast recurrence. Familiar and hereditary breast cancer appears more often in younger women. This enhances the difficulty of weighing age and treatment with regard to prognosis. Survival for young women are equal regardless of mastectomy or BCT.

It is no more considered reason for an upper limit for the extension of DCIS for BCT to be performed, as long as radical excision with free margins can be achieved and the size of the breast is not prohibitory.

Indication

  • Infiltrating breast cancer (tumors < 5 cm)

Special conditions for DCIS

It is no longer perceived to be basis for setting an upper limit to the extent of DCIS that BCT may be conducted as long as it is appropriate for radical excision with free margins and the size of the breast can tolerate this.

Contraindications/relative contraindications to conservative surgery

Absolute:

  • Previous irradiation towards breast or thoracic wall.
  • In pregnancy where irradiation (after possible conservative surgery) cannot be postponed till after termination of the pregnancy.
  • Two or more tumors in different sectors of the breast. When two or more tumors are present in the same quadrant or sector  conservative surgery may be performed.
  • Diffuse suspect microcalcifications on mammography.
  • Extensive disease which cannot be excised locally with adequate cosmetic result.
  • Tumor in resection margin.
  • When radiation may not be performed (for instance cardiac disease or thorax malformation).
  • Primary tumor (invasive) of stage T3 (size > 5 cm or T4; these require adjuvant treatment).

Relative:

  • Active disease of the connective tissue involving skin (for instance sclerodermia and lupus)
  • Large tumor in a small breast
  • Very large breasts; can be problematic to irridiate

  Goal

  • Same survival as for mastectomy
  • Good local control with low risk for ipsilateral recurrence (<1% annually).
  • The cosmetic result must be expected to be as good as for mastectomy with subsequent reconstruction.

Equipment

  • Tray for fine surgery

Preparation

  • The incision is outlined on the skin with the patient in an upright position. 
  • The operation is performed under general anesthesia. 
  • The patient in a supine position with the ipsilateral arm abducted 70-90 degrees.

Implementation

  • Incision as for biopsy. It should be within the excision of a possible later mastectomy. Normally, the tissue between the skin and the pectoral muscle is resected. For tumors close to the skin it may be necessary to remove the skin also. The specimen should be marked in agreement with the pathologist, preferably with the use of margins marker.
  • The resection should be complete and planned to achieve a tumor-free side margin of at least 5 mm. Reresection is not necessary if there is no tumor in the resection margin (”ink not on tumor”).  
  • Onkoplastic (for instance tennis racket operation) may be required for best cosmetic results.
  •  Adequate hemostasis.  
  • The incision is closed with intracuticular sutures. 
  • A compression bandage is applied. 
  • Local anesthesia is applied (20 ml xylocain with/without adrenaline). 

The specimen is sent for a histological examination.

Follow-up

  • Compression bandage is removed before leaving hospital.
  • The procedure is usually done as day surgery.
  • Follow-up by surgeon after 2-3 weeks 
  • The patient should be followed-up with annual mammography for 10 years.

Radiation therapy should start 6 to 8 weeks after the operation.

Axillary surgery increases the risk for development of lymphedema

Mastectomy

General

Mastectomy (mammary ablation) is the surgical removal of the mammary gland with or without underlying fascia. Underlying musculature is not removed.

For invasive cancer and DCIS grade 3, a sentinel node biopsy is performed before a mastectomy.

Axillary lymph node dissection is performed when preoperative spreading in the axilla is present, or for locally advanced disease when spreading in the axilla is present before preoperative treatment. In addition axillary lymph node dissection is performed for locally advanced cancer with skin involment. Or for T-3 tumors when there is little or no tumor response after preoperative treatment, regardless of preoperative axillary status.

Indications

  • When breast-conserving surgery is not indicated, or not wanted by the patient.
  • When radiation therapy is not feasible.

  Goal

  • Curation
  • Palliative for local control (with metastases)

Equipment

  • Tray for fine surgery

Preparation

  • Thrombosis prophylaxis.  
  • Shaving of the axilla. 
  • The surgery is performed under general anaesthesia 
  • The patient supine position with ipsilateral arm abducted 70-90 degrees.

Implementation

  • An ellipse-shaped incision including the areola is made through the preoperative outline. 
  • The mammary gland is dissected from the surrounding tissue down to the pectoralis major muscle. 
  • The gland and fascia over the muscle are removed. 
  • Hemostasis is performed. 
  • A vacuum drain is inserted in the wound and fixed with a suture. 
  • The wound is closed with intracuticular sutures. 
  • Local anesthesia is injected in the edges of the wound (20 ml xylocain with or without adrenaline). 
  • Steri-strips and compression bandages are applied.

Follow-up

  • The vacuum drain is removed 1st postoperative day.
  • The compression bandage is removed 1st postoperative day.
  • The patient is discharged the same day or after one night stay.
  • Follow-up by surgeon after 2-3 weeks.
  • The patient is followed up with annual mammograms for 10 years.

Axilla surgery increases the risk for development of late complications such as lymphedema.

Plastic surgery reconstruction

Even if most breast cancer operated patients adapt themselves to the use of external prosthesis, the patient should be informed about the possibilities of reconstruction.

Radiation therapy does usually contraindicate reconstruction. Surgical reconstruction with incorporation of implants or muscular flap (usually pedunculated or free TRAM Flap) does not reduce life expectancy. The reconstruction does not increase difficulties for discovering local relapse.

In large breasts, breast reduction of the remaining breast may be necessary both for cosmetic and functional reasons. The breast must then be checked by mammography before surgery and histological examination of the operated specimen should be especially meticulous.

Sentinel Node Biopsy

General

Sentinel node biopsy (SNB) is used in the treatment of early stage breast cancer. This procedure is usually performed concomitant with breast conserving surgery or mastectomy.

There is a primary lymph node (sentinel node) which drains the lymph from a certain area.This sentinel node reflects the status of the remaining lymph nodes because the sentinel node is the first node where malignant cells from the primary tumor will locate. If the sentinel node does not contain tumor cells, the other lymph nodes in the axilla will, with a high probability, be free of metastases, and axillary dissection is unnecessary*.

Two methods are used for identifying sentinel nodes: radioactivity and staining. The radioactive isotope, 99m Tc-labeled colloidal human albumin, is injected some hours, or possibly one day, preoperatively. Methylene blue is injected immediately preoperatively. Lymphoscintigraphy is done after injection of radioactive isotope.

By this procedure, blue and/or radioactive lymph nodes are excised, and sent for histological examination or as frozen sections. Sentinel lymph nodes should have activity over 5 and preferably > 10x background activity.

Indications

  • Invasive carcinoma stage T1 -T3 without evidence of lymph node metastasis. 
  • DCIS van Nuys grade 3 histologic where mastectomy will be performed. An axillary dissection should not be performed in this situation if  the sentinel node is not found.
  • If breast conserving surgery for DCIS is to be performed, SNB is not indicated. However, if the final diagnosis is invasive carcinoma, the SNB can be done afterwards.

  Goal

  • Avoid unnecessary axillary dissection
  • Avoid destruction of lymph drainage of the arm

* Kim T et al. Lymphatic mapping and sentinel node biopsy in early stage breast carcinoma. Cancer 2006; 4-16

Equipment

  • 99m Tc-labeled colloid human albumin
  • Patentblau V
  • Gamma detector
  • Surgery tray

Preparation

  • There are no special preparations for the injection of 99m Tc-labeled colloidal human albumin.
  • The line of the incision is drawn on the skin with the patient upright.
  • The operation is performed under general anesthesia.
  • The patient lies in the supine position.
  • The ipsilateral arm is positioned at an angle of 70-90 degrees from the body.

Implementation

Preoperative

  • 99m Tc-labelled colloidal human albumin is injected peritumorally at the department of nuclear medicine.
  • While images are taken, the patient lies on her back with the arm over her head.
  • The first images are taken immediately after the injection.
  • New images are taken after 30 minutes.
  • As needed, images are taken after 4 hours.
  • The position of the sentinel lymph node is marked on the skin, from the front and side.

Preoperative

A gamma detector is used during the operation, which registers the radioactivity.  Methylene blue is used simultaneously to increase the detection rate of the sentinel lymph node.

  • Methylene blue is injected peritumorally at the beginning of the operation.
  • An incision is made in the skin according to preoperative drawing.
  • The sentinel lymph node is identified with the aid of the gamma detector.
  • The sentinel lymph node is removed.
  • The lymph node is verified with the gamma detector, and if there are several, they are also removed.
  • The lymph node is sent for histological examination.

With a negative frozen section, an axillary dissection in not performed. Immunohistochemical tests are then awaited from the pathologist, which usually take about one week.    

If there is evidence of cancer cells, an axillary dissection is performed. This occurs in 5% of cases.

In the event the surgeon does not find the sentinel lymph node, an axillary dissection must be performed.

The procedure is followed by breast conservative treatment or mastectomy.

Follow-up

Allergic reactions to human albumin can occur.
Sentinel Node Biopsy

Axillary Dissection

General

In women with large tumors or with known metastasis to lymph nodes, a routine axillary dissection (AD) is performed without previous sentinel lymph node biopsy (SNB).

By AD, preferably a minimum of 10 lymph nodes are removed. The operation is most often performed together with breast conservative surgery or mastectomy.

Indications

  • Part of the primary treatment if known lymph node metastases (pre-, per-, or postoperative).
  • In the event the sentinel lymph node is not located during operation for invasive cancer.

Special conditions for breast conservative surgery (BCT)

There is no indication for AD for focus of metastasis ≤ 2 mm. AD is indicated when focus of metastasis is > 2mm, but may be omitted, when there are 1 or 2 positive sentinel nodes and if all the following criteria are met: 

  • Planned systemic adjuvant treatment
  • T1/T2 tumor
  • Clinical node-negative axilla
  • Planned BCT with external radiation treatment of the breast
  • No perinodal growth
  • No preoperative chemotherapy

Patients with macroscopic tumor infiltration in the SN will anyway receive radiation therapy to regional lymph node stations (axilla, periclavicular area) in addition to the breast. The current criteria for radiation therapy of pN + status are used to evaluate the treatment of these patients. This means that the axillary level 1-2 also is included in the radiation field as <10 axillary lymph nodes are removed.

Locally advanced  breast cancer

Most studies show that  patients with locally advanced cancer including clinical N0 status in the axilla (US examination included) before start of preoperative systemic treatment may have SN diagnostics after preoperative chemotherapy with satisfactory detection rate and false negative results. For primary clinical N0 stage it is therefore recommended SN subsequent to neoadjuvant treatment if the conditions otherwise permit this. For SN negativity AD is not necessary. For SN positivity (<2mm) AD should be performed. For clinical N1-3 before neoadjuvant treatment there is still indication for AD without SNB, irrespective of tumor response. For T3/4 tumors locoregional irradiation should be performed irrespective of N status and AD. Thereby the axillary treatment wil be adequate even if there is a false negative SNB.

If the frozen section is false negative, but later investigation shows metastasis, AD should be performed later according to previous schedule mentiones above. Imprint can also be performed as a snap diagnostic.

Immunohistochemical examination of SN is not indicated (98). In some centres this is performed on frozen sections ,especially with regard to metastases from lobular carcinoma.

For parasternal uptake on scintigraphy AD should be performed first. The literature is ambiguous with regard to the indication for possible removal of parasternal SN. The major gain will be in the very few cases where positive parasternal lymph nodes will lead to other and more extensive adjuvant treatment as when the SN in the axilla is negative. There is no suggestion that removal of parasternal lymph nodes will influence the rate of recurrence. 

Goal

  • Remove lymph node metastases to cure the disease.

Equipment

  • Surgical fine tray

Preparation

  • The hair of the axilla is removed using a shaving machine.
  • The operation is performed under general anesthesia.
  • The patient in a supine position with the ipsilateral arm abducted 70-90°. 

Implementation

  • The incision is made across the lower part of the axilla. During mastectomy, the incision is extended to the same area.
  • A dissection is performed along the thoracic wall to the axillallary vein while sparing the large nerves and vessels.
  • The specimen is excised en- block and includes lymph nodes in levels 1 and 2.  The specimen should contain at least 10 lymph nodes.
  • Some branches of veins are ligated at the level of the axilla.
  • Hemostasis is performed.
  • A vacuum drain is installed and secured with suture.
  • Marcain 20ml along the wound edges.
  • The incision is closed with intracuticular sutures.
  • Steri-strips and compression bandages are applied.

Follow-up

  • The drain is removed according to the surgeon, usually when < 50 ml has drained during the last 24 h
  • The patient may be discharged after 2-4 days
  • The bandages are changed after 5-6 days or after each shower.
  • Follow-up 14 days after operation.

Physiotherapy

Physiotherapy after an operation for breast cancer is a meaningful contribution for patients to enter an appropriate rehabilitation process. Many women will be adequately helped by instruction of how to perform relevant exercises for the shoulder/arm. When lymph nodes are removed from the axilla, the lymphatic circulation in the arm is permanently reduced and lymphedema may develop. Most women are not troubled by this. Lymphedema is particularly frequent after radiation therapy in combination with axillary surgery. Around 1/3 of patients have a varying degree of problems with movement and shoulder/arm function after the operation.

Axillary DissectionAxillary DissectionAxillary Dissection

Mastectomy with Primary Implant

General

Reconstruction with a simple implant is preferred to reconstruction using the patients own tissue. For patients who will later have radiation therapy, radiation therapy can make the cosmetic outcome some worse, but nevertheless we consider reconstruction with an simple implant to be preferred to own tissue reconstruction.

There can be used an expanding implant which can be changed for a permanent implant later or there can be used a permanent implant immediately.  By using an expanding implant, a collapsed implant is placed and gradually filled with saline through a syringe, weekly in the time after surgery.

Indications

Primary reconstruction with implant can be offered to patients who need to remove the breast of medical reasons or who themselves wants to remove the breast (mastectomy). The patient must be a non-smoker and other health premises may also be appropriate to have a implant reconstruction.

Goals

To carry out reconstruction of a breast in the same operation as the mastectomy.

Equipment

  • Tray for fine surgery
  • Implant (different types of implants should be available)
  • Two drains
  • Possible catheter to deal with pain

Preparation

  • Breast bandage.
  • Thromboprophylaxis by indication.
  • Armpit is shaved.
  • The operation is performed under general anesthesia.
  • The patient in a supine position with the ipsilateral arm abducted 70-90°. 

Implementation

  • An elliptical skin incision including the areola complex is done after the outlining. The cut is sharply done through the skin after the outlining.
  • Mammary gland is released from surrounding tissue down to the pectoralis major.
  • Gland and possibly facies over the muscle is removed.
  • Hemostasis is controlled.
  • A void is created under the large breast muscle and appropriate implant size is entered.
  • By use of an expanding implant, some saline is being sprayed into the implant.
  • Commonly two drainages are used.
  • Layered closure.
  • A bandage and breast bind is applied.
Choice of procedure may vary between hospitals.

Follow-up

The patient is usually hospitalized for a few days postoperatively, and receive follow-up on pain and information about the use of the arm.

In case the patient has got expanding implants, the refilling of saline starts-up.

Check-up with breast surgeon circa 3 weeks postoperatively for information on histology answer and possible need for adjuvant treatment.

Further follow-up as required for refilling of the expanders and replacement to permanent implant.

Secondary Reconstruction with Simple Implant

General

Breast reconstruction with an implant is the most applied surgery after a mastectomy.

Technically the surgery is a relatively simple procedure. The implant is placed in a sub-pectoral pocket. The method is most appropriate for women with small non-ptotic breasts.

Loss of a breast following a mastectomy creates a feeling of being less feminine in some women. Breast reconstruction can strengthen the self-image and is therefore a good option after mastectomy.

Indication

  • A patient's desire for reconstruction of the breast after mastectomy.

Contraindication

  • Previous irradiation can be a relative contraindication

Goal

  • To improve self-image 
  • Cosmetic appearance 
  • Anatomical balance

Equipment

  • Surgery fine tray
  • Retractors, retractor with light
  • Silicone implant(s) 

Preparation

  • The incision is outlined on the patient while in the upright position.
  • Determine the size of the implants based on width, height, and how much the remaining breast protrudes.
  • The surgery is performed under general anesthesia.
  • The patient lies in the supine position.

Implementation

Preoperative antibiotic prophylactic is administered.

  • The incision is made laterally in the mastectomy scar.
  • The submuscular pocket corresponding to the skin outline is prepared.
  • The pocket is filled with compresses to ensure hemostasis.
  • A vacuum drain is installed.
  • The surgeon changes gloves.
  • The implant is placed in the submuscular pocket.
  • The position of the implant is corrected according to the marks on the implant.
  • The incision is closed in three layers.
  • A compression bandage is applied.

Follow-up

The patient is discharged the same day unless there are complications requiring hospitalization, or if the patient lives far from the hospital.

The drain is removed as indicated by the surgeon which is usually when 20-30 ml have drained during 24 hours.

The breast bandage is removed after 4-5 days and the patient should use a sports bra 6-12 weeks.

Capsular contracture is the most common complication.

Prophylactic Mastectomy with Primary Expander Implants

General

The timing of riskreducing mastectomy should be meticuously discussed with each patient as we know the riskincreases from the age of 25 years. For the majority this can be adequately performed around 30 years of age.

Indications

  • Known mutations of BRCA 1.
  • For mutation of BRCA 2 or hereditary breast cancer without a known gene mutation (the indication is not as clear as for BRCA1 mutation, because the prognosis is as good as in sporadic breast cancer).

Goal

  • To avoid development of breast cancer.
  • In some cases, the goal may be to reduce the number of follow-up examinations and possible complications associated with these.

Equipment

  • Microsurgery tray
  • Expander implant 

Preparation

  • Antibiotic prophylaxis 
  • Preoperative outline of the skin incision with the patient sitting upright.
  • The operation is performed under general anesthesia.
  • The patient lies in the supine position.

Implementation

Bilateral skin-sparing mastectomy

  • The surgery is initiated on one side.
  • A boat-shaped incision is made including normally the areola, but it can be preserved when the patient wants it.
  • After suturing, the scar should be horizontal and not askew into the axilla.
  • The skin is spared as much as possible.
  • The breast with surrounding tissue is removed down to the pectoralis muscle, sparing the fascia.
  • The same procedure is carried out on the contralateral side.

Reconstruction with expander prosthesis

A plastic surgeon performs the reconstructive part of the operation.

  • A sub-muscular pocket is made in the midline deep to the pectoral muscle and the serratus fascia.
  • Thorough hemostasis is performed.
  • One or two vacuum drains are positioned and fixed.
  • The expander prosthesis is inserted.
  • The muscle is sutured.
  • The skin is closed in two layers.
  • The procedure is repeated on the remaining side.
  • Both expanders are filled with saline (the volume depends on skin circulation).
  • Dry bandages are applied.
  • The drains are activated.

Follow-up

  • The drains are removed according to the surgeon, usually when 20-30 ml drains during the 24 hours.
  • The patient is discharged usually after 2-4 days.
  • After 4-6 days, the bandage is removed and a soft bra can be worn.
  • The first refilling of the expanders is done 2-3 weeks after the operation.
  • Further filling is done at intervals of 1-2 weeks. The number of refills and volume depend on the size of the breast.
  • The expander implants are exchanged for silicone implants later, usually after 3 months.
  • The patient is informed of the possibility for reconstruction of the areola.

Transverse Rectus Abdominis Myocutaneous Flap (TRAM)

General

A Transverse Rectus Abdominis Myocutaneous flap (TRAM) is a breast reconstruction procedure using transversal skin and subcutaneous tissue below the navel for use as a donor area for a new breast. Small blood vessels of the straight abdominal muscle (rectus abdominus) supply this tissue with blood. When the tissue is transposed, the abdominal muscle with blood supply is used as a "stem" for blood supply to the flap. Following this, it is necessary to reinforce the abdominal wall with an artificial net.

Relocation of autologous tissue for breast reconstruction is resource-demanding and is reserved for a minority of patients. In patients who have been given radiation therapy, it may be difficult to achieve good results with implants. Using autologous tissue is more appropriate in such situations. This method is also appropriate for younger patients, patients with poor cosmetic outcome after breast-sparing surgery, or problems with earlier implant reconstruction. This method is also a good option for patients who do not wish to have implants. Autologous tissue can also be relocated and combined with an implant. 

Indications

  • Reconstruction of the breast after curettage/mastectomy

  • Patient wish for reconstruction with autologous tissue

Contraindications

  • Smoking/nicotine during the last 3 months
  • BMI > 28
  • Other serious comorbidity

Goal

  • Better quality of life
  • Anatomical symmetry 

Equipment

  • Adjustable surgical table
  • Universal tray 
  • Warming blanket (Bearhugger)

Preparation

  • Preoperative outlining on the thorax in standing and lying positions
  • Removal of pubis hair
  • Enema
  • Thrombosis prophylaxis
  • Thigh-high support hose

Implementation

  • Antibiotic prophylaxis is given peroperatively (2 g Cefalotin). An additional dose is given postoperatively. 
  • The surgery is performed under general anesthesia.
  • The patient lies in a supine position.
  • A warming apparatus is used from the pelvis and down.
  • The skin of the epigastrium is undermined.
  • The mastectomy scar is opened. 
  • The patient is raised to a sitting position to determine the lower abdominal incision then laid supine again. The flap is isolated usually based on ipsilateral vessel perforants. The anterior rectus fascia is dissected off the umbilicus/xiphoid. 
  • Rectus abdomnis is devided distally between two clamps. The remaining distal muscle is sutured to the fascia. The flap is pulled through to the thorax where it is temporarily attached with staples. 
  • The fascia defect is closed and the abdominal wall is reinforced with a polypropylene net (7.5-15 cm). The net is attached while the position of the patient is slightly flexed. 
  • The patient is raised to a sitting position.
  • A hole is made for the umbilicus.
  • Two vacuum drains are inserted in equivalent abdominal fields.
  • The abdominal incision is closed with subcutaneous and intracutaneous sutures.
  • The umbilicus is sutured in place.
  • The new breast is modeled with inlay and flap customization.
  • The part of the flap located under the skin of the breast is deepithelialized. The drain is inserted under the new breast and out through the axilla. 
  • Finally, the breast is sutured with running intracutaneous sutures. 

Follow-up

  • The drains are removed when approved by the surgeon (≤ 30 ml in last 24 hours).
  • A light bandage is used. The patient should not wear a bra for 3 weeks.
  • When lying in bed, the hips should be flexed during the first postoperative days. 
  • The patient is discharged after about one week.
  • A follow-up check is performed after 2-3 weeks. A consultation is arranged for adjustment of the contralateral breast and nipple reconstruction. 

Drug Therapy of Breast Cancer

The modern treatment of breast cancer started with the introduction of tamoxifen for hormone-sensitive breast cancer. A series of hormone treatment principles and chemotherapy regimens have since then been established. In more recent years, targeted treatment in the form of antibodies and small molecular agents has become available.

Localized breast cancer

The adjuvant treatment of localized breast cancer clearly results in a higher rate of cure. This is thoroughly documented in a world-wide cooperation where the results from a large number of randomized studies are collected.

Locally advanced breast cancer

Locally advanced breast cancer consists of tumors classified as T3 or T4 and/or breast cancer disease with locally advanced lymph node metastasis (N2-3), and without known distant metastasis. This patient group is heterogeneous.

There is no general consensus concerning treatment of patients with locally advanced breast cancer. Preoperative chemotherapy is recommended in most instances. For selected patients endocrine treatment is an alternative to chemotherapy. The treatment schedule is customized according to the recommendations of NBCG.

Metastatic/advanced breast cancer

Treatment of metastatic breast cancer is not curative.It is important with a total evaluation of the attributes for each patient’s cancer disease, extent of the disease, morbidity, and possibility for toxicity of treatment before a treatment plan is decided upon.

The principle for treatment of metastases is to utilize one treatment principle or drug at a time and to perform regular repeated evaluations of the effect. The treatment which stabilizes and leads to remission of the disease should be continued until progression. A comprehensive reassessment should then be performed before second line treatment is started.

The individual patient may benefit from multiple “treatment lines” to control the cancer. Still, there are large differences in effectiveness. The number of  lines of treatment and their duration with beneficial effect will vary between patients.

Hormone treatments used

  • Antiestrogens (fulvestrant, tamoxifen)
  • Anti-aromatase drugs (anatrozole, exemestane, letrozole)
  • Gestagens (megestrol acetate)
  • Drug-induced, surgical, or radiotherapeutic sterilization

PROSEDYRER

Adjuvant Therapy for Breast Cancer

General

Depending on age, estrogen, and progesterone receptor status, HER2 status and Ki67 expression, systemic adjuvant treatment varies. 

Hormonal treatment

The presence of estrogen and progesterone receptors in tumor indicates the probability for response of hormonal treatment.

Anti-estrogen (tamoxifen - TAM)

Adjuvant tamoxifen for 5 years has shown considerable effects on survival and is the most important single treatment drug. Tamoxifen also has additional estrogenic effects, especially in postmenopausal women. This has proven to give positive side effects on bone and lipid metabolism. Tamoxifen also reduces the risk for contralateral breast cancer. 

Aromatase inhibitors/inactivators

Aromatase inhibitors (AI) are only appropriate for postmenopausal women. Multiple large studies have shown that AI give longer disease-free survival than tamoxifen (6).

Chemotherapy

A series of chemotherapy regimens are used for adjuvant treatment. Use of several cytostatic drugs (polychemotherapy) has been shown to be more effective than use of one drug alone.

Today most often antracyclin- containing treatment regimens (moderate or high dosage (AC, FEC, FAC, EC) and regimens including taxanes(paclitaxel, docetaxel) either simultaneously with or in sequence with antracyclin containing chemotherapy. Different dosages and length of treatment are used within these main treatment groups.

Adjuvant chemotherapy for 4-6 months are considered adequate.

Antracyclin-containing regimens with higher dosage of epirubicin or more frequent administration (14 days interval  instead of 3 weeks) improves survival in high-risk groups. Difference in benefit from more intensive chemotherapy in hormone receptor positive and negative are reported. Hormone receptor positive patients have little or no effect of more intensive chemotherapy while hormone negative patients of high-risk groups can experience considerable improvement of the prognosis.

The last EBCTCG overview shows an average 1/3 reduction in death from breast cancer during optimal use of the presently available chemotherapy. Application of taxan in sequence with antracyclin containing chemotherapy gives 14% reduction in breast cancer deaths (RR 0.86) compared to regimens with lower doses of antracyclin containing regimens while it is not found significant differences if the regimen is compared to non-taxan regimes (including antracyclin) where  an identical number of cycles as in the taxan arm is given.

Chemotherapy and subgroups:

On patients analyzed on subgroups including HER2 / Ki67 in addition to hormonereceptors, the following effects can be achieved by adding taxanes to antracyclin containing thereapy:

Improved survival:

  • For hormonereceptor negative patients
  • For HER2 positive patients (borderline significant)
  • For hormonereceptor positive patients with Ki67 > 14% Ki67 positive cells in tumor (BCIRG001) or ≥ 20% Ki67 positive cells (PACS01) in tumor.

No difference in survival:   

  • For HER2 negative ER positive patients with Ki67 < 14% Ki67 positive cells (BCIRG001) or ER positive patients with <20% Ki67 positive cells (PACS01) in tumor

The indications for application of chemotherapy depends on the actual subtype of cancer (best classified by means of molecular geneprofiles):  

  • Luminal A (HR intensively positive HER2 positive with low proliferation)
  • Luminal B (HR positive HER2 positive or HR positive HER2 negative  Ki67 high/PgR negative/low)
  • ErB2 overexpression type (HER2 positive non luminal; HR negative HER2 positive)
  • Basal like (Tripple negative: HR negative HER2 negative)

Chemotherapy is not recommended to patients with Luminal A subtype. Application of chemotherapy should be considered in relation to tumor volume, other risk factors and patients preference. Analyses suggest that there is very little effect of chemotherapy in Luminal A like breast cancer with low tumor volume.

