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Utskriftsdato (27.6.2017)

Lung cancer

Lung cancers are primarily divided into:

  • non-small cell lung carcinoma (about 85%)
  • small cell lung carcinoma (about 15%)

Together, non-small cell lung carcinoma and small-cell carcinoma constitute about 97% of all carcinomas in the lungs. They have a strong positive correlation with smoking. 

There are several subtypes of non-small cell lung cancers, the most common ones are: 

  • adenocarcinoma
  • squamous cell carcinoma
  • large cell carcinoma

Carcinoid tumors, sarcomas and carcinomas of the salivary gland type are rare and not related to smoking. Mesotheliomas are tumors originating from the pleura and in rare cases from the peritoneum.

Incidence

Compared to other cancers, lung cancer is fairly common and represents 13.3% of all new cancer cases in the United States. Lung cancer is most frequently diagnosed among people aged 65-74 and is more common in men than women. Approximately 6.5% of men and women will be diagnosed with lung cancer at some point during their lifetime.

In 2017, it is estimated to be 222,500 new cases of lung and bronchus cancer in the United States (33).

 

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

Source: Cancer Registry of Norway

 

 

Incidence of lung cancer, 1954–2013.

Source: Cancer Registry of Norway

Etiology of lung cancer

Smoking is the main cause of lung cancer and about 90% of cases are due to this (17,18).

Risk factors

The risk of lung cancer increases with the number of cigarettes smoked, number of smoking years, early smoking age, amount of tar and nicotine content, and use of rolling tobacco and non-filtered cigarettes (19, 20)

Passive smoking is also a risk factor. The risk for developing lung cancer increases by 20–30 % when living with a smoker compared to living with a non-smoker (21).

Other risk factors may be air pollution, radon gas, asbestos, and nickel and chromium exposure (22).

Histology of lung cancer

Primary lung cancers are considered to be of two types:

  • Small cell lung cancer (SCLC)
  • Non-small cell lung cancer (NSCLC)

Small cell lung cancer

Small cell lung cancer (SCLC) consists of small cells with a high nucleo-cytoplasmic ratio that proliferate rapidly. Similar to normal neuroendocrine cells, they contain neurosecretory granules that may produce peptide hormones and/or biogenic amines. About 90% of small cell lung cancers stain positive for neuroendocrine markers. Small cell lung cancers usually develop peribronchially and infiltrate the bronchial submucosa. This tumor type can be diagnosed in cytological material such as fine needle aspirations, brush specimens, or lavage. The diagnosis should, if possible, be confirmed in histological specimens before starting therapy.

Photomicrograph demonstrating small cell lung carcinoma in a cytological specimen. Click to enlarge. Photomicrograph showing a small cell lung carcinoma in a histological specimen. Click to enlarge.

 
Some small cell lung cancers also have areas with squamous cell carcinoma, adenocarcinoma, or large cell carcinoma. They are classified as mixed type.

Non-small cell cancer

Non-small cell lung cancer is divided into four principal subgroups:

  • Adenocarcinoma
  • Squamous cell carcinoma  
  • Large cell carcinoma
  • NSCLC not otherwise specified (NOS). This terminology is used when the NSCLC cannot be clearly diagnosed to be of adenocarcinoma, squamous Cell Carcinoma or large cell carcinoma or some of the other rarer types of carcinoma.

The microscopical subtyping can be difficult, especially in small biopsies or in cytological specimens.

Adenocarcinoma

Surgical specimen with a peripheral lung adenocarcinoma. Click to enlarge. Photomicrograph demonstrating lung adenocarcinoma in a cytological specimen. Giemsa stain. Click to enlarge.

Adenocarcinoma consists of glandular tumor cells producing mucous. They usually grow in the peripheral part of the lung. A special variant is adenocarcinoma in situ, previously named bronchoalveolar carcinoma. The immuno histochemical profile can help differentiate between other various types of NSCLC. About 70% of the Adenocarcinomas are positive for the thyroid transcription factor-1 (TTF-1). They also tend to be cytokeratin (CK) 7 positive and CK 20 negative.

Squamous cell carcinoma

Surgical specimen demonstrating a squamous cell carcinoma. Click to enlarge. Photomicrograph showing a squamous cell carcinoma with keratinization. Click to enlarge.

Squamous cell carcinoma consists of cells that can produce keratin in the same way as normal squamous epithelial cells. Histochemically they tend to be TTF-1 negative, but positive for CK 5, 6 and P63 or P40. Squamous cell carcinomas develop from a precancerous lesion proceeded by squamous metaplasia and squamous cell hyperplasia. These tumors generally grow in the central part of the lung in close relation to the large bronchi.

Large cell carcinoma

The tumor cells are large and there is no special differentiation. A variant is the large cell neuroendocrine carcinoma.

Carcinoid  tumor

A carcinoid tumor is an unusual type of lung tumor with neuroendocrine differentiation.

There are two subtypes:

  • typical carcinoid
  • atypical carcinoid

In the typical carcinoid, there are few mitotic figures and no necrosis. This is the more common type of carcinoid tumor and has a good prognosis.
The atypical carcinoid demonstrates many mitotic figures and necrosis. This type has a somewhat worse prognosis compared to the typical carcinoid. 

Assessment of operational preparation

The pathology report should include:

  • tumor type
  • size
  • localization
  • relation to surgical margins

Molecular pathology

All non-small lung cancers should be tested for the presence of mutations in the gene coding for epidermal growth factor receptor (EGFR). Selected cases should be tested by FISH for the ALK-EML4 translocation. Several other actionable and non-actionable molecular aberrations have been identified and they are now a topic of active investigation (10).

Metastatic patterns of lung cancer

If untreated, lung cancer will, almost without exception, lead to metastasis due to invasion of lymph or blood vessels.

Lymphogenic spread is the most common primary route.

  • Tumors in the lower lobe usually drain via the posterior mediastinum to the subcarinal lymph nodes.
  • Tumors in upper right lobe usually drain to the upper mediastinum.
  • Tumors in the upper left lobe usually drain to the anterior mediastinum, as well as to the upper mediastinum in 1/3 of the cases.
  • Retrograde lymph drainage to the pleura can occur, especially from peripheral tumors.

Hematogenic spread to other organs also occurs frequently. 

The most common localizations are:

  • other lobe of the lungs
  • skeleton
  • liver
  • adrenal glands
  • brain

The primary tumor can also spread by direct invasion of neighboring organs, such as mediastinal pleura, diaphragm, chest wall, or vertebrae.

Staging of lung cancer

TNM classification system

Both the prognosis and choice of treatment depend on the extent of the disease when it is diagnosed.

The TNM classification system is used to stage lung cancer and classify the size and extent of the disease at the time of the diagnosis. "T" describes the size and extent of the local tumor. "N" (node) expresses whether there is metastasis to lymph nodes. "M" expresses the absence or presence of distant metastasis (23).

The TNM system differentiates between the clinical classification based on radiology and clinical examination (cTNM), and the pathology classification (pTNM). Only patients treated with surgery are staged according to pTNM, while patients treated by radiation therapy or chemotherapy are staged according to cTNM. 

The TNM classification is critical for the choice of treatment and must be present before treatment is initiated. However, if distant metastases are present (M1), the T and N stages are of minor importance.

From 2009, the 7th edition of the TNM classification system is being used.

T -  Primary Tumor

  • TX – Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy 
  • T0 – No evidence of primary tumor
  • Tis – Carcinoma in situ
  • T1 – Tumor ≤ 3 cm in greatest dimension, surrounded by lung or visceral pleura without bronchoscopic evidence of invasion more proximal than the lobar bronchus
  • T1a – Tumor ≤ 2 cm in greatest dimension
  • T1b – Tumor > 2 cm but ≤ 3 cm in greatest dimension
  • T2 – Tumor > 3 cm but ≤ 7 cm or tumor with any of the following features (T2 tumours with these features are classified T2a if ≤ 5 cm)   
    • involves main bronchus, ≥ 2 cm distal the carina
    • invades visceral pleura
    • associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung 
  • T2a – Tumor > 3 cm but ≤ 5 cm in greatest dimension
  • T2b – Tumor > 5 cm  but ≤ 7 cm in greatest dimension

 

  • T3 – Tumor > 7 cm, or one of the following:
    • Tumor invades the chest wall, diaphragm, mediastinal pleura, parietal pericardium, or phrenicus nerve 
    • Tumor  in the main bronchus < 2 cm distal to the carina but without involving the carina
    • Atelectasis of the entire lung
    • Separate tumor in the same lobe
  • T4 – One of the following:
    • Tumor invades the mediastinum, heart, great vessels, carina, trachea, esophagus, vertebral body, or recurrence nerve 
    • Separate tumor in other lobe of the same lung 

 

N - Regional Lymph Nodes

  • NX – Regional lymph nodes cannot be assessed 
  • N0 – No regional lymph node metastasis
  • N1 – Metastasis in peribronchial or hilar lymph nodes on the same side as the main tumor
  • N2 – Metastasis in mediastinal nodes on the same side as the main tumor and/or subcarinal lymph node(s)  
  • N3 – Metastasis to hilar or mediastinal nodes on the opposite side of the main tumor, or to supraclavicular or scalene lymph nodes

M - Distant Metastasis

  • MX – Distant metastasis cannot be assessed
  • M0 – No distant metastasis
  • M1 – Distant metastasis
  • M1a –  Distant metastasis to lung on opposite side of the primary tumor, pleural lymph nodes or malignant or pericardial effusion 
  • M1b –  Distant metastasis   

The general health condition of the patient is an important prognostic factor in line with stage division. The WHO performance status is utilized.

Stage division

 

Non-small cell lung cancer    

Occult

carcinoma 

Stage 0 

Stage I 

Stage II

Stage III

Stage IV

TX N0 M0

Tis N0 M0

A B A B A B

TX-T4 NX-N3 M1

T1a-b

N0 M0    

T2a N0 M0

T2b N0 M0

T1a-b N1 M0

T2a N1 M0

T2b N1 M0

T3 N0 M0   

T1a-b T2a-b N2 M0

T3 N1-N2 M0

T4 N0-N1 M0

T4 N2 M0

TX-T4  N3 M0  

The stage is the main determinant for treatment, but prognostic factors may also be of influence.

Small-cell lung cancer

Small-cell lung cancer presents more often with metastasis at the time of diagnosis than other bronchial cancers. The condition is considered systemic regardless of stage and diagnosis, but is separated into limited or extensive disease.

Limited disease

In limited disease (SCLC-LD), the tumor masses can be included in a thoracic radiation field. For practical purposes, this includes stage I, II, IIIA and IIIB.

Extensive disease

Extensive disease (SCLC-ED) includes spread of malignant cells outside the thoracic radiation field or pleural effusion.

Due to the advancement in treatment options for small-cell lung cancer requiring more precise stage determination, the TNM system is also recommended for small-cell lung cancer (26,27).

Symptoms of lung cancer

Lung cancer is often diagnosed at an advanced stage as it causes few and vague symptoms. Early diagnosis is usually due to an incidental finding on a lung X-ray taken in another context.  

The symptoms depend on the localization of the tumor, locoregional spread, and effect of distant metastasis.

Common symptoms:

  • Coughing. Most patients have smoker's cough, therefore it is important to be aware of coughing changes.
  • Dyspnea may be a symptom of lung cancer-related bronchial stenosis, or a malignant pleural effusion, or in some cases, build of pericardial fluid. 
  • Hemoptysis may occur when the tumor has invaded the bronchial mucosa. Serious bleeding is rare, but can occur. This often starts with small tinges of blood in expectorate.
  • Respiratory tract infections are often a subsequent condition of a bronchial obstruction. Sometimes lung cancer is detected after work-up for bronchial pneumonia. 
  • Pain may occur due to large atelectases with infections. Usually, this is symptomatic of advanced cancer with direct involvement of the chest wall or pleura. 
  • In advanced cancer, general symptoms are often observed such as reduced appetite, weight loss, and fatigue.

