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Management of Adverse Effects of Cancer Therapy

By

Robert Peter Gale

, MD, PhD, Imperial College London

Last full review/revision Jul 2018| Content last modified Jul 2018
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NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version
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Patients being treated for cancer frequently experience adverse effects. Managing these effects improves quality of life (see also Overview of Cancer Therapy).

Nausea and Vomiting

Nausea and vomiting are commonly experienced by cancer patients and may result from the cancer itself (eg, paraneoplastic syndromes) or from its treatment (eg, chemotherapy, radiation therapy to the brain or abdomen). However, refractory nausea and vomiting should prompt further investigation, including basic laboratory testing (electrolytes, liver function tests, lipase) and x-rays to investigate possible bowel obstruction or intracranial metastases.

Serotonin-receptor antagonists are the most effective drugs but are also the most expensive. Virtually no toxicity occurs with granisetron and ondansetron aside from headache and orthostatic hypotension. A 0.15-mg/kg dose of ondansetron or a 10-mcg/kg dose of granisetron is given IV 30 min before chemotherapy. Doses of ondansetron can be repeated 4 and 8 h after the first dose. The efficacy against highly emetogenic drugs, such as the platinum complexes, can be improved with coadministration of dexamethasone 8 mg IV given 30 min before chemotherapy with repeat doses of 4 mg IV q 8 h.

A substance P/neurokinin-1 antagonist, aprepitant, can limit nausea and vomiting resulting from highly emetogenic chemotherapy. Dosage is 125 mg po 1 h before chemotherapy on day 1, then 80 mg po 1 h before chemotherapy on days 2 and 3.

Other traditional antiemetics, including phenothiazines (eg, prochlorperazine 10 mg IV q 8 h, promethazine 12.5 to 25 mg po or IV q 8 h) and metoclopramide 10 mg po or IV given 30 min before chemotherapy with repeated doses q 6 to 8 h, are alternatives restricted to patients with mild to moderate nausea and vomiting.

Dronabinol (Δ-9-tetrahydrocannabinol [THC]) is an alternative treatment for nausea and vomiting caused by chemotherapy. THC is the principal psychoactive component of marijuana. Its mechanism of antiemetic action is unknown, but cannabinoids bind to opioid receptors in the forebrain and may indirectly inhibit the vomiting center. Dronabinol is administered in doses of 5 mg/m2 po 1 to 3 h before chemotherapy, with repeated doses q 2 to 4 h after the start of chemotherapy (maximum of 4 to 6 doses/day). However, it has variable oral bioavailability, is not effective for inhibiting the nausea and vomiting of platinum-based chemotherapy regimens, and has significant adverse effects (eg, drowsiness, orthostatic hypotension, dry mouth, mood changes, visual and time sense alterations). Smoking marijuana may be more effective. Marijuana for this purpose can be obtained legally in some states, although federal law still prohibits its use. It is used less commonly because of barriers to availability and because many patients cannot tolerate smoking.

Benzodiazepines, such as lorazepam 1 to 2 mg po or IV given 10 to 20 min before chemotherapy with repeated doses q 4 to 6 h prn, are sometimes helpful for refractory or anticipatory nausea and vomiting.

Cytopenias

Anemia, leukopenia, and thrombocytopenia may develop during chemotherapy or radiation therapy. Blood products should be irradiated to prevent transfusion-induced graft-vs-host disease.

Anemia

Clinical symptoms and decreased efficacy of radiation therapy usually occur at Hct levels of < 24% or Hb levels < 8 g/dL, sooner in patients with coronary artery disease or peripheral vascular disease.

Recombinant erythropoietin therapy may be started when Hb is < 10 g/dL in patients with low erythropoietin levels, depending on symptoms. In general, 150 to 300 units/kg sc 3 times/wk (a convenient adult dose is 10,000 units) is effective and reduces the need for transfusions. Longer-acting formulations of erythropoietin require less frequent dosing (darbepoetin alfa 2.25 to 4.5 mcg/kg sc q 1 to 2 wk). Unnecessary use of erythropoietin should be avoided because it increases the risk of thrombosis.

Packed RBC transfusions may be needed to relieve acute cardiorespiratory symptoms but should generally not be given to asymptomatic patients unless they have significant underlying cardiopulmonary disease.

Thrombocytopenia

Platelet count < 10,000/μL/, especially with bleeding, requires platelet transfusions.

Leukocyte depletion of transfused blood products may prevent alloimmunization to platelets and should be used in patients expected to need platelet transfusions during multiple courses of chemotherapy or for candidates for hematopoietic cell transplants. Leukocyte depletion also lowers the probability of cytomegalovirus infection.

Neutropenia

Neutropenia, usually defined as neutrophil count < 500/μL predisposes to immediate life-threatening infection.

Afebrile patients with neutropenia require close outpatient follow-up for detection of fever and should be instructed to avoid contact with sick people or areas frequented by large numbers of people (eg, shopping malls, airports). Although most patients do not require antibiotics, patients with severe immunosuppression are sometimes given trimethoprim/sulfamethoxazole (one double-strength tablet/day) as prophylaxis for Pneumocystis jirovecii. In transplant patients or others receiving high-dose chemotherapy, antiviral prophylaxis (acyclovir 800 mg po bid or 400 mg IV q 12 h) should be considered if serologic tests are positive for herpes simplex virus.

