Total Plasma Homocysteine Level Assessment and Timing of Folate/B₁₂ Supplementation Prior to Initiation of Pemetrexed-Based Chemotherapy for Nonsquamous Non-Small Cell Lung Cancer Patients: An Irrelevant Investigation, an Unnecessary Delay, or Both?

Abstract

Usefulness of total plasma homocysteine for predicting toxicity from and optimal duration of folate and vitamin B₁₂ supplementation prior to initiation of pemetrexed-based chemotherapy both remain debatable issues following publication of recent data that challenge conventional protocols followed for the same. Randomized trials are needed in an attempt to simplify supportive care schedule during administration of pemetrexed-based chemotherapy for non-squamous NSCLC.

This letter is in reference to the study by Takagi et al. in a recent issue of the journal [1]. The authors assessed total plasma homocysteine (tpHcy) concentrations at baseline in a small cohort of advanced nonsquamous non-small cell lung cancer (NSCLC) patients prior to initiation of chemotherapy (pemetrexed and cisplatin), and then correlation of toxicity profiles with baseline tpHcy levels was assessed [1]. In this context, we wish to point out that we performed a similar assessment in a much larger cohort of patients recently [2]. Our population included 111 patients, and we assessed the association of both baseline tpHcy and graded folic acid supplementation (FAS) with clinical outcomes (hematological and nonhematological toxicity, response rates [RR], and overall survival [OS]) after first-line chemotherapy with pemetrexed-platinum doublet.

There are several important differences between the study by Takagi et al. [1] and our study [2]. First, the number of patients in our study, although it was a retrospective analysis, was more than three times the number of patients in the study by Takagi et al. Second, our assessment of tpHcy was not just at baseline but also at end of treatment; however, we categorized tpHcy only as being less than the upper limit of normal (ULN), one to two times ULN, or more than two times ULN rather than assessing tpHcy as a continuous variable. Third, patients in our study received FAS in relation to the grouping of tpHcy, namely, 400 μg for tpHcy less than ULN, 700 μg for tpHcy one to two times ULN and 1,000 μg for tpHcy more than two times ULN compared with 350–500 μg in the study by Takagi et al. Fourth, the dose of cisplatin used in our study was 65 mg/m², which is the standard dose for this drug at our center [3]. Fifth, the patient population in our study was predominantly those with unknown EGFR gene mutation/ALK gene rearrangement status compared with the study by Takagi et al., in which almost 30% of patients had one of the two actionable molecular targets. Sixth, patients in our study were initiated on oral ferrous sulfate and FAS as well as injectable vitamin B₁₂ from day 1 of the first cycle of chemotherapy compared with the 24- to 48-hour time period between administration of FAS and B₁₂ in the study by Takagi et al. Seventh, intramuscular injection of 1,000 μg vitamin B₁₂ was given with every dose (every 3 weeks) in our study.

The above differences notwithstanding, the results of our study [2] and the study by Takagi et al. [1] are similar in the sense that no association was observed between tpHcy with either hematological or nonhematological toxicity. In addition, in our study, no association was observed with any of the other clinically relevant outcomes assessed, namely, RR and OS. Two other recent studies have also shown that patients receiving FAS and vitamin B₁₂ for less than the recommended pretreatment duration of 5–7 days (including their initiation on the same day as of chemotherapy) have similar outcomes compared with those who did [4, 5].

In light of the above evidence and given the fact that FAS in the recommended range of 350–1,000 μg is routine in the current era, there are a few questions that need to be addressed. First, is it really necessary to delay initiation of chemotherapy merely to give FAS and vitamin B₁₂ supplementation for a week? Second, is it really necessary to restrict vitamin B₁₂ to every 3 cycles (9 weeks) or would it be simpler to allow 1,000 μg with every dose (as is being done at our center)? Excess vitamin B₁₂, as opposed to excess FAS, has not been shown to reduce the efficacy of pemetrexed [6]. Third, is assessment of baseline tpHcy actually relevant, and if so, is there a better way of correlating it with any of the clinically relevant outcomes? Perhaps we need a large randomized trial to answer these questions with the ultimate aim of simplifying pemetrexed-based chemotherapy and its associated supportive care schedule.

Disclosures

The authors indicated no financial relationships.