Cancer of unknown primary site
For cancer in which the primary site is unknown, metastasis exists but the primary tumor is not identified after performing a thorough medical work-up.
In Norway, the term origo incerta is often used instead of "cancer of unknown primary site." In the literature, it is common to use the abbreviation, CUP (metastatic cancer of unknown primary site).
CUP constitutes 3–5% of all malignant cancers and <1 % of pediatric cancers.
The incidence of metastatic cancer of unknown primary site has reduced significantly over recent years. In 2010, The Cancer Registry of Norway reported only about 1.5% of all malignant diseases with this classification. CUP constitutes <1% of pediatric cancers.
The patient group is heterogeneous and there are large variations in disease profiles and tumor histology (1). In an unpublished Norwegian study by Gundersen et al, the most common localizations for metastases are (4):
- lymph nodes (36%)
- abdomen (20%)
- lungs/pleura (9%)
- central nervous system (8%)
Studies have shown that autopsy can reveal CUP in three out of five patients. The most common origins are lung (27%), pancreas (24%), liver/bile duct (8%), kidney or adrenal gland (8%), large intestine and rectum (7%), sex organs (7%) and stomach (6%) (2).
CUP can lead to an increased psychological burden compared to other cancer diagnoses due to the extent of time and unanswered questions, as well the less specific treatment compared to a diagnosis of known origin. Extra awareness should therefore be paid to the increase in psychological stress this uncertainty causes and coupled with good supportive care.
In Norway, the incidence was reduced from 770 patients in 2000, to 496 patients in 2013. Less men than women receive this diagnosis (229 compared to 267, respectively in 2013).
The median age is 60 years.
Age-specific incidence of cancer of unknown primary site, 2009–2013.
Source: Cancer Registry of Norway
Incidence of cancer of unknown primary site, 1954–2013.
Source: Cancer Registry of Norway
Etiology of CUP
The reason why a primary tumor may be difficult or impossible to find may be due to different causes:
- The primary tumor once existed and spontaneously disappeared, however, the metastatic cells are still active, creating tumors and causing symptoms.
- The primary tumor produces metastatic cells continually and in such a large volume that there is no net growth of the primary tumor. The tumor remains small and difficult to detect. These metastatic manifestations grow causing symptoms.
- There is no primary tumor, but the impression of metastasis is due to normal cells in abnormal locations undergoing malignant transformation. Examples may be epithelial cells or nevus cells in lymph nodes.
Histology of CUP
Histopathological evaluation is central when cancer without known origin occur. It is a difficult task to evaluate the origin of some types of carcinoma, because they can have the same appearance despite different origin.
Distribution of histological types (2):
- Well- and moderately differentiated adenocarcinomas (50 %)
- Poorly differentiated carcinomas with or without glandular differentiation (30 %)
- Squamous cell carcinomas (5 %)
- Undifferentiated/anaplastic carcinomas (5 %)
|Photomicrograph of poorly differentiated adenocarcinoma in a lymph node. Click to enlarge.
||Photomicrograph of an adenocarcinoma in the pleura. Click to enlarge.
||Photomicrograph of undifferentiated carcinoma in a lymph node. Click to enlarge.
An extensive immunohistochemical investigation is often performed in these instances, even where specific finding indicates tumor origin.
Some immunohistochemical markers are highly specific and are thus included in most panels, such as: MelanA for malignant melanoma, PSA for prostate and thyroglobulin for thyroid. There are also combinations of markers that strongly indicate special tumor types. However, in a number of cases there are no specific findings, and it must be concluded with carcinoma of unknown origin.
Molecular techniques based on gene analysis can hopefully improve the diagnostic performance in the future.
Staging of CUP
Cancer of unknown origin is a metastatic disease. It is differentiated between single and multiple metastases.
MX– Metastasis cannot be assessed
M0– No metastasis
Metastatic patterns of CUP
Spreading can occur hematogenously, lymphatically, or locally where the primary tumor once existed.
Symptoms of CUP
Symptoms and sign of illness depend on the location of the metastatic tumor. Symptoms may be:
- a lump in the axilla, groin, or throat
- pressure/increasing abdomen size (ascites)
- difficulty breathing
- bone pain
- behavior changes
- epileptic seizures
Common symptoms often observed in this patient group are anorexia, weight loss, and fatigue.
Prognosis of CUP
The median survival for this patient group is approximately 6-9 months, which is often a reflection of the more aggressive cancer types (1).