Antracyclin containing chemotherapy (commonly FEC) is the general basis for adjuvant chemotherapy in Norway. Enhanced dosage of antracyclin should be given to HER2 positive patients. There is also special reason for adding taxans to patients with HER2 positive tumors, triple negative or Luminal B tumors with high proliferation or large tumor volume.

At present the two available taxans seem equally effective and it is not clear whether these should be given in sequence or simultaneously with the antracyclin. A recent study (BIG 02-98) suggests that in sequence can improve DFS compared to synchronous application.

When there is indication for taxan treatment this should be given in sequence with 4 FEC cycles followed by 12 weeks taxan treatment (combined with trastuzumad for HER2 positive)

Influence of Ki67 on the chemotherapy decision:

  • For hotspot Ki67 > 30% (analyzed on the surgical specimen) provides the basis for giving chemotherapy as 4 FEC cycles should be given followed by 12 weeks of taxan medication.
  • For hotspot Ki67 value < 30% the decision for treatment should be based on other tumorcaracteristics and stage of the cancer. For HR positive HER2 negative patients with otherwise reason for chemotherapy, addition of taxans will primarily be appropriate for patients with grade 3 tumors with more extensive spread to the axilla (pN2-3).
  • Hotspot Ki67 value < 15% in HR positive >50% HER2 negative Grade 1-2 pN0-1 patients identifies a subgroup where application of adjuvant chemotherapy may be avoided.
  • Ki67 is usually not used for evaluation of treatment for HER2 positive cancer.

Trastuzumab

Blocking of the activity transferred through HER2 has been successfully attempted by use of the humanized monoclonal antibody trastuzumab. Chemotherapy in combination with trastuzumab is presently being tested.

Trastuzumab added to chemotherapy show a definite effect on disease free survival, and survival without metastases compared to chemotherapy alone (1). Studies show around 50% reduction of risk for recurrence, most recurrences are distant metastases.

Bisphosfanates

For postmenopausal patients comprehensive documentation has shown that zoledronic acid gives rise to additional effects. These patients are also regularly treated with aromatase inhibitors (AI). AI reduces bone density. NBCG therefore recommends:

  • Zoledronic acid 4 mg is given i.v. every 6 months for 5 years in definite postmenopausal women ≥ 55 years with indication for systemic adjuvant treatment The treatment is supervised by an oncologist in with the departments giving adjuvant chemotherapy.   
  • Zoledronic acid treatment for patients with primary operable breast cancer should be initiated within 6 months postoperatively (pragmatic starting point). There is no recommendable absolute upper age limit for the use of zoledronic acid, and it should be applied till the age of minimum 75 years. For age above 70-75 years treatment should be evaluated in regard to comorbidity and expected length of survival.
This treatment ensures optimal bone health and reduces recurrence. Routine bone density measurements are not required in patients receiving zoledronic acid as part of adjuvant therapy. Dental health must be resolved before the treatment starts. Zoledronic acid is not recommended if there are dental problems or dental surgery is planned.
Blood tests are recommended at least once a year. Zoledronic acid is not recommended if creatinine exceeds more than 1.5 times the upper normal limit.

Indications

Indication for chemotherapy and selection of regimen should be based on sybtype classification of the breast cancer in addition to histologic grade and pTpN stage. Even if the best suclassification is performed with geneprofile analyses, these are not generally available yet, and the combination of hormone reseptor status, Ki 67 status and HER2 status may be used as surrogate. When in doubt about application of chemotherapy, Oncotype Dx for instance can help in estimating a possible effect.

Patients with the following tumor caracteristics are candidates for adjuvant systemic treatment:

  • Lymph node positive patients (greatest tumor dimension > 0.2 mm, (pN1-3)
  • Lymph node negative patients (pN0) with the following primary tumor characteristics

    • pT2 (tumor dimension > 20 mm) independent of grade
    • pT1c (tumor dimension 11-20 mm) and simultaneous grade 2 or 3
    • pT1a-c (tumor size 1-20 mm) and simultaneously HER2 positive and/or hormone receptor negative and/or high Ki67. Hormone receptor negative and/or HER2 positive patients are found almost exclusively with histology grade 2-3.
  • Lymph node negative patients (pN0) with age < 35 years or the following primary tumor characteristics:

    • pT1a-b and simultaneous Grade 2 or 3

Goal

  • Cure the disease

Referances

  1. Bouchardy et al. J Clin Oncol. 2007 10;25(14):1858-69
  2. Crivellari et al, J Clin Oncol. 2007 25(14):1882-90
  3. Muss et al., J Clin Oncol. 2007 25(14):1870-5
  4. Goldhirsch et al. Meeting Highlights: International Expert Consensus on the primary therapy of early breast cancer 2005. Annals of Oncology 2005; 16:1569-1583
  5. Goldhirsch et al. Meeting Highlights: International Expert Consensus on the primary therapy of early breast cancer 2005. Annals of Oncology 2005; 16:1569-1583
  6. Ny medikamentell behandling av brystkreft - Adjuvant behandling med trastuzumab ved tidlig stadium brystkreft. Rapport fra Kunnskapssenteret Nr. 2 2006.
  7. Goldhirsch et al. Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 2011 Aug;22(8):1736-47. Epub 2011 Jun 27.

Treatment Plan

Recommended non-hormone treatment

When indicated, adjuvant chemotherapy is recommended up to 75 years. High age alone is not recommended for the omission of chemotherapy. This is especially relevant for triple negative and HER2 positive patients. For higher age chemotherapy application must be carefully evaluated in relation to comorbidity and survival expectancy – and customized treatment may be necessary. Cardiovascular morbidity must be especially scrutinized. MUGA or ECHO should be applied on liberal indications.

Cardiac MUGA and ECHO should be performed on all patients, independent of age, who are to be given high dose FEC (FEC100). This will optimally reveal the cardiac status and tolerability in the treatment.

Recommended hormone treatment

Premenopausal patients

  • Tamoxifen for 5 years

Extended hormonal treatment is recommended as follows:

  • Patients below 40 years of age at the initiation of the treatment may be offered 10 years of tamoxifen treatment if the tolerability/probable - absolute benefit supports this.
  • Patients > 40years of age who will be postmenopausal efter 5 years of tamoxifen treatment should be offered araomatase treatment for 3-5 years (monitoring the hormonal blood values should be performed bimonthly for half a year). For perimenopausal status tamoxifen should be applied, possibly followed by AI if the patient becomes menopausal.
  • Patients >40 years of age who are premenopausal after 5 years with tamoxifen may be further offered 5 years of tamoxifen treatment if the tolerability/probable - absolute benefit supports this.

Postmenopausal patients (≥ 55 (50) years) 

  • Aromatase inhibitor for 2 years followed by tamoxifen for 3 years, or
  • Aromatase inhibitor for 5 years
  • Women already given tamoxifen for 2 to 5 years are recommended to change to AI for 3 years.
  • Women already given tamoxifen for 5 years followed by treatment-free period should not change to AI. Those who are strongly motivated to take an aromatase inhibitor, should be informed of the effect and side effects of the treatment. If the patient still wishes to receive this treatment, this should be accommodated.
  • Women with an inclination to DVT or LE should have AI from immediately after surgery or chemotherapy.
  • Women having DVT or LE during ongoing tamoxifen should change to AI.
  • In cases where it is not relevant to apply AI for 2-3 years, extension of adjuvant treatment with tamoxifen for a total of 10 years should be considered.  

Calcium/Vitamin D (1000 mg/800 IU daily) should be given to all patients treated with aromatase inhibitors (AI), for instance Caligran Forte® chewing tablets.

Preparation

Cardiac MUGA and ECHO should be taken on patients who will have high-dose FEC100. This is to determine the cardiac status of the patient and tolerability for treatment.

The patient should be informed about the treatment and its consequences, and offered a customized wig.

Hormone treatment

Hormone receptor status, HER2 status and Ki67 expression should always be examined. Hormone receptor negative patients do not benefit from adjuvant endocrine treatment.

In connection with the start of treatment with aromatase inhibitor/inactivator (AI), bone density measurement (DEXA-scan) should also be performed.

Bone- density-measurement  (DEXA-scan) is required prior to treatment with aromatase inhibitors (AI). In patients receiving aromatase inhibitors with addition of zoledronic acid, the reason for monitoring the bone density disappears.

Chemotherapy

Neutropenia

During chemotherapy, neutropenia is the usual dose-limiting factor. G-CSF can effectively reduce complications of neutropenia.

For chemotherapy administered every third week (FEC, docetaxel), G-CSF is recommended as follows:

  • The lowest acceptable level for chemotherapy without G-CSF is a neutrophil count of 1.0 x 109/l.
  • For values below 1.0 x 109, the cytostatic treatment is most often applicable when combined with G-CSF. If there are contraindications to the administration of chemotherapy on schedule (very low neutrophils/uncertainty whether neutrophils are increasing), the patient is reassessed after 1-3 days with the goal of administering treatment with supporting G-CSF.
  • If there is a preceding episode of febrile neutropenia, the subsequent chemotherapy cycles is given in combination with G-CSF (secondary prophylaxis).

For weekly treatment, evaluation of the lowest acceptable level for repeated treatment is based on the rate of improvement after a possible fall in neutrophil granulocytes. It is often possible to continue treatment when neutrophil granulocyte values are > 0.7 x 109/l. G-CSF is not given for weekly cycles. If a treatment must be postponed, the patient should be reassessed after 1-3 days.  

Thrombocytopenia

Thrombocytopenia is rarely a problem during adjuvant chemotherapy, but treatment should generally not be given with values < 50.

Other side effects

All the relevant regimens for adjuvant chemotherapy for breast cancer will cause loss of hair in most patients. The patients should be informed about this and that the hair will regrow after the termination of the treatment.

Cyclophosphamide and 5-fluorouracil give rise to nausea and vomiting in at least 50% of the patients. The symptoms may appear from 1 to several hours after the infusion. 5HT3-receptor blockers are at present standard antiemetic treatment  for FEC courses. Usually this is given in combination with dexamethasone. Further reactions/medication should be considered according to individual tolerance. Docetaxel and paclitaxel will usually cause no or slight nausea.

Docetaxel/paclitaxel can cause hypersensitivity/anaphylactic reactions. Monitoring of the patient is therefore necessary, particularly at the initial courses. Specific schedule is prepared (National Register for Medical Cancer Treatment or Cytodose). The risk for serious reactions is minimal if glucocorticoid is combined with the courses, as given in the schemes above. If reactions appear, the infusion is temporarily paused and relevant treatment given. When the symptoms have disappeared, the infusion is started with reduced rate, gradually increasing if the symptoms do not reappear.

If sepsis or hemorrhage has occurred, individual considerations are needed before the next course is given. ECG must be performed in cases of suspect cardiac disease. Epirubicin is highly tissue toxic and must only be given with secure intravenous access to avoid extravasation.

Trastuzumab

The most serious side effect caused by trastuzumab is cardiotoxicity.

Necessary examinations before treatment are:

  • Hematological testing  (ASAT, ALAT, ALP, creatinine, and bilirubin) before starting treatment. After this no blood samples are routinely required. Before starting trastuzumab, blood tests must be within the following limits: 
    • Bilirubin ≤ 2.0 x upper normal limit (ULN)
    • ALAT or ASAT ≤ 2.5 x ULN
    • ALP ≤ 2.5 x ULN
    • Creatinine ≤ 2 ULN
    • Neutrophil ≥ 1.0 x 109/L
    • Thrombocytes ≥ 100 x 109/L
  • ECG
  • Assessment of left ventricular ejection fraction (LVEF) with MUGA-scan or ECHO. LVEF should be ≥ 55% to start with trastuzumab.
  • Previous cumulative epirubicin dose must not be >720 mg/m2
  • The patient must not have serious heart disease such as documented heart failure, high risk for uncontrolled arrhythmia, severe chest pain requiring medical treatment, valve disorder, transmural cardiac infarction, or poorly controlled hypertension (systolic > 180, diastolic > 100).
  • The patient should not have serious lung disease.
  • The patient should not be pregnant.

Implementation

Hormone treatment

Premenopausal women

Treatment starts after adjuvant chemotherapy is terminated. Treatment with tamoxifen daily for five years is recommended in premenopausal women. If recurrence occurs during the treatment, the medication is stopped.

In the event that the patient does not want chemotherapy, an alternative is goserelin injections for three years in combination with tamoxifen for 5 years. There still is insufficient data of the effect of this combination compared to chemotherapy followed by tamoxifen.

Postmenopausal women

If adjuvant chemotherapy is relevant, hormone treatment is started after completion of chemotherapy. 

It is usually recommended to start with aromatase inhibitors, as this has shown improved survival compared to tamoxifen.

There is international consensus that adjuvant endocrine treatment in most cases should include aromatase inhibitor. The BIG 1-98 study supports the indication for initially giving aromatase inhibitor the first 2 years, and thereafter considering switch to tamoxifen. This is comparable in effect to aromatase inhibitor for 5 years (3). Decision on an individual basis depends on the side effects, economy, or other conditions. 

Osteoporosis and marked osteopenia while being treated with AI, requires bisphosphonate treatment.

Mild to moderate osteopenia at the beginning requires a new reassessment of bone density monitoring after one year. With a fall of bone density (BMD) of ≥ 10%, bisphosphonate treatment should be started. Vitamin D/calcium (1000 mg/800IE daily) should be given to all that receive AI adjuvant treatment, regardless of bone density, for instance Calcigran forte, chewing tablets 1 tablet x 2 daily. 

Chemotherapy

Adequate duration of adjuvant chemotherapy is four to six months.

Trastuzumab

The treatment usually starts 3 weeks after the last adjuvant FEC course, and is given simultaneously with the taxane treatment as a combination therapy. If  LVEF < 50%, the trastuzumab treatment is postponed and a new MUGA- or Echo-examination is performed after 3-6 weeks.

After completed taxane treatment, trastuzumab monotherapy is given, regardless of whether the patient receives radiation therapy.

The first infusion with trastuzumab is given as a loading dose of 8 mg/kg. Thereafter, one dose of 6 mg/kg is given every three weeks until 17 courses. The treatment lasts for about one year.

Treatment with trastuzumab does not require blood tests except for prior to the first infusion. The neutrophil granulocyte count should then be  ≥ 1.0 x 109/l.

MUGA- or Echo- examination is performed every 12th. week. Adjustment of the treatment due to this monitoring will be according to the following treatment algorithm:

http://www.nbcg.net/filer/57.ppt.

References

  1. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial.Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists' Group, Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M.  Lancet Oncol. 2008 Jan;9(1):45-53.
  2. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. Coates AS, Keshaviah A, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, et al. J Clin Oncol. 2007 Feb 10;25(5):486-92.
  3. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. BIG 1-98 Collaborative Group, Mouridsen H, Giobbie-Hurder A, Goldhirsch A, Thürlimann B, Paridaens R, Smith I, et al. N Engl J Med. 2009 Aug 20;361(8):766-76.

Follow-up

Hormone treatment

Many women will stop menstruating. This will be depending on the woman’s age; younger women will have a higher propensity to maintain menstruation than women who are near menopause.  Pregnancy must be avoided.

The side effects of endocrine treatment are usually mild to moderate.

The most common side effects are hot flashes. Other side effects, which may occur are:

  • Mild nausea
  • Abdominal discomfort
  • Vaginal symptoms
  • Joint problems, especially with aromatase inhibitors
  • Bone density changes, especially with aromatase inhibitors

Tamoxifen causes a small increased risk for deep vein thrombosis (DVT) and lung embolism (LE) and endometrial cancer.  Women who are predisposed for DVT or LE under tamoxifen treatment should change to AI.

An annual gynecological examination is recommended during tamoxifen treatment.

Chemotherapy

Some side effects of adjuvant cytostatic treatment (1)

(frequent > 1/100, rare < 1/1000)

  FEC    
  Fluorouracil Epirubicin Cyclophosphamide Paclitaxel Docetaxel
Bone marrow depression frequent frequent frequent frequent frequent
Nausea/vomiting low moderate high/moderate low low
Hair loss frequent frequent with high doses frequent frequent
Diarrhea/constipation diarrhea diarrhea dose-dependent diarrhea diarrhea/constipation
Mucositis/stomatitis stomatitis mucositis dose-dependent mucositis stomatitis
Allergic reactions rare rare frequent rare sometimes
Cardiotoxicity rare yes rare rare rare
Neurologic symptoms rare not reported not reported frequent frequent
Nail changes not reported not reported rare frequent frequent
Liver dysfunction rare not reported frequent rare/serious frequent
Skin reaction frequent frequent rare not reported less frequent

*Cardiac failure combined with trastuzumab (comprises 2.2 %)(1).

Adjuvant treatment of breast cancer.

Treatment of Metastatic/Advanced Breast Cancer

General

The introduction of modern systemic treatment appears to increase survival in patients with metastatic disease. Many patients can benefit from multiple treatment options. The treatment course for each individual patient, depends on both tumor characteristics, the effect of each treatment, toxicity, and the patient’s general condition. An oncologist (or specialist with broad medical oncology competence) should be responsible for all cytostatic treatment and all sequential endocrine treatment of advanced breast cancer disease.

For potentially endocrine-sensitive metastatic disease, endocrine treatment is primarily chosen before chemotherapy. Despite chemotherapy may give a higher response rate, there is no survival benefit by starting chemotherapy before endocrine treatment. Also, endocrine treatment causes less side effects. The choice of treatment strategy should primarily be based on: to what degree the disease appears to be endocrine sensitive, extent of the disease (especially visceral), and how quickly the disease progresses (aggressiveness). Patients with rapid progression should be given chemotherapy initially. In most instances this applies to patients with liver involvement and patients with dyspnea from lung carcinomatosis.

The antiestrogen tamoxifen was previously the initial treatment choice for hormone receptor positive metastatic disease because of its efficacy and low toxicity. This changed after the introduction of specific aromatase inhibitors. Anti-aromatase drugs (non-steroidal or steroidal) are now considered to be the first treatment choice in postmenopausal women whether they have previously used adjuvant tamoxifen or not. Of new medications, the antiestrogen fulvestrant has shown efficacy for metastatic breast cancer, also subsequent to use of aromatase inhibitors. Megestrol acetate was used routinely after progression on tamoxifen before aromatase inhibitors were introduced. Today, megestrol acetate is sometimes used after treatment with the above mentioned drugs. There are multiple studies showing effect of using steroidal aromatase inhibitors (exemestane) after non-steroidal (letrozole, anastrozole) while there is less documentation for use of non-steroidal after steroidal. There are also studies showing efficacy of estrogen therapy.

Everolimus in combination with exesmestane is a possible choise after progression on letrozole/anastrozole, usually for 2. or 3. line. Everolimus in combination with tamoxifen may be an alternative when eksmestan has previously been given (applied for through paragraph 3 a).

The two most effective single groups of cystostatic drugs for metastatic breast cancer are athracycline and taxanes. It is uncertain whether their order of sequence is of importance. There may be differences with regard to rate of response and time to progression (TTP), but this will seldom lead to prolonged total survival.

In Norway, as in many other countries, anthracycline containing regimens have been applied as first line treatment since the eighties, so also today.

Cytostatic treatment is relevant as first-line treatment for metastatic breast cancer when the tumor is estrogen and progesterone receptor negative. If the tumor initially is hormone receptor positive, then cytostatic treatment is appropriate after the endocrine regimens are no longer effective. For HER2 positive tumors, trastuzumab should be administered in combination with cytostatic treatment. It is now more usual that HER2 positive patients are given trastuzumab in combination with a non-anthracycline regimen as first-line treatment. Lapatinib can be used in combination with chemotherapy for patients who have progressed on trastuzumab. 

The treatment of metastatic disease is palliative. However, in many cases, remission can be achieved for several years. Current chemotherapeutic regimens have less side effects  than previous ones.

Brain and bone metastases respond very well to radiation treatment. Bone metastases often also respond well to endocrine treatment.

Indications

Hormone treatment

  • ER and/or PgR positive tumor. When disease development permits to await endocrine response (6-8 weeks) and disease is considered to be endocrine sensitive.

Cytostatic treatment

  • ER and PgR negative tumor
  • Rapid disease development regardless of ER/PgR status
  • ER and/or PgR positive tumor which is not considered to be endocrine sensitive

Bisphosphonates

  • Osteolytic metastases, with or without joint pain (given in addition to cytostatic treatment or hormone treatment)

Goal

  • To control the disease over time
  • Suppress symptoms with as little toxicity as possible
  • Prolong survival if possible

Treatment Plan

Hormone treatment

The treatment plan depends on previously completed adjuvant treatment, relapse time, and menopausal status.

When menopausal status is uncertain FSH and LH should be monitored. If the estrogen level has declined well ahead of the presence of metastases, hormone treatment should be given as for first line treatment in postmenopausal patients.

Treatment of pre- and perimenopausal

First-line treatment

  • LHRH analogue (for instance goserelin (Zoladex® 3.6 mg s.c. every 4 week). If effective LHRH analogue should be substituted with ovarial irradiation or oophorectomy.
  • If the estrogen level has declined well ahead of the detection of metastases hormone treatment should be added as for first line treatment in postmenopausal patients.

Second-line and further treatment (from first-line)

Treatment of postmenopausal

There are few results suggesting that one particular sequence of treatment ( within the treatment lines) of endocrine medication for metastatic disease give better results.The oncologist is therefore free to decide within the lines according to the stage of the disease, expected effect and grade of side effects.

Survey of recommended endocrine treatment for metastatic breast cancer

Several recommended treatment options are referred to in the treatment lines. There is no definite data indicating that a particular treatment sequence should be followed.

In some cases it may be appropriate to initiate treatment in accordance with 2nd- and 3rd line treatment below.


Medication Specification Comment
First-line treatment (1s line) Aromatase inhibitors/inactivators Not relevant when there is a short disease-free interval after treatment with adjuvant AI The effect of fulvestrant is comparable to AI. Tamoxifen is a secondary option, but seems to have less effect compared to AI

Fulvestrant (500mg/dose)

Not primary choise for short disease-free interval after previous adjuvant tamoxifen treatment
Second-line (2nd line) and third-line (3rd line treatment)
Eksemestane + everolimus If previous progression during letrozole/anastrole treatment

2nd and 3rd line treatment choice may depend on individual assessment of the beneficial effect for each patient (including stage of disease, expected effect and side-effects of the treatment).

*If progression occur during treatment on non-steroidal AI, steroidal AI can be used (or vice versa)

Tamoxifen + everolimus If previous progression during AI treatment and exemestane is not current treatment option
Aromatase inhibitors/inactivators* If previously not used or if only one type of AI is used before, and everolimus is not the preferred treatment
Fulvestrant (or tamoxifen)

If previously not used

Fourth-line treatment (4rth line treatment) and further A treatment choice not previously used

Megestrol Acetate
Estrogen therapy   If applicable, an oncologist with expertise in endocrine therapy should be in charge.

Special conditions for HER2 positive

Studies support a shortlasting / modest effect of endocrine treatment for HER2 positive. As long as the progression of the disease permits to wait for an endocrine response endocrine treatment should be tried. An effect on progression free survival by combining endocrine treatment with HER2 rettet treatment, compared to endocrine treatment alone ( HR respectively 0.63 and 0.71). The studies are lacking an arm with singel HER2 treatment, leaving an uncertainty with regard to the effect of the combination regimen. In addition we have no data judging sequential treatment versus combination treatment. The results of the studies still support the use of HERB2 specific treatment in combination with endocrine treatment. This is considered a separate treatment option,

Chemotherapy

Cardiotoxicity and anthracycline treatment

Caution is recommended with regard to heart toxicity during long-term use of anthracycline. The threshold for using MUGA/echocardiography in the treatment follow-up should therefore be low. The maximum treatment dosage is 900 mg/m² of epirubicin (550 mg/m² doxorubicin). Clinically the de facto limit can depend on other factors, for instance age and predisposition for cardiac disease.

Recommended treatment

These recommendations are separated according to whether the disease is HER2 negative or positive.

FLOW CHART FOR CHEMOTHERAPY

HER2 negative patients

First-line treatment

Anthracycline containing regimens are relevant when:

  • The patient has not received adjuvant chemotherapy.
  • The patient has received adjuvant chemotherapy which did not contain anthracycline (for example CMF).
  • It's been ≥ 24 months since completed adjuvant/neoadjuvant chemotherapy containing anthracycline (for example FEC, epirubicin).

The Norwegian Breast Cancer Group has decided on the following anthracycline-containing regimens as appropriate:

  • FEC
  • FAC
  • Epirubicin monotherapy
  • Low-dose Adriamycin® (doxorubicin)
  • Pegylated liposomal doxorubicin (PLD). In the treatment of metastatic breast cancer, PLD shows comparable efficacy to doxorubicin, but with reduced risk of heart toxicity. (O’Brien et al. Annals of Oncology 15: 440-449, 2004). Data exists showing that PLD can be used with satisfactory safety above the dose limit used today for anthracycline (Safra et al. Annals of Oncology. 11: 1029-1033, 2000). PLD is beneficial in cases where heart toxicity is a concern due to age, predisposition for heart disease, high cumulative doses, and HER2-positive disease.

Patients who have received anthracycline containing adjuvant/neoadjuvant treatment < 24 months previously are recommended to use taxanes. 

NBCG has decided on the following taxane regimens to be appropriate depending on the condition of the patient, toxicity, age or other factors:   

  • Docetaxel monotherapy 100 mg/m² every 3 weeks has in two phase III studies documented better TTP than other second line chemotherapy.
  • Paclitaxel 80-90 mg/m² weekly. Weekly paclitaxel in doses of 80-100 mg/m² have in multiple phase II studies shown higher response rates, but type 1 evidence is not available. A Norwegian phase II study with weekly dose paclitaxel as first line has shown a response rate of 39.4% and clinical benefit of 66.7%.
  • Docetaxel 75 mg/m² every 3 weeks + capecitabine 1000 mg/m² x 2 day 1-14 every 21 days. The combination docetaxel/capecitabine is known to be better than docetaxel alone in one phase III study, including overall survival benefit. In the study, docetaxel 75 mg/m² was given every 3 weeks + capecitabine 1250 mg/m² x 2 day 1-14 every 21 days. Many had to reduce the capecitabine dose to 1000 mg/m² due to side effects, and it is recommended to use this dosage as the initial dose. NBCGs experience is that this treatment regimen is more toxic than monotherapy. This combination has not been compared with the same drugs in sequence. 
  • Docetaxel 35 mg/m² weekly (6 out of 8 weeks). Response rates between 30 and 40% have been shown for weekly docetaxel in multiple phase II studies. Type 1 evidence is not available. This is not considered to be advantageous with regard to side effects compared to docetaxel every 3 weeks.
  • Albumin-bound paclitaxel. Studies show equal or better efficacy using albumin-bound paclitaxel (Abraxane) compared to docetaxel.

Second-line treatment

After an anthracycline containing regimen as a first-line treatment, the patient should have: 

  • Docetaxel 100 mg/m² every third week (see 1st line treatment)
  • Paclitaxel 80-90 mg/m² weekly (see 1st line treatment)
  • Docetaxel 75 mg/m²  every third week + capecitabine 1000 mg/m² x 2 days 1-14 every 21 days. 
  • Docetaxel 35 mg/m² weekly (6 out of 8 weeks) 
  • Albumin-bound paclitaxel (see 1st line treatment)

If taxanes were used as first-line treatment, but not in combination with capecetabine: 

  • Capecitabine 1000-1250 mg/m²  x 2 days 1-14 every 21 days. Capecitabine has in multiple phase II studies and in a Norwegian study shown response rates of 20-30% after anthracycline and taxanes.
  • Vinorelbine 25-30 mg/m² weekly, or 30-35 mg/m² day 1 and day 8 every three weeks. The documentation is not as good as for capecitabine, This regime is applied in several institutions in Norway where respnses and low grade of side effects are seen.
  • Eribulin 1.23 mg/m² day1 and day 8 (21 days cycle).

