Management of Adverse Effects of Cancer 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 are controversial (1 Cytopenia references Adverse effects are common in patients receiving any cancer therapy, particularly cytopenias, gastrointestinal effects, and tumor lysis and cytokine release syndromes. Patients may also have... read more ).

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. The risk of bleeding is inversely proportional to the platelet count (see table ). Platelet concentrations < 10,000/microL (10 × 10⁹/L) are dangerous and require platelet transfusions. Molecularly cloned hormones, such as eltrombopag and avatrombopag, which stimulate megakaryocytes to produce platelets, have been used.

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 acquiring a cytomegalovirus infection Cytomegalovirus (CMV) Infection Cytomegalovirus (CMV, human herpesvirus type 5) can cause infections that have a wide range of severity. A syndrome of infectious mononucleosis that lacks severe pharyngitis is common. Severe... read more .

A decreased granulocyte concentration is common in patients with cancer. Neutropenia is considered a reduction in blood neutrophil count to < 1500/mcL (< 1.5 × 10⁹/L) in White patients and < 1200/mcL (< 1.2 × 10⁹/L) in people with African ancestry (see also Neutropenia Neutropenia Neutropenia is a reduction in the blood neutrophil count. If it is severe, the risk and severity of bacterial and fungal infections increase. Focal symptoms of infection may be muted, but fever... read more ). 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. The risk of infection is inversely proportional to the granulocyte count. A granulocyte concentration < 500/microL (0.5 × 10⁹/L) markedly increases the risk of infection. Measures to protect against infection, including wearing a mask, 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. In cancer patients receiving chemotherapy in whom there is an expected incidence of febrile neutropenia > 20 %, prophylactic myeloid growth factors such as filgrastrim, sargramostim, or pegfilgastrim are given with the chemotherapy (2, 3 Cytopenia references Adverse effects are common in patients receiving any cancer therapy, particularly cytopenias, gastrointestinal effects, and tumor lysis and cytokine release syndromes. Patients may also have... read more ).

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 (0.5 × 10⁹/L). If fever continues, antifungal drugs should be added. Reassessment for infection, often including CT of the chest and abdomen, is also 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 (2 Cytopenia references Adverse effects are common in patients receiving any cancer therapy, particularly cytopenias, gastrointestinal effects, and tumor lysis and cytokine release syndromes. Patients may also have... read more ). 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.

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 tablets orally at bedtime (maximum 8 tablets/day) or bisacodyl 5 to 15 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 15 mg orally every 24 hours, milk of magnesia 15 to 30 mL orally at bedtime, lactulose 15 to 30 mL (10 to 20 g) every 12 to 24 hours, magnesium citrate 195 to 300 mL once every 24 hours. 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 loperamide 2 to 4 mg orally after each loose stool; or diphenoxylate/atropine 2.5 mg to 5 mg 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 Clostridioides (formerly Clostridium) difficile–Induced Diarrhea Toxins produced by Clostridioides difficile strains in the gastrointestinal tract cause pseudomembranous colitis, typically after antibiotic use. Symptoms are diarrhea, sometimes bloody... read more , 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 4 to 6 mL (400,000 to 600,000 units) 4 times a day, clotrimazole troches 10 mg 4 times a day, or fluconazole 100 mg orally once a 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:

Tumor lysis syndrome occurs because rapid death of cancer cells, resulting from cytotoxic drugs Chemotherapy Systemic cancer therapy includes chemotherapy (ie, conventional or cytotoxic chemotherapy), hormone therapy, targeted therapy, and immune therapy (see also Overview of Cancer Therapy). The number... read more and some types of immune therapy Immune Therapy Systemic cancer therapy includes chemotherapy (ie, conventional or cytotoxic chemotherapy), hormone therapy, targeted therapy, and immune therapy (see also Overview of Cancer Therapy). The number... read more (eg CAR-T-cell treatment), releases intracellular components into the bloodstream, particularly nucleic acids (which are broken down into uric acid, causing hyperuricemia Asymptomatic Hyperuricemia Gout is a disorder caused by hyperuricemia (serum urate > 6.8 mg/dL [> 0.4 mmol/L]) that results in the precipitation of monosodium urate crystals in and around joints, most often causing recurrent... read more ), phosphate, and potassium. Uric acid can precipitate in the renal tubules and cause acute kidney injury Acute Kidney Injury (AKI) Acute kidney injury is a rapid decrease in renal function over days to weeks, causing an accumulation of nitrogenous products in the blood (azotemia) with or without reduction in amount of urine... read more (see also Acute Urate Nephropathy Acute urate nephropathy Tubulointerstitial disorders can result from several metabolic disturbances. (See also Overview of Tubulointerstitial Diseases.) Several metabolic disturbances can cause tubulointerstitial nephritis... read more ). Depending on the phosphate × calcium product, hyperphosphatemia Hyperphosphatemia Hyperphosphatemia is a serum phosphate concentration > 4.5 mg/dL (> 1.46 mmol/L). Causes include chronic kidney disease, hypoparathyroidism, and metabolic or respiratory acidosis. Clinical... read more can cause calcium phosphate deposition in the renal tubules and in the cardiac conduction system; it also may lead to hypocalcemia Hypocalcemia Hypocalcemia is a total serum calcium concentration < 8.8 mg/dL (< 2.20 mmol/L) in the presence of normal plasma protein concentrations or a serum ionized calcium concentration < 4... read more which may cause tetany. Hyperkalemia Hyperkalemia Hyperkalemia is a serum potassium concentration > 5.5 mEq/L (> 5.5 mmol/L), usually resulting from decreased renal potassium excretion or abnormal movement of potassium out of cells. There... read more may cause cardiac arrhythmias. Symptoms of tumor lysis include lethargy, anorexia, nausea, vomiting, and seizures.