Symptoms of acute conditions 

  • Compression of airways (dyspnea/stridor, tachypnea, coughing)
  • Vena cava superior syndrome (dyspnea/stridor, tachypnea, dilated veins on the upper body, edema of the face and neck/arms, chest pain, difficulty in swallowing, vocal cord paralysis)
  • Hypercalcemia (confusion, somnolence, nausea/vomiting, muscle aches, polyuria, constipation, dehydration)
  • Threatening spinal cord lesion (loss of muscle power and/or sensitivity, pain, incontinence, reduced coordination)

Paraneoplastic syndromes

Paraneoplastic syndromes are due to remote effects of malignant tumors. Such side effects are more frequently associated with lung cancer, especially small-cell type, than other cancers.

Some symptoms and findings:

  • Endocrine (hypercalcemia, Cushing's syndrome, Syndrome of inappropriate anti-diuretic hormone secretion (SIADH))
  • Neurological (Lambert-Eaton myasthenic syndrome (gradual weakness of lower extremities) encephalopathy, peripheral neuropathy)
  • Hematological (anemia, leukemoid reactions, thrombocytosis or thrombocytopenia)
  • Cutaneous (hyperkeratosis, dermatomyositis)
  • Other (nephrotic syndrome, anorexia, clubbing)

Differential diagnoses of lung cancer

The symptoms of lung cancer are often sparse and vague such that a series of differential diagnoses may be considered before the diagnosis of lung cancer is made.

An infiltrate on X-ray or CT, may be due to a variety of conditions.

The most common differential diagnoses are:

  • infections, including tuberculosis
  • sarcoidosis
  • fungal infections of the lung
  • abscesses
  • lung infarction
  • fibrosis
  • benign tumors (hamartomas)
  • metastases from other cancer types
  • other primary malignant diseases in the mediastinum, for example lymphoma or thymoma

The age of the patient and smoking status will provide a clue to whether lung cancer is the probable cause of an infiltrate on a lung X-ray. For patients under 30 years without a smoking history, this diagnosis is unlikely. In patients over 40 with a history of smoking, lung cancer is a possible diagnosis.

To approach a diagnosis more closely, the first step is to perform a thoracic CT scan. Comparison with earlier images will show whether the finding is new and provide an indication of tumor growth rate.

Massive calcification is unlikely in lung cancer, while common in hamartomas, tuberculomas, and fungal granulomas.

Invasion of neighboring organs, such as the chest wall, is close to pathognomonic of malignant growth. This is commonly observed in the top of the lung (Pancoast tumor).

Cavitation, large size, and multiplicity either intrathoracic or extrathoracic are other signs of malignancy.

Prognosis of lung cancer

In 2014, there were an estimated 527,228 people living with lung and bronchus cancer in the United States. The earlier lung and bronchus cancer is caught, the better chance a person has of surviving five years after being diagnosed. 15.7% are diagnosed at the local stage and the 5-year survival for localized lung and bronchus cancer is 55.2%.  Lung and bronchus cancer is the first leading cause of cancer death in the United States and the number of deaths is highest among people aged 65-74. Death rates have been falling on average 2.5% each year over 2005-2014 (33).

Five year survival is up to 65 % among operated patients with early discovery of non-small cell lung cancer, while long-term survival is 1% in those with metastasis.

Without surgical intervention, the prognosis is not significantly different for small cell and non-small cell lung carcinoma.

For small cell lung cancer, the long term survival in limited stage disease is 15 % and 0–1 % in extensive stage disease. (28)

 

 

Five-year relative survival for patients with lung cancer, in percent, during the diagnosis period 1974–2013.

Source: Cancer Registry of Norway

 

Prognostic factors

For the prognosis of lung cancer, prognostic factors and the stage of the cancer at the time of diagnosis are more significant than the kind of treatment given.

Poor prognostic factors

  • WHO/ECOG status ≥ 2
  • Greatest tumor diameter ≥ 9 cm
  • Weight loss > 5–10% in the last 3 months

Good prognostic factors

  • WHO/ECOG status < 2
  • Greatest tumor diameter < 9 cm
  • Weight loss < 5–10% in the last 3 months

WHO performance status

  • 0: Asymptomatic (Fully active, able to carry on all predisease activities without restriction.)
  • 1: Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. For example, light housework, office work)
  • 2: Symptomatic, <50% in bed during the day (Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking hours)
  • 3: Symptomatic, >50% in bed, but not bedbound (Capable of only limited self-care, confined to bed or chair 50% or more of waking hours)
  • 4: Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair)
  • 5: Death

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References on lung cancer

    Non-small cell lung carcinoma

  1. Gridelli, C., Langer, C., Maione, P., Rossi, A., Schild, S.E. 2007. Lung cancer in the elderly. J Clin Oncol 25:1898-1907.
  2. Vansteenkiste, J. 2006. Second-line therapeutic options in non-small-cell lung cancer. Lung Cancer 54 Suppl 2:S15-18. 
  3. Winton, T., Livingston, R., Johnson, D., Rigas, J., Johnston, M., Butts, C. et al. 2005. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352:2589-2597.
  4. Shepherd, F.A., Rodrigues Pereira, J., Ciuleanu, T., Tan, E.H., Hirsh, V., Thongprasert, S. et al. 2005. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123-132.
  5. Rusch, V.W., Giroux, D.J., Kraut, M.J., Crowley, J., Hazuka, M., Winton, T. et al. 2007. Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 25:313-318.
  6. Graham, M.V., Purdy, J.A., Emami, B., Harms, W., Bosch, W., Lockett, M.A., et al. 1999. Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 45:323-329.
  7. Giaccone, G. 2005. Epidermal growth factor receptor inhibitors in the treatment of non-small-cell lung cancer. J Clin Oncol 23:3235-3242.
  8. Lally, B.E., Zelterman, D., Colasanto, J.M., Haffty, B.G., Detterbeck, F.C., Wilson, L.D. 2006. Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database. J Clin Oncol 24:2998-3006.
  9. Sundstrøm S, Bremnes R, Aasebø U, Aamdal S, Hatlevoll R, Brunsvig P, Johannessen DC, Klepp O, Fayers PM, Kaasa S. Hypofractionated palliativ radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carsinoma is comparable to standard fractionation for symptom control and survival: a national phase III trail. J Clin Oncol. 2004 Mar 1; 22(5):801–10.
  10. Oxnard G., Binder A., Jänne PA. New targetable oncogenes in non-small-cell lung cancer. J Clin Oncol 2013:31:1097-104.
  11. Small-cell lung carcinoma

  12. Tiseo, M., Ardizzoni, A. 2007. Current status of second-line treatment and novel therapies for small cell lung cancer. J Thorac Oncol 2:764-772.
  13. Blackstock, A.W.,Govindan, R. 2007. Definitive chemoradiation for the treatment of locally advanced non small-cell lung cancer. J Clin Oncol 25:4146-4152.
  14. Turrisi, A.T., 3rd, Kim, K., Blum, R., Sause, W.T., Livingston, R.B., Komaki, R., et al 1999. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340:265-271.
  15. Auperin, A., Arriagada, R., Pignon, J.P., Le Pechoux, C., Gregor, A., Stephens, R.J., et al. 1999. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341:476-484.
  16. Slotman, B., Faivre-Finn, C., Kramer, G., Rankin, E., Snee, M., Hatton, M., et. al. 2007. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357:664-672.
  17. Evans, W.K., Shepherd, F.A., Feld, R., Osoba, D., Dang, P., Deboer, G. 1985. VP-16 and cisplatin as first-line therapy for small-cell lung cancer. J Clin Oncol 3:1471-1477.

    Smoking

  18. Helland A., Brustugun O.T. 2009. Lungekreft hos røykere og aldri-røykere. Tidsskr Nor Laegeforen. 129:1859-62. 
  19. Gandini S, Botteri E, Iodice S. Boniol M, Lowenfels A.B, Maisonneuve P, and Boyle, P. Tobacco smoking and cancer: A meta-analysis. Int J Cancer. 2008 Jan 1; 122(1):155–64.
  20. The 21st century hazards of smoking and benefits of stopping: a prospective study of one million women in the UK. Pirie K., Peto R. Reeves GK, Beral V: Million Women Study Collaborators. Lancet. 2013 Jan. 12: 281 (9861): 133-41.
  21. 21st-century hazards of smoking benefits of cessation in the United States. Jha P., Ramasundarahettige C., Landsman V., Rostron B., Thun M., Anderson R.N., McAfee T., Peto R.
  22.  Active and passive smoking in relation to lung cancer incidence in the Women's Health Initiative Observational Study prospective cohort. Wang A., Kubo J., Luo J.,  Desai M., Hedlin H., Henderson M., . Chlebowski R, Tindle H., Chen C., Gomez S., Manson JE., Schwartz A.G., Wactawski-Wende J., Cote M., Patel M.I., Stefanick M.L., Wakelee H.A. Ann Oncol. 2015 Jan:26 (1):221-30.
  23. Lung cancer in never-smokers: a review. Subramanian J., Govindan R.J Clin.Oncol. 2007 Feb 10:25 (5):561-70.

    Stage division

  24. New pathologic classification of lung cancer: relevance for clinical practice and clinical trials. Travis WD., Brambilla E., Riely GJ., J Clin Oncol. 2013 Mar 10:31 (8): 992-1001
  25. Goldstraw, P., Crowley, J., Chansky, K., Giroux, D.J., Groome, P.A., Rami-Porta, R., et al. 2007. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2:706-714.

    Prognosis

  26. Sagerup CM, Småstuen M, Johannesen TB, Helland A, Brustugun OT. Thorax. 2011 Apr;66(4):301-7.

    Diagnosis/screening

  27. National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, Gareen IF, Gatsonis C, Marcus PM, Sicks JD. 2011. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011 Aug 4;365(5):395-409.
  28. Humphrey LL, Deffebach M, Pappas M, Baumann C, Artis K, Mitchell JP, Zakher B, Fu R, Slatore CG. 2013. Screening for lung cancer with low-dose computed tomography: a systematic review to update the US Preventive services task force recommendation. Ann Intern Med. 2013 Sep 17;159(6):411-20
  29. Surgery

  30. Ginsberg, R.J., and Rubinstein, L.V. 1995. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 60:615-622; discussion 622-613.
  31. Expanding indications for stereotactic radiosurgery in the treatment of brain metastases. Friedman WA. Neurosurgery. 2013 Aug:60 Suppl 1:9-12.
  32. Various

  33. Cancer in Norway 2015, Cancer Registry of Norway, Institute of Population-based Research. Oslo, Norway.
  34. Nasjonalt handlingsprogram med retningslinjer for diagnostikk, behandling og oppfølging av lungekreft (2014), Helsedirektoratet (National guidelines for diagnostic, treatment and follow-up care of lung cancer, Norwegian Directorate of Health)
  35.  Years of life lost as a measure of cancer burden on a national level. Brustugun OT., Møller B., Helland A., Br. J. Cancer. 2014 Aug. 26:111 (5): 1014-20
  36. 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

Diagnostics of lung cancer

The strategy for diagnosing lung cancer depends on the size of the tumor, localization in the lung, whether there are obvious metastases and the patient's clinical condition at the time of the diagnosis. Stage determination of the tumor usually occurs in parallel because the most concise approach depends on the stage of the disease.  

Diagnostic work-up is based on few examinations with high diagnostic precision.

Medical history

The medical history should emphasize the patient's smoking habits/patterns and if there have been any work-related exposures for considering potential compensation claims.

The term "pack years" refers to 20 cigarettes in a packet and it is calculated by how many packets have been smoked. The formula is the number of daily cigarettes/20 x the number of smoking years. Forty cigarettes per day for 5 years is equivalent to 10 pack-years (40/20 x 5 years), while 10 a day for 40 years is equivalent to 20 pack-years.

The performance level (WHO) should always be noted as well as any weight change.

Clinical examinations

The clinical examinations should be focused on:

  • heart
  • lungs
  • abdomen
  • lymph nodes on the neck, supraclavicular, axillar, and inguinal

EKG and spirometry are performed. If necessary, an extended physiological respiration work-up is performed including diffusion capacity (DLCO), walking test, and cycling test.

Laboratory testing

Blood tests are rarely of diagnostic value, but may be useful in diagnosing paraneoplastic phenomena which occur in about 10% of patients.

