Association of Graded Folic Acid Supplementation and Total Plasma Homocysteine Levels With Hematological Toxicity During First-line Treatment of Nonsquamous NSCLC Patients With Pemetrexed-based Chemotherapy.

ABSTRACT

BACKGROUND: Pemetrexed is the preferred treatment of nonsquamous non-small cell lung cancer (ns-NSCLC). Folic acid supplementation (FAS) (350 to 1000 µg daily PO) is recommended to minimize hematological toxicity (HTox). Elevated total plasma homocysteine (tpHcy) predicts increased risk of HTox with pemetrexed in absence of FAS. The current study aimed to assess prevalence of elevated tpHcy levels at baseline and after pemetrexed treatment. Association of graded tpHcy levels/FAS with toxicity was also assessed. MATERIALS AND METHODS: Retrospective analysis of all ns-NSCLC patients undergoing first-line treatment with pemetrexed-containing platinum doublet over 3½ years was carried out. All eligible patients received pemetrexed (500 mg/m) and cisplatin (65 mg/m) each on D1 of a 3-week cycle. FAS was 400 µg for tpHcy< upper limit of normal (ULN), 700 µg for tpHcy 1 to 2 ULN, and 1000 µg for tpHcy>2 ULN. All patients also received oral ferrous sulphate and injectable vitamin B12. Exact 95% confidence intervals (CI) were calculated for comparison with previously published studies. RESULTS: 75.7% of 111 patients had stage IV disease. Prevalence of tpHcy levels 2 ULN were 47.8%, 41.4%, and 10.8% pretreatment and 78.9%, 21.1%, and 0% posttreatment, respectively (P<0.0001). Incidence of any grade and grade 3/4 HTox was 87.4% and 17.1% (anemia), 53.2% and 7.2% (leukopenia), 36.9% and 10.8% (neutropenia), and 39.6% and 7.2% (thrombocytopenia), respectively. HTox, non-HTox, and radiologic responses did not differ among patient groups based upon baseline tpHcy levels or upon graded baseline FAS. Incidence of grade 3/4 anemia was higher in current (17.1%; 95% CI, 11.3%-25.2%) as compared with previous studies.

CONCLUSIONS:

Prevalence of elevated tpHcy levels posttreatment as compared with baseline was reduced significantly with FAS. Among ns-NSCLC patients treated with pemetrexed and with FAS of 400 to 1000 µg daily, HTox was not associated with either baseline tpHcy levels or with graded baseline FAS.