Most patients are advised to contact their oncology centre directly if they experience any side effects. Patients should also be advised to report any side effects to their oncology team when they are reviewed in clinic.
Patients should be advised to bring information about their treatment (e.g. which drugs they are receiving, when the last dose was administered) if they need to be seen in an emergency setting.
Oral chemotherapy carries the same risks as IV chemotherapy and oral targeted drugs also have significant toxicities that should not be underestimated.
Principles of toxicity management
Supportive care
Supportive care aims to minimise treatment toxicities and should always be considered as it is important to try to maintain dose intensity.
Supportive care may include premedication to prevent chemotherapy-induced nausea and vomiting, prophylactic GCSF to prevent profound or prolonged neutropenia or treatment directed at toxicities when they occur, for example loperamide for diarrhoea.
Dose reductions
Drugs may be given at a fixed dose or the dose may be calculated according to a patient’s body surface area, weight or renal function.
A dose reduction may be indicated under certain circumstances, for example severe toxicity, cumulative toxicity (e.g. peripheral neuropathy secondary to oxaliplatin), repeated dose delays due to toxicity, or in accordance with haematological or biochemical parameters.
The amount by which a dose should be reduced is usually indicated in local guidelines/trial protocols. This is usually expressed as a percentage (e.g. a 25% dose reduction).
In general, dose reductions due to toxicity should not be re-escalated in subsequent cycles.
Dose delays
Doses may be delayed because a patient is too unwell for treatment at the scheduled time (e.g. due to infection). Doses may also be delayed in asymptomatic patients due to abnormal haematological or biochemical parameters (e.g. low platelet or neutrophil counts).
Most chemotherapy protocols require haematological values to be above specified cut-off points for chemotherapy to be administered (e.g. platelets may need to be ≥ 75 or 100 and neutrophil counts may need to be ≥ 1.0 or 1.5 depending on the chemotherapy regime). If the values are below these set parameters then treatment may need to be delayed until their counts improve (typically a delay of one week for practical purposes).
Some schedules involve weekly chemotherapy and therefore a dose may be completely omitted rather than delayed.
Discontinuation of one or more drugs
If toxicities cannot be managed successfully following implementation of one or more of the above strategies, then treatment may need to be discontinued.
Some toxicities may be so severe that re-challenging the patient with a particular drug is not appropriate.
If patients are receiving more than one drug then it is important to consider the most likely cause of toxicity. It may not be necessary to reduce the dose or discontinue all of the drugs in a multi-drug regime.
Effects of dose reductions and/or delays on treatment efficacy
Chemotherapy/targeted therapies
The dose intensity is the amount of drug delivered per unit time (mg/m2/week).
Reduced dose intensity may lead to reduced treatment efficacy. A clear relationship between dose intensity and clinical outcomes has been demonstrated in a number of cancers.
Radiotherapy
Radiotherapy causes tumour cell death, but the surviving cells grow more rapidly and repopulate the tumour. This repopulation becomes accelerated approximately 28 days after starting radiotherapy.
Therefore, any delays in treatment that lengthen the overall treatment duration lead to increased tumour repopulation and can cause treatment failure. This is particularly important in certain tumour types (e.g. tumour control in patients with squamous head and neck cancers decreases by 1–2% for each day that treatment is prolonged).
If treatment is delayed for any reason then the schedule may need to be adjusted to compensate for the missed fractions.
The balance between toxicity management and maintaining dose intensity
Consider the aims of treatment when assessing and managing treatment-induced toxicity:
In patients receiving treatment with curative intent, it is particularly important to try to minimise dose delays and reductions whenever possible.
In patients receiving palliative treatment, quality of life is the most important consideration.
Consider the magnitude of benefit from chemotherapy and balance this with the risks of toxicity (including cumulative toxicities, e.g. permanent peripheral neuropathy).
References
Dale RG, Hendry JH, Jones B, Robertson AG, Deehan C, Sinclair JA. Practical methods for compensating for missed treatment days in radiotherapy, with particular reference to head and neck schedules. Clinical Oncology (R Coll Radiol). 2002. 14(5): 382–93.
Foote M. The importance of planned dose of chemotherapy on time: do we need to change our clinical practice? Oncologist. 1998. 3(5): 365–8.
Kim JJ, Tannock IF. Repopulation of cancer cells during therapy: an important cause of treatment failure. Nature Reviews Cancer. 2005. 5(7): 516–25.
Nguyen LN, Ang KK. Radiotherapy for cancer of the head and neck: altered fractionation regimens. Lancet Oncology. 2002. 3(11): 693–701.
