Timing of folic acid/vitamin B12 supplementation and hematologic toxicity during first-line treatment of patients with nonsquamous non-small cell lung cancer using pemetrexed-based chemotherapy: The PEMVITASTART randomized trial

Background Vitamin B12 and folic acid (FA) supplementation (B12-FAS) reduces hematologic toxicity with pemetrexed-based chemotherapy (PEM). However, the basis for recommending 1 week of B12-FAS before PEM initiation has never been proven in a randomized trial. Methods An open-label, randomized trial (PEMVITASTART; clinicaltrials.gov identifier NCT02679443) was conducted to compare hematologic toxicity between patients with locally advanced/metastatic nonsquamous non-small cell lung cancer who initiated PEM after 5 to 7 days of B12-FAS (delayed arm [DA]) versus those who received B12-FAS simultaneously (<= 24 hours) with PEM initiation (immediate arm [IA]). Every 3 weeks, all enrolled patients received pemetrexed (500 mg/m(2)) AND either cisplatin (65 mg/m(2)) OR carboplatin (area under the curve = 5.0 mg/mL per minute) on day 1 for a maximum of 6 cycles. Supplementation consisted of oral FA 1000 mu g daily and intramuscular vitamin B12 1000 mu g every 3 weeks. The primary outcome was any grade of hematologic toxicity and secondary outcomes included grade 3/4 hematologic toxicity, the relative dose intensity delivered, and changes in serum levels of B12/FA/homocysteine. Results Of 161 patients (IA, n = 81; DA, n = 80) recruited, 150 (IA, n = 77; DA, n = 73) received >= 1 cycle and were included in a modified intention-to-treat analysis. Baseline anemia prevalence was 34.7% (IA, 32.5%; DA, 37%; P = .56). The incidence of any grade anemia, leukopenia, neutropenia, and thrombocytopenia was 87% versus 87.7% (P = .90), 37.7% versus 28.8% (P = .25), 20.8% versus 15.1% (P = .36), and 31.2% versus 16.4% (P = .04), respectively, in the IA and DA, respectively. Grade 3/4 cytopenias and median relative dose intensities delivered (pemetrexed, 93.5%; platinum, 91%) were similar in both arms. After cycle 3 (compared with baseline), serum homocysteine levels were lower, whereas FA and B12 levels were higher. In the DA, serum FA and B12 levels on day 1 of cycle 1 (after 5-7 days of B12-FAS) were significantly higher than at baseline, but homocysteine levels were similar. Conclusions Simultaneous B12-FAS initiation with a pemetrexed-platinum doublet chemotherapy regimen is feasible and does not lead to enhanced hematologic toxicity. Serum homocysteine levels are unaffected by 5 to 7 days of B12-FAS.