This article details strategies for managing adverse effects in cancer treatment, focusing on cytopenias, gastrointestinal issues, and tumour-related syndromes, to improve patients' quality of life.

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Adverse effects are common in patients receiving any cancer therapy, particularly cytopenias, gastrointestinal effects, tumour 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 the quality of life.

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Cytopenias

Anaemia

Decreased levels of RBCs are common in patients with cancer and result from a direct effect of cancer (especially in blood and bone marrow cancers such as leukaemias, lymphomas, and multiple myeloma) and the effects of chemotherapy.

Often anaemia 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.

Thrombocytopenia

1. A decrease in platelets results from a direct effect of cancer (especially blood and bone marrow cancers such as leukaemias, lymphomas, and multiple myeloma) and the effects of conventional chemotherapy.
2. The risk of bleeding is inversely proportional to the platelet count. Platelet concentrations < 10,000/microL (10 × 109/L) are dangerous and require platelet transfusions.
3. Molecularly cloned hormones, such as eltrombopag and eltrombopag, which stimulate megakaryocytes to produce platelets, have been used.

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). Decreases in granulocytes result from a direct effect of cancer (especially blood and bone marrow cancers such as leukaemias, lymphomas, and multiple myeloma) and the effects of 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.

When a prolonged interval of low granulocytes is anticipated, prophylactic antibiotics, 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 filgrastim, sargramostim, or pegfilgrastim are given with the chemotherapy.

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.

A 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 is 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. The examination includes possible abscess sites (eg, skin, ears, sinuses, perirectal area), skin and mucosa for the 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.

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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

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. Some steroids, such as testosterone, are contraindicated in patients with prostate or liver cancer.

Constipation

1. Constipation is common in patients with cancer and is often exacerbated by opioids used to treat pain.
2. 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.
3. 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.
4. Enemas and suppositories should be avoided in patients with neutropenia or thrombocytopenia.

Diarrhoea

1. Diarrhoea is common after chemotherapy drugs, targeted therapy drugs, and radiation therapy, especially if the abdomen and/or pelvis are included in the radiation field.
2. 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.
3. 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.

Mouth lesions

1. 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.
2. 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.
3. Mucositis due to radiation therapy can cause pain and preclude sufficient oral intake, leading to undernutrition and weight loss.
4. Rinses with analgesics and topical anaesthetics (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.
5. If not, a feeding tube may be helpful if the small intestine is functional. For severe mucositis and diarrhoea or an abnormally functioning intestine, parenteral alimentation may be needed.

Nausea and vomiting

Nausea and vomiting are common in patients with cancer whether or not they are receiving cancer therapy and decreased 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

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-

1. Serotonin-receptor antagonists are the most effective. 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 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.
2. A substance P/neurokinin-1 antagonist, aprepitant, can limit nausea and vomiting resulting from highly emetogenic chemotherapy. The 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.
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.
4. 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.

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Pain

Pain, including chronic and/or neuropathic pain, is common in patients with cancer and should be anticipated and aggressively treated.

Pain is often undertreated, for several reasons, including-

• Patient reluctance to discuss pain with the physician
• Physician reluctance to discuss pain
• Fear of opioid addiction

Treatment of pain 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).

The use of multiple drug classes may provide better pain control with fewer or less severe adverse effects than the 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.

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.

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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. A frank discussion of a patient’s fears can often relieve anxiety. Treatment of depression with drugs and/or psychotherapy can often be effective.

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Tumour lysis and cytokine release syndromes

Tumour lysis syndrome

Tumour lysis syndrome occurs because rapid death of cancer cells, resulting from cytotoxic drugs and some types of immune therapy (eg CAR-T-cell treatment), which releases intracellular components into the bloodstream.

Diagnostic criteria for tumour 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])

Treatment of tumour 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.

Cytokine release syndrome

Cytokine release syndrome (CRS) is related to but distinct from tumour 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, diarrhoea, 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 (3) is as follows-

1. Grade 1: Symptoms (eg, fever, nausea, fatigue, headache, myalgias, malaise) are not life-threatening and require symptomatic treatment only.
2. 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.
3. Grade 3: Symptoms require and respond to aggressive intervention with oxygen supplementation ≥ 40% FiO2, or hypotension requires high-dose or multiple vasopressors, grade 3 organ toxicity, or grade 4 transaminitis.
4. Grade 4: Symptoms are life-threatening, including the need for ventilator support, or indicate grade 4 organ toxicity (excluding transaminitis).
5. 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.

Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr. Sachin Jain, DM Medical oncologist, PIMS Medical College, Udaipur, Rajasthan.