Approximately 20% of cases have characteristics that correspond to a slightly better prognosis. These include:
- women with papillary carcinomas in the peritoneum
- women with adenocarcinomas in axillary lymph nodes only
- low differentiated tumors with mid-line distribution only
- squamous epithelial carcinoma in cervical lymph nodes only
- adenocarcinomas with colon and rectal cancer profiles (CK20+, CK7-, CDX2+)
- neuroendocrine carcinomas
- men with sclerotic bone metastases and increased PSA
- very limited spreading
Liver metastases, metastases to multiple organs, and reduced health condition are poor prognostic factors, in addition to high LD and ALP, as well as low albumin and lymphopenia. In addition, men have a poorer prognosis than women (2,3).
Five-year relative survival for patients with cancer of unknown primary site, in percent, during the diagnosis period 1974–2013.
Source: Cancer Registry of Norway
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References on CUP
- Hemminki K, Bevier M, Hemminki A, Sundquist J. Survival in cancer of unknown primary site: population-based analysis by site and histology. (2012) Ann Oncol; 23: 1854-63.
- Pavlidis N, Pentheroudakis G. (2012) Cancer of unknown primary site. The Lancet. 14; 379: 1428-35.
- Bahrami A, Truong LD, Ro JY. (2008) Undifferentiated tumor: true identity by immunohistochemistry. Arch Pathol Lab Med; 132: 326-48.
- Pentheroudakis G, Golfinopoulos V, Pavlidis N. (2007) Switching benchmarks in cancer of unknown primary: from autopsy to microarray. Eur J Cancer; 43: 2026-36.
- Jerusalem G, Rorive A, Ancion G, Hustinx R, Fillet G. (2006) Diagnostic and therapeutic management of carcinoma of unknown primary: radio-imaging investigations. Ann Oncol; 17 Suppl 10: x168–76
- Fizazi K, Greco FA, Pavlidis N, Pentheroudakis G; ESMO Guidelines Working Group. (2011) Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol; 22 Suppl 6:vi64-8.
- Pavlidis N. (2012) Optimal therapeutic management of patients with distinct clinicopathological cancer of unknown primary subsets. Ann Oncol; 23 Suppl 10:x282-x285.
- Cancer in Norway 2013, Cancer Registry of Norway, Institute of Population-based Research. Oslo, Norway
- Brustugun OT, Helland Å. (2014) Rapid reduction in the incidence of cancer of unknown primary. A population-based study. Acta Oncol; Jan 53(1):134-7.
Diagnostics of CUP
As a starting point, it is always recommended to do a medical work-up to identify a potentially curable cancer, or to diagnose as accurately as possible in order to influence the choice of treatment (4, 5, 6).
The definition of this disease group indicates that tests have already been performed, for example, blood tests as well as histological and radiological examinations.
For rapid disease progression and poor health status, a time-demanding search for the primary tumor is not indicated, if palliative supportive care is the only treatment alternative.
Localization of metastatic lymph nodes may indicate where the primary tumor originated. Some examples may be:
- Metastatic tumors to the neck often originate from the head/neck area.
- Breast cancer should be considered in middle-aged women with axillary tumors,.
- For metastatic tumors in the groin, the primary tumor may have originated from the anus or gynecological area.
- Spreading to retroperitoneal lymph nodes may originate from prostate, testicular, or ovarian cancer.
- Thyroid, breast, or prostate cancer should be considered for bone metastasis.
- Lymphoma should be considered for lymph node metastases.
- For metastasis in the lungs or liver, the primary tumor can originate from any location.
These examinations should be performed at minimum:
- Thorough anamnesis (including possible risk factors, as well as examination regarding any possibly removed moles)
- Clinical examination (including head/neck, rectal exploration, and breast palpation)
- Histology assessment including relevant immunohistochemical panels (3)
- Laboratory testing (standard hematology and biochemistry)
- CT thorax/abdomen/pelvis, mammography for women
If the histological assessment and/or clinical examination points in a certain direction, this may be conclusive evidence for choice of radiological and other diagnostic procedures. Additional examinations including MRI (including breast MRI in women with axilary node metastsis), skeletal scintigraphy, ultrasound (especially of testicles in young men) and PET should be performed based on individual assessments, but are not performed routinely. Endoscopy and gynecological examination should also be considered.