Imaging

  • CT scan of thorax and upper abdomen
  • PET-CT
  • MRI

MRI or CT scan of the head should be carried out when there are abnormal symptoms or sign from the nervous system. PET-CT should be performed in all cases considered for curative treatment.

Invasive examinations

Bronchoscopy with biopsy

If there is suspicion of a centrally located tumor on a CT or clinical sign of lung cancer, bronchoscopy is decisive for verification of the cancer diagnosis. The diagnosis can be made either by biopsy, or by cytological examination of fine needle aspirate or brush specimens.

Although bronchoscopy is primarily a diagnostic test for lung cancer, the examination may also provide information of disease (T and N classification).

Esophageal and endobronchial ultrasound

Esophageal (EUS) and endobronchial (EBUS) ultrasound are performed when there are enlarged lymph nodes and/or tumors in the mediastinum causing suspicion of infiltration of malignant cells. This examination method has to some extent replaced mediastinoscopy.

Transthoracic percutaneous needle biopsy and fine-needle aspiration

A percutaneous needle biopsy and fine-needle aspiration cytology (FNAC) can be carried out by means of fluoroscopy or guided by CT or by ultrasound if the tumor is close to the pleura.

Mediastinoscopy / anterior mediastinotomy 

For the histological diagnosis of enlarged nodes in the mediastinum shown by CT, which are not available by EUS or EBUS, a mediastinoscopy should be performed. The procedure can also be performed even if the enlarged lymph nodes themselves are not available for mediastinoscopy, because tumor infiltration can be found in normal-size glands of these patients.

If enlarged lymph nodes are localized at level 5 (subaortal) and 8 (phrenic), a left anterior mediastinotomy may be performed.

Thoracoscopy

Detection of malignant cells in pleural fluid is of diagnostic value for M1a tumors. In patients with suspicion of lung cancer and pleural exudate, evacuation of the fluid should occur for cytological diagnosis.

Thoracoscopy with biopsy can also be carried out if there is suspicion of malignancy in a patient who has a solitary nodule and stage I illness based on CT scan of the chest.

(26)

PROSEDYRER

Endobronchial ultrasound bronchoscopy with needle biopsy

General

The location of the tumor or lymph nodes in the mediastinum determines whether an endoscopic ultrasound-guided fine-needle aspiration from the esophagus (EUS), or bronchus (EBUS-TBNA) is performed. EBUS of mediastinal lymph nodes is a minimally invasive procedure which allows the patient to avoid riskier procedures.

Indications

  • Enlarged lymph nodes and/or tumor in the mediastinum
  • To stage lung cancer or to confirm or disprove spread to the lymph nodes of the mediastinum
  • To confirm or disprove suspicion of lung cancer or spread of other cancer in the mediastinum and to confirm the histological type

Goal

  • Make a diagnosis
  • Staging

Equipment

  • Endoscope with accessories
  • Puncture biopsy needle
  • Equipment for preparation of cytological specimen

Preparation

  • The procedure is usually carried out under general anesthesia. In some cases, the procedure is performed with local anesthesia only. 
  • The patient should fast 8 hours before the procedure.

Implementation

  • The bronchoscope is inserted into the airways via an endotracheal tube.
  • The appropriate lymph nodes are visualized by ultrasound.
  • The aspiration needle is inserted through the work channel in the bronchoscope and guided by ultrasound, into the lymph node. 
  • Using back and forth motions with the needle, cells are aspirated from the lymph node.
  • The material is prepared and assessed by a cytologist.
  • The procedure can be repeated until representative material is obtained.

Follow-up

  • The patient may return home the same day.
  • The result from the needle biopsy is usually available after 2-3 days.

Transthoracic percutaneous fine-needle aspiration

General

CT-guided transthoracic fine-needle aspiration cytology (FNAC) or biopsy is carried out when it is difficult to obtain representative material using bronchoscopy. This applies especially if the lesion is situated peripherally in the lung. 

The technique has high diagnostic precision, with a sensitivity and specificity over 90% for identifying malignancy. In patients who are not suitable for surgery and who have a peripheral tumor, this technique may be crucial for making a correct diagnosis. 

If the lesion is in contact with the pleura or thoracic wall, the procedure can often be carried out using ultrasound guidance.

Indication

  • Tumor-suspect lung lesion

Goal

  • Obtain representative material from the lesion to make a cytological or histological diagnosis

Equipment

  • Introducer needle
  • Needle for aspiration
  • Biopsy pistol adjusted for the introducer

Preparation

The patient must have sufficient heart/lung capacity to be able to tolerate a complication such as a pneumothorax or bleeding. The patient must be able to cooperate and hold their breath for at least 10 seconds and without coughing.

If recent CT images are not available, or previous images are not of sufficient quality, a new series are taken before the procedure is performed, usually with intravenous contrast fluid. 

A point for puncture is planned based on the CT images. Images acquisition is done while the patient holds their breath after a "normal" exhalation. If this is not possible, the patient should hold their breath during the inhalation. Based on the measurements from the CT images, the puncture point is marked on the patient's chest. 

  • The patient lies in a position suitable for insertion of the needle.
  • The procedure is carried out using local anesthesia.
  • The area is washed and covered with a sterile surgical drape.

Implementation

  • The anesthesia needle is inserted gradually as the local anesthetic is injected.
  • The position and direction are checked at regular intervals with CT.
  • When the anesthesia needle is by the pleura, the rest of the anesthetic is injected. It is important not to puncture the pleura with the anesthetic needle.
  • The needle is retrieved.
  • An introducer needle with stiletto is inserted through the pleura and into the lesion. The needle should be inserted through the pleura only once.
  • An aspiration needle is placed in the introducer which is connected to the aspiration syringe with an adapter.  
  • The patient should hold their breath during sampling.
  • The material is aspirated from the lesion and is smeared onto a microscope slide and stained. It may be necessary to take samples for microbiological testing and culturing and possibly multiple pistol biopsies with small deviations in the angle of the needle.

A small pneumothorax is relatively common (40%). Most occur during the examination and will disappear without treatment. Occasionally, a chest tube is needed.

Follow-up

Serious complications are very rare.

  • An X-ray of the thorax is taken 2 hours after the procedure.
  • A small amount of bleeding around the puncture canal is common. This is usually minor and stops quickly.
  • The patient may have some bloody expectorate.
  • If there are no complications and the patient does not have serious comorbidities, he/she may return home the same day.
  • The results from the test are usually available after 2 days.

Positron Emission Tomography (PET)

General

Positron Emission Tomography (PET) is a nuclear medical examination method. PET is a well-documented, well-established and very useful tool in oncological imaging.

Indications

Oncological imaging for:

  • Staging the primary diagnosis and recurrence
  • Evaluating the effect of aggressive chemotherapy treatment
  • Evaluating the effect of completed treatment, including differentiating scar tissue from viable residue tissue
  • Suspicion of recurrence (for example, increased level of tumor marker in the blood)

Goal

  • To provide concrete diagnostic information that will provide a basis for the choice of the best possible treatment.

Definitions

PET has a very high sensitivity and can register absorption of radiopharmaceutical agents in extremely low concentrations. Since the central atoms in biochemical compounds (carbon, oxygen, nitrogen) all have positron-emitting isotopes that can be produced in small hospital cyclotrons, it is possible to mark a number of central molecules such as oxygen, water, amino acids, various metabolites, hormones, and neurotransmitters.

For clinical PET, dextrose is usually used where a hydroxide group is replaced by 18F (18-flourine), a compound that is called 18F-FDG (flourine-18 labeled deoxyglucose). 18F-FDG has a high affinity for cells with increased metabolism, for example cancer cells. The substance is transported into the cells and phosphorylates glucose to 18F-FDG-phosphate, but no further break-down occurs. Because cell membranes are impermeable to phosphorylated deoxyglucose, an intracellular accumulation of the substance occurs.

Limitations

  • Small tumors ( < 0,5 cm) and tumors with low to moderate absorption can escape detection.
  • Inflammatory conditions will produce increased absorption.
  • For patients with diabetes (especially those requiring insulin) and non-fasting patients, high muscular absorption will reduce the sensitivity for tumor detection.
  • Some tumor types have low FDG absorption (for example, prostate and bronchoalveolar carcinoma).

Sources of error

  • Infections and inflammatory conditions (including post-operative changes) will result in increased absorption.
  • Normally, the intestine can have a high absorption.
  • Myocardium often displays high absorption, also in fasting patients.
  • 18 F-FDG is excreted through the kidneys and FDG in the urinary tract can be misinterpreted.
  •  Absorption in brown fat tissue can be misinterpreted as a tumor if PET is not compared with CT. PET/CT combined in the same apparatus gives better specificity than PET alone.

Equipment

  • PET/CT-scanner  
  • Radio-pharmaceutical agent: 18F-FDG is formed by radiating a heavier natural variant of oxygen with protons. This occurs in a cyclotron. Fluorine-18 (18F) is produced at the hospital cyclotron located at Rikshospitalet .

Preparation

Patient preparation depends on the clinical diagnosis.

  • Fast for at least 6 hours before the examination in order to increase the absorption of 18F-FDG. But the patient should drink plenty (2-4 glasses per hour. Water, tea, or coffee without sugar or cream/milk added can be substituted for water.
  • Measurement of s-glucose is performed before injection of 18F-FDG.
  • After intravenous injection of 18F-FDG, it is very important that the patient lies relaxed in a quiet room without talking and avoiding all forms of stimuli, in order to avoid non-specific absorption of 18F-FDG in the muscles.
  • Tranquilizers and painkillers are often administered prior to the injection.
  • The patient should be warm and comfortable prior to the injection in order to prevent absorption in the brown fat, which may affect the interpretation.

There will be other precautions for neurological and cardiological diagnoses.

Implementation

  • The patient must lie completely still while the images are being taken.
  • A whole-body examination takes approximately 25 minutes.
  • For PET, tissue absorption is displayed by positron-emitting, radiopharmaceutical preparations.

Registration of emission

  • The positron is considered a positively charged electron.
  • When the positron leaves the radioactive core, it will travel up to a few millimeters before it collides and fuses with an electron and is transformed into energy; this is called annihilation.
  • The mass of the positron and the electron is transformed into energy in the form of two photons, each of 511 keV, which are emitted in diametrically opposing directions (180°).
  • A ring detector around the patient will catch the photons.
  • The two photons will encounter the ring detector at the same time (coincident detection), and because they have moved in exactly opposite directions, the detection will precisely localize the radiation focus (for example, a lymph node with tumor tissue).
  • A modern PET-camera with ring detector can map the entire body in 20 minutes.
  • The PET-scanners have integrated CT, so that the information from PET is accurately localized anatomically.

Examples of findings

  • Anal cancer: Anal tumor and metastasis in lymph node
  • Hodgkin's lymphoma (HL): HL with involvement of: soft tissue in the larynx , vertebra L4 ,  os pubis L  and femur
  • Cancer of the rectum: Adenocarsinom in rektosigmoideum liver metastases
  • Intracranial tumors: Astrocytoma grade II/III, left parietal lobe  high-grade glioblastoma, right frontal lobe 
  • Lung cancer: Lung tumor  lung cancer with lymph node spread
  • Sarcoma: Soft tissue sarcoma in the left thorax
  • Cancer in the esophagus: Tumor in the distal esophagus
  • Colon cancer: Metastasis-suspect lesion in adrenal gland

Follow-Up

  • At the end of the examination, the radioactivity is small, but the patient should keep a distance (about 3 meters) from children and pregnant ladies the day of the scan.
  • The result will normally be available the following day.
Postitron emission (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDG
Postitron emission (PET) with <sup>18</sup>F-FDGPositron emissions tomografi (PET) with <sup>18</sup>F-FDGPositron emission tomography (PET) with <sup>18</sup>F-FDGPositron emission tomography (PET) <sup>18</sup>F-FDG
Positron emission tomography (PET) with <sup>18</sup>F-FDGPositron emission tomography (PET) <sup>18</sup>F-FDGPositron emission tomography (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDG
Postitron emission (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDG
Positron emmissions tomography (PET) with<sup>18</sup>F-FDGPositron emission tomography (PET) with <sup>18</sup>F-FDGPositron emission tomografi (PET) with <sup>18</sup>F-FDG

Endoscopic Ultrasound with Aspiration

General

The location of the tumor or lymph node in the mediastinum determines whether an endoscopic ultrasound-guided fine needle aspiration (EUS) from the esophagus or endobronchial ultrasound (EBUS) should be performed.

