Management of Adverse Effects of Cancer Therapy
Adverse effects are common in patients receiving any cancer therapy. Patients may also have adverse effects resulting from their cancer. Successfully managing these adverse effects is important because it improves quality of life (see also Overview of Cancer Therapy).
Decreased blood concentrations of red blood cells (RBCs), white blood cells (WBC), especially granulocytes, and platelets result from diverse systemic cancer therapies, especially conventional chemotherapy drugs, and radiation therapy.
Decreased levels of RBCs are common in patients with cancer. Decreases in RBCs result from a direct effect of the cancer (especially in blood and bone marrow cancers such as leukemias, lymphomas, and multiple myeloma) and from effects of cancer therapy, especially conventional cancer (chemotherapy) drugs. Often anemia requires no therapy. Some patients, especially those with comorbidities such as arteriosclerotic cardiovascular disease, may benefit from RBC transfusions. Others may benefit from receiving recombinant erythropoietin, which can substitute for RBC transfusions. Some data suggest erythropoietin use can have adverse effects on cancer prognosis and is prothrombotic. Guidelines on RBC transfusion and erythropoietin use are available, but recommendations can be controversial.
Decreased platelet concentration is common in patients with cancer. Decreases in platelets result from a direct effect of the cancer (especially blood and bone marrow cancers such as leukemias, lymphomas, and multiple myeloma) and from effects of cancer therapy, especially conventional chemotherapy drugs. Platelet concentrations < 10,000/microL (10 × 109/L) are dangerous and require platelet transfusions. Recently, molecularly cloned hormones, such as eltrombopag and avatrombopag, which stimulate megakaryocytes to produce platelets, have been used. Other drugs such as fostamatinib are used to treat low platelet levels in other disorders but not cancer.
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.
A decreased granulocyte concentration is common in patients with cancer. Decreases in granulocytes result from a direct effect of the cancer (especially blood and bone marrow cancers such as leukemias, lymphomas, and multiple myeloma) and from effects of cancer therapy, especially conventional chemotherapy drugs. A granulocyte concentration < 500/microL (0.5 × 109/L) markedly increases the risk of infection. Measures to protect against infection, including hand washing and protective isolation, are important. Laminar air flow (LAF) rooms are sometimes used but have not proved effective. Oral nonabsorbable antibiotics are sometimes given prophylactically. When a prolonged interval of low granulocytes is anticipated, prophylactic antifungal and antiviral drugs are sometimes given, including drugs to prevent Pneumocystis jirovecii.
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 orally twice a day or 400 mg IV every 12 hours) should be considered if serologic tests are positive for herpes simplex virus.
Fever> 38.5° C on two or more occasions in a patient with neutropenia is a medical emergency. An extensive evaluation for potential infection sources should be made and blood cultures done. Typically, systemic broad-spectrum antibiotics are given before culture results are known and therapy modified as needed. Patients with persistent fever unresponsive to antibiotics are often started on systemic antifungal and sometimes antiviral drugs. 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, perirectal 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. Other evaluation should be guided by clinical findings.
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 every 8 hours 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 hours after starting empiric antibiotics, they are continued until the neutrophil count is > 500/microL. If fever continues, antifungal drugs should be added. Reassessment for infection, often including CT of the chest and abdomen, is done.
Granulocyte concentrations can be increased by giving molecularly cloned myeloid growth factors such as granulocyte (G) or granulocyte/macrophage (GM) colony stimulating factors (CSFs) such as filgrastim, sargramostim, and peg-filgrastim. Guidelines for appropriate use of these drugs are available. 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 subcutaneously once/day up to 14 days and longer-acting forms (eg, pegfilgrastim 6 mg subcutaneously single dose once per chemotherapy cycle) may be used to accelerate WBC recovery. These drugs should not be given in the first 24 hours 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/microL.
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 twice a day plus amoxicillin/clavulanate 875 mg twice a day or 500 mg 3 times a day. If no defined institutional program for follow-up and treatment of neutropenic fever is available in an outpatient setting, then hospitalization is required.
Gastrointestinal adverse effects are common in patients with cancer. These effects may be caused by the cancer itself, cancer therapy, or both.