Abnormal liver function tests
Abnormal liver function
Deranged liver function can present on blood biochemistry or clinically.
The investigations that are most commonly used are ALT, AST, ALP, GGT and bilirubin. The grading of abnormalities in LFTs is shown in Table 3.1.
Liver synthetic function is best assessed using PT or INR and serum albumin.
Significantly raised ALT, AST and ALP with a normal or near normal bilirubin, is suggestive of an intrahepatic (‘hepatitic’) cause of liver dysfunction.
Significantly raised ALP and bilirubin with a normal or mildly elevated AST or ALT, is suggestive of an obstruction in the biliary tree causing liver dysfunction (‘obstructive’ liver dysfunction).
Table 3.1 CTCAE (V4.03) grading of abnormal liver function tests.
> 1–1.5 x ULN; > 1–1.5 times above baseline if anticoagulated
2
> 3.0–5.0 x ULN
> 2.5–5.0 x ULN
> 1.5–3.0 x ULN
> 2.5–5.0 x ULN
> 1.5–2.5 x ULN; > 1.5–2.5 times above baseline if anticoagulated
3
> 5.0–20.0 x ULN
> 5.0–20.0 x ULN
> 3.0–10.0 x ULN
> 5.0–20.0 x ULN
> 2.5 x ULN; > 2.5 times above baseline if anticoagulated
4
> 20.0 x ULN
> 20.0 x ULN
> 10.0 x ULN
> 20.0 x ULN
ULN = upper limit of normal.
Assessment
History:
Remember to take a drug history (including herbal and over-the-counter preparations).
Note any recent illnesses or procedures.
Symptoms/signs:
Hepatitic liver dysfunction: malaise, jaundice, icteric sclerae, and pruritus.
Obstructive liver dysfunction: as above, plus pale stools and dark urine.
Associated symptoms, for example fever.
The Child-Pugh score and the Model for End-Stage Liver Disease (MELD) scores can be used to evaluate risk of mortality in chronic liver dysfunction. The MELD score uses serum bilirubin, creatinine and INR. The Child-Pugh Score uses serum bilirubin, INR, albumin and the presence of ascites or hepatic encephalopathy.
Causes of hepatitic liver dysfunction
Intrahepatic malignancy
Anti-cancer drug toxicity
Tyrosine kinase inhibitors can cause severe hepatotoxicity, particularly sunitinib, pazopanib, lapatinib and regorafenib:
Onset of toxicity is usually within the first eight weeks of use, but can be delayed.
Usually reversible on withdrawal of drug.
Long-term complications such as cirrhosis are uncommon.
Abiraterone.
Tamoxifen.
Other drugs
Corticosteroids (rare).
Antibiotics.
Herbal and dietary supplements.
Paracetamol.
Biliary sepsis can cause liver dysfunction, but is more likely to cause an obstructive pattern of biochemical abnormalities.
Severe sepsis and hepatic ischaemia.
Portal vein thrombosis.
Viral hepatitis:
Reactivation of hepatitis viruses can occur with chemotherapy regimens containing rituximab and steroids.
It is imperative that hepatitis serology is negative prior to commencing these treatments.
Reactivation of the hepatitis B virus and subsequent fulminant hepatitis has a higher mortality rate than acute hepatitis B.
Radiofrequency ablation (RFA) of HCC or liver metastases.
Transarterial chemo-embolisation (TACE) of HCC or liver metastases.
SIRspheres® treatment for liver metastases.
Causes of obstructive liver dysfunction
Extrahepatic obstruction of biliary tree:
Pancreatic head mass
Porta hepatis lymphadenopathy
Ampulla of Vater lesion
Blockage of common bile duct (CBD) stent
CBD stricture (benign or malignant)
Other biliary pathology, for example primary biliary cirrhosis, primary sclerosing cholangitis
Gallstones
Intrahepatic obstruction of biliary tree:
Cholangiocarcinoma
Intra-hepatic malignant disease – primary or metastatic disease
Steatohepatitis
Oxaliplatin-induced sinusoidal obstruction (rare)
Capecitabine can cause an isolated hyperbilirubinaemia
Gilbert’s syndrome
Investigations
Suspected biliary obstruction – USS of liver and biliary tree to establish the level and cause of obstruction. If ultrasound is not helpful, consider CT or MRI.
Suspected venous thrombosis – doppler scans of the hepatic and portal veins.
If no clear obstructive cause is found, evaluation of conjugated and unconjugated bilirubin may determine whether there is a pre-hepatic cause of hyperbilirubinaemia.