If doxetaxel/capecetabine were used as first-line:

  • Vinorelbine 25-30 mg/m2 weekly, or 30-35 mg/m2 day 1 and day 8 every three weeks, or oral vinorelbine (60 mg/m2 weekly the first 3 weeks before increasing to 80 mg/m2 weekly.)
  • Eribulin 1.23 mg/m² day1 and day 8 (21 days cycle).

Third-line treatment

The indication should be assessed carefully. Depending on what were used as second-line treatment, one of the following may be appropriate:

  • Capecitabine 1000-1250 mg/m2 x 2 day 1-14 every 21 days
  • Vinorelbine 25-30 mg/m2 weekly, or 30-35 mg/m2 day 1 and day 8 every third week, or per oral vinorelbine (60 mg/m² weekly the first 3 weeks before increasing to 80 mg/m² weekly)
  • Eribulin 1.23 mg/m² day 1 and day 8 (21 days cycle).
  • Gemcitabine 1000 mg/m2 i.v. day 1,8 and 15 in 28 day cycle.

Other regimens which NBCG has not decided upon can be found in the literature. The regimens discussed here are considered established and are  found applicable for the most important elements of palliative chemotherapy: to prevent progression of the disease by treatment regimens of low toxicity.

New results suggest that Halaven® (eribulin mesylat) is comparable to capecitabine for patients who have previously been treated with anthracycline and taxane

For triple negative, there is internationally an increasing use of cisplatin/carboplatin regimens. Relatively good response data, with response rates about 33%, have been reported on the combination carboplatin/gemcitabine after use of anthracycline/taxane. The Breast Cancer Group of Norway (NBCG) considers this to be a treatment option for triple negative breast cancer.

HER2 positive patients

Even though very good response rates have been shown by combining chemotherapy with trastuzumab, anthracycline regimens (without trastuzumab) have until recently been the first treatment choice in most cases. The most important argument for starting with an anthracycline regimen has been the risk for cardiotoxicity and falling LVEF due to the long half-life of trastuzumab and fear for increased risk of cardiotoxicity in synergy with anthracycline if given after progression on a trastuzumab regimen. Pegylated liposomal doxorubicine reduces the risk for cardiotoxicity in this context. Antracycline, primarily in the form of liposomal anthracycline, can be used when HER2-directed treatment in combination with non-anthracycline chemotherapies is no longer effective. In addition, after progression on trastuzumab several  patients will be offered lapatinib combined with chemotherapy (second- or third-line), which will eliminate trastuzumab before anthracycline is administered.

First-line treatment

If the tumor is HER2 positive, trastuzumab should either be combined with a taxane or alternatively with vinorelbine. Recently, the HERNATA study was published (randomized phase 3 study) showing that time to progression is identical for trastuzumab in combination with vinorelbine as in combination with docetaxel. The effect of vinorelbine in combination with trastuzumab is supported also by phase 2 studies.

One of the following regimens is recommended for HER2 positive patients:

  • Paclitaxel + trastuzumab
  • Docetaxel+ trastuzumab
  • Vinorelbine 30-35 mg/m² day 1 + day 8 every 3 weeks + trastuzumab
  • Docetaxel (75 mg/m²) + trastuzumab + pertuzumab (420 mg after loading dose) every 3 rd week. (The CLEOPATRA study which randomized HER2 positive pasients between docetaxel + trastuzumab +/- pertuzumab in 1st linje, showed considerable improvement in progression free survival in the pertuzumab arm. Pertuzumab is now accepted in Norway but is not evaluated economically. The combination of docetaxel, trastuzumab and  pertuzumab is now considered an option in first-line treatment

If the patients` general condition, age, expected tolerability or patient preference does not allow the use of taxane or vinorelbine, trastuzumab monotherapy can be considered.

Second-line and third-line treatment

Use of trastuzumab in combination with another type of chemotherapy as second-line after progression of first-line treatment (trastuzumab in combination with first-line chemotherapy) provides additional possibility for clinical benefit. A study has shown effect of continuing trastuzumab in combination with capecitabine, compared to capecitabine as monotherapy, – after progression on trastuzumab combined with other kind of chemotherapy.

The combined HER2/HER1 inhibitor lapatinib in combination with capecitabine has shown a doubling of progression-free survival (4 months) compared to capecitabine alone in patients who have previously taken anthracycline, taxane, and trastuzumab. In addition, lapatinib has shown an effect in monotherapy studies after previous use of trastuzumab. Effect has also been reported in patients with brain metastases. NBCG believes the effect of lapatinib is sufficiently documented to recommend use of this in combination with capecitabine.

The following treatment choices are used for second and third-line treatment:

  • Trastuzumab in combination with the chemotherapy drug not used in first-line treatment.
  • Lapatinib (1250 mg orally x 1 daily) in combination with capecitabine (1000 mg/m² orally x 2 daily for 14 of 21 day cycle). Apply for cost coverage of lapatinib according to paragraph 3a. 
  • Trastuzumab in combination with capecitabine (1000 mg/m² x 2 day 1 – 14 every 21 days).
  • Trastuzumad in combination with lapitinib.

Fourth-line (possibly third-line) treatment

The following treatment choices are possible for fourth-line (possibly third-line) treatment: 

  • Pegylated liposomal doxorubicin. Dosage: 40 mg² i.v. every 28 days.

Pegylated liposomal doxorubicin (PLD) has shown comparable effect with doxorubicin in treatment of metastatic breast cancer, but with a reduced risk for cardiotoxicity (O’Brien et al. Annals of Oncology 15: 440-449, 2004). Further, data show that PLD can be used with satisfactory safety in dosage above limit used today for anthracycline (Safra et al. Annals of Oncology. 11: 1029-1033, 2000).

NBCG holds that PLD can be of special benefit when it is important to consider cardiotoxicity due to age, predisposition for heart disease, high cumulative doses, and for HER2 positive disease. 

Bisphosphonates or denosumab

If osteolytic metastases are present, with or without accompanying pain, treatment with bisphosphonates or denosumab is an appropriate supplement to endocrine treatment or chemotherapy.

Denosumab (subcutaneous administration) has been proven to prevent skeletal-related events to a greater extent than Zoledronic acid.

This treatment does not influence life span but can reduce the extent of skeletal complications (pathologic fractures, surgery for potential fractures, required radiation treatment, compression of the spinal cord and hypercalcemia). When bisphosphonate treatment should be initiated depends on the extent and symptoms of the disease.

 

Treatment recommendations

 

Hormone receptor-negative disease

Hormone receptor-positive disease

Patients starting chemotherapy for metastatic disease having both parenchymal metastases and skeletal metastases should be observed for response for 2-3 months before deciding on addition of bisphosphonates or denosumab. This applies especially to first line chemotherapy. With a good response (CR/PR), it is plausible to postpone treatment with bisphosphonates. Patients with assumed endocrine-sensitive disease in the skeleton should await the effect of this treatment (3-4 months) before treatment with bisphosphonates or denosumab is considered.
Patients who have progressing osteolytic metastases but no parenchymal metastases and where chemotherapy is indicated are recommended a supplement of bisphosphonate or denosumab for 12-24 months or until the first skeletal event. An observation period is usually not indicated as it is difficult to assess a response in the skeleton. At first evidence of osteolytic metastasis which appears to be easily observed, bisphosphonates or denosumab can be awaited, unless otherwise indicated by symptoms. If the patient is considerably pain-ridden at the time of endocrine treatment and the pain is not controlled with traditional analgesics, then bisphosphonates or denosumab should be immediately assessed. The treatment continues for 12-24 months or until the first event in the skeleton.   
In second line chemotherapy where the expectation of response is less and the response duration usually is shorter, the observation time may be reduced. In the absence of response to endocrine treatment, perform the same assessments as described under hormone receptor negative disease.
If the patient has considerable pain when starting chemotherapy and the pain is not controlled by traditional analgesics, the use of bisphosphonates or denosumab should be immediately assessed.  

The treatment continues for 12-24 months or until the first event in the bone.

 

An increased frequency of complications from the jaw, including osteonecrosis and infections has been reported after using intravenous bisphosphonate. This also applies to denosumab.

It is recommended to clarify the patient’s dental status before bisphosphonate and denosumab treatment is initiated since tooth extractions and infections pose an increased risk for osteonecrosis and osteomyelitis.

Invasive dental treatment should be avoided, if possible, in patients undergoing bisphosphonate or denosumab treatment. Dental surgery can exacerbate the condition in patients developing osteonecrosis in the jaw during bisphosphonate or denosumab treatment.

Preparation

  • For advanced/metastatic breast cancer, the status of the hormone receptors and HER2 should be monitored. These have significant consequences for choice of treatment.
  • The patient is explained the treatment and its consequences.
  • If menopausal status is uncertain, estradiol, FSH and LH should be measured.

Hormone treatment

  • In conjunction with the start of treatment with aromatase inhibitors/inactivators (AI), bone density measurement (DEXA-scan) should be performed. This can be postponed until later when it is known whether the treatment is to be continued (if the effect of treatment is appropriate).

Chemotherapy

During chemotherapy for metastatic breast cancer, neutropenia is the most common dose-limiting factor.

  • For weekly cycles, neutrophil granulocyte counts should be 1.0 x 109/l before start of treatment.
  • For tri-weekly cycles, neutrophil granulocytes counts should be ≥ 1.5 x 109/l before the start of treatment. If granulocytes are too low, the treatment should be postponed and it can be necessary to reduce the dosage of subsequent courses, especially for tri-weekly treatments.

The patient is offered a customized wig/scarf/hat.

Implementation

Each principle of treatment is continued until there is evidence for progression or intolerable toxicity.

During chemotherapy a pause in treatment may be acceptable in case of side effects (and continued effect of the treatment) or very good effect of the treatment. The patient should then be cautiously followed.

Follow-up

The effect of treatment is most often evaluated in 2-3 month intervals. Some patients need a first evaluation at a shorter interval. Evaluation often includes use of imaging modalities (UL, CT, scintigraphy).

Hormone treatment

The side effects of endocrine treatment are usually moderate. 

The most common side effect is:

  • hot flashes

Other side effects may be:

  • Nausea
  • Abdominal discomfort
  • Joint problems (especially with LAD)
  • Bone density changes with use of aromatase inhibitors

Tamoxifen poses a small increased risk for deep vein thrombosis (DVT), lung embolism (LE), and endometrial cancer. An annual gynecological examination is recommended during tamoxifen treatment.

Cytostatic chemotherapy

 

 Some side effects of chemotherapy for metastatic treatment

(frequent > 1/100, rare <1/1000)

   Doxorubicin Gemcitabine Capecitabine Vinorelbine
Bone marrow depression frequent frequent frequent frequent
Nausea/Vomiting moderate low frequent low
Hair loss frequent frequent frequent frequent/mild
Diarrhea/constipation diarrhea/rare diarrhea/constipation diarrhea/constipation constipation/diarrhea
Mucositis/stomatitis stomatitis/rare stomatitis stomatitis stomatitis/frequent
Allergic reactions rare rare rare rare
Cardiotoxicity yes rare rare not reported
Neurologic symptoms not reported rare rare frequent
Nail changes frequent not reported frequent not reported
Liver involvement not reported frequent frequent frequent/mild
Skin involvement frequent frequent frequent not reported
Respiratory involvement not reported frequent frequent not reported

Some side-effects of chemotherapy for metastatic treatment (cont’d.) 

                                  FEC    
 

Fluorouracil 

Epirubicin

Cyclophosphamide

Paclitaxel

Docetaxel

Bone marrow depression frequent frequent frequent frequent frequent
Nausea/Vomiting low moderate high/moderate low    low 
Hair loss frequent frequent in high doses frequent frequent
Diarrhea/constipation diarrhea diarrhea dose dependent diarrhea diarrhea/constipation
Mucositis/stomatitis stomatitis mucositis dose dependent mucositis stomatitis
Allergic reactions rare rare frequent rare sometimes
Cardiotoxicity rare yes rare rare rare
Neurologic symptoms rare not reported not reported frequent frequent
Nail changes not reported not reported rare frequent frequent/serious
Liver involvement rare not reported frequent rare/serious frequent
Skin involvement frequent frequent rare not reported less frequent

 

  *Cardiac failure in combination with trastuzumab (comprises 2,2 %)(1).

Flowchart - Cytostatic treatment

Sun Exposure under Drug Therapy

General

Correct information about the possibility of sunbathing may affect patients health and quality of life.

Precautions in connection with sunbathing should be followed under medical cancer treatment and for 2-3 weeks after end of treatment.

Drug cancer treatment includes chemotherapy, antibodies and other drugs used in cancer treatment.

Indication

Sun exposure in connection with drug cancer treatment.

Goal

Prevent sun damage of the skin during and after cancer drug treatment.

Definitions

Photosensitivity

Increased sensitivity to ultraviolet light have been associated with certain drugs used in cancer treatment. Photosensitivity reactions can be expressed in various ways. They can be phototoxic, which is by far the most common, or photoallergic (8,14). Druginduced photosensitivity is mainly caused by wavelengths in the UVA range, but UVB rays may also be involved (8).

Phototoxicity

A phototoxic reaction is reminiscent of a reinforced sunburn, with redness, edema, pain and increased sensitivity in sun-exposed areas of the skin. This is caused by a photochemical reaction of a photosensitive drug and irradiation of sunlight on the skin, which leads to skin cell death. In severe cases, blistering can occur (14). Symptoms may appear immediately or as a delayed inflammatory reaction (3). Higher doses of medication will give an increased risk of skin reaction (14). Healing of skin area will often lead to a hyperpigmentation that can last from weeks to months before they might disappear (8). Although the incidence of drug-induced photosensitivity is unknown, phototoxic reactions is possibly more common than is diagnosed or reported.

Photoallergy

An immunological reaction usually occurring 24-72 hours after sun exposure. The reaction degenerates as an itchy, eczema-like eruptions. In acute cases, one can see rash liquids. The prevalence of eczema is usually limited to sun-exposed skin, but can in severe cases spread to larger areas of the body. Unlike a phototoxic reaction, photoallergy is less dependent on the dose of the causative drug (8).

Photoinstability

Some drugs can be degraded when exposed to light. This can happen both before administration and when the drug is circulating in the body. This degradation can cause redness/rash and edema of the skin. This applies especially for dacarbazine (9). It is unknown whether the effect of the drug is affected and it is therefore recommended that one avoids direct sunlight as long as the drug is active in the body.

PPE ( palmoplantar erythrodysesthesia = Acral erythema )

PPE is also called hand-foot syndrom. The condition starts with altered skin sensation that develops into burning pain, swelling and redness of palm of the hands and soles of the feet. The symptoms can also occur in other parts of the body that is subjected to pressure, for example under tight clothing. In severe cases large blisters and ulceration can develop. The pain can be so severe that daily activities is limited.

PPE is often seen with liposomal doxorubicin (Caelyx®) and high dose cytarabine, but may in principle occur with any anthracyclines, taxanes and fluorouracil (5- FU® ) (9,14) .

Acne-like rash

Pimple-like eruptions in skin areas with a lot of sebaceous glands such as the face, scalp, chest and neck. In contrast to common acne, the liquid-filled blisters does not contain any bacteria (9,10,15).

Hyperpigmentation

Hyperpigmentation is a common side effect in patients receiving chemotherapy, especially alkylating drugs and antibiotics with cytostatic effect. The area that has increased pigmentation may be localized or diffusely distributed. It can occur in the skin, mucous membranes, hair and nails. Pigment changes can be normalized upon discontinuation of the drug, but it may also persist.

Fluorouracil is one of the most common drugs which can provide hyperpigmentation. Others are; metotrexate, busulfan, doxorubicin liposomal, Hydroksyurea®, procarbazine, bleomycin, cyclophosphamide, doxorubicin , ifosfamide, tegafur, mitoxantrone, daunorubicin, fluorouracil, cisplatin, carmustine, thiotepa, docetaxel, vinorelbine, vincristine, imatinib and combination regimens (14).

An increased pigmentation in sun-exposed areas with the use of methotrexate, fluorouracil and capecitabine is described (16,17,18). Beyond that there is little evidence in the literature  that hyperpigmentation aggravates by sun exposure.

Radiation Recall Dermatitis (RRD)/Photo Toxic recall reaction

Flares of an inflammatory skin reaction in an area of ​​previous radiation damaged skin resulting from sunburn or external radiation. RRD can occur from months to years after the initial radiation damage.

Drugs that can provide RRD are; bleomycin, capecitabine, cyclophosphamide, dactinomycin, cytarabine, daunorubicin, docetaxel, doxorubicin liposomal, doxorubicin, etoposide, fluorouracil, gemcitabine, Hydroksyurea® , idarubicin, lomustine, melphalan, methotrexate, paclitaxel, tamoxifen and vinblastine (14). EGFR inhibitors (cetuximab , gefitinib and erlotinib) may also cause other skin reactions that may be exacerbated by sun exposure (9,10,19).

Preparation

The patient is given written and verbal information by the medical responsible doctor and nurse at the start of the drug cancer treatment, and it is repeated as necessary.

Implementation

General Precautions

Prevention and protection:
  • Limit sun exposure during the first days after the cure.
  • Observe skin daily to detect any skin reactions early.
  • Avoid getting sunburned.
  • View extra care between 12.00-15.00 (2).
  • Wear protective clothing and headgear (2,3,4,5,6).
  • Wide-brimmed hats protect better than caps (2.4).
  • Please note that the window glass does not protect against UVA rays (7).
  • Use sunscreen; to protect against UVA and UVB rays, a minimum SPF 15 (3,4,6,8) is applied several times daily.
  • Use mild skin care products without perfumes.

In case of an eruption, sun exposure (including solarium) should be avoided until the skin is healed. Adverse skin reactions can be alleviated with moist and cooling compresses. Mild cortisone salves can also be highly effective. For very severe cases, systemic cortisone might be necessary (3,6,7,9).

When a photosensitive reaction occurs, it is important to consider what other medications the patient is receiving which can also trigger such reactions. For example, steroids, some antibiotics, diuretics and NSAIDs.

Medicaments that most commonly cause skin reactions

Medicament Common reactions Remedial action
Dakarbazin (DTIC)


Phototoxic/photoinstability
See general precautions
Redness in skin, tingling of the scalp and general unwellness
Avoid sunlight completely the day of the treatment (9)
Methotrexate
Phototoxic

See general precautions
Acne-like rash
Avoid direct sun exposure, heat and humidity (9,10). Avoid soap, alcohol based skin products (9). Use moisturizing products and oil bath (4,9,10).
Palmoplantar erythrodysesthesia = Acral erythema (PPE)

Preventive: Pyridoxin (vitamine B6) (2,6,9)

Avoid sunlight, heat, pressure against the skin and tight clothing can according to some studies have an effect (11,12,13). Use moisturizer.

Treatment/relief: Cortisone salves, cortisone tablets, cold compress, cold baths

(2, 9)

Fluorouracil (5-FU®)

 

Phototoxic See general precautions
Palmoplantar erythrodysesthesia = Acral erythema (PPE) Preventive: Pyridoxin (vitamin B6) (2,6,9)

Avoid sunlight, heat, pressure against the skin and tight clothing can according to some studies have an effect (11,12,13). Use moisturizer.

Treatment/relief: Cortisone salves, cortisone tablets, cold compress, cold baths   (2, 9)

Radiation recall
Treatment as with phototoxic

Kapecitabin (Xeloda®)

 

Phototoxic See general precautions
Palmoplantar erythrodysesthesia = Acral erythema (PPE)

Preventive: Pyridoxin (vitamin B6) (2, 6, 9). Preventive: Pyridoxin (vitamin B6) (2, 6, 9)

Avoidance of sunlight, heat, pressure against the skin and tight clothing can according to some studies have an effect (11,12,13). Use moisturizer.

Treatment/relief: Cortisone salves, cortisone tablets, cold compress, cold baths (2, 9)

Vinblastin

 

Phototoxic
See general precautions
Radiation recall Treatment as with phototoxic
Doxorubicin liposomal (Caelyx®)
Palmoplantar erythrodysesthesia = Acral erythema (PPE) Preventive: Pyridoxin (vitamin B6) (2, 6, 9)

Avoidance of sunlight, heat, pressure against the skin and tight clothing can according to some studies have an effect (11,12,13). Use moisturizer.

Treatment/relief: Cortisone salves, cortisone tablets, cold compress, cold baths (2, 9)

Tegafur

 

Phototoxic
See general precautions
Palmoplantar erythrodysesthesia = Acral erythema (PPE) Preventive: Pyridoxin (vitamin B6) (2, 6, 9)

Avoidance of sunlight, heat, pressure against the skin and tight clothing can according to some studies have an effect (11,12,13). Use moisturizer.

Treatment/relief: Cortisone salves, cortisone tablets, cold compress, cold baths    (2, 9)

EGFR-hemmere

(Cetuximab, panitumab, erlotinib, gefitinib, lapatinib, vandetanib)

Phototoxic
See general precautions
Acne-like rash
Avoid direct sun exposure, heat and humidity (9,10). Avoid soap, alcohol based skin products (9). Use moisturizing products and oil bath(4, 9, 10).

Beyond the medications listed in the table the literature gives som evidence that these substances may cause phototoxic skin reactions :

  • paclitaxel (Taxol®)
  • docetaxel (Taxotere®)
  • hydroxycarbamide ( Hydroksyurea® )
  • imatinib ( Glivec® ) and Dapson® and that paclitaxel can provide radiation recall .

References


  1. LOV-1999-07-02-63 Pasientrettighetsloven - pasrl. Lov om pasientrettigheter.
  2. Polovich M, White JM, Kelleher LO. Chemotherapy and biotherapy guidelines: recommendations for practice. Pittsburgh, PA: Oncology Nursing Society; 2005.
  3. González E, González S. Drug photosensitivity, idiopathic photodermatoses,and sunscreens. J Am Acad Dermatol 1996;35:871-85;quiz 886-7.
  4. Liffrig, JR. Phototrauma prevention. Wilderness Environ Med 2001;12:195-200.
  5. Tan E. Skin toxicity of chemotherapy drugs [created 2007, last updated  2010 Mar 5]. Hentet 1. desember 2010 fra: http://dermnetnz.org/reactions/chemotherapy-toxicity.html
  6. Gould JW, Mercurio MG, Elmets CA. Cutaneous photosensitivity diseases induced by exogenous agents. J Am Acad Dermatol 1995;33:551-73.
  7. Payne, AS & Bernandin, RM. Sunburn [topic last updated 2010 Oct 06]. I: BMJ Best Practice. Hentet 23. november 2010 fra http://bestpractice.bmj.com
  8. Zhang AY, Elmets CA. Drug-induced photosensitivity [updated 2010 Jan 15]. Hentet 1. desember 2010 fra: http://emedicine.medscape.com/article/1049648-overview
  9. Ulrich J, Hartmann JT, Dörr W, Ugurel S. Skin toxicity of anti-cancer therapy. J Dtsch Dermatol Ges 2008;6:959-77.
  10. Agero AL, Dusza SW, Benvenuto-Andrade C, Busam KJ, Myskowski P, Halpern AC.Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol 2006;55:657-70
  11. Alley E, Green R, Schuchter L. Cutaneous toxicities of cancer therapy. Curr Opin Oncol 2002;14:212-6.
  12. Mangili G, Petrone M, Gentile C, De Marzi P, Viganò R, Rabaiotti E. Prevention strategies in palmar-plantar erythrodysesthesia onset: the role of regional cooling. Gynecol Oncol 2008;108:332-5.
  13. Tanyi JL, Smith JA, Ramos L, Parker CL, Munsell MF, Wolf JK. Predisposingrisk factors for palmar-plantar erythrodysesthesia when using liposomal doxorubicin to treat recurrent ovarian cancer. Gynecol Oncol 2009;114:219-24.
  14. Payne AS, Savarese DMF. Cutaneous complications of conventional chemotherapy agents. I: UpToDate [version 18.2 2010]. Hentet 1. desember 2010 fra: http://www.uptodate.com
  15. Heidary N, Naik H, Burgin S. Chemotherapeutic agents and the skin: an update. J Am Acad Dermatol 2008;58:545-70.
  16. RELIS Sør. Hyperpigmentering av cytostatika og forverring av sollys. I: RELIS database 2010, Spm.nr 4736. Hentet 1. desember fra: http://relis.arnett.no/Utredning_Ekstern.aspx?Relis=2&S=4736
  17. Hendrix JD Jr, Greer KE. Cutaneous hyperpigmentation caused by systemic drugs. Int J Dermatol 1992;31:458-66.
  18. Schmid-Wendtner MH, Wendtner CM, Volkenandt M, Heinemann V. Clinical picture: leopard-like vitiligo with capecitabine. Lancet 2001;358(9293):1575.
  19. Segaert S, Tabernero J, Chosidow O, Dirschka T, Elsner J, Mancini L, et al. The management of skin reactions in cancer patients receiving epidermal growth factor receptor targeted therapies. J Dtsch Dermatol Ges 2005;3:599-606.

Preparation of Chemotherapy, Spills, and Cleaning a LAF Bench

General

Preparation of chemotherapy outside of a pharmacy

At Oslo University Hospital, the pharmacy primarily prepares chemotherapy for each patient. If it is necessary to dilute/mix the medicine at the department, then this should occur in a designated room with a LAF bench (laminar airflow bench). Many chemotherapy drugs are carcinogenic and teratogenic, and it is extremely important for health personnel to follow directions for preparation of of these medications. At Oslo University Hospital, all chemotherapy should be prepared and administered by a nurse who has completed a cytostatic treatment course at Oslo University Hospital, or by nurses who are certified cancer nurses from Oslo University College.

Pregnant women and employees under physician orders not to temporarily or permanently work with chemotherapy drugs, should not handle or be exposed to these chemicals. Nursing mothers may handle chemotherapy drugs as long as they follow the general guidelines for chemotherapy handling. For each work place, there should be written guidelines for handling of chemotherapy drugs and for first aid for spills and maintenance of fume hoods etc..

Designated room with LAF-bench to dilute/mix chemotherapy

  • The ventilation should be separate from the main ventilation and fumes should be vented to the outside and if necessary, filtered.
  • The room should be well illuminated for visual control of the fluid.
  • The LAF bench should be a workbench having sterile, filtered air from the ceiling with defined speed and an approved fume hood. The bench should be routinely tested and approved.

Goal

  • To protect nurses and surroundings from exposure to cytotoxic chemicals and to preserve the sterility of the drug.

Handling of chemotherapy spills

Chemotherapy drugs are a heterogeneous group of drugs in which many are known mutagens, teratogens and/or carcinogens. Allergic reactions have also been reported. Studies show that there is a health risk during exposure of chemotherapy drugs and there are guidelines for minimizing exposure of health personnel to these chemicals. Workers in daily contact with these drugs will be more at risk due to the increasing use of chemotherapy. Chemotherapy spills refers to spills during preparation and leakage from infusion bags.

Goal

  • To ensure that spills of chemotherapy drugs or waste materials that contain these chemicals are handled in a safe way to protect health and safety.

Cleaning of LAF-bench

The Norwegian Work Authority recommends that each workplace should have written guidelines for handling chemotherapy drugs, first aid for spills, and maintenance of fume hoods etc. A LAF-bench (laminar airflow bench) is a bench protecting workers from the drug being prepared and also protects from microbiological organisms. Those who carry out cleaning should have training and knowledge of the risk for exposure to chemotherapy drugs.

Goal

  • Maintain a clean LAF bench
  • Avoid contamination and preserve the sterility of the drug 
  • Protect people and surroundings from exposure

Source

Applicable directives and guidelines (www.lovdata.no)

  • Warn against exposure to chemicals at the workplace (Kjemikalieforskriften §24), mandated by The Norwegian Labour Inspection Agency from 5 May 2001, last edition from 26 April 2005.
  • Guidance for chemical directives attachment VII Cytostatica from September 2003 (www.arbeidstilsynet.no).