EUS with aspiration of lymph nodes in the mediastinum is a minimally invasive examination whereby patients can avoid examinations associated with more risk. With EUS, the mediastinal lymph nodes can be sampled at most levels of the mediastinum. 

Indication

  • Enlarged lymph nodes and/or tumor in the mediastinum raising suspicion of a serious lung disease, cancer in the esophagus or stomach. 

Goal

  • Establish a diagnosis 
  • Stage determination

Equipment

  • Endoscope with accessories
  • Needle for puncture
  • Equipment for preparation of cytology specimen

Preparation

  • The patient lies on his/her side and is mildly sedated.
  • Application of local anesthesia in the throat.  

Implementation

  • The scope is inserted into the esophagus via a mouthpiece. 
  • The lymph nodes are visualized using ultrasound.
  • The aspiration needle is inserted through the work channel of the scope and by ultrasound guidance, into the lymph node.
  • Using back-and-forth movements with the needle, cells are sucked out of the lymph node.
  • The material is prepared and assessed by a cytologist.
  • The procedure can be repeated until representative material is obtained.

Follow-up

  • The patient can return home the same day.
  • It may take up to one week before the results are available.

Treatment of lung cancer

Treatment for lung cancer includes surgery, radiation, or chemotherapy, either alone or in different combinations.The treatment form is determined by the stage of the disease, tissue type (small or non-small cell) and the general health status of the patient (performance status) or any other comorbid conditions.

Non-small cell lung cancer

Stage I/II

The patient is offered surgery if he/she is technically and medically operable. Co-existing heart or lung disease often excludes the patient from surgery. Postoperative chemotherapy is offered in stage II-situations in fit patients under 70 years. When potential risk of residual cancer tissue, postoperative radiation treatment is recommended. In patients who are medically inoperable, curative radiation treatment is considered. Curative radiation treatment is given either as 30 fractions or more over a time period of 6–7 weeks, or as stereotactic radiation with 3-8 fractions over a period of 1-2 weeks.

Stage III

For locally advanced lung cancer, (stage III) an operation is often not possible due to surgically inaccessible mediastinal lymph node metastasis. If there are positive prognostic factors, curative radiation treatment is the first choice of treatment possibly in combination with chemotherapy. In special cases, treatment with chemotherapy and radiation may render the tumor operable. If there are poor prognostic factors, the patient is offered palliative radiation or chemotherapy.

Stage IV

If the disease has metastasized, the patient will be offered palliative treatment with radiation or chemotherapy. Occasionally, it is best to not give active tumor-directed treatment.

Small cell lung cancer

Limited disease (SCLC-LD)

When the cancer is confined to one hemithorax, the disease is treated with curative intent with chemotherapy combined with radiation. For small peripheral tumors, surgery is considered, followed by chemotherapy. Brain metastasis from small cell lung cancer occur frequently and can be prevented by administering radiation treatment to the brain.

Extensive disease (SCLC-ED)

Treatment for extensive cancer is palliative and usually consists of chemotherapy. Even in extensive disease, prophylactic brain irradiation should be offered if response of initial chemotherapy is achieved. Symptom-causing metastasis can be treated with radiation therapy. Manifest brain metastases from small cell lung cancer will often respond to chemotherapy. This is in contrast to non-small cell lung cancer, where brain metastases are treated with radiation.

Emergency help for acute conditions

The most common acute conditions requiring oncology treatment are:

  • compression of airways
  • superior vena cava syndrome (compression of central venous blood vessels)
  • spinal cord compression syndrome (tumors which can damage the spinal cord)

Treatment should be expedient with high-dose steroids (methyl prednisolone or dexamethasone) and the patient is transferred to a department of radiation therapy to start tumor-reductive treatment within 24 hours of the start of symptoms. For previously untreated intrathoracic disease with small-cell histology chemotherapy should be started without unnecessary delay, whereas in non-small cell carcinomas radiation therapy is therapy of choice.

Symptom-directed treatment

Patients with lung cancer will often have symptoms from the airways, either caused by the tumor, infections, or underlying lung disease. These problems will often become more prominent towards the end of the patient's life. 

Primary cachexia is often present in lung cancer due to metabolic changes from the tumor disease. In all phases of the disease, it is important to stimulate nutrition.  

As treatment of pain, a combination of analgesics with radiation and chemotherapy is optimal. Invasive analgesic methods are also available. Satisfactory pain relief is almost always achievable.

Nausea and vomiting are common symptoms both due to advanced tumors or tumor-directed treatment, but can today be treated with modern antiemetics. 

Dyspnea

Difficulty in breathing is a frequent symptom in all phases of lung cancer and may be caused and exacerbated by a series of conditions:

  • tumor involvement of airways
  • chronic obstructive pulmonary disease
  • infections
  • pleural fluid
  • lung embolism
  • anemia
  • lung fibrosis after radiation therapy
  • anxiety

Treatment may consist of:

Surgery of lung cancer

Surgical treatment is capable of curing lung cancer. For stage IA cancer, more than 60% of the patients are alive 5 years after the operation.   

In Norway, about 20% of all patients with lung cancer are operated. There are reasons to believe that 25% should be offered surgery.

Before operating for lung cancer, sufficient diagnostic clarification is necessary to survey the extent of the disease and the general health of the patient.

This mainly includes:

  • CT imaging
  • Bronchoscopy with biopsy
  • Lung function test
  • Assessment of other possible diseases/risk factors 
  • PET-CT

Planning treatment 

Patients with lung cancer who may be candidates for surgery should be discussed at a multidisciplinary meeting, where an anesthesiologist, oncologist, lung specialist, radiologist, and thoracic surgeon are present. The possibility for surgery or other treatment is assessed.

Operative methods

In Norway, most lung cancer patients are operated by open thoracotomy. An increasing number of patients are operated by thoracoscopy (minimally invasive method).

(28,29)

PROSEDYRER

Lobectomy

General

Commonly, at least one lobe is surgically removed. In patients with reduced lung function, a more limited resection is carried out (wedge or segment resection). If the tumor includes more than one lobe, or is situated centrally, a bilobectomy or pneumonectomy may be necessary.

A pneumonectomy is a greater burden to the patient than a (bi)lobectomy and is therefore avoided unless it is the only way to remove all cancer tissue.

Indication

  • Lung cancer

Contraindications

  • Metastatic disease
  • Spreading to mediastinal lymph nodes
  • Invasion toward the heart and other central structures
  • Severe reduced lung function
  • Other risk factors/diseases

Goal

  • Complete removal of cancer tissue

Equipment

  • Thoracic tray with a large and small self retaining retractor
  • Equipment for stapling lung tissue, vessels, and bronchi
  • Possibly tissue glue or tissue tape to close air leakages from the lung surface after the operation

Preparation

Information should be given by the surgeon about the nature and risks of the operation. It is recommended that the patient's closest relative is present during the preoperative information meeting.

  • The procedure is carried out under general anesthesia and with selective ventilation of the two lungs. This is to stop ventilation of the operated lung so it can be collapsed to lie still. Good surgical access is essential.
  • Most patients will have an epidural catheter before the operation for postoperative pain relief.
  • The patient lies on his/her side.

Implementation

Thoracotomy

The most common surgical entrance to the pleural cavities is through a lateral thoracotomy. An anterolateral incision is the most common surgical entrance, because it minimizes division of muscle tissue.

  • The skin over the area is incised and the soft tissue is split or mobilized.

The entrance to the pleural cavity is usually through 5-7 intercostal spaces depending on the location of the tumor.  

  • The ribs are retracted after the intercostal muscles are split. This gives good access to the pleural cavity and the lung. 
  • The pulmonary ligament is divided up to the lower pulmonary vein, whether a (bi)lobectomy or pneumonectomy is performed.
  • The pleura is opened around the entire lung hilum.
  • The lung lobes are examined to assess how well-defined the lobes are and where they can be separated from each other.

Lobectomy/bilobectomy

Only one lobe is usually removed when the tumor is confined to single lobe. In some cases, the anatomy and/or pathology are such that two lobes must be removed.

  • After the pulmonary ligament is split and the hilum is opened, the lobe fissure is cut to isolate the involved lobe from the rest of the lung tissue.
  • The pulmonary artery (with oxygen-poor blood) and pulmonary veins (with oxygen-rich blood) of the involved lobe are clamped and divided.
  • The bronchus to the involved lobe is dissected and the remaining end is closed.

Pneumonectomy

The incision is the same as for a lobectomy. A pneumonectomy is often more simple and expedient than a lobectomy. 

  • Veins, arteries, and the bronchus are dissected and cut centrally. There are fewer small branches to be divided and it is often unnecessary to open lobe fissures.
  • After the lung/lobe is removed, the operation field is always checked for air leakage and bleeding. 
  • Lymph nodes and lymph node-containing tissue should be resected after the lung is removed.
  • All tissue that is removed is sent to pathology for assessment.

Drain/closure of thoracotomy

After a (bi)lobectomy, two drains are routinely installed. One is placed basally to collect fluid and the other is placed over the top of the lungs to drain air.

  • The drains are connected to active suction equivalent to a column of water of 10–20 cm.
  • After a pneumonectomy, only one drain is installed which should not have active suction.
  • The ribs which are separated are pulled together with thick, absorbable sutures.
  • The muscles as well as the subcutis are adapted with absorbable sutures. Finally, the skin is sutured.

Follow-up

The patient is monitored at the postoperative unit for the first 24 hours. An X-ray check is performed. Heart rhythm and blood gases are monitored. 

  • The drain is usually removed 2-4 days after the operation.
  • The patient may return home after 4-7 days.

The patient is followed-up locally by a lung specialist or general practitioner. When additional treatment with chemotherapy or radiation therapy is needed the patient will be followed up by an oncologist.

Lobectomy

Drug therapy of lung cancer

Drug therapy today is an essential modality for treating both small cell and non-small cell lung cancer.

  • Small cell lung cancer is more sensitive to chemotherapy than non-small cell. Chemotherapy is often the first choice of treatment either combined with radiation therapy (localized cancer) or alone (extensive cancer). 
  • For non-small lung cancer, chemotherapy alone is the treatment of choice when the cancer has metastasized. In stage II and III, adjuvant chemotherapy may be offered after surgery, or given in combination with radiation therapy.

For both small cell and non-small cell lung cancer, platinum-based combination regimens are the primary chemotherapy choices.

  • For small-cell, etoposide is often given in combination with cisplatin, for both localized and extensive cancer.
  • For non-small cell, adjuvant cisplatin and vinorelbine are given together after surgery. Platinum-based chemotherapy is also the first choice in combination with curatively intended radiation therapy, or for extensive cancer in patients without an EGFR mutation.

For metastatic non-small cell lung cancer, a series of palliative regimens are appropriate and in terms of effectiveness, equal. The side effect profile is usually the only differentiating factor, and in Norway, the combination carboplatin/vinorelbin is usually the first choice. For progression after first-line treatment of non-small cell, monotherapy with docetaxel or pemetrexed for non-squamous cell carcinoma can be tried.

Erlotinib, gefitinib or afatinib are now approved as first-line treatment for metastatic disease in EGFR-mutation positive patients. Other molecular targeting substances are in trial phases and patients should be offered inclusion in these studies.

When translocation of the ALK gene is confirmed, ALK inhibitors are appropriate treatment with progression after first-line standard chemotherapy. Crizotinib is approved in this situation. Clinical studies involving ALK-inhibitors are ongoing. Patients can be considered for inclusion in these trials.

PROSEDYRER

Drug therapy for non-small cell lung cancer

General

Chemotherapy for non-small cell lung cancer is used as adjuvant treatment after curative surgery and in combination with radical radiation therapy. It will also often be relevant in palliative situations.