Management
Consider stopping hepatotoxic medication.
Administer specific antidote if appropriate (e.g. N-acetylcysteine for paracetamol overdose).
Abnormal clotting may need to be corrected if there is a significant risk of bleeding or a procedure is planned.
Treat the underlying cause if possible.
Seek hepatology advice if significant liver dysfunction or evidence of acute liver failure.
Biliary obstruction:
Extrahepatic: consider ERCP and retrograde biliary stenting.
Intrahepatic: consider percutaneous drainage and stent insertion.
Patients with biliary obstruction are at risk of biliary sepsis and so there should be a low threshold for initiation of antibiotics until the obstruction is relieved.
Prescribing and liver function
Caution should be exercised when prescribing chemotherapy for patients with intrahepatic disease and compromised liver function. Drugs may be contraindicated or require dose reductions. Advice from pharmacy may be required.
Patients with Gilbert’s syndrome or an isolated hyperbilirubinaemia require an irinotecan dose modification as this may represent a liver enzyme polymorphism that enhances irinotecan toxicity.
Consider the risks of thrombocytopenia and bleeding if liver dysfunction is accompanied by deranged clotting.
Other relevant sections of this book
Chapter 9, sections on biliary drains and stents, chemoembolisation, radioembolisation (SIR-Spheres®), radiofrequency ablation (RFA)
References
Asrani SK, Kim WR. Model for end stage liver disease: end of the first decade. Clinics in Liver Disease. 2011. 15(4): 685–698.
Cholongitas E, Papetheodoridis GV, Vangeli M, Terreni N, Patch D, Burroughs AK. Systematic review: the model for end-stage liver disease – should it replace Child-Pugh’s classification for assessing prognosis in cirrhosis? Alimentary Pharmacology and Therapeutics. 2005. 22(11–12): 1079–89.
King PD, Perry MC. Hepatotoxicity of chemotherapy. Oncologist. 2001. 6(2): 162–176.
Ohishi W, Chayama K. Prevention of hepatitis B virus reactivation in immunosuppressive therapy or chemotherapy. Clinical and Experimental Nephrology. 2011. 15(5): 634–40.
Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Safety. 2013. 36(7): 491–503.
Vietor NO, George BJ. Oxaliplatin-induced hepatocellular injury and ototoxicity: a review of the literature and report of unusual side effects of a commonly used chemotherapeutic agent. Journal of Oncology Pharmacy Practice. 2012. 18(3): 355–9.
Alopecia
Alopecia is defined as a disorder characterised by a decrease in density of hair compared to normal for a given individual at a given age and body location. The grading of alopecia is shown in Table 3.2. Hair loss may affect patients’ eyebrows, eyelashes, nasal hair, moustache, beard, chest, underarm, leg and pubic hair, as well as their scalp.
Hair loss of up to 50% of normal for that individual that is not obvious from a distance but only on close inspection; a different hair style may be required to cover the hair loss but it does not require a wig or hair piece to camouflage.
2
Hair loss of > 50% normal for that individual that is readily apparent to others; a wig or hair piece is necessary if the patient desires to completely camouflage the hair loss; associated with psychosocial impact.
3
—
4
—
5
—
Symptoms and signs
Anagen effluvium:
Involves the loss of growing (anagen) hairs. The majority of hairs are in this phase and therefore this causes profound hair loss.
Usually starts within two weeks and is usually nearly complete within 1–2 months after starting treatment.
Telogen effluvium:
Usually results in hair thinning of < 50% of the scalp.
This is usually worst 3–4 months after starting chemotherapy and although distressing for the patient is less noticeable to others.
Consider the psychological impact, which can be significant (and cause some patients to decline potentially curative treatment). Hair loss is one of the most distressing side effects of chemotherapy for both women and men, serving as a constant physical reminder of their cancer, identifying them to others as a cancer patient and affecting their body image and self-esteem.
Causes
Chemotherapy:
Severity depends on drug combination, dose, duration, route of administration and the patient’s individual response.
Drugs that cause alopecia include: doxorubicin, daunorubicin, epirubicin, cyclophosphamide, ifosfamide, etoposide, topotecan, irinotecan, vincristine, vinblastine, bleomycin, paclitaxel, docetaxel and 5-FU (mild).
Targeted drugs:
EGFR inhibitors can cause changes in hair texture, slower growth of scalp hair, trichomegaly of eyelashes and both scarring and non-scarring alopecia.