Equipment

  Preparation of chemotherapy in a hospital

  • 2 pairs of gloves: vinyl gloves inside and sterile, powder-free latex gloves outside
  • Protective coat with long arms/plastic apron
  • Arm protectors
  • LAF bench
  • Dilution fluid
  • Syringes and cannulas
  • Sterile compresses
  • Disposable cloths
  • 70% ethanol
  • Absorbent benchcoat with plastic underside for the work bench
  • If a LAF bench is not used, use a protective mask with aerosol filter and protective goggles.

Handling of chemotherapy spills

Spill kit includes:

  • 2 pairs of nitrile gloves, long
  • 2 pairs of latex gloves, long
  • 2 pairs of shoe covers
  • Plastic coat\apron
  • 1 mask
  • 2 diapers
  • 1 bed absorbent bed sheet
  • 2 plastic bags with zippers (30 x 40 cm)
  • 4 thin, white plastic bags (60 x 90 cm)
  • Absorbant material   
  • 8 disposable wash cloths

Washing of LAF-bench

  • Plastic apron
  • Arm protectors
  • Gloves: either double vinyl gloves or special gloves
  • Disposable cloths
  • 70% ethanol
  • Bucket and soapy water
  • Waste container with plastic bag for chemotherapy waste (biohazardous waste)

 

 

Preparation

Preparation of chemotherapy outside of the pharmacy

For preparation of chemotherapy drugs, use gloves and a protective lab coat with long arms or tight-fitting cuffs.   Use two pairs of gloves where the inner pair is vinyl or other latex-free material. The outer glove should be sterile and of latex or other material which is impenetrable.  The gloves are recommended to be changed every half hour for preparation of chemotherapy drugs, and right away with spills.

  • Start the LAF-bench a minimum of 30 minutes before use.
  • Wash hands
  • Put on the inner gloves
  • Disinfect the work surface with 70% ethanol
  • Cover the work surface with a benchcoat. This should not cover the vent; otherwise, the bench will not function properly.
  • Read the dilution directions and find the necessary equipment and medications as described.
  • Choice of dilution system/fluids
    • A transfer cannula should be used in preference to a syringe where possible to maintain a closed system as much as possible.
    • If a syringe is used: use a syringe with Luer lock connection. These have a better connection between the syringe and the cannula.
  • Check the expiration on the drug packaging and infusion fluid.
  • Check that the drug in liquid form does not contain particles or visible solids.
  • Check that the packaging does not have any cracks or leakages.
  • Perform necessary calculations, date, and sign the work form.
  • Obtain another nurse to double check: right patient, work form, drug, dosage, fluid type and volume, as well as calculations.  All checks should be against the original ordination. The person doing the check should sign and date it.
  • Set out necessary equipment on the LAF-bench or where the work will take place. The equipment should be placed in the corner within the ventilation of the LAF-bench.  Remove the outer packaging of the sterile gloves and lay the gloves on the bench.
  • Put on the protective clothing (coat/apron and arm protectors)
  • Put on the sterile gloves in the bench
  • Disinfect the rubber membrane on the infusion bag and hood windows as well as the ampules.
  • Make sure the protective glass on the LAF-bench is pulled down to the correct work level as recommended by the manufacturer of the bench.

Handling of chemotherapy spills

All, except the workers who clean the spill, should leave the room.  Preferably, two people should help each other to remove the spill.  This way, one can ensure that proper precautions are taken.

At Oslo University Hospital, a packet is available from the pharmacy for chemotherapy spills.

Washing of LAF-bench

  • The LAF-bench should be operating under cleaning.
  • The sash should be down, as under normal working conditions.
  • Use a plastic apron, arm protectors, and gloves.

 

 

Implementation

Preparation of chemotherapy drugs outside of a pharmacy

Aseptic procedure

  •   To avoid turbulence of the sterile, laminar air stream:
    • Work at least 15 cm inside the perforation with steady movements
    • Avoid hands or other objects from coming between the airflow and the medicine.
  • Make only one medicine at a time.
  • A full syringe or finished bag should be labeled for the next preparation.  The label should be labeled with the patients name, birthdate, drug and dosage, preparation date, expiration, and the name of the person who prepared and checked the medicine.
  • Avoid spills and aerosol formation
    • Use a dry, sterile compress around neck of the ampule when it is broken.
    • When the cannula is removed from the syringe, hold a sterile compress around the barrel neck to catch any spills.
    • Hold the syringe/ampule such that the opening is directed away from the face.
    • For solid substances, solvent should be added along the glass wall to avoid whirling of particles.
    • With positive/negative pressure in the hood glass: apply a filter cannula first to reduce pressure.
    • With use of adapter: place adapter first in the infusion bag and connect to the hood glass with medicine.
    • When the air is removed from the syringe, place the cannula cap on the cannula again while the syringe is held vertically with the cannula upright. A sterile compress should be held around the opening between the cannula and the syringe to collect spillage.
    • Clean up spills at once
  • After each addition, the contents of the infusion container should be mixed well by inverting and repeating 5-6 times.
  • Infusion fluid which has been added to should be marked satisfactorily.
  • The finished solution should be scrutinized for solid or foreign particles. All solid should be dissolved.
  • If visible changes occur under the mixing procedure, the physician should be contacted and the fluid should not be used. Store the infusion fluid and packaging of the added drug and contact the pharmacy (chemist) for further clarification.
  • All used equipment should be rolled up in the benchcoat (alternatively, all used equipment can be placed in a plastic bag which can be tied or closed with zipper) and disposed of in box with plastic bag for chemotherapy waste/biohazardous waste.
  • LAF-bench should be stopped at least 30 minutes after use.

Multiple additions

  • Addition of multiple drugs for chemotherapy solutions should be avoided. If it is still appropriate, there should be clear documentation of the mixture.
  • Different chemotherapies can mix if their mixing properties are documented (and checked with pharmacist).

Handling of chemotherapy spills

  • Use two pairs of disposable latex\nitrile gloves, plastic coat, mask, shoe covers (used with floor spills) and protective goggles.
  • Lay the smallest diaper in the middle of the spilled fluid. Then, place the absorbent bed sheet over the diaper and the rest of the fluid. Use more diapers and absorbent material if necessary.
  • Dispose of used diapers, absorbent material, bed sheets, and gloves is appropriate waste container, which can be closed.
  • Use new gloves and wash thereafter with soapy water and disposable wash cloths a minimum of three times. Use a new cloth before each wash. Used cloths should not be put back in the wash solution.  Used cloths and gloves should be disposed in the appropriate waste containers (in plastic bags which can be closed).
  • The plastic bags with used equipment should be disposed of in the appropriate containers which are properly labeled.

Washing of LAF-bench

  • Other than a cannula bucket, nothing should be stored in the bench after the last preparation.
  • Washing with 70% ethanol is sufficient if there are no visible spills.
  • For visible spills, wash the bench with soapy water and spray afterwards with 70% ethanol (see procedure under). Soapy water is the most effective for removing chemotherapy spills.

Routine washing

  • Washing should be done every 1-4 weeks depending on frequency of use.
  • Spills and dust pose risks for washing.
  • It is important that any remaining solution of chemotherapy is not spread under washing.
  • Use disposable cloths.
  • To avoid contamination of washing water, the washing hand should not be dipped in the water.
  • Wash with slow movements and use a new cloth as needed.
  • Cloths that have been in contact with the bench should not be put back in the washing water and should be discarded in proper waste container.
  • Wash first the walls from top to bottom with soapy water (the cleanest to the most contaminated) – place the cloth on a squeegee for hard-to-reach areas.
  • The filter in the ceiling of the bench should not be washed.
  • Wash the work surface in the bench – wash from back to forward (from the cleanest to the most contaminated).
  • Raise the work surface.
  • Wash the work surface on the underside, especially the closest, perforated part.
  • Then wash the underside bottom of the work surface.
  • Wash thereafter all surfaces (not the ceiling) with 70% ethanol.
  • Remove protective clothing.
  • Discard all protective clothing for one-time use and washcloths in the appropriate waste container.
  • Wash hands.
  • Replace the cannula bucket.
  • There should be a record for bench washing; the employee who washes should sign and date the record.

Follow-up

Aerosol formation with spraying or squirting can occur:
  • when a syringe is used and cannula is retracted for transfer
  • when an ampule is broken
  • when air is removed to measure volume
  • with a leak in a syringe or IV catheter
  • with waste handling

First aid if contact with chemotherapy drugs

  • Skin: Rinse well with water for 15 minutes. Wash contacted area with regular soap.
  • Eyes: Rinse well with water, or use spray bottle with NaCl 9 mg/ml (at least 20-30 minutes of continual rinsing).
  • Contact a doctor.

Radiation Therapy of Breast Cancer

Curative radiation therapy usually includes CT-based drawing of target volumes. This drawing is the basis for dose planning and field definition. The adjustment of radiation field is at present only rarely performed manually.

Radiation therapy after breast conservative treatment

After the tumor is removed by breast conservative surgery, there may still be remaining cancer cells in the breast. Therefore, it is recommended that the entire breast is irridiated. To minimize the risk for recurrence, infiltrating tumors should be removed with free resection margins (“ink not on tumor”) before radiation is started. For DCIS in contrast, a 2 mm minimum (rounded to whole mm) distance between DCIS and the resection margin is required. If these criteria are not met, it is recommended to do a re-resection before radiation treatment, both for invasive carcinoma and DCIS. More narrow margins are accepted if a resection is performed to the skin and down to the muscle fascia.

The present results clearly support the basis for equalization of hypofractionated radiation (2.67Gy x 15) and conventional radiation (2 Gy x 25) for pT1-2 pN0 infiltrating breast cancer treated with BCT.

Radiation therapy after mastectomy

Radiation therapy is recommended in the instances where a mastectomy is performed for invasive breast cancer, where microscopic resection margins are uncertain or not tumor-free.

Radiation therapy for metastases to lymph nodes 

Radiation therapy to the breast/chest wall and regional lymph nodes is recommended for metastasis > 2mm to an axillary lymph node.

Invasive breast cancer stage III (T3-4N0-3, T1-2N2-3)

This patient group is very heterogeneous. It is important that the individual patient is assessed by both a surgeon and an oncologist before treatment is decided. The patient should be referred to a regional oncology department for assessment of multimodal treatment.

Most often, neoadjuvant chemotherapy is followed by surgery before radiation therapy is relevant. In certain cases, operability is not reached by the neoadjuvant treatment. In these cases, radiation therapy may be performed without previous surgery.

Radiation therapy without previous surgery

Radiation therapy without previous surgery is used occasionally for very large tumors or inflammatory breast cancer, or if the patient refuses operative treatment. This approach may be an alternative if the patient cannot undergo surgery for medical reasons. In these cases, the radiation treatment plan will be individualized.

PROSEDYRER

Postoperative Radiation Treatment of the Breast

General

Postoperative radiation therapy requires adequate removal of the primary tumors and completed axillary dissections (sentinel node or adequate axillary dissection levels I and II). A ≥ 5 mm tumor-free margin to the sides should be for the goal during surgery. Re-resection is however not necessary if the resection margins are tumor-free in("ink not on tumor"). Thus there are no specific requirements on the resection margins. If there is uncertainty whether the resection margins are free, the patient must be re-operated and have a re-resection or mastectomy. The exception is when the tumor is localized close to the thoracic wall or to the skin, where smaller margins are accepted, if resected to the fascia or to the skin. 

Postoperative radiation therapy should not be given simultaneously with adjuvant chemotherapy. Radiation therapy must begin within 3-4 weeks after chemotherapy is finished.

Endocrine treatment and trastuzumab (Herceptin®) can be given simultaneously with radiation therapy.

Indications

For infiltrating breast cancer:

  • After breast conserving surgery
  • For large primary tumor (T > 50 mm)
  • For non-radical surgery (after mastectomy)
  • For lymph node positive disease (except for involvement of only intra-mammary lymph node without any other lymph node involvement)

For DCIS:

  • All grade II/III and grade I > 10 mm with BCT
  • Non-radical surgery (after mastectomy)

Radiation therapy after breast conservative treatment

DCIS (all grades II/III, grade I > 10 mm)

Radiation treatment is performed as two tangential fields. The entire breast (not the chest wall) is defined as the target volume. The medial field border will be close to the midline. The radiation must include the lateral part of the breast. Upwards, the field will extend to the sternoclavicular joint, and downwards to 1-1.5 cm under the inframammary fold.

Invasive breast cancer pT1-2pNO

Radiation treatment is performed as two tangential fields. The entire breast (not the chest wall) is defined as the target volume. The medial field border will be close to the midline. Upwards, the field will extend to the sternoclavicular joint and downwards to 1-1.5 cm under the inframammary fold.

To minimalize the cardiac radiation hypofractionated radiation towards the left side should be performed with gatting (breath synchronized radiation). This strives to maintain the heart outside the field borders with a maximal average dose of 2 Gy. On this basis it is accepted that during chemotherapy/immunotherapy the patient have synchronous irradiation. (the organ at risk avoids for the combination of chemotherapy and radiation dose).

Invasive breast cancer pT1-2pN1-2

If there is metastasis to one or more axillary lymph nodes and the largest metastasis is > 2mm, radiation therapy should be given toward the mammary gland and regional lymph nodes.

For elderly patients, an individual assessment is made with emphasis on comorbidity, biological age/expected survival time. 

The target definition for patients in this group should, in addition to the breast, include the axillae and supraclavicular lymph nodes. In large, medial tumors, the upper parasternal lymph nodes are also included. When 10 or more axillary lymph nodes are removed, level I and II of the axilla should not be irradiated. This is independent of how many lymph nodes are tumor-involved. If the surgeon notes that there is possibility for remaining tumor in the axilla or that the lymph node involvement is very wide-spread, level I and II of the axilla should also be included in the target volume to improve regional control. The same applies if there is evidence of macroscopic extranodal extension (> 2 mm) or tumor islands in the fatty tissue, even if ≥ 10 lymph nodes are removed.

After mastectomy

Invasive breast cancer pT1-2pNO or DCIS

The target area includes the chest wall located under the breast and the scar. Radiation treatment is performed as two tangential fields with field borders laterally in the medio-axillary line, medially in the mediosternal line, downwards to 1-1.5 cm under the inframammary fold of the opposite breast and cranially towards the sternoclavicular joint.

Invasive breast cancer pT1-2pN1-2

Radiation therapy after mastectomy is equivalent to what described for breast conservative treatment (largest lymph node metastasis > 2mm) with the following exceptions:

  • A boost is not usually given after mastectomy. The target volume is the chest wall located under the breast and the incision scar, axillary and supraclavicular lymph nodes and possibly the upper parasternal lymph nodes.
  • For elderly patients, an individual assessment is made with emphasis on comorbidity, biological age/expected survival time.

Goal

  • To reduce the risk for local and/or regional relapse.
  • To increase the survival after both breast conservative treatment and mastectomy.

Definitions

Target Volume

Target volume definitions from ICRU
(International Commission on Radiation Units and Measurements)

GTV (= Gross Tumor Volume)

Tumor volume

Palpable or visible/identifiable area of malignant growth. Confirmed lymph nodes may be reported as GTV-N, other metastases as GTV-M.

CTV (= Clinical Target Volume)

Clinical target volume

Tissue volume containing GTV and/or subclinical microscopic malignant disease.

ITV (= Internal Target Volume)

Target volume

Volume containing CTV and an internal margin taking into account internal movements and changes in  CTV. This is the volume that should receive an optimal dose.

PTV (= Planning Target Volume)

Planning volume

Geometric volume containing ITV and one Set-up margin taking into account variation for patient movements, variations in patient positioning, and field modeling.

Planning contour: Beams-Eye-View projection of PTV.

 IM (= Inner margin) and SM (= Setup margin)

IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.

GTV

Gross tumor volume is not applicable for postoperative radiation.

CTV breast

Includes breast and the axillary process of the breast,

Limits

  • Ventrally: 5 mm under skin layer
  • Dorsally: fascia covering the pectoral muscle, possibly anterior surface of ribs in deeply located tumors.

CTV boost

With CT as reference, this volume includes the tumor bed defined as the operative cavity and the visible postoperative reaction, with additional 5-10 mm surrounding tissue, or alternatively as visible operation cavity and possibly staples with about 2 cm surrounding tissue. The scar is not part of the target.

CTV parasternal lymph nodes

Routine radiation is no longer necessary. The method should be considered for:

  • large, medially or centrally localized tumors
  • positive parasternal sentinel lymph node

Limits

  • Medially: lateral border of sternum 
  • Laterally: 2 cm laterally to the medial limit
  • Dorsally: pleura
  • Ventrally: anterior edge of ribs
  • Cranially: immediately caudally to the sternoclavicular joint
  • Caudally: cranial border of ribs IV (often equals 1 cm below carina)

CTV periclavicular lymph nodes

Limits

  • Medially: 1,5 cm from trachea
  • Caudally/laterally: border to the axilla
  • Cranially: equals 1 cm caudal to vocal cords or the lower part of C6
  • Caudally: lower part of the sternoclavicular joint
  • Anteriorly: 5 mm deep to the skin
  • Dorsally: anterior to the transverse process in upper part, the ribs more caudally.

CTV axilla

Level I lateral to pectoralis minor muscle 

Level II posterior to pectoralis minor muscle 

Level III medially to pectoralis minor muscle. Lateral to the supra/infraclavicular region.

CTV thoracic wall

  • Includes the area underlying the breast as well as the operation scar. The outer 5 mm of the skin is not included in the clinical target volume. Over the scar itself and 20 mm to the sides of the scar, the clinical target volume includes the surface of the skin when the distance from the tumor to the skin is short (use of bolus). In the depth the target volume reaches the anterior rib surface. The medial border mimics the edge of the remaining breast. If this is not possible to identify, the medial border should be 25 mm lateral to the lateral edge of the sternum.

ITV=CTV

PTV

Margins are set to 5-7mm, towards the heart 0 mm. The minimum dose in PTV should be 90% of the target dose.

Preparation

  • Review of operation protocol, histology results, receptor status, and indication for radiation therapy as well as adjuvant treatment.
  • The patient is examined and informed by the physician and nurse in an out-patient setting.
  • Routine blood tests and X-ray of thorax are taken. Other necessary examinations if necessary (for example ultrasound and cytology of actual tumors/seroma, bone scintigraphy, ultrasound of liver etc).
  • Patient lies in the supine position with arm support/holder. Breast board. Wing board.
  • Drawing of target volume is CT-based and will be the basis for the treatment planning.
  • Conventional simulation is rarely used, and only when the CT-based treatment planning are not possible to perform (most often due to reduced mobility of shoulder/arm). The target volum is defined by the superficial anatomical structures and by means of X-ray.
  • Fixation (boost)

NBCG recommends that all women having curative irradiation for breast cancer should have fT4, TSH, and anti-TPO taken prior to the irradiation.

Organs at risk

  • Heart
  • Lungs
  • Spinal cord 
  • Contralateral breast
  • Brachial plexus 

Implementation

Treatment is given as a daily fractions (Monday to Friday a total of 5 fractions per week).The treatment lasts for 3-7 weeks, depending on the fractionation and whether there is indication for a boost.

An average cardiac dose of maximally 2 Gy is striven for. If this is not achieved the target volume should be reevaluated (change of CTV to an adjusted dosage volume if this is clinically acceptable) and/or risk/benefit ratio especially considered.

  • For pT1-2 lymph node positive breast cancer is usually given 25 fractions of 2 Gy (2 Gy x 25) towards the chest wall and 23 fractions (2 Gy x 23) towards regional lymph nodes. For clinically suspicion of remaining macroscopic tumor in the axilla  2 Gy x 25 should also be given towards the regional lymph nodes. For breast conserving surgery boost irradiation, 2 Gy x 8, is given towards the tumor bed, in women below 50 years of age. It is recommended that maximally 35 % of the lung should receive a dosage of 20 Gy (V20 < 35 %).
  • After breast conservation for infiltrating cancer without lymph node metastases is either given 2.67 Gy x 15 (usually) or 2 Gy x 25 towards the breast. Additionally boost radiation 2 Gy x 8 is given towads the tumor bed in women < 50 years of age. Hypofractionated irradiation for left sided cancer is performed by gatting (respiratory synchronization of the irradiation). This aims at maintaining the heart outside the field limits with an average maximal radiation dose of 2 Gy. During radiation with 2 Gy x 25 towards the breast only, less than 15% of the lung should receive a maximal dosage of 20 Gy or more. For hypofractionated irradiation with 2.67 Gy x 15 this is equivalent to V18 Gy < 15%.
  • Subsequently to breast conservation surgery for DCIS  2 Gy x 25 is given towards the breast. Usually less than 15% of the ipsilateral lung should receive a maximal dosage of 20 Gy or more.
  • After mastectomy with tumor in the resection margin and without involvement of regional lymph nodes 2 Gy x 25 is given towards the chest wall.
  • For massively non-free resection margins or remaining macroscopic tumor after mastectomy.

Radiation treatment with locally advanced/invasive breast cancer T3-4N0-3, T1-2N2-3

  • After radical surgery, the radiation treatment plan is often equivalent to radiation treatment in pT1-2pN1-3 disease. 50 Gy is given toward the thoracic wall and 46 Gy toward regional lymph node stations (applies also to N0 disease). The axilla (level I and II) is not radiated if ≥ 10 lymph nodes are removed, as long as there is no known extranodal infiltration (> 2 mm) or tumor islands in the fat tissue.

To achieve optimal dosage in the skin after mastectomy a bolus should be individually considered. After breast conservation surgery (less frequently) indication for boost should be considered.

 

Follow-up

During irradiation

  • Regular follow-up
  • Consultation with oncologist at the end of the treatment

At end of irradiation

  • The patient should be followed-up at the remitting hospital or possibly at the general practitioner, and preferentially according to the recommendations from the Norwegian Breast Cancer Group.
  • The first consultation after ended irradiation is usually after 6 months, earlier if there is indication for adjuvant treatment with trastuzumab (Herceptin) or if required. Thereafter mammography and consultation with a physician should take place annually for 10 years.

More frequent follow-ups may be relevant for young patients (below 35 years), patients with locally advanced disease and patients where the cancer developed in relation to pregnancy.

Side effects of irradiation

Acute

  • Skin reaction in the form of redness, heat, soreness and edema. Some develops more pronounced irradiation dermatitis with desquamation and ulcerations.
  • Soreness of the pharynx after irradiation of regional cervical lymph nodes.
  • Nausea, most often slight and passing

Late

  • Permanent changes of the skin in the form of fibrosis, pigmentations and teleangiectasies.
  • Varying degree of fibrosis of the lung
  • Deterioration of/persistent lymphedema of the arm on the irradiated side.
  • Contractures and reduced mobility of the shoulder on the irradiated side.
  • Reduced strength of the skeleton, especially of the ribs/clavicle on the irradiated side
  • Slightly enhanced risk for secondary cancer (very small absolute risk)
  • Previously enhanced risk for cardiovascular disease. This is not seen with modern radiation techniques.

Primary Radiation Treatment of the Breast

General

Primary radiation treatment is often given in combination with other tumor-directed treatment such as chemotherapy, surgery, or endocrine treatment. Dose and target volume are adapted individually.

Sometimes when the tumor is large and the effect of chemotherapy is not satisfactory, surgery is difficult to perform. In such cases, radiation treatment can be performed without prior surgery.

Primary radiation treatment may be an alternative in the event that the patient cannot undergo surgery for medical reasons. Treatment in these cases are individualized and a radiation dose of 60 Gy to the tumor area is striven for.

Indications

  •   Locally advanced/invasive, inoperable breast cancer T3-4N0-3, T1-2N2-3 
  •   Inoperable inflammatory breast cancer
  •   The patient does not want surgical treatment

Goal

  • To reduce tumor volume as preparation for surgical treatment.

Definitions

Target Volume

Target volume definitions from ICRU
(International Commission on Radiation Units and Measurements)

GTV (= Gross Tumor Volume)

Tumor volume

Palpable or visible/identifiable area of malignant growth. Proven lymph nodes may be reported as  GTV-N, other metastases as GTV-M.

CTV (= Clinical Target Volume)

Clinical target volume

Tissue volume containing GTV and/or subclinical microscopic malignant disease.

ITV (= Internal Target Volume)

Target volume

Volume containing CTV and an internal margin taking into account internal movements and changes in  CTV.  This is the volume that should receive an optimal dose.

PTV (= Planning Target Volume)

Planning volume

Geometric volume containing ITV and one Set-up margin taking into account variations for patient movement, patient positioning, and field modeling.

Planning contour: Beams-Eye-View projection of PTV.

 IM (= Inner margin) and SM (= Setup margin)

IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.
 

GTV

Gross tumor volume is not applicable for postoperative radiation.

CTV breast

Includes breast and the axillary process of the breast.

Limits

  • Ventrally: 5 mm under skin layer
  • Dorsally: fascia covering the pectoral muscle, possibly anterior surface of ribs in deeply located tumors.

CTV boost

With CT as reference, this volume includes the tumor bed defined as the operative cavity and the visible postoperative reaction, with additional 5-10 mm surrounding tissue, or alternatively as visible operation cavity and possibly staples with about 2 cm surrounding tissue. The scar is not part of the target.

CTV parasternal lymph nodes

Routine radiation is no longer necessary. The method should be considered for:

  • large, medially or centrally localized tumors
  • positive parasternal sentinel lymph node

Limits

  • Medially: lateral border of sternum 
  • Laterally: 2 cm laterally to the medial limit
  • Dorsally: pleura
  • Ventrally: anterior edge of ribs
  • Cranially: immediately caudally to the sternoclavicular joint
  • Caudally: cranial border of ribs IV (often equals 1 cm below carina)

CTV periclavicular lymph nodes

Limits

  • Medially: 1.5 cm from trachea
  • Caudally/laterally: border to the axilla
  • Cranially: equals 1 cm caudal to vocal cords or the lower part of C6
  • Caudally: lower part of the sternoclavicular joint
  • Anteriorly: 5 mm deep to the skin
  • Dorsally: anterior to the transverse process in upper part, the ribs more caudally.

CTV axilla

  • Level I lateral to pectoralis minor muscle 
  • Level II posterior to pectoralis minor muscle 
  • Level III medial to pectoralis minor muscle. Lateral to the supra/infraclavicular region.

CTV thoracic wall

  • Includes the area underlying the breast as well as the operation scar. The outer 5 mm of the skin is not included in the clinical target volume. Over the scar itself and 20 mm to the sides of the scar, the clinical target volume includes the surface of the skin when the distance from the tumor to the skin is short (use of bolus). In the depth the target volume reaches the anterior rib surface. The medial border mimics the edge of the remaining breast. If this is not possible to identify, the medial border should be 25 mm lateral to the lateral edge of the sternum.

ITV=CTV

PTV

  • Margins set to 5-7 mm, toward the heart 0 mm. Minimum dose in PTV should be 90% over the target dose.

Preparation

  • Review of operation protocol, histology results, receptor status, and indication for radiation therapy as well as adjuvant treatment.
  • The patient is examined and informed by the physician and nurse in an outpatient setting.
  • Routine blood tests and X-ray of thorax are taken. Other necessary examinations if necessary (for example ultrasound and cytology of actual tumors/skin changes etc., bone scintigraphy, ultrasound of liver).
  • Patient lies in the supine position with arm support/holder. Breast board. Wing board.
  • Drawing of target volume is CT-based and will be the basis for the treatment planning.
  • Conventional simulation is rarely used, and only when the CT-based treatment planning are not possible to perform (most often due to reduce mobility of shoulder/arm). The target area is defined by the superficial anatomical structures and by means of X-ray.

NBCG recommends that all women having curative irradiation for breast cancer should have fT4, TSH, and anti-TPO taken prior to the irradiation.

