What are the day-to-day side effects of chemotherapy with cisplatin and pemetrexed?

Day-by-Day Side Effects of Cisplatin and Pemetrexed Chemotherapy

The side effects of cisplatin and pemetrexed follow a predictable temporal pattern over the 21-day cycle, with acute gastrointestinal toxicity occurring within hours of infusion, hematologic nadirs appearing between days 18-23, and some toxicities potentially persisting throughout the treatment course. 1

Immediate to Early Phase (Day 1-7)

Day 1 (Infusion Day)

• Nausea and vomiting begin within 1-4 hours after cisplatin administration and occur in almost all patients, potentially severe enough to require treatment discontinuation 1
• Acute nausea and vomiting typically last up to 24 hours after treatment 1
• Patients should receive aggressive antiemetic prophylaxis given the near-universal occurrence of these symptoms 1

Days 1-7 (First Week)

• Delayed nausea and vomiting can begin or persist 24 hours or more after chemotherapy, even in patients who achieved complete emetic control on day 1 1
• Various degrees of nausea, vomiting, and anorexia may persist for up to 1 week after treatment 1
• Diarrhea can occur during this period 1
• Fatigue, dehydration, and stomatitis are significantly more common with the pemetrexed/cisplatin combination 2
• Grade 3 or 4 nausea is more common with pemetrexed-containing regimens 3

Hematologic Nadir Phase (Days 8-23)

Days 8-15 (Monitoring Period)

• Complete blood counts should be obtained to assess nadir timing during days 8 and 15 4
• Early signs of myelosuppression may begin to appear 1

Days 18-23 (Peak Toxicity)

• Myelosuppression nadirs occur between days 18-23, affecting 25-30% of patients treated with cisplatin 1
• Nadirs in circulating platelets and leukocytes peak during this window (range 7.5 to 45 days) 1
• Leukopenia and thrombocytopenia are more pronounced at higher cisplatin doses (>50 mg/m²) 1
• Anemia (decrease of 2 g hemoglobin/100 mL) occurs at approximately the same frequency and timing as leukopenia and thrombocytopenia 1
• Fever and infection may occur in patients with neutropenia, with potential fatalities due to infection secondary to myelosuppression 1

Recovery and Late Phase (Days 24-39+)

Days 24-39 (Recovery Period)

• Most patients recover from hematologic toxicity by day 39 (range 13 to 62 days) 1
• Repeat courses should not be given until platelets ≥100,000/mm³ and WBC ≥4,000/mm³ 1

Cumulative and Delayed Toxicities (Throughout Treatment)

Renal Toxicity

• Nephrotoxicity can occur despite 6-8 hour infusion protocols with hydration and mannitol 1
• Impairment of renal function is associated with renal tubular damage 1
• Repeat courses should not be given until serum creatinine is below 1.5 mg/100 mL and BUN is below 25 mg/100 mL 1

Ototoxicity

• Ototoxicity can occur during treatment or be delayed, manifested by tinnitus and/or hearing loss in the high frequency range (4,000 to 8,000 Hz) 1
• Hearing loss tends to become more frequent and severe with repeated cisplatin doses 1
• Audiometric monitoring should be performed prior to initiation, before each subsequent dose, and for several years post-therapy 1

Neurotoxicity

• Peripheral neuropathies usually occur after prolonged therapy (4-7 months), though neurologic symptoms can occur after a single dose 1
• Symptoms of neuropathy may begin 3-8 weeks after the last dose of cisplatin, and may progress even after stopping treatment 1
• Preliminary evidence suggests peripheral neuropathy may be irreversible in some patients 1

Critical Monitoring and Prevention Strategies

Mandatory Vitamin Supplementation

• Vitamin B12 1000 μg intramuscularly must be started at least 1 week before first pemetrexed dose and continued every 9 weeks 5, 4
• Folic acid 0.4-1.0 mg orally daily must be started at least 1 week before first dose and continued throughout treatment 5, 4
• These vitamins reduce bone marrow and mucosal toxicity without compromising antitumor efficacy 6

Hydration Protocol

• Pretreatment hydration with 1-2 liters of fluid for 8-12 hours prior to cisplatin is mandatory 1
• Adequate hydration and urinary output must be maintained during the following 24 hours 1

Comparative Toxicity Profile

• Grade 3 or 4 neutropenia, anemia, thrombocytopenia, febrile neutropenia, and alopecia are significantly lower with cisplatin/pemetrexed compared to cisplatin/gemcitabine 3
• However, grade 3 or 4 nausea is more common with cisplatin/pemetrexed 3
• Overall, 62% of patients receiving pemetrexed plus cisplatin experience grade 3-4 adverse events 2