Fever> 38° C in a patient with neutropenia is an emergency. Evaluation should include immediate chest x-ray and cultures of blood, sputum, urine, stool, and any suspect skin lesions. Examination includes possible abscess sites (eg, skin, ears, sinuses, peri-rectal area), skin and mucosa for presence of herpetic lesions, retina for vascular lesions suggestive of infectious emboli, and catheter sites. Rectal examination and use of a rectal thermometer should be avoided.

Febrile neutropenic patients should receive broad-spectrum antibiotics chosen on the basis of the most likely organism. Typical regimens include cefepime or ceftazidime 2 g IV q 8 h immediately after samples for culture are obtained. If diffuse pulmonary infiltrates are present, sputum should be tested for P. jirovecii, and if positive, appropriate therapy should be started. If fever resolves within 72 h after starting empiric antibiotics, they are continued until the neutrophil count is > 500/μL. If fever continues, antifungal drugs should be added. Reassessment for infection, often including CT of the chest and abdomen is done.

In selected patients with neutropenia related to chemotherapy, especially after high-dose chemotherapy, granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) may be started to shorten the duration of neutropenia. G-CSF 5 mcg/kg sc once/day up to 14 days and longer-acting forms (eg, pegfilgrastim 6 mg sc single dose once per chemotherapy cycle) may be used to accelerate WBC recovery. These drugs should not be given in the first 24 h after chemotherapy, and for pegfilgrastim, at least 14 days should elapse until the next planned chemotherapy dose. These drugs are begun at the onset of fever or sepsis or, in afebrile high-risk patients, when neutrophil count falls to < 500/μL.

Many centers use outpatient treatment with G-CSF in selected low-risk patients with fever and neutropenia. Candidates must not have hypotension, altered mental status, respiratory distress, uncontrolled pain, or serious comorbid illnesses, such as diabetes, heart disease, or hypercalcemia. The regimen in such cases requires daily follow-up and often involves visiting nurse services and home antibiotic infusion. Some regimens involve oral antibiotics, such as ciprofloxacin 750 mg po bid plus amoxicillin/clavulanate 875 mg po bid or 500 mg po tid. If no defined institutional program for follow-up and treatment of neutropenic fever is available in an outpatient setting, then hospitalization is required.

Gastrointestinal Effects

GI adverse effects are common among cancer patients.

Oral lesions

Oral lesions, such as ulcers, infections, and inflammation, are common.

Oral candidiasis can be treated with nystatin oral suspension 5 to 10 mL qid, clotrimazole troches 10 mg qid, or fluconazole 100 mg po once/day.

Mucositis due to radiation therapy can cause pain and preclude sufficient oral intake, leading to undernutrition and weight loss. Rinses with analgesics and topical anesthetics (2% viscous lidocaine 5 to 10 mL q 2 h or other commercially available mixtures) before meals, a bland diet without citrus food or juices, and avoidance of temperature extremes may allow patients to eat and maintain weight. If not, a feeding tube may be helpful if the small intestine is functional. For severe mucositis and diarrhea or an abnormally functioning intestine, parenteral alimentation may be needed.

Diarrhea

Diarrhea due to pelvic radiation therapy or chemotherapy can be alleviated with antidiarrheal drugs as needed (eg, kaolin/pectin suspension 60 to 120 mL regular strength, or 30 to 60 mL concentrate, po at first sign of diarrhea and after each loose stool or prn; loperamide 2 to 4 mg po after each loose stool; or diphenoxylate/atropine 1 to 2 tablets po q 6 h). Patients who underwent abdominal surgery or received broad-spectrum antibiotics within the preceding 3 mo should undergo stool testing for Clostridium difficile.

Constipation

Constipation may result from opioid use. A stimulant laxative such as senna 2 to 6 tablets po at bedtime or bisacodyl 10 mg po at bedtime should be initiated when repeated opioid use is anticipated. Established constipation can be treated with various drugs (eg, bisacodyl 5 to 10 mg po q 12 to 24 h, milk of magnesia 15 to 30 mL po at bedtime, lactulose 15 to 30 mL q 12 to 24 h, Mg citrate 250 to 500 mL po once). Enemas and suppositories should be avoided in patients with neutropenia or thrombocytopenia.

Anorexia

Appetite may decrease secondary to cancer treatment or to a paraneoplastic syndrome. Corticosteroids (eg, dexamethasone 4 mg po once/day, prednisone 5 to 10 mg po once/day) and megestrol acetate 400 to 800 mg once/day are most effective. However, the primary benefits are variably increased appetite and weight gain, not improved survival or quality of life.

Pain

Pain should be anticipated and aggressively treated. Use of multiple drug classes may provide better pain control with fewer or less severe adverse effects than use of a single drug class. Aspirin and NSAIDs should be avoided in patients with thrombocytopenia.