Tumor lysis syndrome occurs mainly in leukemias and lymphomas but can also occur in other hematologic cancers and, uncommonly, after treatment of solid cancers. T-cell vaccines Active Specific Immunotherapy A number of immunologic interventions, both passive and active, can be directed against tumor cells. (See also Immunotherapeutics.) In passive cellular immunotherapy, specific effector cells... read more used to treat B-cell leukemias may precipitate life-threatening tumor lysis and cytokine release days to weeks after vaccination.

Diagnostic criteria for tumor lysis syndrome include

Treatment of tumor lysis syndrome is with allopurinol 200 to 400 mg/m² once a 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. 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 > 7 should be avoided. Treatment of hyperkalemia Treatment Hyperkalemia is a serum potassium concentration > 5.5 mEq/L (> 5.5 mmol/L), usually resulting from decreased renal potassium excretion or abnormal movement of potassium out of cells. There... read more is given depending on the serum potassium level and may involve oral potassium-lowering drugs, IV calcium, and IV glucose and insulin. Treatment of hypocalcemia Treatment Hypocalcemia is a total serum calcium concentration < 8.8 mg/dL (< 2.20 mmol/L) in the presence of normal plasma protein concentrations or a serum ionized calcium concentration < 4... read more is with IV calcium, but because this can cause increased precipitation of calcium phosphate, calcium should not be given for asymptomatic hypocalcemia unless the hyperphosphatemia is corrected. Symptomatic patients with hypocalcemia (eg, with arrhythmias, tetany) should receive IV calcium regardless of the serum phosphate level.

Prevention of tumor lysis syndrome is desirable. Often it is possible to anticipate development of tumor lysis syndrome (eg, when treating cancers with rapid cell turnover) and to give large volumes of fluids and allopurinol or rasburicase before starting chemotherapy and sometimes prior to immune therapy (such as bispecific monoclonal antibodies or CAR-T-cells) to protect the kidneys from damage from uric acid. Patients should receive vigorous IV hydration to establish a urine output of at least 100 mL/hour before treatment. Patients also 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. Rasburicase is an enzyme that oxidizes uric acid to allantoin (a more soluble molecule) and is given at 0.15 to 0.2 mg/kg IV over 30 minutes once a day for 5 to 7 days, typically started 4 to 24 hours before the first chemotherapy treatment. Adverse effects may include anaphylaxis, hemolysis, hemoglobinuria, and methemoglobinemia.

Guidelines regarding evaluation and management of tumor lysis syndrome are available (1, 2 Tumor lysis syndrome and cytokine release syndrome references Adverse effects are common in patients receiving any cancer therapy, particularly cytopenias, gastrointestinal effects, and tumor lysis and cytokine release syndromes. Patients may also have... read more ).

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 Immune Therapy Systemic cancer therapy includes chemotherapy (ie, conventional or cytotoxic chemotherapy), hormone therapy, targeted therapy, and immune therapy (see also Overview of Cancer Therapy). The number... read more 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 (3 Tumor lysis syndrome and cytokine release syndrome references Adverse effects are common in patients receiving any cancer therapy, particularly cytopenias, gastrointestinal effects, and tumor lysis and cytokine release syndromes. Patients may also have... read more ) is as follows:

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 cancer patients 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 Tumor lysis syndrome and cytokine release syndrome references Adverse effects are common in patients receiving any cancer therapy, particularly cytopenias, gastrointestinal effects, and tumor lysis and cytokine release syndromes. Patients may also have... read more ).

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.