Organs at risk

  • Heart
  • Lungs
  • Spinal cord 
  • Contralateral breast
  • Brachial plexus 

Implementation

The treatment is given in the form of daily 2 Gy fractions (Monday to Friday, a total of 5 fractions per week). Usually, 25 or more fractions are given toward the thoracic wall and other macroscopic tumors.

The treatment will last about 5-7 weeks.

The total dose is usually 50 Gy or higher (up to 60 Gy) toward the macroscopic tumor.

Follow-up

During radiation treatment

  • Routine follow-up by nurses during the course of radiation.
  • The patient will have a consultation with a doctor toward the end of the treatment. The patient is offered a consultation during treatment as needed.

After concluding radiation treatment

  • In preoperative/primary radiation treatment, the first follow-up check is usually at the regional hospital after 4-6 weeks. This includes evaluation by oncologist of the radiation effect, as well as by surgeon of operative result.
  • Further follow-up depends on the treatment plan. The first followed-up is preferably at a regional hospital. Thereafter, follow-up continues at the referring hospital.  
  • A yearly check and mammogram is recommended for the following ten years.

Side Effects of Radiation therapy

Acute

  • Skin reactions in the form of redness, heat, soreness, and edema. Some may develop more serious radiation dermatitis with peeling skin and formation of ulcerations.
  • Soreness while swallowing (after radiation treatment toward regional lymph nodes of the neck).
  • Nausea, often low-grade and manageable.

Delayed

  • Lasting skin changes in the form of scarring/fibrosis, pigment changes, and telangiectasia.
  • Lung fibrosis to a varying degree.
  • Lymph edema in the arm of the treated side.
  • Reduced movement in the shoulder of the involved side.
  • Weakness of the skeletal structure, especially in the ribs/clavicle of the treated side.
  • Small increase in risk for secondary cancer.
  • Previously, an increased risk for cardiovascular disease was observed especially when irradiating toward the left thorax, but with today’s radiation treatment technique, the risk is small.

 

 

Palliative Radiation Treatment of Breast Cancer

General

Palliative radiation therapy for breast cancer is administered to reduce symptoms from metastases.

Radiation therapy is offered liberally for local symptoms.

There must be a definite connection between the actual metastasis(es) and the symptom(s).

Indications

  • Metastases which cause for example pain, pressure symptoms, airway obstruction, bleeding, and secretion.

Goal

  • To relieve painful or uncomfortable symptoms.

Definitions

Target Volume

 

 

Target volume definitions in accordance with ICRU
(International Commission on Radiation Units and Measurements)
GTV (=Gross Tumor Volume)

Palpable or visible/identifiable spread of malignant growth.

CTV (=Clinical Target Volume)

Tissue volume containing GTV and subclinical microscopic malignant disease.

ITV (=Internal Target Volume)

Volume containing CTV and an internal margin taking into account internal movements and changes in  CTV.  This is the volume that should receive an optimal dose.

PTV (=Planning Target Volume) Geometric volume containing ITV and one set-up margin taking into account patient movement, patient positioning, and field modeling.

 

 

Preparation

  • To prepare a treatment plan, it is necessary to have overview of tumor localization in both the actual treatment area and in other regions.
  • It is usually necessary to perform imaging of the treatment area: X-ray, bone scintigraphy, MRI for skeletal metastases, CT of the chest for lung metastases, ultrasound, or CT for lymph node or soft tissue/subcutaneous metastases. MRI of the head is preferable for brain metastases.

Simulation

  • "Simplified" CT-based dose planning is often performed.
  • It is important that the patients are well medicated for pain and can lie on their back during simulation.

Implementation

  • Most often, 10 fractions of 3 Gy are used for palliative purposes.
  • Painful skeletal metastases may be alternatively treated with 8 Gy x 1. In studies, it has been shown to be as effective for pain reduction as 3 Gy x 10, but is thought to give less re- mineralisation of bone than 3 Gy x 10. The treatment with 8 Gy x 1 is most often given to patients with assumed short life expectancy when rapid symptom reduction and short treatment time is the most important. This treatment may be repeated for recurrent pains.
  • Risk for fracture of the spine and long bones are usually given 3 Gy x 10. For localized spread 2 Gy x 25 may be relevant. Operative fixation should be considered prior to radiation therapy for patients with good general status.
  • For multiple brain metastases, 3 Gy x 10 towards the entire brain is administered.
  • For 1-2 brain metastases up to 2 cm, resection may be considered followed by radiation therapy 3 Gy x 10 towards the entire brain (or stereotactic treatment). Postoperative radiation treatment starts when the operation area is totally healed, usually after 2-4 weeks. One may also consider referring the patient for treatment with stereotactic radiation.

Follow-up

Most of the side effects, which may occur during the treatment develop from other tissues/organs in the radiation area. The dosage used for pure symptom palliation is kept low to reduce the risk of acute side effects as much as possible.

The total radiation dose is most often at a level (3 Gy x 10), which reduces the risk of delayed side effects.

These patients are at late stage of their cancer. Frequent follow-up is important to achieve satisfactory reduction of symptoms.

Follow-up usually occurs locally at the referring hospital or general practitioner.

Complication Treatment of Breast Cancer

Surgery, systemic treatment, and radiation therapy cause side effect to varying degrees.

It is usually necessary to provide supportive care in order for the patient to complete and achieve the full effect of planned treatment.

Supportive care can also be given to reduce the side effects and to improve the patient's quality of life during and after treatment.

PROSEDYRER

Smoking cessation in connection with cancer treatment

General

In patients treated with surgery, radiation and/or chemotherapy, the treatment efficacy may be affected by smoking. Smoking has an impact on both metabolism and pharmacokinetics.

Smoking may inhibit wound healing after surgery and increase the probability of surgical site infections. Because smokers generally have more mucus in the airways and are less able to remove it, they also may have a increased risk of serious lung complications during anesthesia. However, it is disputed whether or not it is beneficial to quit smoking directly prior to surgery and this should be considered in each case individually. (28,30-33). Smokers are more prone to stagnation of bronchial secretion than non-smokers and rapid postoperative extubation is important. 

Patients who continue smoking during radiation therapy have a lower risk of complete respons, development of secondary cancer, increased toxicity and several other side effects compared to non-smokers and smokers that quit before treatment. Continued smoking during radiation therapy is also associated with oral mucositis, impaired ability to taste, dry mouth, reduced voice quality, weight loss, cachexia, fatigue, pneumonia, bone-and soft tissue necrosis.

Tobacco may have an effect the metabolism and the mechanisms of chemotherapy and in this way may make the treatment less effective. Smokers undergoing chemotherapy may also experience a weakened immune system, increased rates of infection, exacerbation of common side effects, weight loss, cachexia, fatigue and cardiac or pulmonary toxicity. Some findings suggest that it may also apply to monoclonal antibodies.

Cancer patients who quit smoking before chemo- and radiation therapy get a total symptom burden equal to that of non-smokers, but those who continue to smoke state a higher symptom burden. Targeted measures in smoking cessation may increase quality of life and lead to less treatment interruptions.

A lot of patients wonder if there is any point to quit smoking after receiving a cancer diagnosis. tudies show that continued smoking is associated with increased treatment-related toxicity, increased risk of second primary cancers, reduced quality of life, reduced treatment effect and reduced survival in patients with cancer. This applies to both cancer diagnoses where smoking is a known causal factor, as with lung- and head and neck cancers and in cases where smoking has no known correlation with the diagnosis. Studies conducted on smoking and cancer diagnoses such as breast cancer, prostate cancer, colorectal cancer, esophageal cancer, cervical and ovarian cancer as well as leukemia and lymphoma cancers show that to continuation of smoking after a proven cancer diagnosis is associated with increased risk of mortality.

Studies support that quitting smoking improves cancer, and emphasizing the potential importance of targeted smoking cessation in cancerpatients during and after treatment. The link between tobacco and impact on cancer and cancer treatment is a complex matter.

Regarding the significance of the various components much is still unkown. When it comes to tobacco use in cancer treatment research is primarily done on the link between cigarette smoking and efficacy of cancer treatment. Nevertheless, it cannot be excluded that using other smokeless tobacco products such as snuff and chewing tobacco, may also impact the cancer treatment. According to international guidelines all tobacco use should be stopped during cancer treatment.


Benefits of smoking cessation and risks of continued smoking in patients with cancer
Quitting smoking results in the following benefits: Continued smoking results in a risk of :
  • improved treatment results.
  • less side effects
  • fewer infections
  • improved respiration and circulation
  • increased survival
  • reduced efficacy of treatment.
  • postoperative complications and longer recovery.
  • cardiovascular and respiratory complications.
  • recurrence of cancer, and secondary cancer.
  • shortened life expectancy.

 

Indication

Weaning of nicotine in connection to cancer treatment. 

Goal

Healthcare providers should convey evidence-based information to patients about how smoking affects cancer treatment, the risk of side effects and prognosis and also provide guidance and relevant treatment for smoking cessation.

Preparation

Patients require clear, formalized and fact-based guidance and continuous follow-up. Many patients want encouragement for smoking cessation early in the disease. Being hospitalized is a good opportunity because patients have access to support and help to reduce nicotine withdrawal symptoms and discomfort.

A patient recently diagnosed with cancer is often motivated to quit smoking and also receptive to conversations about how to do this. Motivation or willingness to quit often changes during the treatment, and use of tobacco and motivation should therefore be discussed at every consultation.

Clarifying the patient´s smoking habit is important. The time of day the patient lights their first cigarette says something about the degree of addiction. Making the patient aware of the situations in which he or she smokes most; at work, at home or in social settings, can help break unwanted patterns of behavior.

Implementation

The best and most direct approach to motivate the patient is telling that tobacco use will decrease the effectiveness of treatment and the most important thing the patient can do himself is to stop using tobacco.

  • Speak directly to the patient about how tobacco use may decrease the effectiveness of treatment.
  • Discuss smoking cessation with the patient at each visit.
  • Clarify any misunderstandings about the risks of tobacco use. Point out the importance of quitting.

Sometimes there may be misunderstandings about what kind of health risk smoking during and after cancer treatment may entail.

Advice to those who are not ready for smoking cessation
The smokers statement The response of health care professionals
Justifications
The damage from smoking is already done.
Some damage is done, but continued smoking will still damage your health and reduce the effects of treatment. Quitting smoking is more important now than ever.
This response tells the patient that it is not too late to quit smoking, and the effect of treatment will be positive.

I have reduced smoking.
That is great, and now you need to focus on quitting completely. What do you think keeps you from quitting altogether?
This response tells the patient the importance of quitting completely, as the benefits of quitting at baseline are documented.
This is not a good time to quit smoking.
The benefits of quitting are greatest now, before treatment begins. What is needed to make you feel ready to quit smoking?
 
This response make the patient aware of the fact that quitting smoking optimizes the cancer treatment.

Health professionals must assist the patient identifying realistic expectations and goals for smoking cessation. For some, it may feel easier to scale down the number of cigarettes than to quit completely. The patient should know that every puff affects their health, and that the total health benefits can only be achieved through smoking cessation. For patients unable to stop completely, a gradual reduction may be a step in the right direction.

The probability of success for smoking cessation significantly increases for those who receive professional help in combination with nicotine replacement therapy (NRT) or non-nicotine based products. For the best possible effect of NRT the patient needs professional guidance to find the right product and dosage. For some patients combining two products or receiving a higher dosage than recommended will give the best effect. Sometimes the product must be replaced during the treatment.

Treatment with nicotine replacement therapy

Topical products are patches (Nicorette®, Nicotinell®), chewing gum (Nicorette®, Nicotinell®), lozenges (Nicorette®, Nicotinell®), inhalator (Nicorette®) or a combination of these. These products contain nicotine and therefore reduce the withdrawal symptoms experienced after smoking cessation.

  • Patch: Nicorette® 5 mg,10 mg and 15 mg/16 hours up to 6 months or Nicotinell® 7 mg,14 mg og 21 mg/24 hours up to 3 months.
  • Chewing gum: Nicorette®/Nicotinell® 2 mg and 4 mg, 8-12 pcs/day up to 12 months.
  • Lozenges: Nicorette® 2 mg and 4 mg, typically 8-12 pcs/day, maximum respectively 15 pcs/day up to 9 months or Nicotinell® 1 mg and 2 mg, typically 8-12 pcs/day, maximum is respectively
    25 and 15 pcs/day up to 12 months.
  • Inhalator: Nicorette® 10 mg/dosage container, 4-12 pcs/day up to 6 months.

Combination therapy means combining patches with chewing gum, lozenges or an inhalator.

  • Nicorette® patch15 mg/16h and Nicorette chewing gum 2 mg. 5-6 chewing gums daily. Maximum 24 pcs/day
  • Nicorette® patch 15 mg/16h and Nicorette® inhalator 10 mg: 4-5 dosage-container daily. Maximum 8 pcs/day

Nicotine replacement therapy increases the chance of smoking cessation by 50 to 70% after six months. Two products used in combination increase the chance of smoking cessation compared to the use of only one product.

Side effects

  • Headache, dizziness, nausea, flatulence and hiccup.
  • Irritation in the mouth and esophagus using chewing gum/ lozenges/inhalator
  • Skin irritations while using patches.

Precautions

  • Precaution in acute cardiovascular disease, peripheral arterial disease, cerebrovascular disease, hyperthyroidism, diabetes mellitus, kidney- and liver failure and peptic ulcers.
  • Should not be used during pregnancy, unless the potential benefit outweighs the potential risk.
  • The products should not be used during breastfeeding.

Treatment with non-nicotine medications

Bupropion (Zyban®) is a selective reuptake inhibitor of dopamine and norepinephrine. The mechanism behind why the ability to refrain from smoking increases by using bupropin is unknown. A should be set for smoking cessation for the second week of treatment.

Bupropion increases the chance of smoking cessation after 6 months by nearly 70%.

Side effects

  • Dry mouth, nausea, insomnia, hypersensitivity reactions and seizures (convulsions)

Precautions

  • Contraindicated in people with disease that can cause convulsions,  people with substance abuse or other circumstances lowering the seizure threshold.
  • Depression, which in rare cases includes suicidal thoughts and – behavior including  suicide attempt.
  • Safety and efficacy have not been established for people under 18 years.
  • Should not be used during pregnancy.

Varenicline (Champix®) is a partial agonist by a subtype of nicotinic receptors. It has both agonistic activity with lower intrinsic efficacy than nicotine and antagonistic activity in the presence of nicotine.

A date for smoking cessation should be set. Treatment should start 1-2 weeks, or up to 35 days, before that date. The starting dose is 0,5 mg one time daily on days 1-3, then 0,5 mg two times daily on days 4-7, then 1 mg two times daily on day 8 and until the end of treatment. The treatment should last for 12 weeks.

Side effects

  • Nausea, sleep disturbances, headache, constipation, flatulence and vomiting

Precations

  • Links have been reported between the use of varenicline and an increased risk of cardiovascular events, suicidal thoughts, depression and aggressive and erratic behavior
  • Safety and efficacy have not been established for people under 18 years of age
  • Should not be used during pregnancy

Follow-up

If the patient experiences a relapse, it is important to inform them that this is completely normal, and encourage them to continue. If the most common measures do not work,
consideration should be given both to increase the NRP and to provide closer follow-up by health care providers.

Guidance in smoking cessation is described in the literature as brief and clear advice and then further follow-up with a telephone helpline offering treatment for addiction and behavior change/issues. It is not necessary for the patient to have decided to quit smoking in order to be referred to a quitline. If the patient agrees to receive a call from quitline, he or she will be followed up by a supervisor. Supervisors are bound by confidentiality, are up-to-date professionally and offer free follow-up counseling calls for up to a year.

References

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  2. ASCO ASoCO. Tobacco Cessation Guide for Oncology providers,. 2012 (02.12.2014).
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  10. Kenfield SA, Stampfer MJ, Chan JM, Giovannucci E. Smoking and prostate cancer survival and recurrence. JAMA - Journal of the American Medical Association. 2011;305(24):2548-55.
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  12. Phipps AI, Baron J, Newcomb PA. Prediagnostic smoking history, alcohol consumption, and colorectal cancer survival: The Seattle Colon Cancer Family Registry. Cancer. 2011;117(21):4948-57.
  13. Kountourakis P, Correa AM, Hofstetter WL, Lee JH, Bhutani MS, Rice DC, et al. Combined modality therapy of cT2N0M0 esophageal cancer. Cancer. 2011;117(5):925-30.
  14. Waggoner SE, Darcy KM, Fuhrman B, Parham G, Lucci J, Monk BJ, et al. Association between cigarette smoking and prognosis in locally advanced cervical carcinoma treated with chemoradiation: A Gynecologic Oncology Group study. Gynecol Oncol. 2006;103(3):853-8.
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  16. Nagle CM, Bain CJ, Webb PM. Cigarette smoking and survival after ovarian cancer diagnosis. Cancer Epidemiol Biomarkers Prev. 2006;15(12):2557-60.
  17. Ehlers SL, Gastineau DA, Patten CA, Decker PA, Rausch SM, Cerhan JR, et al. The impact of smoking on outcomes among patients undergoing hematopoietic SCT for the treatment of acute leukemia. Bone Marrow Transplant. 2011;46(2):285-90.
  18. Talamini R, Polesel J, Spina M, Chimienti E, Serraino D, Zucchetto A, et al. The impact of tobacco smoking and alcohol drinking on survival of patients with non-Hodgkin lymphoma. International Journal of Cancer. 2008;122(7):1624-9.
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Treatment of Nausea Induced by Chemotherapy

General

The majorities of chemotherapy drugs are emetic to varying degrees and may cause nausea and vomiting. Today, there are efficient antiemetic drugs that can significantly reduce the side effects.

Other factors that can aggravate or prolong the presence of nausea and vomiting are: pain, anxiety, electrolyte disturbances, constipation, dyspepsia, and ulcers.

There is a distinction between acute nausea, which occurs within the first 24 hours, and late nausea, which occurs later than 24 hours after the treatment.

Acute nausea can be effectively treated with 5HT3-antagonists (ondansetron, tropisetron, palonosetron), and possibly combined with steroids. Dopamine antagonists (metoklopramid, metopimazine) also have some effect on acute nausea. If this treatment is not effective, it may be improved with aprepitant.

If standard prophylaxis and treatment of nausea is not satisfactory, other nausea regimens should be tried.

Indication

  • Nausea induced by chemotherapy drugs.

Goal

  • Prevention and treatment of nausea and vomiting.

Definitions

Chemotherapies according to emetic potential

High emetogenicity   

Group 1

Moderate emetogenicity   

 Group 2

Low/minimal emetogenicity

Group 3

All cisplatin-containing regimens (CiFu, GemCis, BEP, TIP, VIP, PV, AP, EDP, DHAP, ECX, weekly dose cisplatin, and others) BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosfamide, vincristine, prokarbazine, prednisolone)
Doxorubicin/epirubicine weekly dose
Doxorubicin/ifosfamide Bendamustine
Docetaxel
FEC-60 og FEC-100
(fluorouracil, epirubicin, cyklophosfamide)
Carboplatin
ENAP (etoposide, mitoxsantrone, cytarabine, prednisolone)
ABVD (doxorubicin, bleomycin, vinblastine, dakarbazine Carboplatin/pemetrexed
FLv (fluorouracil)
FOLFIRINOX
Carboplatin/vinorelbine
FuMi (fluorouracil, mitomycin)

CHOP (cyclophosfamide, doxorubicin, vincristine, prednisolone)
Gemcitabine

CHOEP (cyclophosfamide, doxorubicin, vincristine, etoposide, prednisolone)
Methotrexate weekly dose
   Dakarbazine
Navelbine
      ECO/ACO (epirubicin/doxorubicin, cyclophosfamide, vincristine)
Paclitaxel
       EOX (epirubicin, oxaliplatin, capecitabine)
Pemetrexed
      EPOCH-F (etoposide, prednisolone, vincristine, cyclofosfamide, doxorubicin, fludarabine)

    EPOCH-F (etoposide, prednisolone, vincristine, cyclophosfamide, doxorubicin, fludarabine)
 
    FLIRI (fluorouracil, irinotecan)
 
    FLOX (fluorouracil, oxaliplatin)    
   Gemcitabine/carboplatin      
   HD-Cytarabine
   
    HD-Methotrexate    
  IGEV (ifosfamide, gemcitabine, vinorelbine)
  
   IME (ifosfamide, methotreksate, etoposide)  
   Irinotecan  
   Streptozocin  
   Vorphase (cyclophosfamide)
 

References

  1. Lehne G, Melien Ø, Bjordal K, Aas N, Mella O. Kvalme og oppkast ved cytostatikabehandling i: Dahl O, Christoffersen T, Kvaløy S, Baksaas. Cytostatic Medication cancer treatment. 7. edition. Oslo. Department of Pharmacotherapeutics and The Norwegian Cancer Society, 2009, p 119-130.

Preparation

Nausea regimens are selected according to the emetogenicity of the relevant drugs.

  • Inform about the risk for and treatment of nausea. 
  • In the event of anxiety or conditional nausea, give tranquilizers if necessary.

Implementation

  • Start with an optimal antiemetic regimen starting with the first cycle of chemotherapy in order to counteract the amplification of the nausea that often occurs with a new treatment.
  • Start the oral antiemetic regimen 1-2 hours before chemotherapy and approx. 15-30 minutes before an intravenous injection.
  • If the patient is already nauseous, the medication should be administered parenterally or rectally.

Antiemetic regimens

Mildly emetic chemotherapy

  • Metoclopramide 10 mg is given intravenously before treatment with cytostatic agents.
  • Metoclopramide 10 mg is given orally uptil 3 times.

Moderately emetic chemotherapy

Ondansetron 8 mg orally 2 x daily. In the event of nausea before treatment, give ondansetron intravenously. If this has little effect, try ondansetron 8 mg x 3 or change to a 5HT3-antagonist, for example, tropisetron 5 mg orally/intravenously or palonosetron 250 µg intravenously.

Highly emetic chemotherapy, or if other treatment does not help

For highly emetic chemotherapy drugs, or if other treatment is not adequate, a 5HT3-antagonist can be given orally or intravenously. It should be combined with dexamethasone 8-16 mg intravenously ½-1 hour before treatment, and further, 8 mg x 2 intravenously or orally on the first day.

In addition, dopamine antagonists may be given, for example, metoclopramide 10 mg x 3.

In some cases, traditional nausea treatment is not sufficient. In this case, the patient can be treated with aprepitant. Aprepitant is used for highly emetic regimens and for patients where the usual antiemetic treatment has failed during moderate emetogenic treatment. Aprepitant is given orally 1 hour before chemotherapy and is combined with dexamethasone and 5HT3-antagonists:  125 mg capsules orally on day 1, then 80 mg orally on days 2-5, depending on the duration of the treatment. Aprepitant can enhance the effect of taxane and etoposide, as well as vinorelbine, and can reduce the effect of warfarin.

The regimen is repeated daily if highly emetic treatment is given over a number of days.

Delayed nausea

Aprepitant in combination with dexamethasone and 5HT3-antagonists is preferable if there is a high risk of delayed nausea and vomiting. This is offered especially to patients who have previously experienced delayed nausea.

Conditional nausea

In the event of conditional nausea, diazepam or other tranquilizers may be considered. Diversion or desensitization can be tried in more serious cases.

Follow-up

Ondansetron can have a constipating effect. Use of a laxative for several days should be considered.

Smoking cessation in connection with cancer treatment

General

In patients treated with surgery, radiation and/or chemotherapy, the treatment efficacy may be affected by smoking. Smoking has an impact on both metabolism and pharmacokinetics.

Smoking may inhibit wound healing after surgery and increase the probability of surgical site infections. Because smokers generally have more mucus in the airways and are less able to remove it, they also may have a increased risk of serious lung complications during anesthesia. However, it is disputed whether or not it is beneficial to quit smoking directly prior to surgery and this should be considered in each case individually. (28,30-33). Smokers are more prone to stagnation of bronchial secretion than non-smokers and rapid postoperative extubation is important. 

Patients who continue smoking during radiation therapy have a lower risk of complete respons, development of secondary cancer, increased toxicity and several other side effects compared to non-smokers and smokers that quit before treatment. Continued smoking during radiation therapy is also associated with oral mucositis, impaired ability to taste, dry mouth, reduced voice quality, weight loss, cachexia, fatigue, pneumonia, bone-and soft tissue necrosis.

Tobacco may have an effect the metabolism and the mechanisms of chemotherapy and in this way may make the treatment less effective. Smokers undergoing chemotherapy may also experience a weakened immune system, increased rates of infection, exacerbation of common side effects, weight loss, cachexia, fatigue and cardiac or pulmonary toxicity. Some findings suggest that it may also apply to monoclonal antibodies.

Cancer patients who quit smoking before chemo- and radiation therapy get a total symptom burden equal to that of non-smokers, but those who continue to smoke state a higher symptom burden. Targeted measures in smoking cessation may increase quality of life and lead to less treatment interruptions.

A lot of patients wonder if there is any point to quit smoking after receiving a cancer diagnosis. tudies show that continued smoking is associated with increased treatment-related toxicity, increased risk of second primary cancers, reduced quality of life, reduced treatment effect and reduced survival in patients with cancer. This applies to both cancer diagnoses where smoking is a known causal factor, as with lung- and head and neck cancers and in cases where smoking has no known correlation with the diagnosis. Studies conducted on smoking and cancer diagnoses such as breast cancer, prostate cancer, colorectal cancer, esophageal cancer, cervical and ovarian cancer as well as leukemia and lymphoma cancers show that to continuation of smoking after a proven cancer diagnosis is associated with increased risk of mortality.

Studies support that quitting smoking improves cancer, and emphasizing the potential importance of targeted smoking cessation in cancerpatients during and after treatment. The link between tobacco and impact on cancer and cancer treatment is a complex matter.

Regarding the significance of the various components much is still unkown. When it comes to tobacco use in cancer treatment research is primarily done on the link between cigarette smoking and efficacy of cancer treatment. Nevertheless, it cannot be excluded that using other smokeless tobacco products such as snuff and chewing tobacco, may also impact the cancer treatment. According to international guidelines all tobacco use should be stopped during cancer treatment.


Benefits of smoking cessation and risks of continued smoking in patients with cancer
Quitting smoking results in the following benefits: Continued smoking results in a risk of :
  • improved treatment results.
  • less side effects
  • fewer infections
  • improved respiration and circulation
  • increased survival
  • reduced efficacy of treatment.
  • postoperative complications and longer recovery.
  • cardiovascular and respiratory complications.
  • recurrence of cancer, and secondary cancer.
  • shortened life expectancy.

 

Indication

Weaning of nicotine in connection to cancer treatment. 

Goal

Healthcare providers should convey evidence-based information to patients about how smoking affects cancer treatment, the risk of side effects and prognosis and also provide guidance and relevant treatment for smoking cessation.

Preparation

Patients require clear, formalized and fact-based guidance and continuous follow-up. Many patients want encouragement for smoking cessation early in the disease. Being hospitalized is a good opportunity because patients have access to support and help to reduce nicotine withdrawal symptoms and discomfort.

A patient recently diagnosed with cancer is often motivated to quit smoking and also receptive to conversations about how to do this. Motivation or willingness to quit often changes during the treatment, and use of tobacco and motivation should therefore be discussed at every consultation.

Clarifying the patient´s smoking habit is important. The time of day the patient lights their first cigarette says something about the degree of addiction. Making the patient aware of the situations in which he or she smokes most; at work, at home or in social settings, can help break unwanted patterns of behavior.

Implementation

The best and most direct approach to motivate the patient is telling that tobacco use will decrease the effectiveness of treatment and the most important thing the patient can do himself is to stop using tobacco.

  • Speak directly to the patient about how tobacco use may decrease the effectiveness of treatment.
  • Discuss smoking cessation with the patient at each visit.
  • Clarify any misunderstandings about the risks of tobacco use. Point out the importance of quitting.