Dasatinib and sunitinib can cause reversible hair depigmentation but do not cause alopecia.
Radiotherapy: causes hair loss within the radiation field.
Management
Scalp cooling
Scalp cooling with cryogel caps or caps connected to cooling devices can limit hair loss in 50–80% of patients. It may be less effective for patients with impaired liver function due to the potential for persistently high circulating drug levels.
Scalp cooling causes vasoconstriction, which reduces the amount of drug received by hair follicles. The decreased temperature also leads to a reduction in the metabolic rate of hair follicles.
Scalp cooling can be uncomfortable and also leads to longer hospital stays as cooling needs to start at least 15 minutes prior to chemotherapy and continue for at least 30 minutes after chemotherapy.
Scalp cooling is not suitable for all patients (e.g. patients receiving very high dose chemotherapy or patients having continuous chemotherapy via a pump). There is a theoretical risk of scalp metastases, but the risk is very small. Scalp cooling is not recommended for patients with haematological malignancies.
General management
Avoid bleaching, perming or colouring hair as this can weaken it and worsen hair loss.
Protect the scalp from heat/sun and the cold.
Camouflage hair loss with a wig, scarf, hat or turban.
Wigs:
May be made of synthetic materials or animal or human hair.
Some patients prefer to obtain a wig before hair loss occurs so that it can be matched to their normal hair colour and texture.
NHS wigs are free in Wales and Scotland and for certain groups of patients in England.
Consider using false eyelashes/eyebrows, redrawing eyebrows with an eyebrow pencil or specialist eyebrow tattoos.
Hair re-growth
Hair usually starts re-growing 1–3 months after completing chemotherapy. Permanent alopecia following chemotherapy is rare but can occur.
Hair may grow back a different colour, texture or waviness.
Hair can usually be tinted or permed once it is about three inches long if the patient’s scalp is healthy. Advise patients to seek professional advice to check that colours/perms, etc. will not damage the hair or cause an allergic reaction.
A 2% topical minoxidil solution is not effective in preventing hair loss but has shown promise in accelerating hair regrowth following chemotherapy.
Hair usually starts to grow back within 3–6 months of finishing radiotherapy but this depends on the radiation dose and duration. However, hair does not always grow back after radiotherapy, may grow back in patches or not as thickly as before.
References
Chon SY, Champion RW, Geddes ER, Rashid RM. Chemotherapy-induced alopecia. Journal of the American Academy of Dermatology. 2012. 67(1): e37–47.
Katsimbri P, Bamias A, Pavlidis N. Prevention of chemotherapy-induced alopecia using an effective scalp cooling system. European Journal of Cancer. 2000. 36(6): 766–71.
Anaemia is common amongst cancer patients, affecting over 40% of patients. The severity of anaemia due to treatment varies between individual patients and the grading of anaemia is shown in Table 3.3.
Anaemia can significantly impact on quality of life and influence the biology of the tumour and its response to treatment, particularly in radiotherapy. Cancer-related anaemia also has prognostic value, with reduced haemoglobin levels at the start of treatment associated with worse outcomes.
Causes
Anaemia is usually multi-factorial and can be broadly divided into three categories which are intrinsically intra-linked. Comorbidities are also important, with hereditary anaemia, chronic renal insufficiency and inflammatory conditions contributing to anaemia. The categories are:
Blood loss:
Overt or occult blood loss: GI, head and neck, genitourinary, uterine cancers
Bleeding into tumours: for example sarcoma, bulky melanomas, hepatomas, ovarian cancer and adrenocortical tumours
Coagulopathies: resulting from cancer or treatment
Reduced red cell production:
Bone metastases: stem cell destruction secondary to invasion – most commonly seen in breast and prostate cancer patients
Secondary to chemotherapy, particularly with platinum agents – most commonly seen in lung and ovarian cancer patients
Secondary to radiotherapy – bone marrow stem cells are very sensitive to radiation
Haematological malignancies
Cytokine or chemical mediated mechanism by tumour
Surgical bowel resection: leading to malnutrition or malabsorption of essential vitamins/nutrients (e.g. B12 or folate)
Reduced red cell survival:
Antibody production: for example CLL, lymphoma and some solid tumours may lead to immune haemolytic anaemia
Hypersplenism
Microangiopathic haemolytic anaemia: resulting from procoagulant factors released by some solid tumours (e.g. gastric, breast, pancreatic, colon and prostate cancers)
Symptoms and signs
The symptoms experienced vary depending on the rate of blood loss and the patient’s capacity to accommodate this. Older patients and those with coronary artery disease may present with symptoms of hypoxia to the brain and heart.