Adjuvant chemotherapy

Adjuvant chemotherapy has been shown to increase survival after surgery for patients with stage II and stage III cancer, but this effect is not seen for patients in stage IA. Benefit may be seen in stage IB cancers more than 4 cms in maximal dimension. Five year survival increases by 5-15% in absolute figures. Chemotherapy can be given in combination with curative radiation therapy (concomitantly). Neoadjuvant chemotherapy is usually not given for non-small cell lung cancer, except in some cases of Pancoast syndrome (apical lung tumors invading the thoracic wall).

Palliative chemotherapy

At the time of diagnosis, 70% of patients with non-small lung cancer are in a palliative stage. In patients of this group, platinum-based chemotherapy may relieve symptoms or delay the appearance of such, and thereby improve quality of life. Furthermore, palliative chemotherapy prolongs survival for some months. A prerequisite is that the patient is in good general health, i.e. performance status (PS) 0-2. Response to palliative conventional chemotherapy is expected in about 3 of 10 patients in first-line situations and in 1 of 10 by second-line treatment. At present it is not possible to predict whether a patient will benefit from chemotherapy.

Patients with activating mutations in the gene that codes for epidermal growth factor receptor (EGFR), about 10% of all, should be offered peroral treatment with tyrosin kinase inhibitors, such as erlotinib, gefitinibor or afatinib. Such therapy has shown significantly better efficacy than conventional chemotherapy. The response rate are approximately 70% in patients positive for this mutation. Time to disease progression is on average about one year.

About 5% of the patients with non-small cell lung cancer have changes in the ALK gene.
The ALK inhibitors have shown effectiveness in these patients similar to patients treated with EGFR inhibitors mentioned above. Crizotinib is an oral ALK inhibitor and approved as second line treatment in ALK-positive patients.

EGFR-mutation status should also be analyzed in conjunction with histopathological diagnostics whenever a NSCLC of non-squamous cell carcinoma subtype.

Predictive factors

The most important predictive factor for chemotherapy effect, except for the TNM stage, is performance status. The risk of serious side effects increases in patients with a performance status of 3 or 4. In these cases, chemotherapy is not recommended. Norwegian data indicates that performance status 2 has the greatest benefit from treatment in terms of improved quality of life, since symptom relief exceeds side effects to a greater degree than in those with better general health condition. Tyrosin protein kinase inhibitors have a different side effect-profile than conventional chemotherapeutics, and can be tried out in mutation-positive patients with performance status 3.

Chemotherapy in elderly patients with non-small cell lung cancer

Over half of patients with non-small cell lung cancer are older than 65. However, elderly patients are underrepresented in clinical studies and the evidence for chemotherapy in this group is therefore limited. Functional level, comorbidity with polypharmacy, socioeconomic and cognitive factors, as well as nutritional status, can vary significantly among this heterogeneous patient group. The decision to administer chemotherapy should be based on a total geriatric assessment of these factors. Patients in good general health status (PS 0-2) with normal organ function may benefit from platinum-based doublet chemotherapy. Elderly patients of a reduced general health condition are offered monotherapy with a newer drug such as vinorelbine, gemcitabine, pemetrexed (only non-squamous carcinoma), docetaxel or, in mutation-positive patients, tyrosine kinase inhibitors.

Indications

  • Postoperative chemotherapy – patients in stage II and III who have been operated. 
  • Chemotherapy in combination with curative radiation treatment - patients in stages IIIa and IIIb who can receive curative radiation treatment.
  • Palliative chemotherapy – patients with stage IV.

Goal

  • For postoperative chemotherapy and chemotherapy given in combination with curative radiation therapy, the goal is to increase the probability of curing the disease.  
  • Relieve symptoms and ailment, and prolong life, in palliative treatment.

Treatment Plan

The treatment plan for patients with non-small cell lung cancer is available via the interactive flow chart. This is a function which provides overview of treatments for the patient groups.

Click to open the flow chart

Choice of medication

The available documentation for adjuvant chemotherapy applies to a platinum-based doublet. Cisplatin combined with vinorelbine is recommended for 4 cycles. 

For non-mutated metastatic cancer, there is convincing documentation that first-line treatment should be platinum-based chemotherapy (either cisplatin or carboplatin) combined with a newer drug such as vinorelbine, gemcitabine, docetaxel, paclitaxel or pemetrexed. None of the regimens seems superior, but in Norway the combination carboplatin and vinorelbin is used most frequently. Non-platinum-based regimens should not be used outside of studies in first-line treatment. Gefitinib, erlotinib or afatinib is used in first-line treatment in EGFR-mutation positive patients. Patients should be asked whether they would like to participate in a clinical study prior to starting treatment. There is documentation that patients participating in studies benefit in terms of survival.

Recurrence/second-line treatment

Patients to be treated for recurrence will often be asked to participate in studies.

If the patient has previously only received radiation, the first choice treatment is a platinum-based doublet or inclusion in studies as mentioned above.

Possible treatments in second-line include monotherapy with docetaxel or pemetrexed (in non-squamous cell carcinomas). Unfortunately, the response rates for second-line conventional chemotherapy are low, at about 10%. If previously responsive or after three months from concluded first-line treatment, the same drug combination could be repeated.

Afatinib, erlotinib or gefitinib is treatment of choice in EGFR-positive patients, if EGFR-inhibitor was not used in the first-line treatment. Crizotinib should be offered to ALK-positive patients. These peroral inhibitors, may also be suitable as a third-line medication with performance status up to PS 3, if not given previously. Otherwise, for PS 3-4, good supportive care without tumor-directed treatment is often the optimal treatment.

Preparation

The patient is thoroughly oriented, verbally and in writing, about the goal of the treatment, how it will be carried out, what side effects can be expected, and what is expected from the patient during the treatment period. 

For treatment of lung cancer with chemotherapy, neutropenia is the most common cause of dose reduction. Blood tests must therefore always be performed before starting a new course of treatment. 

For cisplatin-containing chemotherapy regimens, kidney function must also be monitored. 

The patient will be offered a customized wig.

Implementation

Adjuvant chemotherapy

  • Postoperatively, 4 courses of cisplatin and vinorelbine are administered intravenously.  
  • For chemotherapy in combination with radiation therapy for stage III, two courses of cisplatin and etoposide (PV) are usually given concominantly with radiation.  
  • Preoperatively in Pancoast syndrome 2 courses of a cisplatin-based combination at three week intervals, combined with radiation therapy, 2 Gy x 25 can be administered.

Palliative chemotherapy

Three-four courses with three week intervals are given. Carboplatin/vinorelbine is administered with carboplatin day 1, and vinorelbine day 1 and 8, with new treatment course starting on day 22.  

Follow-up

The treatment effect is most often evaluated at 2-3 month intervals. The first follow-up should take place 4-8 weeks after treatment is concluded.

Evaluation often includes pulmonary X-ray or CT.

 

Some side effects of chemotherapy for non-small cell lung cancer (1)

(Frequent> 1/100, rare < 1/1000)

Side Effect      Cisplatin Carboplatin Vinorelbine Docetaxel  Gemcitabine  Premed-
trexed
Erlotinib
Bone marrow depression Frequent Frequent Frequent Frequent Frequent Frequent Not reported
Nausea/Vomiting Highly
emetic
Moderately
emetic

Mildly
emetic

Mildly
emetic
Mildly
emetic

Mildly emetic

Moderately
emetic
Hair loss Rare Frequent Frequent Frequent Frequent Frequent Frequent
Diarrhea/
Constipation
Diarrhea/
frequent
Frequent

Frequent

Frequent Frequent Rare Diarrrhea/
frequent
Mucositis/
Stomatitis
Not reported Not reported

Stomatitis/
frequent

Stomatitis Stomatitis Frequent

Stomatitis/
frequent

Allergic reactions Rare Frequent Rare Frequent Rare Rare Not reported

Cardiotoxicity

Rare Frequent Not reported Frequent Rare Rare Not reported
Neurological symptoms Frequent Frequent Frequent Frequent Rare Rare Not reported
Skin/nails Rare Frequent Rare Frequent Frequent Frequent Frequent
Liver Frequent Frequent Frequent/
mild
Frequent Frequent Rare Frequent
Airways Not reported Not reported Not reported Rare Frequent Not reported Rare

Ototoxic side effects are experienced in about 30% of patients receiving cisplatin.

 

Reference

  1. Felleskatalogen [online] [retrieved 14.09.2007]; Available at: URL: http://www.felleskatalogen.no
Flowchart - non-small cell lung cancer

Chemotherapy for small cell lung cancer

General

Chemotherapy is used in combination with radiation treatment for limited disease small cell lung cancer (SCLC-LD), and alone for extensive disease small cell lung cancer (SCLC-ED). Response is expected in about 90% and 50% of the patients, respectively. Ten to 15% of patients with localized cancer and 1-2% of patients with extensive cancer will live for more than 5 years.

In patients with T1-2N0-1 disease, surgical treatment may be appropriate. It is assumed that up to 10% of patients with localized cancer may be candidates for a successful resection. Postoperative chemotherapy is required since small cell lung cancer are at high-risk to metastasize, also in early stage.

First choice chemotherapy for localized cancer, and in younger patients (< 75 years) with extensive cancer, is platinum and etoposide. Cistplatin seems superior to carboplatin combined with radiation treatment. In extensive disease, carboplatin might be chosen due to less toxicity and ease of administration.  

Recurrence treatment

About 80% of patients with limited cancer and virtually all with extensive cancer will have recurrence of the disease. A few phase II-studies have been presented in the second line setting of SCLC. Topoisomerase inhibitors (irinotecan/topotecan) and the triple-combination with cyclophosphamide, vincristin and doxorubicin has shown activity and might be used. The expected treatment benefit must be weighed against the patient's general health status and expected survival time. For relapse three months or more after ended first line treatment, it may be appropriate to try the same regimen again. For early recurrence, another chemotherapy regimen should be considered. Radiation therapy will often provide successful symptom relief and may be considered instead of chemotherapy.

Chemotherapy for reduced general health condition and elderly patients with small cell lung cancer

Even patients with reduced general health status due to localized cancer, can achieve significant benefit from treatment. The goal is curative also for these patients. If the reduced status of the patient is due to another illness, the treatment chosen should have few side effects.

For extensive cancer, the threshold for treatment should be higher, especially in older patients or patients with reduce general health status. It should be considered whether active treatment should be given at all.  

Indication

  • Small cell lung cancer

Goal

  • For localized cancer, the treatment is intended to cure the disease.
  • For extensive cancer, the treatment is primarily palliative. 

Treatment Plan

The treatment plan for patients with small cell lung cancer is available in an interactive flow chart. This is a feature to provide an overview of treatment for the different patient groups.

Click here to open the flow chart

Small cell cancer – Limited disease

Many chemotherapy drugs have been tried for small cell lung cancer, but platinum-based regimens have proven to be more effective than other regimens such as anthracycline combinations. In Norway, as in most other countries, a combination of cisplatin and etoposide (PV regimen) is most commonly used. Carboplatin can be used instead of cisplatin (CV regimen), but has somewhat less documentation. The latter is easier to manage because the patient does not require hydration during the treatment. Treatment beyond 6 courses has not been shown to be of any benefit.

Chemotherapy in combination with radiation for limited disease

For localized cancer, a combination treatment with PV-regimen and radiation therapy has shown a synergistic effect and prolongs survival compared to chemotherapy or radiation alone. Only platinum-based regimens have this documentation. Four courses of chemotherapy are usually administered with radiation starting after 2 or 3 chemotherapy cycles (alternating with radiation therapy). Concomitant treatment (simultaneous treatment) has the greatest effect but also the most side effects such as esophagitis and hematological toxicity. For patients in reduced general health status, it is therefore advantageous to start the next course of chemotherapy after the radiation treatment is completed. For a more agressive treatment, chemotherapy is administered every 3 weeks regardless of ongoing radiation treatment.

Small cell cancer – Extensive disease

For extensive cancer, treatment is palliative and is usually not combined with radiation treatment. Platinum-based treatments are also first choice treatment due to the greater effect than anthracycline-based treatments and can be expected to give an objective response in 50-80% of patients. The median survival time increases from 2 to 10 months, and symptom control and life quality improves. Unfortunately, complete remissions are rare and the response duration is short.