Sometimes there may be misunderstandings about what kind of health risk smoking during and after cancer treatment may entail.

Advice to those who are not ready for smoking cessation
The smokers statement The response of health care professionals
Justifications
The damage from smoking is already done.
Some damage is done, but continued smoking will still damage your health and reduce the effects of treatment. Quitting smoking is more important now than ever.
This response tells the patient that it is not too late to quit smoking, and the effect of treatment will be positive.

I have reduced smoking.
That is great, and now you need to focus on quitting completely. What do you think keeps you from quitting altogether?
This response tells the patient the importance of quitting completely, as the benefits of quitting at baseline are documented.
This is not a good time to quit smoking.
The benefits of quitting are greatest now, before treatment begins. What is needed to make you feel ready to quit smoking?
 
This response make the patient aware of the fact that quitting smoking optimizes the cancer treatment.

Health professionals must assist the patient identifying realistic expectations and goals for smoking cessation. For some, it may feel easier to scale down the number of cigarettes than to quit completely. The patient should know that every puff affects their health, and that the total health benefits can only be achieved through smoking cessation. For patients unable to stop completely, a gradual reduction may be a step in the right direction.

The probability of success for smoking cessation significantly increases for those who receive professional help in combination with nicotine replacement therapy (NRT) or non-nicotine based products. For the best possible effect of NRT the patient needs professional guidance to find the right product and dosage. For some patients combining two products or receiving a higher dosage than recommended will give the best effect. Sometimes the product must be replaced during the treatment.

Treatment with nicotine replacement therapy

Topical products are patches (Nicorette®, Nicotinell®), chewing gum (Nicorette®, Nicotinell®), lozenges (Nicorette®, Nicotinell®), inhalator (Nicorette®) or a combination of these. These products contain nicotine and therefore reduce the withdrawal symptoms experienced after smoking cessation.

  • Patch: Nicorette® 5 mg,10 mg and 15 mg/16 hours up to 6 months or Nicotinell® 7 mg,14 mg og 21 mg/24 hours up to 3 months.
  • Chewing gum: Nicorette®/Nicotinell® 2 mg and 4 mg, 8-12 pcs/day up to 12 months.
  • Lozenges: Nicorette® 2 mg and 4 mg, typically 8-12 pcs/day, maximum respectively 15 pcs/day up to 9 months or Nicotinell® 1 mg and 2 mg, typically 8-12 pcs/day, maximum is respectively
    25 and 15 pcs/day up to 12 months.
  • Inhalator: Nicorette® 10 mg/dosage container, 4-12 pcs/day up to 6 months.

Combination therapy means combining patches with chewing gum, lozenges or an inhalator.

  • Nicorette® patch15 mg/16h and Nicorette chewing gum 2 mg. 5-6 chewing gums daily. Maximum 24 pcs/day
  • Nicorette® patch 15 mg/16h and Nicorette® inhalator 10 mg: 4-5 dosage-container daily. Maximum 8 pcs/day

Nicotine replacement therapy increases the chance of smoking cessation by 50 to 70% after six months. Two products used in combination increase the chance of smoking cessation compared to the use of only one product.

Side effects

  • Headache, dizziness, nausea, flatulence and hiccup.
  • Irritation in the mouth and esophagus using chewing gum/ lozenges/inhalator
  • Skin irritations while using patches.

Precautions

  • Precaution in acute cardiovascular disease, peripheral arterial disease, cerebrovascular disease, hyperthyroidism, diabetes mellitus, kidney- and liver failure and peptic ulcers.
  • Should not be used during pregnancy, unless the potential benefit outweighs the potential risk.
  • The products should not be used during breastfeeding.

Treatment with non-nicotine medications

Bupropion (Zyban®) is a selective reuptake inhibitor of dopamine and norepinephrine. The mechanism behind why the ability to refrain from smoking increases by using bupropin is unknown. A should be set for smoking cessation for the second week of treatment.

Bupropion increases the chance of smoking cessation after 6 months by nearly 70%.

Side effects

  • Dry mouth, nausea, insomnia, hypersensitivity reactions and seizures (convulsions)

Precautions

  • Contraindicated in people with disease that can cause convulsions,  people with substance abuse or other circumstances lowering the seizure threshold.
  • Depression, which in rare cases includes suicidal thoughts and – behavior including  suicide attempt.
  • Safety and efficacy have not been established for people under 18 years.
  • Should not be used during pregnancy.

Varenicline (Champix®) is a partial agonist by a subtype of nicotinic receptors. It has both agonistic activity with lower intrinsic efficacy than nicotine and antagonistic activity in the presence of nicotine.

A date for smoking cessation should be set. Treatment should start 1-2 weeks, or up to 35 days, before that date. The starting dose is 0,5 mg one time daily on days 1-3, then 0,5 mg two times daily on days 4-7, then 1 mg two times daily on day 8 and until the end of treatment. The treatment should last for 12 weeks.

Side effects

  • Nausea, sleep disturbances, headache, constipation, flatulence and vomiting

Precations

  • Links have been reported between the use of varenicline and an increased risk of cardiovascular events, suicidal thoughts, depression and aggressive and erratic behavior
  • Safety and efficacy have not been established for people under 18 years of age
  • Should not be used during pregnancy

Follow-up

If the patient experiences a relapse, it is important to inform them that this is completely normal, and encourage them to continue. If the most common measures do not work,
consideration should be given both to increase the NRP and to provide closer follow-up by health care providers.

Guidance in smoking cessation is described in the literature as brief and clear advice and then further follow-up with a telephone helpline offering treatment for addiction and behavior change/issues. It is not necessary for the patient to have decided to quit smoking in order to be referred to a quitline. If the patient agrees to receive a call from quitline, he or she will be followed up by a supervisor. Supervisors are bound by confidentiality, are up-to-date professionally and offer free follow-up counseling calls for up to a year.

References

  1. Gritz E, Fingeret M, Vidrine D. Tobacco control in the oncology setting. American Society of Clinical Oncology, eds Cancer Prevention An ASCO Curriculum Alexandria, VA: American Society of Clinical Oncology. 2007.
  2. ASCO ASoCO. Tobacco Cessation Guide for Oncology providers,. 2012 (02.12.2014).
  3. Zevallos JP, Mallen MJ, Lam CY, Karam-Hage M, Blalock J, Wetter DW, et al. Complications of radiotherapy in laryngopharyngeal cancer: Effects of a prospective smoking cessation program. Cancer. 2009;115(19):4636-44.
  4. Obedian E, Fischer DB, Haffty BG. Second malignancies after treatment of early-stage breast cancer: Lumpectomy and radiation therapy versus mastectomy. Journal of Clinical Oncology. 2000;18(12):2406-12.
  5. Park SM, Lim MK, Jung KW, Shin SA, Yoo K-Y, Yun YH, et al. Prediagnosis smoking, obesity, insulin resistance, and second primary cancer risk in male cancer survivors: National Health Insurance Corporation Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007;25(30):4835.
  6. Van Den Belt-Dusebout AW, De Wit R, Gietema JA, Horenblas S, Louwman MWJ, Ribot JG, et al. Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. Journal of Clinical Oncology. 2007;25(28):4370-8.
  7. Warren GW, Kasza KA, Reid ME, Cummings KM, Marshall JR. Smoking at diagnosis and survival in cancer patients. International Journal of Cancer. 2013;132(2):401-10.
  8. Hooning MJ, Botma A, Aleman BMP, Baaijens MHA, Bartelink H, Klijn JGM, et al. Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. Journal of the National Cancer Institute. 2007;99(5):365-75.
  9. Li CI, Daling JR, Porter PL, Tang M-TC, Malone KE. Relationship between potentially modifiable lifestyle factors and risk of second primary contralateral breast cancer among women diagnosed with estrogen receptor–positive invasive breast cancer. Journal of Clinical Oncology. 2009;27(32):5312-8.
  10. Kenfield SA, Stampfer MJ, Chan JM, Giovannucci E. Smoking and prostate cancer survival and recurrence. JAMA - Journal of the American Medical Association. 2011;305(24):2548-55.
  11. Joshu CE, Mondul AM, Meinhold CL, Humphreys EB, Han M, Walsh PC, et al. Cigarette smoking and prostate cancer recurrence after prostatectomy. Journal of the National Cancer Institute. 2011;103(10):835-8.
  12. Phipps AI, Baron J, Newcomb PA. Prediagnostic smoking history, alcohol consumption, and colorectal cancer survival: The Seattle Colon Cancer Family Registry. Cancer. 2011;117(21):4948-57.
  13. Kountourakis P, Correa AM, Hofstetter WL, Lee JH, Bhutani MS, Rice DC, et al. Combined modality therapy of cT2N0M0 esophageal cancer. Cancer. 2011;117(5):925-30.
  14. Waggoner SE, Darcy KM, Fuhrman B, Parham G, Lucci J, Monk BJ, et al. Association between cigarette smoking and prognosis in locally advanced cervical carcinoma treated with chemoradiation: A Gynecologic Oncology Group study. Gynecol Oncol. 2006;103(3):853-8.
  15. Schlumbrecht MP, Sun CC, Wong KN, Broaddus RR, Gershenson DM, Bodurka DC. Clinicodemographic factors influencing outcomes in patients with low-grade serous ovarian carcinoma. 2011. p. 3741-9.
  16. Nagle CM, Bain CJ, Webb PM. Cigarette smoking and survival after ovarian cancer diagnosis. Cancer Epidemiol Biomarkers Prev. 2006;15(12):2557-60.
  17. Ehlers SL, Gastineau DA, Patten CA, Decker PA, Rausch SM, Cerhan JR, et al. The impact of smoking on outcomes among patients undergoing hematopoietic SCT for the treatment of acute leukemia. Bone Marrow Transplant. 2011;46(2):285-90.
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Transfusions

General

Transfusions of blood components are often necessary for the patient to complete the planned cancer treatment.

Blood transfusions are appropriate for low hemoglobin (Hb) and thrombocyte transfusions for low thrombocytes (trc) which also poses a risk for serious bleeding.

Normal values

  • Hemoglobin 13.4–17 g/dl
  • Platelets 145–348 109/l

Indications

Blood transfusion

Assessment for a blood transfusion based on:

  • Hb/hct
  • symptoms/sign/function level
  • underlying disease (heart/lung, serious infection)
  • expected development of anemia (marrow function, current bleeding)
  • acute blood loss > 15% of total blood volume
  • Hb < 8.0 g/dl and symptom causing chronic anemia
  • Hb < 8.0 g/dl and reduced bone marrow production without sign of regeneration
  • Hb < 8.0 g/dl in perioperative period
  • Hb < 7.0 g/dl in patients without symptoms of other disease
  • Hb < 10.0 and receiving radiation therapy

Platelet transfusion

The patient is assessed for thrombocyte transfusion based on:

  • clinical status (bleeding, bleeding tendency, or fever/infection)
  • ongoing bleeding and thrombocytopenia < 50x19/l
  • degree of thrombocytopenia and cause of thrombocytopenia (reduced production or increased consumption)

Prophylactic platelet transfusion

  • For values < 10x109/l secondary to previous chemotherapy
  • Before invasive procedures
  • For spinal puncture and installation of central vein catheter, thrombocytes should be 30x109/l and 
  • Puncture biopsies (liver/kidney/tumor) > 40x109/l
  • For major surgeries, thrombocytes should be > 50x109/l. After surgery, thrombocytes should be monitored and transfusion repeated, if necessary.

Remember clinical evaluations: possible bleeding, other risk factors for bleeding, diagnosis, treatment, prognosis.

Goal

  • Complete the planned treatment
  • Ensure hemostasis 
  • Ensure adequate oxygen transport to peripheral tissue.
  • Maintain intravascular fluid volume for adequate circulations of vital organs

Definitions

Blood

For a blood transfusion for anemia, SAGMAN erythrocytes are used. One unit is obtained from 450 ml blood. Most of the plasma is removed and replaced with 100 ml SAGMAN solution (Saltwater-Adenine-Glucose-Mannitol). Hematocrit is about 0.60%.

Platelets

One unit contains 240-300 x 109 platelets and is prepared from blood donors with type O and A. In acute situations, the receiver's blood group is of minor importance.
Two kinds of platelet products are available:
  • Apheresis platelets produced from thrombophereses from one donor
  • Buffcoat platelets produced from buffy coat from 4 donors

All cellular blood products should be leukocyte filtered. Leukocyte filtration is done to remove antigen-presenting and virus-bearing cells. 99.99% of leukocytes in the unit are removed.

Radiation

Blood and thrombocytes are irradiated to a minimum of 25 Gy in the blood bank to eliminate T-lymphocytes.

This is done for:

  • Bone marrow transplant or stem cell transplant (1 month before or 3 months after HMAS until 1 year after allogeneic stem cell transplant)
  • For use of HLA-compatible platelet concentrations
  • For all transfusions from relatives
  • For use of fresh blood
  • For use of fludarabine

Preparation

Blood tests

Before the first blood transfusion, the following blood tests are performed:
  • Virus antigens
    • HCV
    • HBV
    • HIV
Every three days, and as needed, pre-transfusion tests are taken.

Compatibility

Erythrocyte concentration—Rh(D) negative products can usually be given to everyone while Rh(D) positive can only be given to Rh(D) positive receivers.

Thrombocyte concentration—Rh(D) negative girls and women in fertile ages who obtain Rh(D) positive thrombocyte products should be given a prophylaxis for Rh immunization. Boys/men and women who are over the fertile age may obtain thrombocytes regardless of Rh(D) type.

Implementation

Blood components should never be given together with other medications.
  • Premedication if the patient has reacted to previous transfusions.
  • Secure venous access
  • The blood product is checked to ensure the correct unit is given to the correct patient.
  • Use blood set with filter
  • Give SAGMAN over 1 hour and thrombocytes 20-30 minutes per unit.
  • Rinse the set with NaCl 9 mg/ml at the end of the infusion
  • Store the blood product bag for one day before discarding

Observations

The patient should be observed during the transfusion with emphasis on reactions. Most serious transfusion reactions occur within the first 20 minutes.

Symptoms of transfusion reaction:
  • chills
  • fever
  • feeling of heat in the face
  • breathing difficulty
  • itching
  • nervousness
  • fall in blood pressure
  • shock
Suspect/manifest blood transfusion reaction:
  • Stop transfusion immediately
  • Start treatment if necessary (intravenous fluid, adrenalin, steroids, oxygen, respirator)
  • Check blood bag and compatibility form. The residue should be sent to the blood bank.

Follow-up

Hemoglobin and thrombocytes are checked.

If poor effect of platelet transfusion, platelet value should be checked after approximately one hour. The value should have increased by approximately 30x109/l or more after a standard dose.

If the increase is drastically less, the cause may be:
  • Abnormally high consumption. This is an indication for more frequent transfusions.
  • Antigens against HLA or platelet-specific antigens. The patient must be examined in cooperation with the blood bank to find compatible donors.

Febrile Neutropenia

General

Febrile neutropenia occurs in compromised immune systems due to a low number of leukocytes, especially granulocytes. Patients with a declining number of granulocytes after chemotherapy, can during bacterial sepsis, quickly develop extensive neutropenia and become critically ill. Febrile neutropenia can be a life-threatening condition.

A patient with neutropenia and simultaneous fever or clinical suspicion of systemic infection should be treated as quickly as possible with broad spectrum antibiotics including gram-negative and gram-positive coverage as soon as the required microbiological samples are taken.

The clinical situation is most critical in patients who have not yet started antibiotic treatment. When broad-spectrum antibiotic treatment is started, monitoring the fever may be permitted.

Fever is often the only symptom. Some have septicemia without fever. One should therefore also be aware of other symptoms such as lethargia, diarrhea, or visible sign of infection. The local clinical symptoms and signs (redness, pain, temperature increase, swelling (boil), and reduced organ function) are most often very much reduced or completely absent during neutropenia.

Indications

  • A patient with neutropenia and simultaneously fever or clinical suspicion of systemic infection

Goals

  • Avoid septicemia.
  • The patient is able follow the planned scheme of treatment.

Definitions

Fever is defined as:

  • a single (rectal) temperature ≥ 38.5 °C or
  • temperature ≥ 38 °C for more than 2 hours or
  • temperature ≥ 38 °C measured three times during 24 hours

There is a known increase of infections when neutrophil < 1.0 x 109/l.  The infection risk increases with degree and duration of neutropenia. The neutropenia is considered severe when granulocytes are ≤ 0.5 x 109/l.

Preparation

The following diagnostic tests should be performed:

  • Adequate microbiologic tests: blood culture x 2-3, throat/nasopharynx, urine, catheter opening any surgical incisions. All blood cultures should be taken simultaneously to avoid losing valuable time.
  • Blood culture and other microbiological samples should be taken before antibiotic treatment is started
  • Blood tests with differential count of leukocytes, thrombocytes, Hb, CRP, SR, creatinine
  • X-ray of chest

Information

Before initiation of chemotherapy, the patient should be extensively informed, both verbally and in writing, of febrile neutropenia and  its consequences.

A patient who can develop febrile neutropenia should obtain a written statement of the condition to present to other treatment providers.

Use of an isolated or private room

Patients with neutrophil granulocytes ≤ 0.3 x 109/l should have a private room if possible. Guidelines for protective isolation should be followed. Thorough washing of hands is especially important.

 

Implementation

  • Treatment is started as soon as possible.  Treatment may be postponed a maximum of 30 minutes to complete microbiological testing.
  • Start septicemia treatment for fever if neutropenia is expected, regardless of granulocyte value.

Antibiotic regimen

  • Benzylpenicillin sodium 5 mg IE x 4 tobramycin or gentamicin 5-10 mg/kg x1
  • Tazocin® 4 g x 3
  • Cefotaxime® 1 g x 4 if aminoglycoside should be avoided
  • Ceftazidim® 1 g x 4  with suspicion of pseudomonas infection
  • Meronem ® 0.5 g x 4 usually 2nd or 3rd choice

When using aminoglycoside, the first dose should be high. Keep in mind the following:

  • age
  • sex
  • kidney function
  • fat index   

Otherwise, the dose should be decided from concentration of aminoglycoside determined after the second day and thereafter monitored 2x per week. 

Serum concentration of tobramycin and gentamycin

For single dose in 24 hours

  • Trough concentration (0-test = 24 hour test) < 0.5 mg/l
  • Top concentration (30 minute after infusion is completed) > 12 mg/l

For multiple doses in 24 hours

  • Trough concentration < 2 mg/l, top concentration (30 minutes after the infusion is completed) preferably > 8-10 mg/l 
  • Avoid aminoglycoside :
    • If kidney function is reduced. Avoid aminoglycoside if cisplatin is used. If cisplatin has been previously used, many patients will have subclinically reduced kidney function. If necessary, use aminoglycoside for a short period and monitor kidney function closely.
    • If carboplatin is used, determine glomerulus filtration rate (GFR) for each new treatment. Penicillin/aminoglycoside can be used if GFR is stable (has not declined more than 15% if initial value is in the normal range)
    • With sarcoma: Protocols with very high doses methotrexate and ifosfamid (> 5 g/m2) should be used in sarcoma treatment. It is not abnormal for these patients to have an increase in creatinine.
    • with massive ascites
    • with suspicion of or documented myeloma kidney (myelomatosis)
    • If aminoglycoside has been used in the past two weeks
  • Suspicion of staphylococcus aureus as a cause of infection (relatively rare)
    • Give penicillinase-stable penicillin, cloxacillin, or dicloxacillin, possibly clindamycin instead of ordinary penicillin. Yellow staphylococci are also killed by cefotaxime and by merop
  • Gram-positive cocci in multiple blood cultures and if the patient has clinical signs of infection
    • Use vancomycin 500 mg x 4 until resistance determination is available
  • Poor patient condition and suspicion of gram-negative septicaemia
    • Use “double gram-negative” with for example ceftazidim or tobramycin
    • Other preparations with good effects against most gram-negative bacteria are meropenem and ciprofloxacin
  • Suspicion of anaerobic infection
    • Use an anaerobic drug: Metronidazol 500 mg x 3, clindamycin 600 mg x 4, piperacillin/tazobactam 2g x 4 or meronem 500 mg x 4.  This especially applies if there is suspicion of anaerobic infection under the diaphragm such as gallbladder, intestines, perforation, abscess.
    • penicillin is often adequate for anaerobic infections above the diaphragm.

With continuing clinical signs of infection, adjust the antibiotic treatment according to resistance determination in blood culture. Maintain gram-negative coverage.

Systemic fungal treatment

By persistent fever after multiple days with broad spectrum antibiotic treatment, one should consider empirical treatment of possible candida-sepsis, for example with fluconazole 600 mg the first 24 hours, and thereafter 400 mg x 1.

If candida is documented without adequate response to fluconazole, a fungicide drug should be used, for example amphotericin B.

If suspected infection with Aspergillus apply voriconazole, amphotericin B or caspofungin.

Follow-up

Observe for symptoms of a new infection.

Bone Marrow Stimulation with G-CSF

General

Bone marrow stimulation with G-CSF (Neupogen®, Granocyte®) is only recommended for febrile neutropenia which does not respond to antibiotic treatment, severe neutropenia (granulocytes < 0.5 x 109 /L for more than 1 week), and in cases where it is necessary to administer curative treatment with sufficient dosage intensity.

Indications 

  • To maintain dosage intensity for curative treatment; when a reduction in dosage will significantly reduce the chance of cure.
  • As prophylaxis for treatments associated with a high risk for febrile neutropenia (> 40 %)
  • Febrile neutropenia that does not respond quickly to antibiotic treatment
  • Long-lasting neutropenia

Goal

  • Maintain treatment intensity

Preparation

The patient should be adequately informed about the treatment.

Implementation

  • The dosage of Neupogen® is 5 µg/kg daily. The treatment is initiated, at the earliest, 48 hours after the treatment is completed. The treatment continues for 10 days.
  • The dosage of Neulasta® is 6 mg subcutaneously administered 24 hours after chemotherapy is completed. The neutrophil cells are counted on day 15.
  • The subsequent course is started on day 21, if the neutrophil count is 0.5 or higher, and the patient has not had febrile neutropenia.
  • It is important not to postpone the treatment if the neutrophil count is 0.5 or higher. The neutrophil count will compulsory decline after ending Neupogen® stimulation. Low values at the start of treatment should not be alarming if the values during hospitalization have been high enough to avoid febrile neutropenia.
  • Stimulation late in the cycle should only be performed for long-lasting, severe neutropenia. At least 48 hours should pass after completed stimulation treatment before the next chemotherapy course  is started. In these cases, it is always important to check that the doses are correct and to recalculate GFR etc. Continuation of chemotherapy will either require a drastic dosage reduction or secondary prophylaxis with G-CSF.

 

Follow-up Care

It is of utmost importance that the patient is informed of the risk of infections associated with a low neutrophil count.

Patients at risk for developing  very low values, must be  informed to take their temperature if they feel unwell or  febrile. In case of  a temperature above 38 °C they should contact their doctor immediately.

Pleural Tap

General

Pleural fluid (pleural effusion) is an accumulation of fluid in the pleural space. The fluid compresses the lungs and disrupts its normal function. Symptoms and clinical findings vary and partially depend on the volume of the pleural effusion. Less than about 1/2 L will provide few or no symptoms.

An increase in the amount of pleural fluid can occur acutely or over a long period of time. The pleural fluid may be clear (serous) or bloody, or contain pus if infection is present. In rare cases, the fluid may be rich in fat (chylothorax). The most common causes of pleural effusion are heart failure, pneumonia, malignancy, or lung embolism.

Pleural fluid develops in almost half of all malignant tumors or metastases in the thorax. Lung cancer, breast cancer, gynecological cancer, mesothelioma, lymphoma, and leukemia often give rise to pleural fluid.

Indications

  • Diagnostic—pleural effusion of unknown cause
  • Therapeutic—pleural effusion sufficient to cause dyspnea

Goal

  • Cytological examination of pleural fluid
  • Reduce dyspnea
  • Instillation of chemotherapy

Equipment

  • Pleural tapping set
  • Washing set
  • 5 ml syringe for local anesthesia 
  • Subcutaneous or intramuscular cannula
  • Sterile gloves
  • Secalon catheter or pigtail catheter 

 

Preparation

  • Ultrasound
  • Blood tests according to local scheme.
  • Inform the patient.
  • Hydrocodone tablet to reduce coughing during the tapping can be given as premedication according to the doctor's prescription. 

Implementation

  • The procedure is carried out aseptically and takes approximately 30 minutes.
  • The patient lies in the supine position with the upper body raised, either in bed or on an examination table. The sitting position is also an alternative.
  • The skin is cleaned with chlorhexidine 5 mg/ml.
  • The puncture is made where there is optimal access to the fluid.
  • Xylocain 1% is used for local anesthesia without adrenaline.
  • Local anesthesia is injected in all tissue layers of the thoracic wall, especially the parietal pleura.
  • The position of the needle is shown by ultrasound.
  • A small incision is made in the skin and a Secalon or pigtail catheter is inserted into the pleural space. A three-way tap with bag is connected.
  • The fluid can either be tapped passively or aspirated with a syringe from the tapping set.
  • When the tap is concluded, the catheter is removed unless otherwise specified.
  • The puncture point is bandaged.
  • The pleural fluid is sent in a sterile container for bacterial examination and possibly biochemical or immunological examination.

Complications which can occur:

  • Pneumothorax
  • Bleeding
  • Sowing of malignant cells or microbes in the puncture canal (delayed complication)

Follow-up

  • No follow-up for uncomplicated procedures.
  • For complications, follow-up is individualized depending on severity of complication. 
  • The result will be available after 2-3 days.
Pleural TapPleural TapPleural Tap

Scalp Cooling Treatment

General

Scalp cooling has long been a well-known technique to prevent hair loss. In 1996 in Great Britain, a machine was developed for the technique, which has a thermostat cooling system of glycol and water. The fluid circulates in a silicon cap placed on the head of the patient. Today there about 450 cooling cap machines in use, most of which are in Europe. Of these, about 60 are in the Nordic countries, 30-35 of which are in Norway. At Oslo University Hospital, 2-3 patients receive this treatment daily. A cooling machine reduces the temperature in the scalp to about  10 ºC using a cooling cap and is effective at preventing hair loss caused by chemotherapy of moderate intensity.

The mechanism of action appears to be partly vasoconstriction, but more importantly, temperature-dependent reduction of cellular uptake of chemotherapy drugs. Successful results are achieved with taxane.

The effect of cooling cap treatment is individual, but experience shows that most patients using this technique are able to avoid using a wig.

In order for the patient to gain the optimal effect of cooling treatment, it must be applied from the first to the last treatment. Since not all patients receive chemotherapy at Oslo University Hospital, it must be determined whether the patient can receive scalp cooling treatment during all chemotherapy courses before starting. Some patients apply for treatment at a hospital where they know scalp cooling treatment is available.

Indications

To what degree scalp cooling affects the temperature conditions in the bone marrow of the cranium does not appear to be sufficiently documented. In the literature, concern has been expressed that cooling may conserve micrometastases in the scalp; however, documentation of this is scarce. Due to this lack of documentation, Oslo University Hospital has decided that scalp cooling treatment is not recommended during chemotherapy with curative intention for cancers where micrometastases in the scalp or bone marrow is a problem (breast cancer, malignant lymphoma, leukemia). 

For palliative chemotherapy however, it appears the method is acceptable as well as for chemotherapy with curative intention for cancer where metastasis to the skin, subcutis or bone marrow is uncommon.

For gynecological cancers, bone metastases are very rare. Scalp cooling is therefore not contraindicated during chemotherapy for such cancers. For many women, hair loss is significant for their self image. We recommend offering gynecological cancer patients the option of scalp cooling to prevent hair loss during chemotherapy. 

Goal

  • Prevent chemotherapy-induced hair loss (alopecia).

