Safety of Same-Day Vitamin B12 Supplementation in Patients Receiving Pemetrexed for the Treatment of Non–Small-Cell Lung Cancer or Pleural Mesothelioma: A Retrospective Analysis

Abstract

Background

Pemetrexed is a folate analog inhibitor for the treatment of non–small-cell lung cancer (NSCLC) and malignant pleural mesothelioma. Folic acid and vitamin B12 supplementation before initiating pemetrexed is necessary because of high rates of cytopenias without supplementation. However, the timing of supplementation has not been thoroughly investigated.

Patients and Methods

This was a single-center, retrospective study investigating patients receiving pemetrexed from January 1, 2012, to June 30, 2015, who received same-day vitamin B12 supplementation versus ≥ 1 day before pemetrexed. The objective was to evaluate safety outcomes in patients who received vitamin B12 on the same day as pemetrexed (group A) versus vitamin B12 ≥ 1 day (group B) before pemetrexed.

Results

Two hundred eighty-one patients met the inclusion criteria: 137 patients in group A (same-day administration of vitamin B12) and 144 patients in group B (median time of vitamin B12 administration before pemetrexed, 7 days; range, 1-42 days). Mean changes in hematologic indices from cycle (C) 1 to C2 or C2 to C3 did not differ significantly between groups. There were no significant differences in clinical events between C1 and C2 or C2 and C3 requiring supportive care. There was a significant difference noted in treatment delay in C3 [28/114 (24.6%) group A vs. 14/118 (11.9%) group B, P = .0164]. In group A, significant predictors of delay in C3 were baseline hemoglobin (mean 13.3 g/dL vs. 12.4 g/dL, P = .0137) and ANC (mean 6 × 10⁹/L vs. 5 × 10⁹/L, P = .0003).

Conclusion

Same-day vitamin B12 and pemetrexed administration is a safe practice in NSCLC and malignant pleural mesothelioma patients.

Introduction

It is estimated that 234,030 new cases of lung cancer will be diagnosed in 2018, and the majority will be non–small-cell lung cancer (NSCLC).¹ In addition, mesothelioma is estimated to occur in 2500 people in the United States annually, with malignant pleural mesothelioma (MPM) being the most common type. Unfortunately, MPM is difficult to treat because most patients present with advanced disease.²

Pemetrexed (Alimta) is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processes necessary for cell replication; it is commonly used in the first-line setting for NSCLC and mesothelioma.1, 2 It was approved by the US Food and Drug Administration (FDA) in 2004 and is considered a first-line option, with or without a platinum agent, for both nonsquamous NSCLC and MPM.³

Several early-phase clinic trials with pemetrexed reported the frequent occurrence of severe adverse effects, including grade 3/4 neutropenia, thrombocytopenia, and anemia.4, 5, 6, 7 A multivariate analysis of laboratory data by Niyikiza et al⁸ revealed that pretreatment levels of plasma homocysteine and methylmalonic acid were predictors of these adverse events. Plasma homocysteine is a marker for both folic acid and vitamin B12 deficiency, and methylmalonic acid is a marker for vitamin B12 deficiency.

This study prompted investigators of an ongoing phase 3 trial comparing cisplatin plus pemetrexed versus cisplatin alone in patients with MPM to supplement patients with vitamin B12 1000 μg intramuscularly every 9 weeks and folic acid 350 μg to 1000 μg by mouth daily throughout treatment.⁹ Patients who received supplements had reduced toxicity with pemetrexed.⁹ Grade 3/4 neutropenia occurred in 52% (117/226) of patients who did not receive or who only partially received supplements after the initiation of pemetrexed. The rate of grade 3/4 neutropenia in patients who received supplements at the initiation of pemetrexed was significantly less (9.4%, 109/226 patients). In a phase 2 study in 2003, which evaluated pemetrexed with and without folic acid and vitamin B12 supplementation in the treatment of MPM, patients who received full supplementation received a median of 6 cycles of pemetrexed compared to a median of only 2 cycles of treatment for patients who did not receive any vitamin supplementation. Patients who received vitamin B12 and folic acid supplements tolerated the treatment better and had a 5-month greater median overall survival than those who did not received supplements.¹⁰

Following these results, the final FDA-approved package insert for pemetrexed specifies that patients should initiate folic acid 400 to 1000 μg orally once daily beginning 7 days before the first dose of pemetrexed and to continue folic acid through pemetrexed treatment and 21 days after the last dose.³ Additionally, it was recommended that vitamin B12 1000 μg intramuscularly be administered 1 week before the initiation of pemetrexed and every 3 cycles thereafter.² However, subsequent administrations of vitamin B12 may be provided on the same day as pemetrexed.³

Despite these recommendations, there is clinical evidence to suggest that supplementation less than 7 days before pemetrexed treatment may be safe.11, 12, 13 A small retrospective study by Griffin et al¹² reviewed patients who received less than 1 week of folic acid supplementation before pemetrexed treatment. Of the 8 patients evaluated, none experienced major adverse events that were related to a shortened course of folic acid supplementation.

In a prospective phase 2 multicenter, single-arm, open-label study by Tagaki et al,¹³ vitamin B12 1000 μg was administered 24 to 48 hours before receiving pemetrexed. Thirty patients received vitamin B12 supplementation 24 to 48 hours before receiving pemetrexed. There were no treatment deaths or grade 4 toxicities. The rate of both hematologic and nonhematologic adverse effects grade 3 or higher was 13%. The rate of these toxicities was no greater than in the previously published literature, which described patients receiving supplements more than 24 to 48 hours before pemetrexed administration. Notably, a vitamin B12 study from 1971 mentioned by Tagaki et al showed that parenteral vitamin B12 begins to invade the main organs within 1 hour after administration, with a plateau reached 24 hours later.¹⁴ Another phase 2 trial evaluating the safety and efficacy of pemetrexed in extensive-stage small-cell lung cancer patients demonstrated that while pemetrexed monotherapy showed minimal activity in this patient population, vitamin B12 administered < 7 days before pemetrexed did not result in more frequent serious toxicities.¹⁵

At Roswell Park Comprehensive Cancer Center (RPCCC), there is provider variability in instituting vitamin B12 supplementation, with many NSCLC and MPM patients receiving vitamin B12 supplementation on the same day that pemetrexed is initiated. Although there is evidence to suggest that shortening the lead-in time with vitamin B12 and folic acid to less than 7 days as recommended by the manufacturer is safe, there are no published studies to date evaluating the safety of same-day administration of vitamin B12 and pemetrexed in this patient population. Clinical trials with pemetrexed continue to stipulate the administration of vitamin B12 at least 7 days before pemetrexed administration.

Therefore, the objective of this study was to evaluate safety outcomes in patients with NSCLC and MPM treated with pemetrexed with or without a platinum agent who received vitamin B12 the same day as pemetrexed versus those who received it one or more days before initiating pemetrexed.