PV courses are appropriate as for limited disease, but CV courses are considered equally effective and are often chosen due to fewer side effects.  

For ages over 75 years or reduced general health status, ACO treatments are a good choice due to sparse side effects.

Preparation

The patient is thoroughly informed verbally and in writing about the goal of the treatment, how it will be carried out, what side effects can be expected, and what is expected of the patient during the treatment period. 

During treatment of lung cancer with chemotherapy, neutropenia is the most common cause of dose reduction. Blood tests must therefore always be performed before starting a new course of treatment. 

For cisplatin-containing chemotherapy regimens, kidney function must also be checked. 

The patient will be offered a customized wig.

Implementation

PV regimen (cisplatin and etoposide)

Four treatment courses are usually given.

  • Day 1: cisplatin and etoposide intravenously.
  • Day 2 and 3: etoposide intravenously or day 2-4 etoposide orally.
  • Day 22: start of new treatment course.

CV regimen (carboplatin and etoposide)

Four treatment courses are given. The carboplatin dose is calclulated according to the Calvert formula.

  • Day 1: carboplatin and etoposide intravenously.
  • Day 2 and 3: etoposide intravenously or day 2-4 etoposide orally. 
  • Day 22: start new treatment course.

ACO regimen (doxorubicin, cyclophosphamide and vincristine)

Four treatment courses are given.

  • Day 1: doxorubicin, vincristine, and cyclophosphamide intravenously.
  • Day 22: start new treatment course.

Dose reduction

Dose reduction for low blood values
Leukocytes or Thrombocytes Chemotherapy dose
³ 3.0 ³ 100 100 %
2.5–2.9 75–99  75 %
2.0–2.4 50–74  50 %
< 2.0 < 50 Postpone treatment 1 week

Follow-up

The treatment effect is most often evaluated in 2-3 month intervals. The first check should take place 4-8 weeks after treatment is completed.

Evaluation often includes chest X-ray or CT.

If there is objective, good, or complete objective response after the first treatment, both for localized and extensive cancer, the patient should be referred for radiation therapy of the brain to prevent brain metastasis. 

 

Some chemotherapy side effects for small cell lung cancer (1)

(Frequent > 1/100, rare < 1/1000)

Side Effect  Cisplatin Etoposide  Carboplatin Doxorubicin Vincristine Cyclophosphamide
Bone marrow depression Frequent Frequent Frequent Frequent Frequent Frequent
Nausea/Vomiting   High Mild Moderate Moderate Minimal High/
moderate
Hair loss Rare Frequent Frequent Frequent Frequent In high doses
Diarrhea/
Constipation
Diarrhea/
Frequent
Frequent Frequent Diarrhea/
Rare
Constipation/
frequent
Dose-dependent
Mucositis/
Stomatitis
Not reported Frequent Not reported Stomatitis/
Rare
Stomatitis/
Frequent
Dose-dependent
Allergic reactions Rare Rare Frequent Rare Rare Frequent
Cardiotoxicity Rare Not reported Frequent Frequent Rare Rare
Neurological symptoms Frequent Rare Frequent Not reported Frequent Not reported
Skin/nails Rare Not reported Frequent Frequent Not reported Rare
Liver Frequent Rare Frequent Not reported Not reported Frequent
Airways Not reported Rare Not reported Not reported Not reported Rare

With use of cisplatin, about 30% of the patients experience ototoxic side effects.

PV regimen = cisplatin and etoposide

CV regimen = carboplatin and etoposide

ACO regimen = doxorubicin, cyclophosphamide, and vincristine 

Flowchart - small cell lung cancer

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.

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.

Radiation therapy of lung cancer

Most lung cancer patients will  benefit from radiation therapy during the course of the disease. It is assumed that 65% of patients will need this treatment modality. In Norway, there is still too few who are offered radiation treatment.

Radiation treatment is suitable for both non-small cell and small cell lung cancer, as part of curative treatment and in palliative situations. For thoracic tumors, metastases to the brain and most other localizations, high-energy photon radiation is used. For superficial skin metastasis, electron rays which abruptly decelerate within the tissue are used.

Curative radiation therapy

For limited stage small cell lung cancer, radiation therapy of the thorax is included as part of the curative schedule in practically all lung cancer patients, combined with chemotherapy before and after radiation. In addition, radiation therapy to the brain is offered to prevent metastasis in patients who achieve partial or complete response on initial therapy.

For non-small cell lung cancer, radiation treatment is offered after surgery in special situations, as curative-directed treatment instead of surgery or as part of combined chemoradiotherapy for locally advanced cancer.

Palliative treatment

For extensive lung cancer or in cases of reduced general health, radiation treatment of tumor masses in the central thorax may relieve symptoms in the majority of patients.

For metastases, radiation could be the first choice for both cancer types. However, chemotherapy may be more appropriate for metastases to internal organs.

For brain metastases of small-cell lung cancer, chemotherapy is often a better option than radiation therapy. This in contrast to non-small cell lung cancer, where radiation is usually the treatment of choice for brain metastases.

Fractionation patterns

A series of treatment schedules are appropriate depending on treatment goal, tissue type, localization of the radiation field, and the patient's general health condition.

PROSEDYRER

Curative Radiation Treatment of lung cancer

General

Non-small cell lung cancer

Patients unfit for surgery, or not willing to undergo a surgical procedure, will be offered curatively intended radiation therapy. In stage I, this will be given as stereotactic radiation, with a high radiation dose in few fractions. In stage II or III, fractionated therapy given over several weeks is offered, either alone or in combination with chemotherapy.

Many patients with clinically localized cancer (stage III) have subclinical micrometastases and this group of patients is given systemic chemotherapy simultaneously with curative radiation therapy.

Combinations

  • Induction chemotherapy of 2-3 courses before radiation treatment 
  • Chemotherapy given in parallel with curative radiation therapy as a radiation sensitizer (concomitant treatment)
  • A combination of the above alternatives
  • Adjuvant chemotherapy after concluded curative radiation therapy

There is no evidence for a benefit from routinely postoperative radiation therapy.

Each additional treatment of curative radiation doses causes increased side effects. Internationally, concomitant chemoradiation treatment is recommended. Patients who are not suitable for inclusion of a protocol study, but who still meet the prognostic factors which indicate a curative treatment arrangement, are given radiation alone in doses of 60–74 Gy. 

Stereotactic radiation is first-line treatment of choice for medically inoperable stage I patients.

Small cell lung cancer

Radiation therapy given in addition to chemotherapy provides a survival benefit. Radiation should commence early in the treatment course. 

Indications

Non-small cell lung cancer

  • Stage I and II with good prognostic factors and considered surgically inoperable, or surgery not wanted.  
  • Stage IIIA with good prognostic factors and considered inoperable or inappropriate for neoadjuvant chemotherapy.
  • For stage IIIB, curative radiation treatment is possible if the patient has good prognostic factors.

Small cell lung cancer

  • Localized cancer, stage I–III 

Goal

  • Cure the disease

Definitions

The tumor, including pathologically enlarged lymph nodes in the ipsilateral hilum and mediastinum define the target volume (GTV). Margins of 1.5–2 cm are used to compensate for microscopic spreading, tumor movement with respiration, and tuning variations (CTV, PTV). The volume of risk organs in the radiation field such as the medulla, heart, and healthy lung, must be minimized according to the maximum tolerable dosage.

Target Volume

 

 

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

GTV (= Gross Tumor Volume)

Tumor volume

Palpable or visible/demonstrative area of malignant growth. 

CTV (= Clinical Target Volume)

Clinical target volume

Tissue volume which contains GTV and/or subclinical microscopic malignancy.

ITV (= Internal Target Volume)

Target volume

Volume containing CTV and a inner margin taking into account inner movements and revisions of CTV.

PTV (= Planning Target Volume)

Planning volume

Geometric volume containing ITV and a Setup margin taking into account assumed variations for patient movements, variations in patient arrangement, and field modeling.

 

Preparation

Target volume and radiation technique

The radiation fields are formed based on the CT images  .

  • The patient meets for imaging on a dedicated CT machine, with or without contrast.
  • The localization of the tumor and risk areas are drawn directly into the images and create a 3D radiation volume. 
  • Radiation therapists suggests a radiation field set-up which is eventually adjusted and approved by a medical physicist and the treating doctor. Ideally, there should be a uniform dose distribution over the target volume and no radiation to critical organs. In reality, this is impossible to achieve. The dose distribution is therefore a compromise between what is desired and what is possible.
  • During a CT scan, it is very important that the patient is well medicated for pain and is able to lie still on their back when the images are taken. If necessary, a premedication is given or extra dose of opiates for those who are taking them.
  • The patient lies flat on a bench with only a thin mattress.
  • An abdominal pressure can be applied during stereotactic radiation to minimize diaphragm-caused respiratory movements. 

Implementation

Non-small cell lung cancer

  • Stage I – The radiation field is limited to only include the tumor (GTV) and margins (CTV + PTV) without the hilum and mediastinum. A 3D CT-based dosage plan is prepared. The treatment is given over 3 fractions of 15 Gy or 8 fractions of 7 Gy. This treatment takes 2-3 weeks including planning. Alternatively 2 Gy x 30–37 are given within 6-8 weeks.
  • Stage II – A larger radiation field using CT-based 3D dosage plan toward the tumor is applied, including pathologically enlarged lymph nodes (GTV), in addition to uncertainty and tuning margins (CTV + PTV). Schedules of 2 Gy x 30–35 are given. Adjuvant chemotherapy is usually given.
  • Stage IIIA/B – Radiation treatment is given using a CT-based 3D dosage plan with the same technique and dose as in stage II. Treatments are fractioned into 2 Gy x 30–33. Concomitant chemotherapy is usually given

Postoperative treatment

After surgery, radiation therapy is appropriate under the following circumstances:

  • For N2 cancer after lung surgery (pN2), postoperative radiotherapy should be given. CT-based 3D dosage planning technique to the mediastinum, 60 Gy with 2 Gy per daily fraction.
  • For involved histopathological margins (both R1 (microscopic) and R2 (macroscopic)) 50–60 Gy should be given, CT-based 3D dosage plan, 2 Gy per daily fraction.

For radically operated N0-1 cancer, there is no indication for postoperative radiation therapy.

Small cell lung cancer

Toward the tumor and mediastinum with margins, fractionated CT-dosage planned treatment is given e.g. 1,5 Gy twice daily, 30 fractions as a total dose (alternatively 2.8 Gy x 15 is given). Pathological lymph nodes observed with CT/PET before starting chemotherapy must be included in the radiation field. Early initiated radiation therapy gives a small, but significant survival benefit compared to a late start. Radiation should therefore be started no later than just after the second course of chemotherapy. The third course should not be postponed.

In case of partial or complete response upon evaluation at 4–6 weeks after the last course of chemotherapy, patients with small cell lung cancer should be offered prophylactic radiation therapy to the brain.

Follow-up

Patients should be monitored at 4–6 weeks after concluded curative radiation therapy (or the last chemotherapy course for small cell cancer), for side effects and evaluation for adjuvant chemotherapy.

Monitoring thereafter should be about every third month and include imaging with either thoracic X-ray or CT. The frequency of CT monitoring should be individualized, but not less than once a year for the first years.

Early reactions

Fatigue

Radiation therapy may render the patient more fatigued and lethargic. Reduced appetite, nausea, diarrhea, and pain lead to fatigue. The fatigue does not always disappear when treatment is ended. In outpatients, fatigue may also be caused by stressful transportation.

Skin reactions

Reactions in the skin from radiation are normal and worsen with increasing doses. Soreness may last and/or increase until at least a couple of weeks after treatment has finished. Intertriginous areas (for example under the breasts) are especially susceptible. Airing, salt water compresses, and perfume-free creams may help. Ointment and creams should not be applied to the radiation field for the last hours before each treatment session. 

Problems swallowing

Radiation treatment which includes larger or smaller parts of the mediastinum and neck, leads to irritation and soreness in the throat and esophagus, and subsequent swallowing problems. Diet advice, "lubrication" with cream or ice cream just before eating may help, otherwise, local analgesics or systemic pain medication will help. In rare cases, tube feeding is necessary.