Bone marrow evaluation – important for persistent anaemia
Urine dipstick, faecal occult blood
Management
General management
Treat underlying cause and stem any bleeding
Address nutrition
Aim to maintain an Hb of ≥ 120 g/L in patients undergoing radical radiotherapy for head and neck, oesophageal or cervical cancer. An Hb < 120 g/L may reduce treatment effectiveness.
Red cell infusion
Urgent transfusion in severe haemorrhage, electively planned for chronic symptomatic anaemia.
One adult unit should raise the haemoglobin level by 10 g/L (or 1 g/dL).
Risks and side effects – transfusion reactions, congestive cardiac failure, iron overload, viral or bacterial infection.
Some patients may require irradiated and/or CMV negative blood:
Irradiated blood is required for:
All patients with Hodgkin’s lymphoma
After treatment with fludarabine, pentostatin or cladribine
Stem cell transplant patients from prior to harvesting and for six months post-transplant until lymphocytes > 1.
CMV negative blood is required for:
All new patients with AML, ALL, non-Hodgkin’s lymphoma and CML and other candidates for stem cell transplant
CMV negative stem cell transplant recipients
CLL patients < 70 years (unless not a candidate for alemtuzumab)
Pregnant women
Erythropoietin-stimulating agents (ESA)
ESA initially demonstrated reduced blood transfusion rates and increased quality of life but Phase III trials have shown mixed results.
Associated with increased mortality during treatment and thereafter; increased venous thrombo-embolism (VTE) and possible tumour progression (although this has been contested more recently).
NICE guidelines (2008) – for use in ovarian cancer patients with Hb < 80 g/L or in severe persistent anaemia without ability to transfuse blood. This guideline is currently under further review.
Current advice is to use only in anaemia secondary to cancer treatment and to use with caution in curative patients. Further research is required regarding the safety of ESAs, particularly into the possibility of an association with tumour progression.
Iron replacement
Iron supplementation may be required for anaemic patients.
Data suggest IV iron concomitantly with ESA may improve Hb response compared to oral iron or no iron.
Oral iron is limited by oral tolerance (primarily GI side-effects) and there is debate over its effectiveness.
Refusal of blood products
Some patients will have concerns about the use of blood products. This may stem from a concern regarding the complications of blood transfusion, such as reactions or infections, or a religious belief. The largest community within Britain who do not wish to receive blood products are the Jehovah’s Witnesses.
In these circumstances, the wishes of the patient should be sought early. Alternative products may be discussed if appropriate, such as albumin or coagulant factors. Each person may have a different view on each individual product.
The GMC is clear that a patient with capacity should have their wishes respected. There should be a clear discussion about the consequences of refusing treatment and this should be recorded accurately in the patient’s notes. A patient with capacity may decline any treatment, independently of the consequences.
Treatment
In emergency situations check if an advanced directive is in the notes or carried by the patient. This should be respected. Friends or relatives may accompany a patient unable to give or withhold consent; if they raise concern that treatment should not be given then appropriate measures should be undertaken to check if there is an advanced directive in place.
Elective surgery may be undertaken; this should be in close liaison with the patient, a liaison officer and the blood transfusion service.
Palliative care
In advanced cancer, up to 70% of patients are anaemic. The utility of blood transfusion in these patients should be balanced against symptoms and prognosis. Blood transfusion has inherent risks and the logistics of administering transfusion may not be appropriate in terminal care.
It was noted in a recent Cochrane review that fatigue and dyspnoea may quickly dissipate following blood transfusion but this effect starts to reduce after approximately 14 days. There was a noted increase in 14-day mortality after blood transfusion. This has raised the question about the appropriateness of blood transfusion in advanced cancer, particularly within a hospice setting, and further studies are required to identify the benefit on quality of life.
Dicato M and Plawny L. Erythropoietin in cancer patients: pros and cons. Current Opinion in Oncology. 2010. 22(4): 307–311.
Dicato M, Plawny L, Diederick M. Anemia in cancer. Annals of Oncology. 2010. 21(7): 167–172.
General Medical Council. Consent: Patients and Doctors Making Decisions Together. GMC: London. 2008.
McClelland BDL. Handbook of Transfusion Medicine. United Kingdom Blood Service, fourth edition. TSO Publishers: London. 2007.
Mercadante S, Gebbia V, Marrazzo A, Filosto S. Anaemia in cancer: pathophysiology and treatment. Cancer Treatment Reviews. 2000. 26(4): 303–311.
