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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

Singh, Navneet MD, DM; Aggarwal, Ashutosh N. MD, DM; Kaur, Jyotdeep PhD; Behera, Digambar MD

American Journal of Clinical Oncology: February 2017 - Volume 40 - Issue 1 - p 75–82
doi: 10.1097/COC.0000000000000111
Original Articles: Thoracic

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/m2) and cisplatin (65 mg/m2) 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 <ULN, 1 to 2 ULN and >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.

Departments of *Pulmonary Medicine

Biochemistry, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

The authors declare no conflicts of interest.

Reprints: Navneet Singh, MD, DM, Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Sector 12, Chandigarh 160012, India. E-mail:;

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