Dose Adjustment After Chemotherapy Toxicity

Dose adjustment keeps patients safe and on treatment. The balance depends on intent: in curative treatment, delay and use growth factor before reducing the dose; in palliative treatment, reduce early. Adjust for the toxicity that occurred and the drug most likely to have caused it.

Hierarchy of response. Delay the cycle until recovery, add supportive care (growth factor, antiemetics, antidiarrhoeals), reduce the dose of the responsible drug, and stop the drug if toxicity is severe or recurs after reduction.

Grading. Use a validated toxicity scale: grade 1 mild, grade 2 moderate, grade 3 severe, grade 4 life-threatening.

Marrow suppression.

• Day of treatment: neutrophils 1.0 x 10⁹/L or more (1.5 x 10⁹/L for curative regimens) and platelets 100 x 10⁹/L or more. If either count is lower, delay by 1 week and repeat counts.
• Febrile neutropenia, grade 4 neutropenia lasting over 7 days, or grade 4 thrombocytopenia: reduce the dose by 20 to 25% in the next cycle unless growth factor is added in curative treatment.
• Platelets under 75 x 10⁹/L or bleeding: delay and reduce carboplatin, gemcitabine and temozolomide by one dose level.

Gastrointestinal.

• Grade 3 to 4 mucositis or diarrhoea: hold fluorouracil or capecitabine until grade 1, then restart at 75% (one dose level lower).
• Hand-foot syndrome with capecitabine: grade 2 hold until grade 1 and resume at the same dose on the first episode, 75% on the second; grade 3 hold and resume at 75% then 50%.
• Loperamide 4 mg then 2 mg after each loose stool (maximum 16 mg daily) for chemotherapy diarrhoea; admit for diarrhoea with fever or dehydration.

Neurotoxicity.

• Oxaliplatin: persistent grade 2 neuropathy, reduce to 75%; grade 3, stop.
• Paclitaxel and vincristine: grade 2 sensory or motor neuropathy, reduce by 20 to 25%; grade 3, hold and stop if no improvement.

Kidney toxicity. Cisplatin: if creatinine rises over 50% from baseline or eGFR falls under 60 mL/min, hold and switch to carboplatin or stop. Methotrexate (high dose): give leucovorin rescue by the level thresholds on the regimen sheet.

Cardiac toxicity. Anthracyclines: stop if ejection fraction falls by 10 points or more to under 50%; trastuzumab: hold if ejection fraction falls by 10 points or more to under 50%, repeat in 3 weeks.

Hypersensitivity. Stop the infusion, give adrenaline 500 micrograms IM for anaphylaxis, hydrocortisone 200 mg IV and chlorphenamine 10 mg IV; mild reactions may be rechallenged with premedication and slower infusion.

Dose levels. Define level 0 as full dose, level -1 as 80 to 75%, and level -2 as 60 to 50%. Do not re-escalate after reduction for haematological toxicity unless the oncologist agrees.

DPYD deficiency. Complete loss of activity: avoid fluorouracil and capecitabine. Partial deficiency: start at 50% and escalate if tolerated. Severe toxicity in the first cycle (rapid onset mucositis, diarrhoea, neutropenia): stop and give uridine triacetate where available.

Kidney and liver impairment. Reduce doses of renally cleared drugs (carboplatin, methotrexate, capecitabine, pemetrexed) and hepatically cleared drugs (doxorubicin, paclitaxel, vincristine, irinotecan) before applying toxicity-based reductions.

Older adults. Apply earlier dose reduction and add growth factor.

Pregnancy and breastfeeding. Not relevant to dose adjustment; stop breastfeeding.

Regional. Where counts cannot be checked quickly, set a lower threshold for delaying a cycle and give supportive care more generously, since delayed recognition of neutropenia is the main cause of treatment deaths.

Document. Record the toxicity, grade, action taken, the new dose level and the planned date of review in the notes and on the regimen sheet.

Recheck. Full blood count within 7 days of a grade 3 to 4 count; creatinine within 48 hours after a rise.

Stop and escalate. Stop treatment for life-threatening toxicity, second occurrence of a grade 4 event on a reduced dose, cardiomyopathy, pneumonitis, or hypersensitivity to the same drug after premedication. Refer to the oncologist the same day for any grade 4 event.