NICE TA142. Anaemia (cancer-treatment induced) – erythropoietin (alfa and beta) and darbepoetin. May 2008.
Preston N, Hurlow A, Brine J, Bennett MI. Blood transfusions for anaemia in patients with advanced cancer. Cochrane Database of Systematic Reviews. 2012, Issue 2. Art No: CD009007. DOI: 10.1002/14651858.CD009007.pub2.
Tonia T, Mettler A, Robert N, Schwarzer G, Seidenfeld J, Weingart O, et al. Erythropoietin or darbepoetin for patients with cancer (review). Cochrane Database for Systematic Reviews. 2012. Issue 12. Art. No: CD003407. DOI: 10.1002/14651858.CD003407.pub5.
Anorexia and nutrition
Anorexia
Loss of appetite (anorexia) is very common, particularly in patients with advanced disease or GI malignancy. The grading of anorexia is shown in Table 3.4.
Subsequent weight loss is distressing for both patients and carers and can be the predominant feature of cachexia.
Definition: a syndrome of ongoing loss of lean muscle mass which is not reversible using standard nutritional intervention and leads to a deterioration in function.
Cachexia correlates with a reduction in performance status, lower tolerance of anti-cancer treatment, increased risk of complications and treatment delays and a reduction in overall survival.
There are no predictive biochemical markers of cachexia, though CRP is recognised as an indicator of systemic inflammation.
Causes of reduced calorific intake
Disseminated malignancy: can cause early satiety, dyspnoea, nausea, ascites and constipation.
Dysphagia or physical GI obstruction.
Anti-cancer and supportive treatments: can affect GI motility, lead to changes in taste and smell, mucositis or nausea/vomiting.
Depression: can influence oral intake and exacerbate weight loss.
Management
General management
Assess oral intake, weight loss and contributory symptoms and address potential reversible factors.
Refer patients to a dietician. A multidisciplinary approach to nutrition is necessary for cachectic patients.
Provide dietary counselling. A variety of low-volume, high-calorie oral supplements are available.
Re-introduction of nutrition by any route after a period of malnutrition may result in refeeding syndrome.
Ingestion of a carbohydrate load can cause acute electrolyte shifts, resulting in clinically significant hypophosphatemia, hypokalaemia, hypocalcaemia, cardiac arrhythmias and systolic heart failure.
Patients may require close monitoring with twice daily blood tests and in-patient electrolyte replacement until feeding is re-established.
Management: artificial nutrition
Patients with refractory cachexia:
Parenteral nutrition in terminally ill patients has not been shown to improve survival or symptom control.
A subset of patients may derive some benefit, for example prevention of delirium, but these patients are yet to be identified.
Complications of artificial nutrition include sepsis and catheter complications.
ASCO guidelines recommend that artificial nutrition should only be considered in patients with a prognosis of at least a month.
Patients without a functional GI tract:
For example patients with malignant bowel obstruction.
Consider parenteral or artificial nutrition – results in a better quality of life for patients with a performance status of ≤ 2 and a survival of > 3 months.
Patients undergoing treatment:
Feeding via an artificial route may be considered in certain clinical situations (e.g. radical chemoradiotherapy in head and neck cancer, chemotherapy in oesophageal cancer) to help patients tolerate therapy.
A systematic review of different artificial feeding routes during head and neck cancer treatment found no difference in weight between NG and PEG fed patients six months following treatment. Due to limited evidence, a preferred feeding route was not recommended.
Management: pharmacological interventions
Corticosteroids: corticosteroids (e.g. methylprednisolone 32–125 mg daily, prednisolone 10 mg daily or dexamethasone 3–8 mg daily) can be beneficial, although usually only for a short number of weeks.
Megestrol acetate: may lead to improvements in appetite and weight but has mixed effects on quality of life and other symptoms.
Medroxyprogesterone acetate: some evidence of improvement in appetite and quality of life.
Other relevant sections of this book
Chapter 3, sections on bowel obstruction, dysphagia, mucositis, nausea and vomiting
Argiles JM, Lopez-Soriano FJ, Busquets S. Mechanisms and treatment of cancer cachexia Nutrition, Metabolism & Cardiovascular Diseases. 2012. 23(Suppl. 1): S19–24.
Dav R, Dalal S, Bruera E. Is there a role for parenteral nutrition or hydration at the end of life? Current Opinion in Supportive and Palliative Care. 2012. 6(3): 365–70.
Dolan EA. Malignant bowel obstruction: a review of current treatment strategies. American Journal of Hospice and Palliative Medicine. 2011. 28(8): 576–82.