Applicable tumor markers in serum include alpha-fetoprotein (AFP), human choriongonadotropin (hCG), chromogranin A and PSA to exclude extragonadal germinal cell tumors, neuroendocrine tumors and prostate cancer. CEA and CA125 are relatively unspecific markers for adenocarcinomas and will rarely be of value, but may point in the direction of ovarial/germinal cell cancer in women with abdominal or mediastinal metastases.
For suspicion of a primary tumor in the head/neck, the following is also performed:
- Ear/nose/throat exam including nasoscopy, epipharyngoscopy, and flexible laryngoscopy
- Fine needle cytology, possibly biopsy. If a biopsy is necessary, an incision should be made such that the scar can be removed in a later lymph node resection.
Evaluation of general health condition (WHO PS status) and LD level are of significance in determining a prognosis. WHO class 0-1 and normal LD indicate a relatively good prognosis, which should benefit from combination chemotherapy.
Fine needle biopsy is a simple and cost-effective method causing little discomfort for the patient.
It can be used for palpable tumors in patients with cancer or where possible spreading can be confirmed or excluded. It can also be used on patients without a previous cancer diagnosis, either to achieve a diagnosis or to determine further relevant examinations. This method gives the quickest result/diagnosis.
- Fine needle biopsy is performed on palpable surface nodes
- To obtain a specimen which provides a basis for making a diagnosis.
- 1 x 20 ml syringe filled with air
- Cannulas, size depending on lesion
- Colorless chlorhexidine, 1 mg/ml
- 3–4 slides
- 3–4 cover glasses
- Labels to mark slides and RPMI-glass
- Staining solutions (haemacolor)
- Water for rinsing
- 6 tubs for staining/rinsing
- Gauze pads
- Fan or hairdryer for drying specimens
- Microscope, 10X or 20X objective
- Examination table
Explain to the patient precisely what will happen and why.
The patient should sit or lie on the examination table - whatever gives the best result.
- Wash the area for puncture with colorless chlorhexidine 1 mg/ml.
- Allow the skin to dry.
- Palpate the node/tumor.
- Find the best position for puncturing.
- Fix the lymph node/tumor between your fingers.
- Puncture quickly through the skin with the cannula.
- Move the cannula back and forth into the node in different directions (approximately 2–3 movements/second).
- When (after 3–4 seconds) the material is visible in the upper part of the cannula passage, the cannula is retrieved.
- Put a pressure on the point of puncture if needed.
- Connect the cannula to the syringe filled with air.
- Carefully spray the specimen from the cannula onto the slide.
- If the suspicion of lymphoma or tumor is difficult to confirm, repuncture and put some material in the RPMI medium from a new puncture (for flow cytometry/molecular examination etc. Which type of examination is determined after microscopic examination.)
- Smear the specimen on the slide.
- Dry the specimen under a fan or hairdryer.
- Staining: fixation fluid with methanol + haemacolour + rinsing in water
- 5 dips in fixation fluid. Allow the solution to drip off on paper.
- 3 dips in staining solution 1.
- 6 dips in staining solution 2. Allow the solution to drip off onto paper.
- Rinse in two tubs with clean water.
- Examine the specimen under the microscope with a 10X or 20X objective.
- After the puncture, slight bleeding may occur.
- Other complications are very rare.
Positron Emission Tomography (PET) is a nuclear medical examination method. PET is a well-documented, well-established and very useful tool in oncological imaging.
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)
- To provide concrete diagnostic information that will provide a basis for the choice of the best possible treatment.
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.
- 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.
- 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 .
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.
- 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
- 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.
Treatment of CUP
Most patients appear to have a carcinoma of unknown primary site. Other tumors may be difficult to classify. Some cancer forms are sensitive to chemotherapy, but multiple studies have concluded that chemotherapy does not increase survival for patients with CUP. The realistic benefit of treatment is usually symptom-relief and improvement in quality of life, but only a moderate improvement in survival in patients with good prognostic signs.
ESMO (European Society for Medical Oncology) has created a treatment recommendation for the unknown primary site diagnosis based on histology and extent (6,7).
Surgery of CUP
Appropriate surgeries for metastases to the spine are mainly laminectomy, decompression, and spinal fusion. In peripheral bone, orthopedic surgery may be appropriate for manifest fractures, threatening fractures, or in some cases of pain.
For certain manifestations of metastasis (for example lymph node station or a solitary brain metastasis) surgery may be considered.
Drug therapy of CUP
Chemotherapy as a treatment alternative is assessed based on the patient's age and general condition of health, as well as tumor histology and localization. Due to relatively low response rates and little effect on survival (if any), elderly patients and patients with poor general status should not be treated with chemotherapy.