Anorexia is common in patients with cancer and may be caused by the cancer directly or as a consequence of cancer therapy(ies). Loss of more than 10% of ideal body weight predicts an adverse prognosis. Efforts should be made to maintain reasonable nutrition. Sometimes partial or total parenteral nutrition (TPN) is needed. Patients with surgical interruption of the gastrointestinal tract may need a feeding gastrostomy. Drugs that may increase appetite include corticosteroids, megestrol acetate, androgenic steroids, and dronabinol. Whether these drugs convincingly reduce anorexia, reverse weight loss, improve quality of life, or prolong survival is unclear. Some steroids, such as testosterone, are contraindicated in patients with prostate or liver cancer.
Constipation is common in patients with cancer and is often exacerbated by opioids used to treat pain. A stimulant laxative such as senna 2 to 6 tablets orally at bedtime or bisacodyl 10 mg orally 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 orally every 12 to 24 hours, milk of magnesia 15 to 30 mL orally at bedtime, lactulose 15 to 30 mL every 12 to 24 hours, magnesium citrate 250 to 500 mL orally once). Enemas and suppositories should be avoided in patients with neutropenia or thrombocytopenia.
Diarrhea is common after chemotherapy drugs, targeted therapy drugs, and radiation therapy, especially if the abdomen and/or pelvis is included in the radiation field. It is usually treated with diphenoxylate/atropine or loperamide 2 to 4 mg orally after each loose stool; or diphenoxylate/atropine 1 to 2 tablets orally every 6 hours. However, doses can vary depending on various factors. Patients with cancer who are taking broad-spectrum antibiotics may become infected with Clostridioides (formerly Clostridium) difficile, which should be tested for and treated with vancomycin. Patients with lower colorectal cancers may have a diverting colostomy, which complicates diarrhea management.
Mouth lesions such as inflammation and ulcers are common in patients receiving chemotherapy drugs and/or radiation therapy. Sometimes these lesions are complicated by infection, often with Candida albicans. Candidiasis is usually treated with nystatin.
Oral candidiasis can be treated with nystatin oral suspension 5 to 10 mL 4 times a day, clotrimazole troches 10 mg 4 times a day, or fluconazole 100 mg orally 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 every 2 hours 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.
Nausea and vomiting are common in patients with cancer whether or not they are receiving cancer therapy and decrease quality of life. Variables that predict the likelihood of causing nausea and vomiting secondary to cancer drugs are
Some chemotherapy drugs are especially likely to cause nausea and vomiting, including platinum-containing drugs such as cisplatin and oxaliplatin. Patients treated with other cancer modalities, including radiation therapy, hormones, targeted therapy drugs, and immune therapy can also have nausea and vomiting. Several drugs are effective in controlling and/or preventing nausea and vomiting:
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 minutes before chemotherapy. Doses of ondansetron can be repeated 4 and 8 hours after the first dose. The efficacy against highly emetogenic drugs, such as the platinum-containing drugs, can be improved with coadministration of dexamethasone 8 mg IV given 30 minutes before chemotherapy with repeat doses of 4 mg IV every 8 hours.
A substance P/neurokinin-1 antagonist, aprepitant, can limit nausea and vomiting resulting from highly emetogenic chemotherapy. Dosage is 125 mg orally 1 hour before chemotherapy on day 1, then 80 mg orally 1 hour before chemotherapy on days 2 and 3.
Other traditional antiemetics, including phenothiazines (eg, prochlorperazine 10 mg IV every 8 hours, promethazine 12.5 to 25 mg orally or IV every 8 hours) and metoclopramide 10 mg orally or IV given 30 minutes before chemotherapy with repeated doses every 6 to 8 hours, 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 orally 1 to 3 hours before chemotherapy, with repeated doses every 2 to 4 hours 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 orally or IV given 10 to 20 minutes before chemotherapy with repeated doses every 4 to 6 hours as needed, are sometimes helpful for refractory or anticipatory nausea and vomiting.
Pain is often under treated, for several reasons, including
None of these is a sensible reason not to achieve adequate pain control in a patient with cancer.
Initial therapy might include aspirin, acetaminophen, or ibuprofen. However, these drugs are often ineffective in controlling cancer pain, and opioids, including morphine, oxycodone, hydromorphone, fentanyl methadone, and oxymorphone, may be needed. An appropriate dose and schedule of these drugs are essential for adequate pain control (see table Opioid Analgesics). Often the patient with cancer is the best judge of when analgesics are needed. Patient-controlled anesthesia (PCA) using an indwelling pump allows the patient to manage dose and timing of analgesics.