Dy SM, Lorenz KA, Naeim A, Sanati H, Walling A, Asch SM. Evidence-based recommendations for cancer fatigue, anorexia, depression, and dyspnea. Journal of Clinical Oncology. 2008. 26(23): 3886–95.
Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncology. 2011. 12(5): 489–95.
Marinella MA. Refeeding syndrome: an important aspect of supportive oncology. Journal of Supportive Oncology. 2009. 7(1): 11–6.
Nugent B, Lewis S, O’Sullivan JM. Enteral feeding methods for nutritional management in patients with head and neck cancers being treated with radiotherapy and/or chemotherapy. Cochrane Database Systematic Reviews. 2010. 17(3): CD007904.
Yavuzsen T, Davis MP, Walsh D, LeGrand S, Lagman R. Systematic review of the treatment of cancer- associated anorexia and weight loss. Journal of Clinical Oncology. 23(33): 8500–8511, 2005.
Ascites
Ascites is defined as the abnormal accumulation of intraperitoneal fluid. The grading of ascites is shown in Table 3.5. Of cancer patients with ascites, 95% have measurable metastatic disease and 90% have peritoneal disease. The presence of ascites is a poor prognostic factor associated with survival of a few months (except in ovarian cancer).
Most commonly associated with ovarian cancer. Also associated with pancreaticobiliary, gastric, oesophageal and breast cancer.
Portal hypertension, splenomegaly or chronic liver impairment may contribute to transudative ascites.
Inferior vena cava obstruction or compression may also contribute to the development of ascites.
Management
There is currently no clear professional guidance on the management of malignant ascites.
Pharmacological interventions
Use of diuretics
Serum albumin – ascites gradient (SAAG):
SAAG = serum albumin – ascites albumin.
Response to diuretics is seen in patients with a SAAG of > 1.1 g/dL or evidence of portal hypertension, but not in those with a SAAG of < 1.1 g/dL.
Start spironolactone at a dose of 50–100 mg daily, with a dose increase every 3–7 days up to a maximum of 400 mg daily as required. Consider adding in 40 mg of furosemide if renal function is still satisfactory. Monitor electrolytes.
Other interventions
Therapeutic paracentesis and permanent peritoneal catheters:
There are no randomised trials comparing paracentesis with diuretics in malignant ascites.
Patients who have significant symptoms (grade 3) or do not respond to medical treatment should be considered for therapeutic paracentesis. Paracentesis results in temporary relief of symptoms for 90% of patients.
Recurrence of ascites following paracentesis has driven the development of permanent peritoneal catheter drainage systems (e.g. PleurX® drains).
Peritoneo-venous shunts:
Allows drainage from the peritoneal cavity into a large vein using tubing with a uni-directional valve.
Haematogenous metastases due to the shunt and tumour growth along the shunt tract have been reported.
Studies have shown a much better outcome with shunts in ovarian and breast cancer and a poor outcome in GI cancer; therefore most literature advises against use in patients with ascites secondary to GI cancer.
Other management approaches
Intraperitoneal chemotherapy:
Intraperitoneal chemotherapy prior to ascitic drainage has been attempted for control of peritoneal metastases and prevention of ascites reaccummulation.
A range of chemotherapeutics have been evaluated (with varying success), including cisplatin, 5-FU, carboplatin, etoposide, doxorubicin, paclitaxel and methotrexate.
This is not in routine UK clinical practice but used as a treatment option in the USA following optimal debulking surgery in ovarian cancer.
Activity of some chemotherapeutics (e.g. cisplatin, carboplatin, doxorubicin and mitomycin C) is enhanced in a hyperthermic medium at 40–43°C.
Best suited to patients with a good performance status and potentially resectable peritoneal disease. Optimal duration, dose and temperature are as yet unknown.
Studies with small numbers of patients have shown control of ascites and potential tolerability, but experience is limited to specialist centres.
Further trials are needed to evaluate the use of surgery followed by HIPEC.
Future agents
Catumaxomab:
A CD3 and Epithelial Cell Adhesion Molecule (EpCAM) monoclonal antibody.
Trials in patients with EpCAM positive tumours and malignant ascites have shown encouraging results with a significantly delayed time to paracentesis. A randomised Phase IIIb study is in process.
Octreotide: Small case series have suggested that octreotide may also control ascites and a Phase III placebo-controlled trial is in process.
