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) agents.

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 (1). Guidelines on RBC transfusion and erythropoietin use are available (2).

A decrease in the platelet count 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 agents. 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 stem cell transplantation. Leukocyte depletion also lowers the probability of acquiring a cytomegalovirus infection.

A decreased granulocyte count is common in patients with cancer. Neutropenia is defined as a reduction in the blood neutrophil count to < 1500/mcL (< 1.5 × 10⁹/L); however, baseline neutrophil counts tend to be lower in Black patients than in White patients (3). Decreases in granulocytes can 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 agents.

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 antivirals are sometimes given, including medications to prevent Pneumocystis jirovecii. In patients with cancer who are receiving chemotherapy, in whom there is an expected incidence of febrile neutropenia >4, 5).

Afebrile patientsPneumocystis jirovecii

Fever > 38.5° C on ≥ 2 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 that is unresponsive to antibiotics are often started on systemic antifungal and sometimes antivirals. Evaluation should include immediate chest radiographs 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 rectal thermometers 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, antifungals should be added. Reassessment for infection, often including CT of the chest and abdomen, is also done.

4< 500/microL (0.5 × 10⁹/L).

Clinical Calculators

Absolute Neutrophil Count

1. 1. Heregger R, Greil R: Erythropoiesis-stimulating agents—benefits and harms in the treatment of anemia in cancer patients. memo 16: 259–262, 2023. https://doi.org/10.1007/s12254-023-00902-4

2. 2. 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

3. 3. Borinstein SC, Agamasu D, Schildcrout JS, et al: Frequency of benign neutropenia among Black versus White individuals undergoing a bone marrow assessment. J Cell Mol Med 26(13):3628–3635, 2022. doi:10.1111/jcmm.17346

4. 4. 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

5. 5. 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

testosterone, are contraindicated in patients with prostate or liver cancer.

Clostridioides (formerly Clostridium) difficile

Mouth lesions such as inflammation and ulcers are common in patients receiving chemotherapy and/or radiation therapy. Sometimes these lesions are complicated by infection, often with Candida albicans

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 therapy are

• Type of medication(s)

• Route of administration

• Dose

• Dosing frequency

• Drug-drug interactions

• 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 relieving nausea and vomiting 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.

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). Tumor lysis syndrome also causes hyperphosphatemia, hypocalcemia, and hyperkalemia. Uric acid can precipitate in the renal tubules and cause acute kidney injury (see also Acute Urate Nephropathy). Depending on the phosphate × calcium product, hyperphosphatemia can cause calcium phosphate deposition in the renal tubules and in the cardiac conduction system; it also may lead to hypocalcemia 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

• Acute kidney injury

• 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 >calcium phosphate deposition in patients with hyperphosphatemia, and a pH of > 7 should be avoided. Treatment of hyperkalemiaTreatment of hypocalcemia 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. Patients with hypocalcemia who have symptoms (eg, arrhythmias, tetany) should receive IV calcium regardless of the serum phosphate level.

Prevention

Guidelines regarding evaluation and management of tumor lysis syndrome are available (1, 2).

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 bispecific monoclonal antibodies or CAR-T-cells (3).

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

• Increased blood urea nitrogen (BUN), D-dimer, liver enzymes, and bilirubin

• Low fibrinogen level

Grading of cytokine release syndrome (4) 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 including hypoxia that requires and responds to moderate intervention with oxygen supplementation up to 40% fraction of inspired oxygen (FiO2) or hypotension that is responsive to fluids or low-dose vasopressor. These abnormalities represent grade 2 organ toxicity.

• Grade 3: Symptoms including hypoxia that requires and responds to aggressive intervention with oxygen supplementation ≥ 40% FiO2 or hypotension requires high-dose or multiple vasopressors, indicating grade 3 organ toxicity, or marked increase in liver tests, indicating grade 4 transaminitis.

• Grade 4: Symptoms are life threatening, including need for ventilator support, indicating 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 occurs in some but not all patients with cytokine release syndrome 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 (4).

1. 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. 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. 3. Shi X, Wu H: Recent advances in the prevention and management of cytokine release syndrome after chimeric antigen receptor T-cell therapy. European Journal of Inflammation 2022;20. doi:10.1177/1721727X221078727

4. 4. 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