Opioids are the mainstay of treatment, given around the clock in generally efficient doses, with supplemental doses given for occasional worse pain. If the oral route is unavailable, fentanyl is given transdermally. When opioids are given, antiemetics and prophylactic bowel regimens are often needed.

Neuropathic pain can be treated with gabapentin; the dose required is high (up to 1200 mg po tid) but must be started low (eg, 300 mg tid) and then increased over a few weeks. Alternatively, a tricyclic antidepressant (eg, nortriptyline 25 to 75 mg po at bedtime) may be tried.

Useful nondrug treatments for pain include local radiation therapy, nerve blockade, and surgery.

Depression

Depression is often overlooked. It may occur in response to the disease (its symptoms and feared consequences), adverse effects of the treatments, or both. Patients receiving interferon can develop depression. Alopecia as a result of radiation therapy or chemotherapy can contribute to depression. Frank discussion of a patient’s fears can often relieve anxiety. Depression can often be treated effectively.

Tumor Lysis and Cytokine Release Syndromes

Tumor lysis syndrome

Tumor lysis syndrome may occur as a result of release of intracellular components into the bloodstream due to tumor cell death after chemotherapy. It occurs mainly in acute leukemias and non-Hodgkin lymphomas but can also occur in other hematologic cancers and, uncommonly, after treatment of solid tumors. It should be suspected in patients with a large tumor burden who develop acute kidney injury after initial treatment. Seizures and cardiac arrhythmias may occur. T-cell vaccines used to treat B-cell leukemias may precipitate life-threatening tumor lysis and cytokine release days to weeks after vaccine administration.

The diagnosis is confirmed by some combination of the following findings:

  • Renal failure

  • Hypocalcemia (< 7 mg/dL)

  • Hyperuricemia (> 8 mg/dL)

  • Hyperphosphatemia (> 6.5 mg/dL)

  • Hyperkalemia > 6 mEq/L

Allopurinol 200 to 400 mg/m2 once/day, maximum 600 mg/day, and normal saline IV to achieve urine output > 2 L/day should be initiated with close laboratory and cardiac monitoring. Patients who have a cancer with rapid cell turnover should receive allopurinol for at least 2 days before and during chemotherapy; for patients with high cell burden, this regimen can be continued for 10 to 14 days after therapy. All such patients should receive vigorous IV hydration to establish a diuresis of at least 100 mL/h before treatment. Although some physicians advocate sodium bicarbonate IV to alkalinize the urine and increase solubilization of uric acid, alkalinization may promote calcium phosphate deposition in patients with hyperphosphatemia, and a pH of about 7 should be avoided.

Alternatively, rasburicase, an enzyme that oxidizes uric acid to allantoin (a more soluble molecule), may be used to prevent tumor lysis. The dose is 0.15 to 0.2 mg/kg IV over 30 min once/day for 5 to 7 days, typically initiated 4 to 24 h before the first chemotherapy treatment. Adverse effects may include anaphylaxis, hemolysis, hemoglobinuria, and methemoglobinemia.

Cytokine release syndrome

Cytokine release syndrome (CRS) is related to but distinct from tumor lysis syndrome. It is a frequent complication of cell-based therapies such as CAR-T cells and some monoclonal antibodies.

Symptoms include fever, fatigue, loss of appetite, muscle and joint pain, nausea, vomiting, diarrhea, rashes, rapid breathing, headache, confusion, and hallucinations. 

Signs include tachycardia, tachypnea, low blood pressure, tremor, loss of coordination, seizures, and delirium.

Laboratory tests and clinical monitoring show hypoxia, widened pulse pressure, increased cardiac output (early), potentially diminished cardiac output (late), high nitrogen levels in blood, elevated D-dimer level, elevated transaminases, fibrinogen deficiency, and hyperbilirubinemia. Cytokine release syndrome occurs when large numbers of white blood cells, including B cells, T cells, natural killer cells, macrophages, dendritic cells, and monocytes are activated and release inflammatory cytokines.

Cytokine release syndrome is graded based on the severity of symptoms and signs. In general, treatment for mild CRS is supportive, addressing symptoms such as fever, muscle pain, or fatigue. Moderate CRS requires oxygen therapy and giving fluids and one or more antihypotensive drugs to raise blood pressure. For moderate to severe CRS, immunosuppressive drugs such as corticosteroids may be necessary. Tocilizumab, an anti-IL6 monoclonal antibody, is also used in severe CRS.

Drugs Mentioned In This Article

Drug Name Select Trade
LOMOTIL
No US brand name
ARANESP
COMPRO
REGLAN
CILOXAN, CIPRO
OZURDEX
NEULASTA
AVENTYL
MYCELEX
PROMETHEGAN
DIFLUCAN
ZYLOPRIM
AMOXIL
ACTEMRA
ELITEK
SANCUSO
ZOFRAN
FORTAZ, TAZICEF
MARINOL
RAYOS
EMEND
IMODIUM
NEURONTIN
XYLOCAINE
CHOLAC
ATIVAN
MEGACE
DULCOLAX
ZOVIRAX
NYSTOP
ACTIQ, DURAGESIC, SUBLIMAZE
MAXIPIME
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NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version

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