Other relevant sections of this book
Chapter 9, section on ascitic drains (paracentesis)
References
Barni S, Cabiddu M, Ghilardi M, Petrelli F. A novel perspective for an orphan problem: old and new drugs for the medical management of malignant ascites. Critical Reviews in Oncology/Hematology. 2011. 79(2): 144–53.
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Bone metastases and osteoporosis
Bone metastases
Bone metastases are very common, particularly in patients with breast, prostate or lung cancer. The most common site of metastasis is the axial skeleton.
Metastases may be predominantly osteolytic (e.g. in lung cancer), predominantly osteoblastic (e.g. in prostate cancer) or both osteolytic and osteoblastic.
Symptoms, signs and complications
Pain and decreased mobility.
Spinal cord compression.
Bone marrow infiltration, which can cause anaemia or pancytopenia due to impairment of bone marrow synthetic function.
Pathological fractures (more common in the femur or proximal parts of other long bones).
Cranial nerve abnormalities (secondary to base of skull metastases).
Hypercalcaemia.
Increased retention of calcium in the bones can also cause hypocalcaemia, leading to secondary hyperparathyroidism and further bone loss.
Investigations
Solitary lesions (especially lytic lesions) should be thoroughly investigated as they may not represent a bone metastasis. If there is doubt about the diagnosis, a biopsy should be considered.
ALP may be raised (but may be normal).
Plain X-rays: have a low sensitivity, particularly for small or early lesions.
Isotope bone scans:
Detect osteoblastic activity, which causes an increase in tracer uptake. Can therefore miss purely osteolytic lesions.
Other causes of increased tracer uptake include: trauma, pelvic insufficiency fractures (e.g. secondary to pelvic radiotherapy or steroids), infection, osteoarthritis or inflammatory disease.
Systemic therapy can lead to increased tracer activity due to increased osteoblastic activity and care should be taken not to mistakenly interpret this as disease progression.
CT and MRI: usually used to image specific body areas, rather than look for widespread metastatic disease. Have a high sensitivity and are also more specific than isotope bone scans, but it can still be difficult to determine whether vertebral fractures are due to osteoporosis or metastases.
PET scans: not widely used, but can help to identify early bone metastases and assess response to treatment.
Management of bone metastases
General management
Consider the patient’s prognosis when deciding on the best treatment modality. Patients may live for years with bone metastases, for example approximately 25% of patients with bone metastases secondary to breast cancer are alive after five years.
If there is a lesion in a long bone it is important to assess the risk of fracture and consider whether elective surgical intervention is indicated.
Pain control can be problematic and often requires opioids, but NSAIDs can be particularly effective.
Radiotherapy
Is effective in relieving pain in 60–80% of patients and results in complete pain relief in 20–30%. Also used for malignant cord compression as an oncological emergency.
The onset of benefit is variable, ranging from a few days to weeks. Some patients have pain that is unresponsive to radiotherapy, whereas some have a long and durable response.
There is debate about the most appropriate regime, but a systematic review has shown that 8 Gy as a single fraction is equivalent to fractionated regimes for palliation of pain.
The spinal cord and other organs have a limited tolerance to radiotherapy, dependent on fraction size and total dose. Repeated fractions to the same area are not always possible.
Surgery
May be indicated for cord compression, long bone fractures or for metastases at high risk of pathological fracture (e.g. lytic lesions, lesions causing functional pain, > 50% destruction of a single cortex of a long bone or avulsion of the lesser trochanter).
Bones may not heal after pathological fractures (particularly secondary to lytic lesions). This leads to higher rates of fixation failure and the choice of procedure should reflect this (e.g. avoidance of sliding hip screws).
Prophylactic internal fixation should usually be followed by radiotherapy to inhibit further tumour growth.
Radiopharmaceuticals
Radionucleotides such as strontium-89 chloride, samarium-153, rhenium-186 or rhenium-188 localise to regions of high bone turnover and administer high local doses of radiation.
Can be useful for the palliation of bone pain, particularly in patients with prostate cancer with diffuse multifocal disease.
Pain relief usually starts within 1–3 weeks and lasts for 3–6 months.
Percutaneous vertebroplasty, kyphoplasty or cementoplasty
Involves the injection of bone cement, usually into collapsed vertebral bodies, but can also be used in the scapula and ribs.
Is effective at reducing pain and effects are seen more quickly than with radiotherapy. May also be used for prophylactic spinal fixation before significant vertebral collapse occurs.
The procedure may be performed as a day case or involve an overnight stay in hospital.
Complications are rare, but include cement PE and cord compression due to cement leakage into the spinal canal.
Bisphosphonates
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