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 nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in patients with thrombocytopenia.
Neuropathic pain can be treated with gabapentin; the dose required is high (up to 1200 mg orally 3 times a day) but must be started low (eg, 300 mg 3 times a day) and then increased over a few weeks. Alternatively, a tricyclic antidepressant (eg, nortriptyline, 25 to 75 mg orally at bedtime) can be tried. Doses can vary to a large degree between patients.
Other approaches may be needed to control pain under special circumstances. For example, radiation therapy often is needed for bone pain. Nerve blockade and surgery may be done to interrupt the nerve pathways.
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 syndrome occurs because of rapid death of cancer cells with release of intracellular components into the bloodstream. It occurs mainly in leukemias and lymphomas but can also occur in other hematologic cancers and, uncommonly, after treatment of solid cancers.
Criteria for diagnosis of tumor lysis syndrome include
Seizures and cardiac arrhythmias may occur.
Often it is possible to anticipate development of tumor lysis syndrome and to give large volumes of fluids and allopurinol or rasburicase before starting chemotherapy and sometimes immune therapy (such as bispecific monoclonal antibodies or CAR-T-cells) to protect the kidneys from damage from uric acid. T-cell vaccines used to treat B-cell leukemias may precipitate life-threatening tumor lysis and cytokine release days to weeks after vaccine administration.
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/hour 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 minutes once/day for 5 to 7 days, typically initiated 4 to 24 hours before the first chemotherapy treatment. Adverse effects may include anaphylaxis, hemolysis, hemoglobinuria, and methemoglobinemia.
Cytokine release syndrome (CRS) is related to but distinct from tumor lysis syndrome. Cytokine release syndrome occurs when large numbers of immune cells are activated and release inflammatory cytokines, including interleukin (IL)-6 and interferon gamma. It is a frequent complication of immune therapies such as bi-specific monoclonal antibodies or CAR-T-cells.
Clinical features include fever, fatigue, loss of appetite, muscle and joint pain, nausea, vomiting, diarrhea, rash, and headache. Tachypnea, tachycardia, hypotension, tremor, loss of coordination, seizures, and delirium may occur.
Typical features include
Grading of cytokine release syndrome (1) is as follows:
Grade 1: Symptoms (eg, fever, nausea, fatigue, headache, myalgias, malaise) are not life-threatening and require symptomatic treatment only
Grade 2: Symptoms require and respond to moderate intervention with oxygen supplementation up to 40% FiO2 or hypotension responsive to fluids or low-dose vasopressor or grade 2 organ toxicity
Grade 3: Symptoms require and respond to aggressive intervention with oxygen supplementation ≥ 40% FiO2 or hypotension requiring high-dose or multiple vasopressors or grade 3 organ toxicity or grade 4 transaminitis
Grade 4: Life-threatening symptoms, including need for ventilator support or grade 4 organ toxicity (excluding transaminitis)
Grade 5: Death
Therapy of low-grade CRS is supportive. Moderate-grade CRS requires oxygen therapy and fluids and one or more antihypotensive drugs to raise blood pressure. Moderate and severe-grade (ie, grades 3 and 4) CRS are treated with immune suppressive drugs such as corticosteroids. Tocilizumab, an anti-interleukin-6 (IL-6) monoclonal antibody, is also used in severe CRS.
Immune effector cell-associated neurotoxicity syndrome (ICANS) is a neuropsychiatric syndrome that can occur in some patients with cancer treated with immune therapy. It is also related to cytokine-mediated toxicity and has been called cytokine release encephalopathy syndrome (CRES). Symptoms include confusion, depressed level of consciousness, disturbance in attention, lethargy, mental status changes, delirium, dizziness, muscle spasms, and muscle weakness (1).
Mild neurotoxicity is managed supportively. More severe neurotoxicity is treated with dexamethasone or methylprednisolone. Patients with severe neurotoxicity may need treatment in the intensive care unit.
1. Lee DW, Santomasso BD, Locke FL, et al: ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant 25(4):625–638, 2019. doi: 10.1016/j.bbmt.2018.12.758