Navneet Singh1, Milind Baldi1, Jyotdeep Kaur2, Valliappan Muthu1, Kuruswamy T Prasad1, Digambar Behera1, Amanjit Bal3, Nalini Gupta4, Rakesh Kapoor5. 1. Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India. 2. Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India. 3. Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India. 4. Department of Cytology and Gynecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India. 5. Department of Radiotherapy, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Abstract
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/m2 ) AND either cisplatin (65 mg/m2 ) 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 μg daily and intramuscular vitamin B12 1000 μg 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.
RCT Entities:
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/m2 ) AND either cisplatin (65 mg/m2 ) 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 μg daily and intramuscular vitamin B12 1000 μg 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.
Authors: Nikki de Rouw; Berber Piet; Hieronymus J Derijks; Michel M van den Heuvel; Rob Ter Heine Journal: Drug Saf Date: 2021-11-06 Impact factor: 5.606