Lung/respiratory symptoms

Swelling in the radiated tissue/mucosa can lead to temporary deterioration of breathing after the first treatments. Radiation-induced pnemonitis with fever can also occur. Steroid treatment may become necessary for this.

Late reactions

A late reaction to radiation treatment to the lungs may be reduced lung capacity.

Curative radiation therapyCurative radiation therapyCurative radiation therapy

Palliative radiation therapy of lung cancer

General

Palliative radiation therapy is a useful first-choice treatment in patients with non-small cell lung carcinoma in stages III and IV, where a positive effect from systemic chemotherapy is unlikely. 

Symptoms in patients with small cell lung carcinoma are usually effectively relieved by chemotherapy. Patients with recurrence of small cell lung carcinoma, where additional chemotherapy is not considered beneficial, may obtain successful palliative results from radiation therapy.

Thoracic radiation

Locally advanced lung cancer may cause many different symptoms. Palliative radiation therapy is a relatively mild treatment and the majority of the patients are relieved of bothersome symptoms by this treatment. 

    
Symptoms

Subjective improvement reported by patients

Cough 50-70%
Hemoptysis 70-100%
Pain 50%
Dyspnea 20-40%
Vena cava superior syndrome 90-100%
Atelectasis 20-25%
Hoarseness 8-10%

Palliative radiation therapy is often given in fractions that optimize the therapeutic effect while minimizing unwanted side effects and with short treatment time. In this way, a high total dose is given to the tumor tissue while damage to the normal tissue is minimized.

When the treatment is given as palliation it is very important that the acute side effects are insignificant and of short duration.

Palliative radiation therapy is used for primary tumors, local recurrence, and metastasis.

Indications

  • Incurable lung cancer 
  • Symptomatic metastases

Goal

  • Relieve symptoms
  • Prevent new symptoms

Definitions

The tumor, including pathologically enlarged lymph nodes in the ipsilateral hilum and mediastinum define the target volume (GTV). Margins of 1.5–2 cm are used to compensate for microscopic spreading, tumor movement with respiration, and tuning variations (CTV, ITV and PTV). The volume of risk organs in the radiation field such as the medulla, heart, and healthy lung, must be minimized according to the maximum tolerable dosage. Asymptomatic parts of the tumors are not included if the field gets too big. Maximum field size should as a rule of thumb not exceed 200 cm2.

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

GTV (= Gross Tumor Volume)

Tumor volume

Palpable or visible/demonstrative area of malignant growth. 

CTV (= Clinical Target Volume)

Clinical target volume

Tissue volume which contains GTV and/or subclinical microscopic malignancy.

ITV (= Internal Target Volume)

Target volume

Volume containing CTV and one inner margin taking into account inner movements and revisions of CTV.

PTV (= Planning Target Volume)

Planning volume

Geometric volume containing ITV and one Setup margin taking into account assumed variations for patient movements, variations in patient arrangement, and field modeling.

Preparation

Target volume and radiation technique

The radiation fields are formed based on the CT images  .

  • The patient meets for imaging on a dedicated CT machine, with or without contrast.
  • The localization of the tumor and risk areas are drawn directly into the images to create a 3D radiation volume. 
  • Radiation therapists suggests a radiation field set-up which is eventually adjusted and approved by a medical physicist and the treating doctor. Ideally, there should be a uniform dose distribution over the target volume and no radiation to critical organs. In reality, this is impossible to achieve. The dose distribution is therefore a compromise between what is desired and what is possible.
  • At the CT imaging session, it is very important that the patient is well medicated for pain and is able to lie still in a supine position when the images are taken. If necessary, pain-releiving premedication is given.
  • The patient lies flat on a bench with only a thin mattress.

It is very important that the patient is well medicated for pain and is able to lie still.

Implementation

Practical recommendations

8.5 Gy x 2

All patients in Norway with metastatic disease are normally given hypofractionated treatment of 8.5 Gy x 2, if radiation towards the central airways is necessary.

This applies to patients with: 

  • stage IV cancer
  • stage III (A and B) cancer and poor prognostic factors
  • a large tumor (diameter > 9-10 cm)
  • reduced general health (WHO PS > 2)
  • significant weight loss (> 5-10% in the last 3 months)

The patient will receive steroids the day before treatment, day of treatment, and day after treatment to reduce side effects.

3 Gy x 10-13

This fractionation scheme is given for both small cell and non-small cell lung carcinoma. The number of fractions depends on the extent of the disease. By 13 treatments, the field composition must be tuned in order to adjust the dose to the spinal cord. The total treatment time is 2-3 weeks with one daily treatment, 5 days per week.  

Pancoast tumor 3 Gy x 13

Pancoast tumors are non-small cell lung carcinomas in the superior sulcus which often have rib or nerve involvement. These tumors often cause significant pain and the patient often survives longer than for other tumor localizations. The total treatment time is 2-3 weeks with one treatment every day for 5 days per week. In some cases, additional 2-3 treatments to the primary tumor may be necessary.

Pancoast tumors without lymph node involvement, which are initially inoperable, may in some cases be given neoadjuvant chemoradiotherapy (2 Gy x 25 with concomitant platinum-based chemotherapy) and subsequently evaluated for surgery.

Endocavitary radiation therapy (brachytherapy)

For local recurrence in the central airways, radiation can be given endobronchially. Brachytherapy is usually used for recurrence which causes symptoms in previously irradiated patients. This treatment is sometimes combined with laser coagulation and stenting.

Radiation therapy to metastasis

Lung cancer frequently metastasizes, especially to other parts of the lungs, skeleton, and brain. Palliative radiation treatment to skeletal and soft tissue metastases provides symptom relief. Pain from skeletal metastasis can be relieved in 60-80% of the patients. Single fractions of 8–10 Gy provides a satisfactory effect. For larger soft tissue components and also for weight-carrying bones with fracture risk, it may be appropriate to provide fractionated treatment such as 3 Gy x10. Symptomatic brain metastases are often relieved by radiation. Liver metastases are rarely treated with radiation but this may be appropriate when there is resistance to chemotherapy or they are symptomatic. Stereotactic radiation with one (against brain/columna metastases) or three (extracranial metastases) fractions may be appropriate in the presence of a single or few metastases (oligometastases).

Follow-up

Most of the side effects occurring during treatment arise from healthy organs included in the radiation field. The dose levels used for pure symptom relief are kept low to minimize the risk of acute side effects. 

The total dose is at a level which renders the risk for delayed reactions low.

Good follow-up care is important to achieve satisfactory relief of symptoms and usually takes place locally at the referring hospital or primary care doctor.

Early reactions

Fatigue

Radiation therapy may render the patient more fatigued and lethargic. Reduced appetite, nausea, diarrhea, and pain cause fatigue. The fatigue does not always go away when treatment is over.

Skin reactions

Reactions in the skin from radiation are normal and worsen with increasing doses. Soreness may last and/or increase until at least a couple of weeks after treatment is finished. Intertriginous areas (for example under the breasts) are especially susceptible. Airing, application of salt water compresses and perfume-free creams may help. Salves and creams should not be applied to the radiation field in the last hours before each treatment session. 

Problems swallowing

Radiation treatment which includes larger or smaller parts of the mediastinum and neck, leads to irritation and soreness in the throat and esophagus, which leads to problems swallowing. Lubricating with cream or ice cream right before eating may help, otherwise local analgesics or systemic pain medication will help. In rare cases, tube feeding is necessary.

Lung/respiratory symptoms

Swelling in the radiated tissue/mucosa can lead to temporary worsening of breathing difficulty after the first treatments. Radiation-induced lung inflammation (pneumonitis) with or without fever can also occur, and may be treated with steroids.

Delayed reactions

A delayed reaction to radiation treatment to the lungs is reduced lung capacity.

Palliative radiation therapyPalliative radiation therapyPalliative radiation therapy

Radiation treatment to the brain of lung cancer

General

For small cell lung cancer, radiation therapy to the brain is performed as prophylactic treatment when chemotherapy to the primary cancer has resulted in partial or complete response, or as palliative relief treatment for established brain metastases from either small or non-small cell lung cancer.

Based on clinical studies and autopsy data, it is known that up to 25% of all lung cancer patients develop brain metastasis within two years of the diagnosis. 10% of patients with small cell lung cancer have brain metastases at the time of diagnosis and an additional 20 % develop such during treatment.

Radiation is usually given towards the entire brain as opposing directional fields. For 1-3 metastases up to 4 cm in diameter, stereotactic radiation therapy to the tumor(s) may be appropriate. Treatment is given as a single fraction of 15–25 Gy. Total brain radiation is administrated for small cell lung cancer even with only 1–3 metastases, due to the high risk of micrometastases outside the visible metastases. Stereotactic radiation can be administered for this patient group if total brain radiation already has been delivered.

Indications

  • Complete or partial response of initial therapy in small cell lung cancer
  • Established brain metastasis

Goal

  • Prevent brain metastasis
  • Reduce the extent of metastasis
  • Relieve and prevent symptoms

Definitions

Target Volume

 

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

GTV (= Gross Tumor Volume)

Tumor volume

Palpable or visible/demonstrative area of malignant growth. 

CTV (= Clinical Target Volume)

Clinical target volume

Tissue volume which contains GTV and/or subclinical microscopic malignancy.

ITV (= Internal Target Volume)

Target volume

Volume containing CTV and a inner margin taking into account inner movements and revisions of CTV.  

PTV (= Planning Target Volume)

Planning volume

Geometric volume containing ITV and a Setup margin taking into account assumed variations for patient movements, variations in patient arrangement, and field modeling.

Preparation

Before the first radiation treatment, an individually adjusted plastic mask is prepared for the head in order to immobilize the patient.

During the CT scan for dosage planning, the patient must stay immobile in a supine position on a thin mattress. He/she must therefore be well medicated for pain, either by premedication or an additional dose of opiates.

Planning of the radiation field (contouring, determining radiation field, necessary adjustments, and checks as well as preparation of documentation) for simulation usually takes a few days.

Simulation in cases of palliative treatment occurs only "virtually," i.e. only as data simulation. The patient will meet for their first treatment a few days after the CT scan.

In the head region, there are many risk organs with limited tolerance for radiation such as:

  • spinal cord
  • brain stem
  • parotid gland
  • optic chiasm
  • inner ears
  • optic nerves
  • lenses
  • bulb of the eye

Ideally, a uniform dose distribution over the target volume is achieved with no radiation to critical organs. This is impossible to achieve. A compromise between what is possible and what is desired is therefore made.

Implementation

Prophylactic treatment

Patients with small cell lung cancer who achieved partial or complete response in the thorax 4-6 weeks after concluded chemotherapy should be offered prophylactic radiation to the brain.

2,5 Gy x 10 is given. Five treatments per week are given and the total treatment time is therefore 2 weeks.

Palliative treatment

For established brain metastases, palliative treatment is given in a dosage of 3 Gy x 10 or 4 Gy x 5. Five treatments per week are administered and the total treatment time is 1-2 weeks.

For 1–3 metastases under about 4 cm, stereotactic radiation therapy is appropriate, usually in one fraction of 15–25 Gy.

Follow-up

Side effects of radiation therapy

Fatigue

Radiation therapy may render the patient more fatigued and lethargic. Reduced appetite, nausea, diarrhea, and pain cause fatigue. The fatigue does not always go away when treatment is over.

Skin reactions

Reactions in the skin from radiation are normal and worsen with increasing doses. Soreness may last and/or increase until at least a couple of weeks after treatment is finished.  

Nausea

Radiation therapy to the head causes nausea in rare cases. If the patient is also receiving chemotherapy, nausea may be intensified.

Headache

At the start of radiation therapy to the head, the brain tissue can swell leading to headache. Paracetamol and steroids may prevent the headache. Generally when whole brain radiation is being administered, concomitant use of steroids are recommended during the course of radiation to prevent cerebral edema. Steroids may be tapered off after the conclusion of the radiation.

Hair loss

Radiation to the head often causes hair loss. In most cases, hair will grow again after the treatment is concluded. However, large radiation doses can cause permanent damage to hair follicles in which hair and facial hair do not grow back in the radiated areas.