 

Equipment

  • Scalp cooling machine
  • Scalp cap with coupling  
  • Paper cap
  • 5 unsterile compresses 10 x 10 cm
  • Towel
  • Chair or bed for the patient
  • Blanket or warm water bottle   

Preparation

Preparation for use of scalp cooling machine

Before the machine is turned on

  • Check that the plug is in the outlet and is connected.
  • Check the level of the fluid in the window on the back of the apparatus and fill if necessary.
  • Check that the tubes to the fluid are not twisted or broken.
  • Check that there is no visible leakage of cooling fluid.

When the machine is turned on

  • When the power is on, the light should be green.
  • Make sure that both tubes for the cooling fluid are connected to the recirculation ports.
  • Press PUMP ”on” when the left display shows a temperature of -4 °C to -5 °C.
  • Listen for the motor.
  • The temperature of the cooling fluid is shown on a designated thermometer.
  • When the right display shows HI and a sound alarm starts, push the MUTE button on the control panel. When only one arm is used, the available arm is connected to the machine.

After 15 minutes

  • The display will show a slow decreasing temperature.
  • When the left display shows -4 °C to -5 °C, and the right display shows lower than 5 °C, the system is ready for use. This may take from 1 hour to 90 minutes after PUMP "on" is pressed, depending on the temperature of the room.

Preparation of the patient

Choose the correct size of the cap (small, medium, large).

Recommended cooling times for common chemotherapy drugs
  Before After
FEC/EC
30 minutes 1–1 ½ hour
Paclitaxel weekly 90 mg/m2 30 minutes 1 hour
Paclitaxel triweekly 175 mg/m2 30–45 minutes 1 ½ hour

Implementation

  • The patient sits in a chair or lies in a bed 45 minutes before the chemotherapy infusion starts. 
  • The strap from the cap should be fastened under the chin - the patient may do this to make sure it is comfortably tight.
  • Make sure the cap fit snugly to the scalp, especially on the upper part of the head.
  • Tighten the straps on the cap - this is critical for maximal effect.
  • Place compresses between the chin and chin strap.
  • Protect the patient's ears and forehead with compresses if the patient feels that they become too cold. A towel can be placed around the neck.
  • Turn off the pump on the machine and connect the cap. 
  • Turn on the pump again and check that the cooling fluid is circulating and the cap becomes cold.
  • Ensure the patient is as comfortable as possible.
  • The patient usually experiences the first 10-15 minutes as the coldest but adapts to the temperature.
  • The patient sits/lies with the cap on for 30-45 minutes before the chemotherapy infusion starts depending on the type of chemotherapy. 
  • The chemotherapy infusion is connected to the patient.
  • The patient sits with the cap on during the entire infusion. If the patient needs to visit the toilet, the pump is turned off and the cap is disconnected. The patient must keep the cap on while using the toilet.
  • The patient sits with the cap for 1-2 hours after the infusion is completed depending on the type of chemotherapy. 
  • When the treatment is finished, the pump is turned off.
  • Remove the cap, compresses, and paper cap.
  • The machine is turned off and the cap is disconnected from the machine.
  • The cap should be washed in warm soap water and dried.

Follow-up

Recommended hair care for optimal results  

Certain chemotherapy drugs and dosages cause hair loss after treatment is finished. Losing hair is a very sensitive issue for most, even if a wig is an option. 

Scalp cooling treatment can contribute to preventing or reducing hair loss to avoid use of a wig.

Experience with scalp cooling treatment shows that 70-90% of patients do not need to use a wig, provided that recommended cooling times both before and after the infusion are followed (see preparation).

The result can be maximized by following these recommendations:

  • Use a neutral pH shampoo and conditioner.
  • Do not wash your hair less than 24 hours before treatment.
  • Limit hair washing and always use a conditioner.
  • Wash your hair in cool water with light finger motions.
  • Allow your hair to dry naturally without rubbing with a towel and do not use a hair dryer.
  • Use a soft, satin-like pillowcase for sleeping.
  • Use a wide-toothed comb instead of a brush.
  • Allow your hair to hang naturally instead of pulling it up/back.
  • Do not use hairspray or other products.
  • If you wish to color your hair, environmentally friendly products should be used.
  • Show this information when you visit the hair dresser.
  • Follow these recommendations for 6-8 weeks after the last treatment.  

For successful results, do not use harsh methods which will weaken your hair.

If you lose hair despite treatment and optimal care, continued cooling can further hasten growth.

Scalp Cooling TreatmentScalp Cooling TreatmentScalp Cooling TreatmentScalp Cooling Treatment
Scalp Cooling TreatmentScalp Cooling Treatment

Cold Gloves and Socks

General

Clinical studies (Journal of Clinical Oncology – July 1, 2005 from Southwest Technologies) have shown that use of cold gloves and socks reduces nail loss and skin damage in patients receiving docetaxel and pegylated liposomal doxorubicin.

Indications

  • Docetaxel treatment for prostate and breast cancer
  • Pegylated liposomal doxorubicin treatment for ovarian cancer

Contraindications

  • Should not be used in patients with curative treatment (adjuvant/neoadjuvant treatment of breast cancer)
  • Raynaud's disease
  • Distal metastases
  • Distal arterial insufficiency
  • Cold intolerance

Goal

  • To avoid loosening/loss of nails or skin damage
  • Preventing neuropathy

Equipment

The gloves and socks are made of a glycerine gel which maintains its elasticity also when frozen. The outer fabric is water-proof and elastic. The Velcro holds the products securely in place.

  • Elasto-Gel cold gloves and/or socks
  • Disposable gloves/socks for use inside

Preparation

  • The products should be stored in the plastic bag in a freezer which maintains a temperature of -25 to -35°C for at least 12 hours before use. The elasticity is maintained in temperatures down to -30 °C.
  • Gloves/socks should be used at each treatment to maintain the effect.

Implementation

  • Wear disposable gloves/socks inside for hygienic reasons.
  • Put on gloves/socks 15 minutes before treatment and remove at the earliest 15 minutes after the end of treatment.
  • If the treatment lasts 1-1 ½ hours, the gloves/socks should be changed. This should take place after 45 minutes (or more often) if the patient feels they become too warm.
  • Change the gloves/socks as quickly as possible to avoid reflexes caused by dilatation of blood vessels.

Follow-up

  • Allow the gloves/socks to dry after use before they are put in the freezer again.
  • As needed, clean the surfaces in contact with skin with soapy water and dry thereafter. Never immerse the gloves/socks in water.
Hypothermia gloves and socksHypothermia gloves and socksHypothermia gloves and socksHypothermia gloves and socks
Hypothermia gloves and socks

Ovarian Tissue Freezing

General

Presently, ovarian tissue freezing is still in a trial stage. Optimal indication, clinical efficacy, and technical conditions for freezing tissue are still being explored and changing. 

The treatment is authorized by law in the regulation for biotechnology § 2–17 in Norway. The Womens' Clinic at Oslo University Hospital located at Rikshospitalet performs ovarian tissue freezing for Norway.  

Thawing and reintroduction of tissue, and possibly in vitro fertilization, are possible techniques for reestablishing fertility after full remission of cancer. On a world basis, only a minority of births have been documented after reintroduction of ovarian tissue. Until now, it has not been relevant to reintroduce ovarian tissue for women in Norway who have stored tissue at Oslo University Hospital. Due to the experimental nature of the method, the patient must be well informed of the uncertainty surrounding the technique and the need for further method development.

Indications

The indication for ovarian tissue freezing is gonadotoxic treatment including chemotherapy and radiation therapy which lead to a high probability (> 50%) of sterility. The treating oncologist makes the final decision for the procedure.

Ovarian tissue freezing provides women who are treated for cancer the possibility of maintaining their fertility.

Examples of diagnoses where ovarian tissue freezing may be relevant:

  • Cancer in pediatric and adolescent years:
    • leukemia
    • lymphoma
    • sarcoma
  • Cancer in women of reproductive age:
    • breast cancer
    • leukemia
    • lymphoma
  • Benign hematological diseases, for example thalassemia or major aplastic anemia. Freezing of ovarian tissue is rarely indicated in other benign diseases.

Theoretically, there is no lower age limit for removing ovarian tissue, but an individual assessment must be done in each case.

Contraindications

  • Age > 35 years
  • HIV infection, hepatitis B, hepatitis C or syphilis
  • Conditions which exclude a laparoscopic ovariectomy
  • Treatment which prevents future pregnancy such as a hysterectomy or life-long treatment where pregnancy is contraindicated.
  • Ovarial reserve is already lost due to, for example, previous chemotherapy or induction treatment. Previously completed chemotherapy with preserved ovarial reserve is not a contraindication.
  • Disseminated systemic cancer is a relative contraindication. Risk of micrometastases in frozen tissue makes reintroduction of tissue in these cases inappropriate. In vitro fertilization of egg cells is a technique apparently several years into the future. These patients should therefore be well under 35 years. 

Goal

  • Maintain fertility in females £ 35 years undergoing treatment that will eradicate or strongly reduce fertility.

Background

Radiation and chemotherapy are gonadotoxic which can lead to ovarian failure and infertility by inducing apoptosis and/or DNA damage in egg cells and surrounding cells.

Depending on the type of cancer and regimen for chemotherapy and radiation therapy, the treatment can lead to ovarian failure and infertility. The age of the female is significant. Young girls and women maintain menstruation and reproduction ability to a larger degree than women over 30 years, however they also become menopausal earlier than expected.   

Preparation

Oncologist at the treating institution

  • Consider oncological indications and contraindications regarding the procedure
  • Inform the patient about the option
  • Contact the department for childlessness and assisted fertilization

Physician at the department for childlessness and assisted fertilization

  • Assess the patients situation according to the requirements of the biotechnology laws and regulations, surgical risk, ovarian reserve, and planned treatment course.

  • Obtain written consent for freezing of tissue.
  • Decide the day for the operation.

Implementation

  • The procedure is carried out under general anesthesia.
  • An entire ovary or biopsies from the ovaries are retrieved by laparoscopy.
  • After preparation in the laboratory, the tissue is frozen and stored at -196 °C.

Follow-up care

Storage of preserved ovarian tissue

The preserved ovarian tissue can only be stored as long as it is required by the donor and as long as it is considered medically justifiable after individual assessment. The tissue should be destroyed when the woman dies. 

The option to freeze and store ovarian tissue does not provide an automatic right for future reintroduction of tissue or other form of treatment. The decision is made by the treating doctor according to guidelines set by biotechnology laws and other relevant regulations.

Intravenous Extravasation of Cytotoxic Drugs

General

Intravenous extravasation occurs when there is an accidental leak of intravenous cytotoxic fluid (chemotherapy drug) from the vein to surrounding tissue.  

If chemotherapy is given in a peripheral vein, a large vein should be used, which is preferably in the underarm. Before the infusion begins, the vein should be checked for leaks by injecting NaCl 9 mg/ml or glucose 50 mg/ml. Backflow should also be checked. The patient must be informed that pain or burning in the area is not normal and they must inform the doctor.

Cytotoxic chemotherapy drugs should always be given through a central vein catheter to reduce the risk of intravenous extravasation.

Risk factors for intravenous extravasation:

  • Small veins (infants and children)
  • Brittle veins (elderly patients)
  • Reduced physical health (cancer patients)
  • Sclerosizing veins
  • Rolling veins
  • Poor circulation (if the needle is placed in an arm with edema)
  • Obstructed vena cava (raised venous pressure may cause leakage)
  • Conditions such as diabetes and radiation damage
  • Obesity

Chemotherapeutic drugs are separated into three groups according to the degree of toxicity:

  • Non-cytotoxic/irritating
  • Tissue irritant
  • Cytotoxic

Cytotoxic drugs can cause blisters or ulcerations leading to skin necrosis if extravasation occurs. If intravenous extravasation is left untreated, it can lead to permanent tissue damage, necrosis, scar formation around ligaments, nerves and joints, infections, abscesses, contractures, and in the worst case, amputation.

Indication

  • Intravenous extravasation of cytotoxic drugs. 

Goal

  • Limit damage of tissue from intravenous extravasation.

Definitions

Non-cytotoxic drugs or non-irritants

Non-cytotoxic/non-irritant drugs normally do not cause skin necrosis.

Irritants

Drugs that are tissue irritants can cause pain in and around the injection site and along the vein. They can also cause inflammation. Some tissue irritating drugs cause ulceration if a large amount leak extravasally.

Cytotoxic drugs

Cytotoxic drugs are categorized into subgroups according to the mode of damage. This categorization is important for the choice of treatment.

DNA-binding

DNA binders absorb locally into the cells, bind to DNA, and cause cell death. After cell death, the drug molecule can be liberated from the dead cell and start killing healthy cells. This group is divided into these subgroups:  

  • Anthracycline
  • Alkylating drugs
  • Other

For doxorubicin and mitomycin, progrediating tissue damage has been reported over weeks, and in some cases, months after intravenous extravasal injection.

Non DNA-binding

This group of medications can lead to cell death through other mechanisms than DNA binding drugs. This group is divided into:

  • Vinca alkaloids
  • Taxanes

 

Chemotherapy cytotoxicity (1)
Cytotoxic, necrosis

Irritant, can cause flaking or inflammation

Non-cytotoxic or non-irritant
Amsacrine Cisplatin Aldesleukin
Decarbazine Doxorubicin liposomal Alemtuzumab
Dactinomycin Estramustine** Asparaginase
Docetaxel**** Etoposide Bleomycin
Doxorubicin* Floxuridine Bevacizumab
Epirubicin* Florouracil Bortezomib
Daunorubicin* Irinotecan Cetuximab
Idarubicin* Carboplatin Cyclophosphamide**
Irinotecan Carmustin** Cytarabine
Kloremtin** Oxaliplatin Fludarabine
Mitoguazon Pemetrexed Gemcitabine
Mitomycin-C Ralitrexed Ibritumomab tiuxetan
Mitoxanthrone Temoporfin Ifosfamide**
Paclitaxel**** Teniposide Interferon
Plicamycin Topotecan Cladribine
Streptozocin Methylene blue***** Clofarabine
Verteporphin   Melfalan**
Vinblastine***   Methotrexate
Vindesine***   Rituximab 
Vincristine***   Tiotepa**
Vinorelbine***   Trastuzumab

 * = Anthracycline

** = Alkylating agents

*** = Vinca alkaloids

**** = Taxanes

*****= Methylene blue is not a chemotherapy drug, but is used for ifosfamide-induced encephalopathy, and is therefore included on the list.  

All chemotherapy drugs can damage tissue in high concentrations.

References

 

  1. Allwood M, Stanley A WP. The Cytotoxics Handbook. Ed. 4th ed. 2002. 2001
  2. Ekstravasation Guidelines Implementeringsværktøj [Online] 2007 [hentet 10. mars 2009]; Tilgjengelig fra URL: http://www.cancerworld.org/CancerWorld/getStaticModFile.aspx?id=2726

Preparation

Identification of an extravasal injection

  • A burning, stinging pain or other acute change of the puncture site.
  • Local redness or inflammation of the skin around the puncture site.
  • The infusion rate slows/stops.
  • Swelling of the puncture site.

Extravasation has probably also occurred if blood cannot be aspirated, resistance is felt on the plunger when a syringe is used, and/or there is no current if the drug is infused. 

 

Implementation

Flow chart for treatment of intravenous extravasation of cytotoxic drugs:

Emergency response:

  • Stop the infusion immediately.
  • Allow the needle to remain and aspirate with as much water as possible. Avoid applying direct pressure on the area of extravasation.  
  • The volume, type, and time of extravasation should be recorded.
  • A doctor/plastic surgeon should be called for to examine the patient.
  • The damaged area and skin manifestations should be marked/photographed.
  • The affected area should be kept elevated.
  • The remaining chemotherapy should not be discarded.
  • The patient should be informed about what is happening and what must be done. 
  • The needle is removed while aspirating.
  • Pain medication is administered if necessary.

Based on which medication has leaked extravasally, the doctor or plastic surgeon will decide whether conservative treatment or primary surgery is necessary.

Conservative treatment

Conservative treatment consists of two different treatment strategies to limit the damage by extravasation: localize/neutralize and spread/dilute (2).

Localize and neutralize:

  • Place an ice pack on the area for 15-20 minutes, at least 4 times daily for multiple days. A coldpack is used to limit spreading of the drug. Studies have indicated that there is reduced cellular uptake of drugs at lower temperatures (2).
  • The drug that has leaked extravasally is neutralized by a specific drug if the instructions are followed.
  • The affected area of the body should be kept elevated.

Spread and dilute (applies to vincristine, vinorelbine, vindesine, and vinblastine):

  • Warm compresses are placed on the area for 15–20 minutes, at least 4 times daily, for multiple days.
  • To dilute the drug that has leaked extravasally, many subcutaneous injections are given with hyaluronidase diluted with sterile water.

If the patient has lasting pain or blisters, surgical treatment should be considered by excising the area with direct sutures, skin transplant, or flap reconstruction.

Another type of reconstruction may be necessary at a later time. 

Treatment 

Dexrazoxan (Savene®)

Dexrazoxan is an EDTA analong used to treat extravasation of anthracycline (doxorubicin, daunorubicin, epirubicin, idarubicin). The mechanism of action is not fully understood, but it is believed that it may work through two mechanisms. By chelating iron, the formation of the iron-doxorubicin complex and  iron-mediated hydroxy radicals are hindered, which cause oxidative damage to cell membranes and proteins. Another possible mechanism is inhibition of topoisomerase II (3).

Treatment lasts for 3 days. In all cases of extravasation of anthracycline, this treatment should be assessed by an oncologist and surgeon/plastic surgeon.

  • The first infusion should start as soon as possible and within 6 hours after extravasation. 
  • On the following two days, the infusions should occur at the same time as the previous infusion (+/- 3 hours).
  • If possible, the infusion should be placed in a vein where there is no extravasation.
  • An ice pack or cooling element used on the area must be removed at least 15 minutes before the infusion starts to ensure sufficient blood circulation.

Cost

A package costs about NOK 100,000.-. If the expiration date runs out, the drug is replaced by the pharmaceutical company free of cost.

Dimethylsulfoxide (DMSO)

DMSO (70–90% solution) quenches free radicals and prevents formation of sores. The solution can be used after extravasation of cytotoxic drugs (anthracycline, mitomycin C, doxorubicin, idarubicin, epirubicin andactinomycin D) together with cooling of the area when other treatment methods cannot be used (5, 6). DMSO cannot be used in combination with dexrazoxan (3, 4).

  • An area twice as big as the affixed area is treated with the solution every 8 hours for one week.(6)

Hyaluronidase

Hyaluronidase is an enzyme that breaks down hyaluronic acid found in connective tissue. This leads to permeability and increased diffusion of the drug that is leaking extravasally, and is used only to spread the drug out into the tissue (spread and dilute).  

  • Hyaluronidase is administered subcutaneously or intradermally in 5-10 locations on the border of the area where the drug has leaked extravasally (7).

Surgical treatment

"Wash-out"

The washing out technique can be used with chemotherapy drugs when tissue damage is likely. When used with anthracycline, it is important that this is performed before the chemotherapy drug goes intracellularly.

In most cases, this is a very successful method if it is performed within 6 hours after the extravasation.

  • The patient receives regional anesthesia.
  • Multiple small incisions must be made to ensure sifficient access to the damaged subcutaneous tissue.
  • With an infiltration needle, which is usually used for liposuction, isotonic NaCl is flushed through the tissue and drains through the incisions.
  • The infiltrated fluid is then carefully removed by suction through a small needle used for liposuction.
  • The procedure is repeated until 300-500 ml fluid is used.

References

  1. Ekstravasation Guidelines Implementeringsværktøj [Online] 2007 [hentet 10. mars 2009]; Tilgjengelig fra URL: http://www.cancerworld.org/CancerWorld/getStaticModFile.aspx?id=2726
  2. Hasinoff BB. Dexrazoxane use in the prevention of anthracycline extravasation injury. Future Oncol 2008; 2006: 1–15.
  3. Statens legemiddelverk. Preparatomtale. 2008
  4. Langstein HN, Duman H, Seeling D, Butler CF, Evens GR. Retrospective study of the management of chemotherapeutic extravasation injury. Ann Plastic Surg 2002; 49: 369–74. 
  5. Bertelli G, Gozza A, Forno GB, Vidili MG, Silvestro S, Venturini M et al. Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: A prospective clinical study. J Clin Oncol 1995; 13: 2851–5.
  6. Clinical Pharmacology© 2008 database. Hyaluronidase. 2008.

Follow-Up

For conservative treatment 

The damaged tissue should be observed for multiple weeks (with mitomycin at least 13 weeks) since necrosis can occur after months.

For emergency surgical treatment

Patients treated by a plastic surgeon should receive follow-up care by the surgeon until the wound has healed.

 

Intravenous extravasation of cytotoxic drugs.Intravenous extravasation of cytotoxic drugs.Extravasation of tissue toxic chemotherapy

Movement and strict bed rest for threatening spinal cord lesion

General

Approximately 5% of the patients with advanced malignancies develop symptoms of threatening spinal cord lesion. The condition is most frequently in patients with cancer originating from lungs, prostate or breast, but is also seen in other types of cancer where bone metastases may occur.

Symptoms

  • Pain in the back, possibly in the neck
  • Changes in existing pain (increased intensity, changed character, radiance of pain)
  • Pain that worsens with exertion (for example cough, sneeze or going to the toilet)
  • Walking difficulties and inability to control the extremities
  • Paralysis of the legs and-/or arms
  • Loss of sensation
  • Urinary problems and/or defecation problems

The stability in columna

  • Ambulatory patients without neurological deficits do not need strict bed rest.
  • For other patients, it may be appropriate to have strict bed rest until the stability of columna is assessed. The need of strict bed rest is assessed by a physician based on the risk of increased neurological deficits and the degree of pain. When columna is considered stable enough (usually clarified 2 to 4 days after the initiation of radiotherapy), gradually mobilization until pain threshold should quickly get started. Increasing pain or neurological deficits should be observed during mobilization.
  • For strict bed rest, the head end of the bed can be elevated up to 30 ° C.
  • If flat bed rest causes increased pain, the head end of the bed should be raised until pain reduction.

Indication

  • Threatening spinal cord lesion caused by tumor/metastases.

Goal

  • Limit spinal cord damage so that  functions may be maintained.

Preparation

The patient and their family should receive proper information and guidance regarding to disease, treatment and restrictions. For advanced disease, small chance of getting better and short life expectancy, quality of life rather than strict restrictions should be emphasized.

The patient should, if he/she wishes, be involved in decisions regarding to treatment and further training.

Implementation

Use of cervical collar and corset

  • Lack of documentation of the effect of using cervical collar and corset, require the patient's wishes to be taken into account in assessing whether this should be used.
  • Cervical collar may be relevant for spinal cord lesions in the cervical level of the spinal cord. Some patients find this pain relieving. A neurologist/neurosurgeon will decide whether there is a need for cervical collar.
  • A corset are generally not used preoperatively, but if prescribed by a surgeon, it may be used postoperatively.
  • The corset must be adjusted by a prosthetist or physiotherapist.
  • The corset is put on in either supine position, sitting position or in standing position, initially by competent personnel. The patient is instructed to put on the corset unassisted.

Bed rest and positioning

  • The patient should be referred for physical therapy at an early stage. To avoid accumulation of mucus in the lungs, the physiotherapist should give instructions in appropriate breathing exercises, consider use of mini-pep and need for chest physiotherapy.
  • Patients who need strict bed rest must have electrically controlled bed with a pressure relieving mattress.

Movement in bed

  • The patients must be instructed in how to move to lateral position in bed using logrolling. Logrolling involves moving to lateral position without rotation or flexion/extension in columna. The healthcare staff are performing the movement to lateral position by rolling the patient while their hands are securely placed over the patient's hips and back/shoulder.
  • If the patient has mobility in the legs, he/she may, using bent knees and hips and feet down in the mattress as well as arms straight up in the air as levers, roll over to lateral position.
  • When the patient needs to be moved higher up in bed, the bed should be tilted a bit backward, the patient is lifted calmly with the sheet close to the body by means of the draw sheet and two persons.
  • Slingbar is not recommended for cervical or thoracic lesions.

Activity during bed rest

  • By instructions from a physiotherapist, nurses can assist the patient to do appropriate activity and exercises. Passive exercises when paresis or paralysis is present, otherwise active exercises.
  • Activity that causes pain must be interrupted.
  • Individually customized movements of upper and lower extremities, passive or active, are carried out in a supine position with a low strain on columna.
  • A footboard made of compact foam at the end of the bed is an aid to prevent the patient from sliding down in the bed and provides a resistant surface against which the patient can push for a good venous-/muscle pump.
  • Strength training of arms by static resistance to the mattress and without movement of the columna, is recommended. Light hand weights for arm exercises are only considered when the affection is in the lumbar level.
  • The need for contracture prophylaxis is considered, and if there is a drop foot a footboard should be customized.
  • Instructions in self-training will be given, preferably also as a written program as well.

Thrombosis prophylaxis

  • Bedridden patients should have compression stockings in thigh/- possibly knee length, unless contraindicated.
  • Patients at high risk of venous thrombosis should also have subcutaneous thrombosis prophylaxis with low molecular weight heparin.
  • The duration of thrombosis prophylactic treatment is considered individually based on current risk factors, general health condition and mobilization of the patient.

Pressure relief and prevention of pressure ulcers

  • Patients who must have strict bed rest is particularly prone to pressure ulcers.
  • Prevention of pressure ulcers must be followed in relation to risk assessment, assessment of the patient's skin, skin care, nutrition, pressure relieving underlay, change of position in bed/chair and mobilization.
  • For patients with/having strict bed rest, change of positions in bed must be in accordance with the restrictions.

Bladder function

  • An assessment of  the bladder function is done at arrival. An accuracate anamnesis is obtained: Last urination, episodes of incontinence, frequency, painful urination and abdominal pain.
  • Evaluate the  bladder function at least once a day for any changes.
  • If incontinence, insert a permanent catheter.
  • If it turns out to be permanent muscle tone, evaluate eventually intermittent catheterization or insertion of suprapubis catheter.
  • Bedpan/urinal bottle should be easily accessible at strict bed rest. When using bed pan, loggrolling is required.

Gastrointestinal function

  • An assessment of  the gastrointestinal function is done at arrival.
  • An accuracate anamnesis is obtained: Last bowel movements, frequency, consistency, nausea/vomiting, abdominal pain and previous ailments.
  • Evaluate the gastrointestinal function evaluated at least once a day.

Pain relief

  • Spinal cord compression can cause severe pain that may be difficult to treat. If so, contact the pain -/palliative team.

Mobilization

  • The patient and the healthcare staff collaborate to find the right level of activity.
  • Go gradually from an increased angle on the bed`s back rest to sitting position, to sitting position on the bedside and then to standing position. The back rest is gradually raised to about 45 ° and the bed´s leg-rest is angled and the patient can try this sitting position, further to 60 °. By worsening of pain and/or neurological outcomes, the patient is returned to the previous position for reconsideration. If the increase of the back-rest is unproblematic, the patient can further be mobilized to the bedside.
  • The first time the patient is moved to sitting position on the bedside, this is preferably done by a physiotherapist together with a nurse by rolling over to lateral position (logrolling). The patient sits up assisted by two persons, one at the upper body and one supporting the legs over the edge of the bed.
  • When affection in the cervical region only, the patient can be mobilized up to a sitting position by raising the head of the bed and bring the legs over the bedside. The patient is allowed to sit for a little while, blood pressure and pain are evaluated.
  • Exercises to increase circulation and good breathing exercises are recommended. Balance in a sitting position is considered.
  • When the patient is moved to standing position, custom walking aids must be used (pulpit walker or forearm walker). To ensure safe mobilization the first time, assistance of two persons are recommanded.
  • For lasting paresis, a high-back reclining wheelchair with leg rests should be customized.
  • The need of other aids, like transfer slide board, drop foot brace, grasping forceps and similar equipment, should be considered.
  • Instruction in self-training should be given, preferably after a written program in standing exercise and walking exercice with support.
  • Gradually, the patient can sit  for short periods of time, using a good armchair with a high seat and good backrest.