If there is indication for chemotherapy, platinum or taxane-containing duo combinations are often used. Second-line chemotherapy is generally not recommended.
|Suggested treatment regimens for selected cancer types of unknown origin
|Unknown origin types
Mild differentiated carcinosis,
mainly lymph node involvement
|Peritoneal carcinosis in women
As for ovarian cancer FIGO III: platinum and taxane.
|Isolated axillary metastasis in women
||As for breast cancer with equivalent lymph node affection including mastectomy or breast irradiation, lymph node dissection and adjuvant treatment.
|Squamous cell carcinoma in neck glands
Radiation therapy for N1-N2 disease.
|| For more advanced disease, cisplatin-based induction therapy is recommended.
| Sclerotic bone metastasis with raised PSA
|| As for prostate cancer with endocrine therapy and possibly palliative bone irradiation.
| Adenocarcinoma with colon cancer profile
|| Combination therapy such as colon cancer therapy.
| Neuroendocrine differentiation
|| Poorly differentiated variants should be considered for treatment with platinum-containing drugs (such as PV), possibly a platinum/taxane combination. Well differentiated variants can be attempted to be treated with somatostatin analogs or interferon, or chemotherapy.
| Mid-line distribution
|| With suspicion of extragonadal germinal cell tumors, platinum-containing chemotherapy is recommended.
|Liver, bone or multiple metastases from adenocarcinoma
||Mildly toxic palliative chemotherapy or supportive care alone are recommended.
Radiation therapy of CUP
CUP in the head/neck area is treated with radiation therapy as for primary head/neck cancer and may cure the disease. The epipharynx is always included in the radiation field.
Palliative radiation therapy is otherwise appropriate for symptom-causing metastases and is normally given as a single fraction of 8 Gy, or fractionated over two weeks as 3 Gy x 10.
The goal of treatment is:
- pain management
- local control
- fracture prevention
- prevention of neurological symptoms
Stereotactic radiation treatment (15-25 Gy x 1) to the brain is appropriate for 1-3 brain metastases of greatest diameter < 4 cm.
Radiation therapy should be fractionated depending on expected survival time, localization, field size, and assumed diagnosis (assumed radiosensitivity).
Complication treatment of CUP
Cancer treatment causes side effects to varying degrees.
It may be necessary to provide supportive care in order for the patient to complete and obtain 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.
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.
- Nausea induced by chemotherapy drugs.
- Prevention and treatment of nausea and vomiting.
|Chemotherapies according to emetic potential
|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
|FEC-60 og FEC-100
(fluorouracil, epirubicin, cyklophosfamide)
| ENAP (etoposide, mitoxsantrone, cytarabine, prednisolone)
|ABVD (doxorubicin, bleomycin, vinblastine, dakarbazine
| FLv (fluorouracil)
| FuMi (fluorouracil, mitomycin)
|CHOP (cyclophosfamide, doxorubicin, vincristine, prednisolone)
|CHOEP (cyclophosfamide, doxorubicin, vincristine, etoposide, prednisolone)
|Methotrexate weekly dose
||ECO/ACO (epirubicin/doxorubicin, cyclophosfamide, vincristine)
||EOX (epirubicin, oxaliplatin, capecitabine)
||EPOCH-F (etoposide, prednisolone, vincristine, cyclofosfamide, doxorubicin, fludarabine)
||EPOCH-F (etoposide, prednisolone, vincristine, cyclophosfamide, doxorubicin, fludarabine)
||FLIRI (fluorouracil, irinotecan)
||FLOX (fluorouracil, oxaliplatin)
||IGEV (ifosfamide, gemcitabine, vinorelbine)
|| IME (ifosfamide, methotreksate, etoposide)
|| Vorphase (cyclophosfamide)
- 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.
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.
- 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.
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.
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.
In the event of conditional nausea, diazepam or other tranquilizers may be considered. Diversion or desensitization can be tried in more serious cases.
Ondansetron can have a constipating effect. Use of a laxative for several days should be considered.
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.
Weaning of nicotine in connection to cancer treatment.
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.
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.
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
|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.
- Headache, dizziness, nausea, flatulence and hiccup.
- Irritation in the mouth and esophagus using chewing gum/ lozenges/inhalator
- Skin irritations while using patches.
- 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%.
- Dry mouth, nausea, insomnia, hypersensitivity reactions and seizures (convulsions)
- 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.