 

Complication treatment of lung cancer

Surgery, chemotherapy, and radiation therapy cause side effects to varying degrees.

It may be necessary to provide supportive care in order for the patient to complete and gain the full effect of planned treatment.

Supportive care can also be provided to reduce side effects and 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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  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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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.

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

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.

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.

Nutrition during Cancer Treatment

General

Monitoring the patient's nutritional status is an important part of cancer treatment. The goal is to identify malnutrition as early as possible in order to initiate treatment as quickly as possible.

Measures include diet according to symptoms and the nutritional condition. The patient should be offered nutrition-rich food, snacks, nutritional drinks, tube feeding and intravenous nutrition.

Because cancer treatment breaks down both cancer cells and normal cells, the body requires an adequate supply of nourishment to increase growth of new cells. 

In cancer patients, the sensation of hunger is not always present to the necessary degree. In these cases, it is important to take actions to improve the nutritional status of the patient. The nutritional condition is easiest followed by monitoring body weight over time.

Indication

  • Cancer treatment (chemotherapy, radiation, surgery).

Goal

  • Maintain nutritional status in order for the patient to have the best possible conditions for implementing treatment.

Definitions

Subjective Global Assessment (SGA)

Subjective Global Assessment (SGA) is a scheme for classifying the patient's nutritional status.

Other tables that are frequently used are Malnutrition Universal Screening Tool (MUST), Mini Nutritional Assessment (MNA) and Nutrition Risk Score (NRS). In principle, these schemes are prepared in the same way as SGA, but they are not validated for patients with cancer.

Weight loss is one of the most important signs of change in nutritional status. A weight loss of more than 15% over the past 6 months or more than 5% over the last month is a significant and serious weight loss. If the weight loss occurs in combination with low BMI (body mass index) (< 20 kg/m2 for adults) and/or a food intake of less than 60% of the calculated requirement over the past 10 days, the patient will be malnourished or be at nutritional risk.

Calculation of nutrition and fluid requirements

  • Ambulatory patients:  30-35 kcal/kg/day
  • Bed-ridden patients:  25-30 kcal/kg/day
  • Elderly above 70 years:  Recommended amount is reduced by 10%
  • Fluid requirement:  30-35 ml/kg/day

Nutritionally enriched diet / enrichment of food and beverages

Nutritional beverages may be used as a meal in itself or between meals. Nutritional drinks can be a more valuable snack than "normal" food, because it is often easier for the patient to drink than to eat. It has been shown that if nutritional drinks are introduced as snacks, it does not affect the energy intake during the main meals.

There are a number of ready-made nutritional drinks on the market. Some of the products are of nutritionally complete. They contain carbohydrates, protein and fat and are supplemented with all the necessary vitamins, minerals and trace minerals and possibly fiber. Some of these products can be used as the sole source of nutrition. The energy content varies from 85-200 kcal/100 ml and some products have a high protein content. Other nutritional drinks are supplement drinks adjusted to individual needs such as allergies, intolerance and special conditions associated with illnesses.

The products are also adapted to age, and the dose is determined individually by a clinical dietician/doctor.

Many patients prefer homemade nutritional drinks based on full fat milk, cream, ice cream, fruit and possibly flavor supplements. These are free of additives and have a fresher taste. The energy and protein content is close to the commercial products and at the same time they are more sensibly priced.

Tube feeding

Tube feeding is preferable to total parenteral nutrition (TPN) when the digestive system is working. Nutrition supply to the intestine is more physiological. It protects against bacterial growth, maintains the intestine's mucous membrane structure and function, and promotes motility. Tube feeding involves less risk of metabolic complications.

Tube feeding is used in the event of

  • insufficient food intake (less than 60% of energy requirements) over the past 5-7 days despite oral intake
  • weight loss >2 % over the past week, >5 % over the past month or >10% over the past 6 months
  • danger of weight loss due to planned treatment
  • low albumin values (under 35 g/l, lower limit for normal area)
  • stenosis with feeding obstacles in pharynx/gullet

Tube feeding must not be used for the following conditions.

  • Paralysis or ileus of the alimentary tract
  • Short bowel syndrome
  • Serious diarrhea
  • Serious acute pancreatitis
  • Obstruction of the intestine
  • Serious fluid problems

Tube feeding solutions

The tube feeding solution must be nutritionally complete because they shall be used as the sole source of nourishment. The most frequently used are standard (1 kcal/ml), fiber-containing (1 kcal/ml) or energy-rich (1.5 kcal/ml). There are also tube feeding solutions which are adapted to patients with digestion and absorption problems, patients with diabetes or lactose allergy, and intensive care patients.

Tube feeding solutions, which are adapted to cancer patients are energy-rich (1.5 kcal/ml). They contain extra omega-3 fatty acids, rich in MCT acid and enriched with extra vitamins and minerals. Recommended dosage is 500 ml/day.

Parenteral nutrition

Parenteral nutrition should only be used if food by mouth or tube feeding cannot be maintained. Parenteral nutrition can also be used as a supplement to tube feeding or ordinary food. 

Precautions must be taken for kidney failure, heart failure, lung failure, large fluid and electrolyte loss, diabetes mellitus and liver failure.

Preparation

The patient is classified as well-nourished, somewhat malnourished or seriously malnourished on the basis of information about weight development, food intake, symptoms and physical functioning. This classification has been shown to correlate well with more objective measurements of nutritional status and morbidity, mortality and quality of life.

Actions include individual adjustment of diet according to symptoms and nutritional status.

Tube feeding

The end of the tube is often inserted into the stomach. In the event of poor gastric function, total gastrectomy or pancreatic resection, the feeding tube should be inserted in the duodenum or jejunum. The position of the feeding tube is vital for the choice of feeding-tube solution and mode of administration.

The most common solution is to insert the tube nasogastrically, but it can also be done through the abdominal wall (PEG).

Parenteral nutrition

It is preferable to use intravenous or parenteral nutrition as a supplement to oral/tube feeding instead of only TPN (total parenteral nutrition).

  • Central veins must be used for TPN with high osmolality.
  • Peripheral veins can be used for short-term parenteral nutrition. In this case, a large vein on the forearm is used and a small needle. Nutrition is then given as more diluted solutions.

Implementation

All patients are weighed regularly (1–2 times each week). This is a prerequisite to being able to register changes in the nutritional status.

Varied and healthy food contributes to the growth of new cells and enhances the immune system.

  • Fruit, berries and vegetables are rich in vitamins, minerals, antioxidants and fiber, which contribute to enhances the immune system and contributes to keeping the digestive system working.
  • Fish, shellfish, poultry, meat, eggs, cheese, milk, beans and nuts are rich in proteins, which are the building blocks of new cells.
  • Bread, rice, pasta, porridge and breakfast cereals supplement the diet with proteins, carbohydrates, fiber, vitamins and minerals.
  • Oil, margarine, butter, mayonnaise products, nuts, cream, heavy cream, desserts etc. are fat and energy rich products, which are important to maintain the energy intake at a satisfactory level.
  • Cancer patients also have a requirement for plenty of fluid, especially during treatment, to discharge waste.

Often, the patients must have an individually adjusted diet. In the event of lack of appetite, it is generally more important that you eat (enough food) than what you eat (the right food). It is beneficial to have small portions and for the food to be as abundant in energy as possible. These patients will often have a need for 6–8 small meals everyday to obtain their energy requirements.

Enrichment of food and drink is done in order to increase the energy content of the food product without increasing the volume. Full-fat products such as full-fat milk, cream, butter, heavy cream, mayonnaise, sugar, honey, eggs and cheese etc. are primarily used. Enrichment powders from pharmacies may also be used. Some powders are nutritionally complete, i.e. they contain everything the body requires in terms of energy and nutrients, while others only contain pure energy (carbohydrates, fat and/or protein). 

Tube feeding

Tube feeding is given continuously with a low drop rate or by interval/bolus administration (individually adapted meals with high drop rate).

When the patient's energy and fluid requirements are fulfilled, it will be decided whether the patient will be given bolus or continuous supply at night, in order to increase mobilization during the day. However, this requires that the patient does not have diarrhea, nausea or other complaints associated with the supply of nutrition.

For a running feeding tube:

  • Every 4-8 hours, it should be aspirated in order to monitor the gastric emptying. This applies especially to immobile and weak patients.
  • Weekly or more often, the nutrition program/fluid balance, evaluation, edema control, blood tests (albumin, K, Mg, P, blood glucose) should be monitored weekly or more often.
  • Every 4-6 weeks, the tube should be changed. Alternate the uses of nostrils avoid irritation in the nose through prolonged feeding.

Experience shows that the use of infusion pumps causes fewer side effects and ensures correct volume and rate.

Bolus supply

Initiation of tube feeding with bolus supply is only recommended

  • if the patient been taking any food until the last 24 hours
  • if the patient is taking some food and requires tube feeding for additional nourishment

It is recommended to use pumps for bolus supply for the first 1–2 days.

Continuous supply

If the patient cannot tolerate bolus supply (vomiting, abdominal discomfort, nausea, diarrhea), reverting to continuous supply should be considered.

Tube feeding should always be administered continuously to very malnourished patients or if the tube end is located distally to the pylorus.

Parenteral nutrition

If the patient has a satisfactory nourishment status, begin with 100% of the requirement. If the patient is seriously malnourished, start with 80 % of the requirement and increase slowly to 100% over the course of three days.

The patient must be monitored closely in relation to

  • electrolytes (potassium, phosphate and magnesium).
  • infusion rate.
  • twenty-four hour urine sample and fluid balance should be calculated daily.
  • glucose in the blood and urine, and electrolyte in the blood should be examined daily at the start.
  • liver tests, kidney function tests and triglycerides should be taken examined at least once every week.

For TPN treatment longer than 1 month, vitamins and trace elements should be examined.

Follow-up

The patient's nutrition status should be monitored at follow-up visits after the end of treatment.

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.

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.

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

Follow-up care after treatment of lung cancer

To discover recurrence of the disease or a new primary tumor, checks should be carried out every three to six months for the first two years, thereafter annually. Follow-up regarding complications should be done by a thoracic surgeon, lung specialist, or oncologist in one to three months after treatment.

Examination should include: 

  • patient history
  • clinical examination
  • image analysis (chest X-ray, more rarely chest CT scan)
  • blood tests

These checks can be completed at a local hospital, possibly in dialog with the patient's primary doctor. Patients should be informed of possible symptoms and encouraged to contact the hospital if they develop new symptoms or a worsening of pre-existing symptoms.  

Routine PET scans do not have any documented role in patient follow-up at the present time. Tumor markers such as CEA, NSE or proGRP are only of value if they were elevated before starting treatment. 

At the time of diagnosis, about sixty percent of patients smoke while forty percent of these have stopped two years after the diagnosis. Smoking cessation at the time of the diagnosis reduces the risk for developing metachronous tumors. Potentially cured lung cancer patients who smoke are highly encouraged to stop smoking.

Complications after curative treatment 

The most common complications after a lung resection are loss of lung function and chronic pain.

Complications from radiation therapy can affect the lungs, skin, esophagus, or muscles. More rare complications are damage to the pericardium and heart. Acute radiation pneumonitis can often be treated successfully with steroids. However, delayed radiation pneumonitis often represents irreversible lung damage, but is rarely seen.  

Most side effects of chemotherapy occur during treatment. An exception is peripheral neuropathy from vinca alkaloids or taxanes. 

Recurrence or development of a new primary tumor after curative treatment

Recurrence is frequent. Even with stage I cancer, five year recurrence rates up to thirty-nine percent are reported. Most recurrences occur within four years after treatment.

For small cell lung cancer, a new tumor occurring more than two years after primary treatment will often be a new primary tumor as most recurrences occur within a short period after initial treatment.

Palliative treatment

For the patient's feeling of security and ensuring a good palliative treatment, it is important to provide relatively frequent follow-up.

Due to the greater need for treatment to relieve symptoms, it may be necessary to request the patient to be checked every three months for the first year and then to increase the intervals. Resource-demanding examinations should be avoided except for work-up of new symptoms or clinical findings. 
 

PROSEDYRER

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