Follow-up Care

  • Patients with a long life expectancy should be considered for further training at a suitable institution.
  • Patients with a short expected life expectancy are usually not recommended for stay at rehabilitation institutions.

The website www.physiotherapyexercises.com is recommended for obtaining exercises.

Follow-up Care after Treatment of Breast Cancer

Follow-up after completion of primary treatment of breast cancer has many aspects both medically, functionally, and financially. The individual needs of each patient for support will vary. All patients need some practical guidance. The most important aspect is early diagnosis of local regional relapse.

Usually a 10-year follow-up is performed after primary treatment of breast cancer. A growing tendency is that general practioners have early responsibility for medical follow-up of both breast conservative treatment and mastectomy. All patients must be informed about the risk of local regional relapse or a new tumor in the contralateral breast. The patients must be encouraged to regularly perform breast self-examination. In addition information about the benefit and need of regular mammograms should be provided.

The following groups with more complicated problems should be followed up a a hospital:

  • Patients below 35 years
  • Patients with primary locally advanced cancer
  • Patients with breast cancer related to pregnancy/breastfeeding

Many patients may have torments/problems which may need special consideration the first time after the treatment. This may concern fatigue, problems with concentration/memory, symptoms from lack of estrogen, sexual problems, mental disorder, lymphedema, and regional torments.

Even if there are different ways of organizing the follow-up many of the patients prefer to maintain the connection with the treating hospital. The treatment will also for many of the patients give a medical basis for seeing the patients at some important points of time:

  • First year (side effects)
  • After 2 years (change of hormone treatment for many)
  • After 5 years (usually for ending hormone treatment)

Due to the planned implementation of The Norwegian Breast Cancer Registry (NBCR) it is also reasonable to structure the follow-up to simplify and secure the reports for NBCR. Reporting is planned for 10 years after treatment.

The following guidance for registration should be the minimum:

  • The first 2 years: Annual follow-up visit at the treating hospital. Consultation and examination by physician.
  • Year 3 and 4: Annual contact with the treating hospital through telephone consultations (nurse or physician) or nurse-driven controls at the treating hospital. Clinical examination (and consultation, if needed) by general practitioner or physician at treating hospital.
  • Year 5: Follow-up visit at the treating hospital. Consultation and examination by physician.
  • Year 6 - 9: The need for contact with the treating hospital is discussed at the year 5 follow-up visit. If needed, yearly contact with the treating hospital through telephone consultations combined with clinical examination/consultation by general practitioner. If no need for contact with the treating hospital, only follow-up visits with general practitioner.
  • Year 10: Follow-up visit at the treating hospital. Consultation and examination by physician.

Mammographic follow-up:

Mammography is to be carried out annually after primary treatment for stage 1 - 3 have been completed.

  • After breast conservative treatment, irrespective of age. Both breast are examined. The first time within a year after preoperative mammography, thereafter annually for 10 years. The examinations should preferably be performed at the treating hospital.
  • After mastectomy. Annual follow-up at treating hospital for 10 years. The Norwegian Mammograpy Programme may  take care of the mammography biannually after 50 years of age.

Patients being followed up for 10 years and being more than 50 years of age may further follow the breast cancer screening programme. Younger patients should continue their mammography control at the treating hospital until 50 years of age.

Gynecologic examination

The physician should inform women taking tamoxifen on the risk of endometrial proliferation, endometrial hyperplasia and uterine cancer in postmenopausal status. Routine gynelogical examination with ultra sound is not necessary in women without gynecological symptoms. Gynecologic symptoms like for instance vaginal bleeding should be immediately gynecologically examined.

Monitoring of thyroid function

Women treated for breast cancer have an increased risk of hypothyroidism. Irradiation towards supra/infraclavicular lymph nodes may contribute to this. After locoregional irradiation we therefore recommend lifelong testing of FT4 and TSH (or more frequently in case of deviations). During follow-up for women treated for breast cancer, FT4 and TSH should be checked where there is suspicion of hypothyroidism, even for sparse symptoms.

Reconstructions

Patients may be offered reconstruction with implant or autologous tissue. Various techniques are applied for transposition of own (autologous) tissue.

Locoregional recurrence

Locoregional recurrence after treatment for breast cancer can develop both early and late during the follow-up. A considerable percentage appears during the first 5 years. The frequency of locoregional recurrencies with nodepositive patients is considerably reduced subsequent to routinely application of locoregional radiation

Both the treatment and prognosis varies, depending on both the primary treatment, the location of the locoregional recurrence and the interval from primary surgery. Additionally several other factors may be of importance.

The major groups of locoregional recurrences are:

  • Thoracic wall after mastectomy
  • Recurrence in regional lymph nodes
  • Recurrence in the breast after conservation treatment
  • Locoregional recurrence with synchronous metastasis

A well taken anamnesis and careful clinical examination of the locoregional area is most important for the detection of recurrence. When recurrence is suspected additional examinations will be relevant. The clinical picture will decide which examinations shall be performed.

Relevant examinations are:

  • Extended hematological profile:
    • Hematological tests: creatinine, electrolytes including s-Ca, albumin, and liver tests.
    • Possibly tumor markers (MUC1,CEA)
  • CT, ultrasound and MRI may reveal important  information for the diagnoasis of a locoregional diagnosis. In som cases where these examinations are inconclusive, PET can give additional information. The recurrence should always be confirmed by biopsy. Radiation fibrosis can be a differential diagnosis.
  • Metastases should be routinely screened for (ultrasound or CT of the liver, bone scintigraphy or MRI).
  • CT of the chest (possibly x-ray of the chest) should be considered depending on the type of recurrence.

PROSEDYRER

Lymphedema

General

According to etiology, there are two general classifications of lymphedema primary and secondary lymphedema. Primary lymphedema is caused by deficient or faulty development of the lymph system. Secondary lymphedema occur as a complication from trauma or diseases which damage the lymphatic vessels or lymph nodes. The primary cause of lymphedema in the western world, is impaired or disrupted flow of lymph fluid caused by cancer or cancer treatment (secondary lymphedema).

Lymphedema occurs when the transport capacity of the lymph system is reduced significantly.
The swelling is caused by an accumulation of fluid (rich in protein) in the tissue, due to reduced drainage of lymph fluid (1,2). The swelling is often chronic. A lymphedema can lead to pain/discomfort and changes in the soft tissues in the affected area (fibrosis) (3,4). Lymphedema occurs most often during the first 2-3 years after cancer treatment (5 6). Without treatment, lymphedema can lead to progressive swelling.

In some cancer treatment the lymph nodes and fatty tissue are removed, most often in the axilla, pelvis and the groin. This treatment causes damage to the lymphatic wessels and reduces the number of lymph nodes. The subsequent reduced capacity for drainage of lymph fluid in the arm and leg may result in lymphedema.

Radiation therapy may cause tissue scarring and fibrosis. The combination of surgery and radiation therapy to the axilla additionally increases the risk of developing lymphedema.

Cancer related lymphedema can also occur due to metastasis in areas where blocking the central lymph vessels in advanced disease.

Factors which may increase the risk for developing lymphedema are:

  • obesity
  • infection in the area where lymphedema occurs
  • overheating/sunburn
  • trauma of the arm/leg on the operated side

Indications for treatment

Lymphedema in the arm/hand, breast, leg, groin, face and neck after treatment of:

  • breast cancer where axillary dissection is performed
  • gynecologic cancer where the lymph nodes in the pelvis or the groin are removed
  • melanoma where the lymph nodes in the axilla or the groin are removed
  • lymphoma and cancer of the head and neck region where lymph nodes in the neck region are removed
  • prostate cancer where the lymph nodes in the pelvis or the groin are removed
  • sarcoma where lymph nodes are removed

Without treatment the lymphedema can increase in size. This may cause skin changes (fibrosis), increased swelling and therefore more discomfort in the area (3).

Contraindications

Absolute
  • acute infections, local or general (erysipelas)
  • arterial insufficiency with risk of necrosis
  • thrombosis and embolism
Relative

Untreated cancer disease, heart failure, or kidney failure

Goal

  • reduce lymphedema
  • relieve tormenting side effects
  • improve function 
  • prevent complications such as skin changes and inflammation in the area (erysipelas)

References

1. Rockson SG. Diagnosis and management of lymphatic vascular disease. J Am Coll Cardiol 2008;52:799-806.
2. Lawenda BD, Mondry TE, Johnstone PAS. Lymphedema: (Review) A primer on the identification and management of a chronic condition in oncologic treatment. CA Cancer J Clin 2009;59:8-24.
3. Mortimer PC. The patophysiology of lymphedema. Cancer 1998;83(12 Suppl American): 2798-802.
4. Erickson VS, Pearson ML, Ganz PA, Adams J, Kahn KL. Review: Arm edema in breast cancer patients. J Natl Cancer Inst 2001;93:96-111.
5. Nesvold IL, Dahl AA, Løkkevik E, Mengshoel AM, Fosså SD. Arm and shoulder morbidity in breast cancer patients after breast-conserving therapy versus mastectomy. Acta Oncol 2008;47:835-842.
6. Norman SA, Russel Locario A, Potashnik SL, et al (2009) Lymphedema in breast cancer survivors: incidence, degree, time course, treatment, and symptoms. J Clin Oncol 2009;27:390-397.
7. Johansen J, Overgaard J, Blichert Toft M, Overgaard M. Treatment morbidity associated with the management of the axilla in breast-conserving therapy. Acta Oncol 2000;39:349-54

Definitions

Complete psysical therapy treatment of lymphedema

Consists of manual lymph drainage, compression therapy, skin care and instruction in exercises and self-treatment (1). The treatment is performed by physical therapists with special expertise.
The treatment may be extensive at the start. In cases of severe swelling one usually start with manual lymph drainage followed by bandaging of the arm/leg (1).

Manual Lymph Drainage

This is a kind of massage which requires guided training to perform optimally. The goal is to encourage the drainage of lymph fluid and thereby reduce the swelling of the tissue (2). It is quite different from other kinds of massage applied within physiotherapy. The anatomical conditions of the lymph system is the basis for manual lymph drainage. These are: the course of the large lymph veins, the borders of different lymphatic functional regions (watershed), natural anastomoses crossing these lines, and the lack of valves in the lymphatic vessels .

Bandaging

Bandaging is used mostly at the start of a treatment to reduce swelling. When the swelling is reduced a compression stocking is adjusted.

Compression stocking

Clinical experience and research show that compression is the most important treatment. (3;4) Accordingly it is of great importance to adjust a compression stocking for the arm or leg. If there is swelling of the hand, a compression glove might help.
A compression stocking is used to increase tissue tension. The pressure from the stocking increases absorption of tissue fluid. The stocking provides a graded pressure highest distally and lowest proximally. To adjust the stocking, the circumference of the arm or leg is measured at several defined points. There are several compression classes, but the most commonly used are class 1 and 2. The stocking should provide a constant pressure without causing discomfort. It may take some time to get used to the compression stocking. Some choose to use the stocking occasionally, while others wear it daily.
A facemask at night is recommended to treat lymphedema in the neck and face region (5). Patiens with lymphedema in the groin can be helped by using a bike pant or a panty. Bandaging, tubigrip or bike pants may benefit if there is swelling of the penis and scrotum .

Intermittent pressure massage with pulsation

Treatment is carried out with an electronically powered apparatus which blows air in a double-walled cuff. The cuff, covering the whole arm or leg, has multiple channels and creates a peristaltic pressure wave in proximal direction. The treatment encourages the lymph drainage and thereby reduces the swelling (4).

References

1. The diagnosis and treatment of peripheral lymphedema. Consensus document of the International Society of Lymphology Executive Committee. Lymphology 2003;36:84-91.
2. McNeely ML, Peddle CJ, Yurick JL, Dayes IS, Mackey JR. Conservative and dietary interventions for cancer-related lymphedema: A systematic review and meta-analysis. Cancer 2010.
3. Badger C, Preston N, Seers K, Mortimer P. Physical therapies for reducing and controlling lymphedema of the limbs. Cochrane Database Syst Rev 2004;CD003141.
4. Johansson K, Albertsson M, Ingvar C, Ekdahl C. Effects of compression bandaging with or without manual lymph draining treatment in patients with postoperative arm lymphedema. Lymphology 1999;32:103-110.
5. Deng J, Ridner SH, Murphy BA. Lymphedema in patients with head and neck cancer. 2011;38:1-10.

                                                                          

Preparation

Main points of information

Information should be given to patients who have received surgery only or combined with radiotherapy with increased risk of getting lymphedema. The patient usually gets information about lymphedema after the surgery. Sufficient information and guidance is important and crucial for both avoiding getting lymphedema and being able to identify lymphedema at the very beginning.

  • The function and purpose of the lymphatic system
  • Causes of lymphedema
  • Symptoms of lymphedema
  • Different treatment options
  • Precaution
  • Complications/side effects caused by the disease and treatment
  • The importance of maintaining mobility in the arm or leg

Symptoms of lymphedema

  • A feeling of uncomfortable change
  • A feeling of heaviness
  • Bursting pain
  • Changes of consistency (visible or palpable) in the soft tissues
  • Suspicion of increased circumference
  • Swelling may disappear overnight, but usually returns during daytime
  • Some have swelling sporadically

The dominating symptom is lasting swelling in the involved area. Other symptoms will to a large extent depend on the amount, duration, and localization of the edema.

Moderate swelling after cancer surgery, can be a reaction which often spontaneously disappears.

Diagnostics

Lymphedema is usually measured using a clinical method. There are multiple methods to measure the extent of lymphedema. The gold standard is the water displacement method, which measures and compares the volumes of both arms/legs. But a method of comparing volume by using several circumferential measurements of the arms/legs is often used in research and sometimes in the clinical setting. The most widely used method is measurement of circumference at multiple anatomic points on the arm/leg with comparison with the contralateral arm/leg. A difference in circumference of ≥2cm is often defined as lymphedema. Stemmer sign is also used.

Implementation

With development of lymphedema, it is important to take precautionary measures as soon as possible. Treatment with compression is the component which seems to be most effective in reducing the swelling. Manual lymph drainage is often used in combination with bandaging in the first 1-2 weeks of the treatment. This complete decongestive therapy is a composite treatment including multiple techniques which are performed by a specially trained physical therapist.

The intensive phase

  • Compression treatment – possibly with bandaging and thereafter adjustment of an elastic stocking
  • Manual lymph drainage
  • Circulation and drainage inducing exercises
  • Skin care

During the intensive phase, the patient is usually treated 5 days a week with continuously bandaging until the desired volume reduction is achieved. This usually takes one to two weeks.

Bandaging

After stimulating the lymphatic flow by manual lymph drainage, a compression stocking is used or the whole arm is bandaged for one to two weeks. The bandages should be worn as long as they are not too uncomfortable. Correct bandaging with short, elastic bandages provide the tissue with high pressure under activity and low pressure while resting.

  • An ointment with a low pH (5.5) should be applied to the skin.
  • A light tube gauze should be worn.
  • The padding is then applied.
  • The bandaging starts distally to the lymphedema.
  • The bandages are laid evenly, circularly, and in multiple layers.
  • The pressure should decrease gradually from distal to proximal.
  • The pressure is regulated partially with the bandaging technique and mainly by the number of layers of bandages.

Compression stocking

  • The stocking may be removed at night.
  • At night an ointment is preferably applied to the skin.
  • With incipient  lymph edema, wear the stocking during activity.
  • In moderate and extensive lymph edema, the stocking is usually worn all day.
  • The stocking should be washed at least every third day.

A poorly customized stocking may create faulty compression. The most frequent error is that the compression stocking is used after it has lost its elasticity (worn out) and therefore has less effect.

Manual Lymph Drainage

The massage strokes should be performed in the direction of the lymphatic drainage with light pressure and with slow motions. The treatment should not be painful.

Manual lymph drainage has four main movements: standing circles, pumping grip, turning grip, and corkscrew grip.

Pressure massage with pulsator

Pulsation is never a first choice for treatment of lymphedema, but could be a measure over time when monitoring has shown that the treatment is effective. At the start, the patient should be informed about possibly complications. Sometimes, an increase in edema is seen proximal to the cuff. Further pulsation treatment should then be postponed until manual lymph drainage and exercises have improved the condition. If the pressure is too high, the lymphatic vessels may be damaged and the amount of interstitial fluid may increase.
The pressure should be moderate and the patient should experience the treatment as comfortable. It is not the amount of pressure that is important, but uniform rhythmic pressure wave. Tuning of rate and pressure are adjusted for each patient.
Usually, the treatment should last for twenty minutes at the start increasing gradually to thirty to forty minutes. Can be used daily or when needed. Pulsation treatment may also be performed by the patient at home.

Skin Care

Regardless of whether the patient has lymphedema or not, it is important to hinder the occurrence of scratches, sores, and unnecessary skin irritation. Use of gloves is appropriate in some situations. The patient should also be cautious of overheating and sunburn. The main goal of skin care is to prevent infections, because this can trigger an eruption of lymph edema.

Regular use of bandages and compression stockings dries out the skin. Use of skin care products and cleansers with a low pH (5.5) are recommended. Good skin care keeps the skin soft and supple and maintains the skins natural ability to fight infection.

Disinfecting ointment and adhesive tape should be used in the event of an ulcer or scratch or if there is danger of infection.

Maintenance phase

  • Use of elastic stocking and/or glove as needed
  • Skin care
  • Regular exercises to facilitate the muscle-joint pump
  • Possible intermittent pressure massage with pulsator

The patient obtains some treatment during the maintenance phase and may have treatment by a physical therapist if necessary. In the short term, the treatment is almost always satisfactory. In the long run, the result depends on the patient practicing the measures recommended. The pulsator may usually be borrowed from a health care center.

Exercises to improve mobility and lymph flow of the shoulder/arm

Dynamic exercises with a relaxation phase are optimal. "Throwing" movements may feel uncomfortable. Many experience that it is better to walk with poles, but it is important to maintain a loose grip of the pole.

Correctly adjusted movement exercises:

  • induce circulation without straining the reduced lymphatic system
  • provide adequate joint movements
  • stimulate dynamic change between tension and relaxation, preferably in conjunction with respiration

Movement therapy in a heated pool may be favorable for some lymphedema patients. Water pressure stimulates lymphatic drainage and simultaneously activates circulation and movement.

 

Follow-Up

If necessary, the patient may obtain a referral for physical therapy in their home area for further follow-up. Follow-up and guidance by a physical therapist with the necessary skills is important. Some with serious lymphedema will need frequent treatment for the rest of their life. But others will be able to manage the treatment themselves by adhering to the guidelines that they have learned. Compression with stockings and skincare are often sufficient treatment. So many patients do not need physical therapy as treatment, but rather information and functional guidance.

Moderate physical activity improves joint movement, circulation, and well-being, as well as stimulation of lymph drainage. Blood pressure should not be measured and vaccinations should not be given in the treated arm. Gloves are recommended for gardening.

Complications

Fibrosis of the dermis and epidermis with affects some persons with lymphedema. The skin loses its elasticity and is more easily traumatized than normal skin.

The immune system is weakened in the edematous area. This may be for multiple reasons, among others, weakened transport of dendritic cells, lymphocytes, and proteins. If the area’s regional lymph nodes are removed, this will also weaken the local immune system.

In some edema patients, especially secondary lymphedema, a distinctive reaction (erysipelas) may occur in the skin of the affected area. This will usually start acutely with a strong feeling of malaise with high fever, hyperemia with flushing, and increased swelling of the skin. The area of skin involvement is often limited. The symptoms are usually improved after four to six days but it is not uncommon for the edema to deteriorate. The condition should be treated with antibiotics (penicilin) as quickly as possible.

Lymph edema in the armLymph edema in the arm.Lymph edema in the legLymph edema in the leg
Lymph edema in the arm.Lymph edema in the arm.

Fatigue before, during, and after Cancer Treatment

General

There are many reasons why cancer patients feel fatigued. In many patients, the causes are synergistic. Cancer patients are often very sick during treatment periods and may experience extreme fatigue during intensive chemotherapy. It is also very important to be aware that fatigue is a symptom of many other medical conditions, both physical and psychological, which also affects cancer patients. Some known causes of fatigue associated with cancer and cancer treatment are: 

  • Cancer itself
  • An operation
  • Current or recently concluded chemotherapy
  • Current or recently finished radiation therapy
  • Severe anemia
  • Other symptoms such as pain and nausea 
  • Fever or infection
  • Too little fluid or food intake
  • Reduced lung function
  • Changes in sleep
  • Worries, anxiety, stress, or depression

For some of these conditions, such as infections, there is medical treatment available. Fatigue that occurs after an operation or during chemotherapy and radiation therapy will, for most, gradually disappear when strength is regained. If a patient was feeling healthy after treatment and all of the sudden experiences fatigue, they should contact their doctor. If a patient feels fatigue and at the same time feels stressed, worried, or down, they may be reluctant to speak to their doctor or health personnel about it. It is still recommended to talk about these problems. Talking about it may be therapeutic, and provides room for discussing measures with a qualified person with experience with patients that have the same problems. For cured patients experiencing chronic fatigue, it may be difficult to pinpoint a specific cause. Many of these patients experience improvement by changing their lifestyle to a lower tempo than before the diagnosis.

Definition

Everyone knows what it feels like to be tired, fatigued, or lethargic when sick. This feeling is the most common side effect of cancer and cancer treatment. A symptom is a condition or state that something is not right in the body. Other frequent symptoms associated with cancer and cancer treatment are reduced appetite and nausea. Most patients who experience fatigue associated with cancer say that the feeling does not improve with rest, and many describe a lack of energy or exhaustion.  

If fatigue arises during chemotherapy or radiation therapy, most patients experience that it will gradually go away when treatment is over and their strength is regained. This type of fatigue is considered acute. Improvement may take time depending on the intensity of treatment. Some patients experience that fatigue lasts for months, or even years. This is considered chronic fatigue. The ability to carry out daily activities, a lack of humor, health-related worries, a reduced capacity to carry out work functions, or less energy for family, can also accompany chronic fatigue. Most patients will find it difficult to be told by their doctor that they are considered healthy, while their friends and family expect them to be normal again, despite having a lack of energy and ability to perform activities they want to.  

For many, feeling fatigued is often accompanied by having difficulty concentrating, poor memory, and an increased need for sleep. Most patients will need more sleep than before they became sick. For many, sleep is not restful, and it may take time to "get going" in the morning. Many also experience that they quickly become drained of strength if they exert themselves, and that it takes a long time before regaining strength after exertion. Exertion in this context can mean both physically and mentally such as working on a task that requires concentration.

Preparation

Fatigue can occur in all phases of cancer illness. Some patients feel it before the diagnosis, and almost all patients experience fatigue during radiation therapy or chemotherapy. A minority of patients experience long term fatigue after cancer treatment is over and the disease is cured. Patients who cannot be cured will almost always feel tired, worn-out, and exhausted. The degree of fatigue in these patients varies depending on the cancer type, spreading, and other symptoms of the disease.

The patient should be given necessary information on both causes of fatigue and measures he/she can take.

Implementation

General measures that can reduce feeling tired and fatigued

Following suggestions are meant as general advice that may not necessarily apply to everyone in all situations. This advice is based on results from studies, experiences from cancer patients, and recommendations from experts. Each patient should assess what works for them. It is recommended to express concerns and seek advice for what measures you can take and what you should avoid.

General advice
  • Try to live as "normal" as possible.
  • Try to plan your day to include time to rest.
  • Take many small breaks during the day instead of a few long ones.
  • Rest after strenuous activity.
  • Plan your daily activities and do those that are most important for you.
  • Set realistic goals for yourself and try to be happy with those you accomplish.
  • Try to recognize activities that make you especially tired/fatigued and limit them, or spread them out over longer intervals. 
  • Try to accept that you do not have the energy to do the things you could previously.
  • Assess what is important for you to do yourself and what you can allow others to do.
  • Assume you will be tired after something strenuous even if you experience the activity as positive.

Physical activity and exercise

Exercise and physical activity that is appropriate for you will reduce the feeling of fatigue. Regular exercise is the most effective measure against chronic fatigue in cancer patients. Nevertheless, both too much and too little exercise can worsen fatigue, therefore, it is important to find a level (frequency and intensity) that suits you. You should never exercise so intensely that you must stop a session or exercise period because you are exhausted. Remember that daily form varies for everyone and adjust your exercise routine accordingly. Make long-term goals (months) and gradually increase activity, and carefully for a period. 

  • Activities such as walking, biking, swimming, dance, and aerobics are recommended.
  • Light exercise periods at regular intervals are better than intense, sporadic periods.
  • Always start with a slow tempo and increase gradually before finishing with a slow tempo again.
  • Always sit down and rest after exercise but try not to lay down and sleep.
  • Physical therapists and sport pedagogs can provide advice on exercises that are right for you. The principles are the same for all exercise, but it should be adjusted for your energy level.  

Sleep

Many cancer patients with chronic fatigue have sleep pattern disturbances. It is important to maintain a normal rhythm even if you feel like sleeping during the day.

  • Try to wake up at the same time every day and keep a regular bedtime.
  • Avoid too much activity right before bedtime.
  • Try not to sleep during the day because this will disturb your biological rhythm.
  • But, a short afternoon nap may be energizing!
  • Rest during the day by relaxing in a good chair, but try not to fall asleep.
  • Speak to your doctor about lasting sleep disturbances.

Nutrition

Having a reduced appetite or intake of food can also result in a lack of strength and energy. We recommend eating healthy food regularly, and to follow the national guidelines on nutrition. Special diets or supplements do not improve fatigue unless there is a deficiency.

Work situation

Some patients do not have the strength to continue working, or they must reduce their hours because of chronic fatigue. Consulting with a social worker may be beneficial for guidance regarding your work situation, your welfare rights, and financial situation. 

Some adjustments that you and your employer can make:

  • Discuss the possibility for more simple or easier tasks, especially if you have a physically demanding profession.
  • Assess the possibility of reducing your hours.
  • Remember to take regular breaks also at work, if possible.
  • Assess the possibility of flexi-time to work during the hours you have energy, as well as the possibility of working from home.

Care for children

Caring for children or adolescents may be very difficult when you are fatigued or lack energy and strength. There are, however, some measures you can take:

  • Explain to your children that you are tired and are not able to do as much as you used to.
  • Discuss what the children can help you with and allow them to take part in household chores.
  • Try to establish permanent household chores for all family members.
  • Try to do activities that suit you that do not require too much energy, and can be performed without too much exertion. 
  • Ask and accept help from others for driving to and from activities, school, etc. if this relieves you.

Drug therapy

In Norway, there is currently no specific drug therapy for chronic fatigue associated with cancer. If the fatigue is due to specific conditions, this is of course treated with medication, if possible. Sometimes, such treatments improve the fatigue, but other times they do not. Examples of treatment that often reduce fatigue are treatment for infections and depression. 

Treatment with medications that stimulate production of red blood cells is not recommended for cancer patients due the the danger of serious side effects.

Follow-up

Information about fatigue

Healthcare workers in cancer care will often have knowledge about fatigue and cancer. Most general care physicians have general experience with fatigue but meet relatively few cancer patients. There is a lot of information available on the internet of varying quality. Below is a list of web adresses and some literature. Be aware that you may find opposing advice because knowledge on treatment especially, is limited.

Some articles/books:

  • Armes J., m.fl. (2004). Fatigue in cancer. Oxford University Press.
  • Berger A.M., m.fl. (2009). NCCN Clinical Practice Guidelines in Oncology. Cancer-Related Fatigue. www.nccn.org
  • Patarca-Montero R. (2004). Handbook of cancer-related fatigue. Haworth Medical Press