Chemotherapy Toxicity & Supportive Care

Chemotherapy-induced nausea and vomiting

Match prophylaxis to emetic risk. Highly emetogenic chemotherapy, chiefly cisplatin or the combination of an anthracycline with cyclophosphamide (AC), is covered with four drugs: an NK1 antagonist (aprepitant or fosaprepitant), a 5-HT3 antagonist (ondansetron, granisetron, palonosetron), dexamethasone, and olanzapine. Moderate-risk regimens usually need a 5-HT3 antagonist plus dexamethasone. Aprepitant inhibits CYP3A4 and raises dexamethasone levels, so the steroid dose is reduced when the two are combined.

Anticipatory nausea. Patients who vomited during earlier cycles may become nauseated at the sight of the infusion center. Standard antiemetics do not prevent this learned response; lorazepam and behavioral therapy treat it, and the best prevention is complete control of emesis from the first cycle. Breakthrough symptoms are treated with an agent from a different class, such as olanzapine, metoclopramide, or prochlorperazine.

Myelosuppression and marrow support

Nadir. Counts fall to their lowest 7–14 days after most cytotoxic regimens and recover by about 3–4 weeks; nitrosoureas such as carmustine and lomustine cause a delayed nadir at about 4–6 weeks. A temperature of 38.3 °C or higher with an ANC below 500/µL during the nadir is febrile neutropenia, an emergency requiring immediate empiric antibiotics.

Myeloid growth factors. Filgrastim or pegfilgrastim is given as primary prophylaxis when a regimen carries a febrile-neutropenia risk of 20% or more, and considered at 10–20% when patient factors such as age 65 or older or prior febrile neutropenia add risk. Growth factors are not routine for afebrile neutropenia. Pegfilgrastim is given at least 24 hours after chemotherapy. Bone pain is common; splenic rupture is rare.

Erythropoiesis-stimulating agents. Epoetin or darbepoetin may be used for chemotherapy-induced anemia only when hemoglobin is below 10 g/dL and treatment intent is noncurative, after iron deficiency is corrected. ESAs increase venous thromboembolism and may shorten survival or accelerate tumor growth, so the lowest dose that avoids transfusion is used; they are not given to cancer patients who are not receiving chemotherapy. Symptomatic anemia, or anemia during curative-intent treatment, is managed with red-cell transfusion.

Cardiac, pulmonary, renal, and bladder toxicity

Anthracyclines. Doxorubicin and daunorubicin generate free radicals and poison topoisomerase IIβ in cardiomyocytes, causing myocyte death and a dose-dependent, largely irreversible dilated cardiomyopathy. Risk rises with cumulative dose, chest radiation, and concurrent or sequential trastuzumab. Baseline and serial LVEF (echocardiogram or MUGA) are required, and dexrazoxane, an iron chelator, is cardioprotective at high cumulative doses. Red urine after an anthracycline is harmless.

Anthracyclines are vesicants. For extravasation, stop the infusion, aspirate residual drug through the catheter, elevate the limb, apply cold compresses, and start IV dexrazoxane within 6 hours. Vinca alkaloid extravasation is treated differently, with warm compresses and hyaluronidase.

Bleomycin. Bleomycin causes dose-related pneumonitis that progresses to pulmonary fibrosis, with dry cough, dyspnea, a restrictive pattern, and a falling DLCO, the earliest sign. Older age, renal impairment (the drug is renally cleared), smoking, and chest radiation increase risk. PFTs with DLCO are followed, the drug is stopped for a significant DLCO decline or symptoms, and anesthesiologists keep FiO2 low because high oxygen concentrations worsen the injury. Bleomycin spares the marrow and can cause flagellate hyperpigmentation.

Cisplatin. Cisplatin damages the proximal tubule, causing AKI and renal wasting of magnesium and potassium; hypomagnesemia in turn produces hypokalemia and hypocalcemia that do not correct until magnesium is replaced. Vigorous saline hydration with magnesium and potassium replacement is standard, and amifostine, a free-radical scavenger, can reduce cumulative nephrotoxicity. Cisplatin also causes high-frequency sensorineural hearing loss (monitored with audiometry), sensory neuropathy, and severe emesis. Carboplatin is gentler on kidneys, ears, and nerves but more myelosuppressive, especially for platelets.

Cyclophosphamide and ifosfamide. Both release acrolein, which causes hemorrhagic cystitis; hydration, frequent voiding, and mesna, a thiol that binds acrolein in the urine, prevent it. Ifosfamide also causes encephalopathy (confusion, somnolence, seizures), treated or prevented with methylene blue, and proximal tubular Fanconi syndrome. Cyclophosphamide can cause SIADH and later bladder cancer.

Methotrexate and fluoropyrimidines

High-dose methotrexate. In acidic urine methotrexate precipitates in the renal tubules, causing AKI that delays its own clearance and amplifies mucositis and myelosuppression.

5-FU and capecitabine. These fluoropyrimidines inhibit thymidylate synthase and cause mucositis, diarrhea, myelosuppression, and hand-foot syndrome (palmar-plantar erythrodysesthesia), especially with oral capecitabine. Coronary vasospasm can cause angina or ST elevation during infusion; the drug is stopped and nitrates or calcium channel blockers are given. Patients with dihydropyrimidine dehydrogenase (DPD) deficiency from DPYD variants cannot break down 5-FU and develop severe or fatal toxicity; FDA labeling advises considering pretreatment DPYD testing, and the antidote uridine triacetate must be started within 96 hours of the last dose. Capecitabine potentiates warfarin, so the INR is monitored closely.

Irinotecan and neurotoxic drugs

Irinotecan. This topoisomerase I inhibitor causes two distinct diarrheas. Early diarrhea within 24 hours is part of a cholinergic syndrome with cramps, sweating, and salivation, and responds to atropine. Late diarrhea after 24 hours reflects mucosal injury by the active metabolite SN-38; it can be life-threatening and is treated with high-dose loperamide and fluids, adding octreotide if refractory. UGT1A1*28 homozygotes (the Gilbert genotype) glucuronidate SN-38 poorly and suffer more diarrhea and neutropenia.

Vincristine. Its dose-limiting toxicity is peripheral neuropathy (paresthesias, lost ankle reflexes, foot drop), with autonomic neuropathy causing constipation and paralytic ileus, so a bowel regimen accompanies it; SIADH also occurs. It spares the marrow, whereas vinblastine is myelosuppressive.

Intrathecal vincristine causes fatal ascending myeloencephalopathy; it is dispensed only in IV mini-bags to prevent route errors.

Paclitaxel. Hypersensitivity reactions, largely caused by the Cremophor vehicle, are prevented by premedication with dexamethasone plus H1 and H2 blockers. A cumulative stocking-glove sensory neuropathy is dose-limiting.

Oxaliplatin. Acute dysesthesias of the hands, mouth, and throat are triggered by cold, so patients avoid cold drinks and cold air for several days after each dose; throat dysesthesia can feel like choking even though the airway and oxygen saturation are normal. With repeated cycles a cumulative sensory neuropathy develops.