- Nausea, sleep disturbances, headache, constipation, flatulence and vomiting
- 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
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.
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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.
- Cancer treatment (chemotherapy, radiation, surgery).
- Maintain nutritional status in order for the patient to have the best possible conditions for implementing treatment.
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 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 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 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.
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.
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).
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.
ImplementationAll 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 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.
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.
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.
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.
The patient's nutrition status should be monitored at follow-up visits after the end of treatment.
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.
- Hemoglobin 13.4–17 g/dl
- Platelets 145–348 109/l
Assessment for a blood transfusion based on:
- 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
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.
- Complete the planned treatment
- Ensure hemostasis
- Ensure adequate oxygen transport to peripheral tissue.
- Maintain intravascular fluid volume for adequate circulations of vital organs
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%.
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.
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
Before the first blood transfusion, the following blood tests are performed:
Every three days, and as needed, pre-transfusion tests are taken.
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.
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
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:
- feeling of heat in the face
- breathing difficulty
- fall in blood pressure
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.
Hemoglobin and thrombocytes are checked.
If poor effect of platelet transfusion, platelet value should be checked after approximately one hour. The value should have increased by approximately 30x109
/l or more after a standard dose.
If the increase is drastically less, the cause may be:
- Abnormally high consumption. This is an indication for more frequent transfusions.
- Antigens against HLA or platelet-specific antigens. The patient must be examined in cooperation with the blood bank to find compatible donors.
Febrile neutropenia 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.
- A patient with neutropenia and simultaneously fever or clinical suspicion of systemic infection
- Avoid septicemia.
- The patient is able follow the planned scheme of treatment.
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.
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
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.
- 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.
- 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:
- 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.
Observe for symptoms of a new infection.
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.
- 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
- Maintain treatment intensity
The patient should be adequately informed about the treatment.
- 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.
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.
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
Chemotherapeutic drugs are separated into three groups according to the degree of toxicity:
- Tissue irritant
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.
- Intravenous extravasation of cytotoxic drugs.
- Limit damage of tissue from intravenous extravasation.
Non-cytotoxic drugs or non-irritants
Non-cytotoxic/non-irritant drugs normally do not cause skin necrosis.
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 are categorized into subgroups according to the mode of damage. This categorization is important for the choice of treatment.
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:
- Alkylating drugs
For doxorubicin and mitomycin, progrediating tissue damage has been reported over weeks, and in some cases, months after intravenous extravasal injection.
This group of medications can lead to cell death through other mechanisms than DNA binding drugs. This group is divided into:
|Chemotherapy cytotoxicity (1)
Irritant, can cause flaking or inflammation
|Non-cytotoxic or non-irritant
* = 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.
- Allwood M, Stanley A WP. The Cytotoxics Handbook. Ed. 4th ed. 2002. 2001
- Ekstravasation Guidelines Implementeringsværktøj [Online] 2007 [hentet 10. mars 2009]; Tilgjengelig fra URL: http://www.cancerworld.org/CancerWorld/getStaticModFile.aspx?id=2726
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.
Flow chart for treatment of intravenous extravasation of cytotoxic drugs:
- 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 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.
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.
A package costs about NOK 100,000.-. If the expiration date runs out, the drug is replaced by the pharmaceutical company free of cost.
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 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).
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.
- Ekstravasation Guidelines Implementeringsværktøj [Online] 2007 [hentet 10. mars 2009]; Tilgjengelig fra URL: http://www.cancerworld.org/CancerWorld/getStaticModFile.aspx?id=2726
- Hasinoff BB. Dexrazoxane use in the prevention of anthracycline extravasation injury. Future Oncol 2008; 2006: 1–15.
- Statens legemiddelverk. Preparatomtale. 2008
- 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.
- 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.
- Clinical Pharmacology© 2008 database. Hyaluronidase. 2008.
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.
Follow-up care after treatment of CUP
The patient is usually followed up by their local hospital or by their primary doctor as required. If chemotherapy is given, the effect of treatment should be evaluated after two to three courses. Quality of life should be highly emphasized in the assessment of patient benefit.
It is important to be aware of the increased psychological burden that may be a result of the time required for the medical work-up, the lower specificity of treatment compared to cancers of known origin, and that the prognosis is generally poor. Both the patient and family/friends may therefore have a greater need for psychosocial follow-up.
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.
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.
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.
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.
- 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.
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.
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.
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.
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.
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.
- 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