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 adverse effects resulting from their cancer (eg, depression, pain). Successfully managing these adverse effects is important because it improves quality of life (see also Overview of Cancer Therapy).
Cytopenias
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.
Anemia
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).
Thrombocytopenia
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 Count and Bleeding Risk). Platelet concentrations < 10,000/microL (10 × 109
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.
Neutropenia
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). 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 >2, 3).
Afebrile patientsPneumocystis jirovecii
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.
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.
2< 500/microL.
Cytopenia references
1. Bohlius J, Bohlke K, Castelli R, et al: Management of cancer-associated anemia with erythropoiesis-stimulating agents: ASCO/ASH Clinical Practice Guideline Update. J Clin Oncol 37(15):1336–1351, 2019. doi: 10.1200/JCO.18.02142
2. Crawford J, Becker PS, Armitage JO, et al: Myeloid Growth Factors, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 15, 12; 10.6004/jnccn.2017.0175
3. Smith TJ, Bohlke K, Lyman GH, et al: Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 33(28):3199–3212, 2015. doi: 10.1200/JCO.2015.62.3488
Gastrointestinal Effects
Gastrointestinal adverse effects are common in patients with cancer. These effects may be caused by the cancer itself, cancer therapy, or both.
Anorexia
Constipation
Diarrhea
Mouth lesions
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
Nausea and vomiting
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
Type of drug(s)
Dose
How the drug is given
How frequently the drug is given
Interactions between cancer drugs
Interactions between cancer drugs and drugs given to treat cancer-related pain
2 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.
Pain
Pain, including chronic and/or neuropathic pain, is common in patients with cancer and should be anticipated and aggressively treated.
Pain is often under treated, for several reasons, including
Patient reluctance to discuss pain with the physician
Physician reluctance to discuss pain
Fear of opioid addiction
None of these is a sensible reason not to achieve adequate pain control in a patient with cancer.
Treatment of painOpioid 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.
Opioids are the mainstay of pain control in patients with cancer and are often underused. Pain medication should be given at doses and schedules which achieve the target level of pain control. Too often people with cancer receive inadequate pain control.
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
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. Treatment of depression with drugs and/or psychotherapy can often be effective.
Tumor Lysis and Cytokine Release Syndromes
Tumor lysis syndrome
Tumor lysis syndrome occurs because rapid death of cancer cells, resulting from cytotoxic drugs and some types of immune therapy (eg CAR-T-cell treatment), releases intracellular components into the bloodstream, particularly nucleic acids (which are broken down into uric acid, causing hyperuricemia), phosphate, and potassium. Uric acid can precipitate in the renal tubules and cause acute kidney injury (see also Acute Urate Nephropathy). Depending on the phosphate × calcium product, hyperphosphatemiahypocalcemia which may cause tetany. Hyperkalemia 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 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
Hypocalcemia (calcium < 7 mg/dL [< 1.75 mmol/L])
Hyperuricemia (uric acid > 8 mg/dL [> 0.48 mmol/L] )
Hyperphosphatemia (phosphorus > 6.5 mg/dL [> 2 mmol/L])
Hyperkalemia (potassium > 6 mEq/L [> 6 mmol/L])
Treatment2 once a day, maximum 600 mg/day, and normal saline IV to achieve urine output >Treatment of hyperkalemiaTreatment of hypocalcemia
Prevention
Guidelines regarding evaluation and management of tumor lysis syndrome are available (1, 2).
Cytokine release syndrome
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
Hypoxia
Widened pulse pressure
Increased or decreased cardiac output
Low fibrinogen level
Grading of cytokine release syndrome (3) 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 that is 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 requires high-dose or multiple vasopressors, or grade 3 organ toxicity, or grade 4 transaminitis.
Grade 4: Symptoms are life threatening, including need for ventilator support, or indicate grade 4 organ toxicity (excluding transaminitis).
Grade 5: Death
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
1. Cairo MS, Coiffier B, Reiter A, et al: Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol 149(4):578–586, 2010. doi: 10.1111/j.1365-2141.2010.08143.x
2. Coiffier B, Altman A, Pui CH, et al: Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 26(16):2767–2778, 2008. doi: 10.1200/JCO.2007.15.0177
3. 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
