Abstract
Background Serum homocysteine (Hcy) and vitamin B12 (VitB12) were investigated as serological markers for the prediction of pemetrexed induced haematological toxicity in patients with adenocarcinoma of the lung.
Material and Methods A total of 35 lung adenocarcinoma patients who received pemetrexed chemotherapy as first-line treatment were included in the present study. The patients received pemetrexed 500 mg/m2 once every three weeks until disease progression. Serum Hcy and VitB12 levels were analysed prior to chemotherapy. Haematological toxicities (leucopenia, neutropenia and thrombocytopenia) were graded for each cycle of chemotherapy. Serum Hcy and VitB12 concentrations were compared between grades 0-1 and 2-4 haematological toxicity groups.
Results A total of 151 chemotherapy cycles were administered to 35 lung adenocarcinoma patients. However, the serum Hcy and VitB12 concentration were only examined and recorded in 61 out of the 151 chemotherapy cycles. For the 61 cycles, grade 2-4 leucopenia, neutropenia and thrombocytopenia were observed in 21, 20 and 10 cases, respectively. Serum Hcy levels were 14.91±4.67 μg/ml, 15.50±4.35 μg/ml and 16.04±4.90 μg/ml for grade 2-4 leucopenia, neutropenia and thrombocytopenia, respectively, which were significantly higher than those of grade 0-1 groups (p<0.05). However, serum VitB12 were not statistically different between grade 0-1 and 2-4 haematological toxicity groups (p>0.05). The area under the ROC curve (AUC) were 0.73 (0.58-0.88), 0.80 (0.66-0.94), 0.75 (0.57-0.93) for serum Hcy and 0.65 (0.50-0.79), 0.64 (0.49-0.78), 0.68 (0.49-0.87) for serum VitB12 as predictive biomarkers of grade 2-4 leucopenia, neutropenia and thrombocytopenia, respectively.
Conclusion Pre-chemotherapy serum Hcy appeared to correlate with haematological toxicity and may be a useful biomarker for predicting severity of pemetrexed induced haematological toxicity.
References
1. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017;67:7-30.10.3322/caac.21387Search in Google Scholar
2. Cao M, Chen W. Epidemiology of lung cancer in China. Thorac Cancer 2019;10:3-7.10.1111/1759-7714.12916Search in Google Scholar
3. Cao S, Teng J, Xu J, Han B, Zhong H. Value of adjuvant chemotherapy in patients with resected stage IB solid predominant and solid non-predominant lung adenocarcinoma. Thorac Cancer 2018.10.1111/1759-7714.12942Search in Google Scholar
4. Cortellini A, Gambale E, Cannita K, Brocco D, Parisi A, Napoleoni L, et al. Multicentric retrospective analysis of platinum-pemetrexed regimens as first-line therapy in non- squamous non-small cell lung cancer patients: A “snapshot” from clinical practice. Thorac Cancer 2018;9:241-252.10.1111/1759-7714.12570Search in Google Scholar
5. Hayashi H, Chiba Y, Sakai K, Fujita T, Yoshioka H, Sakai D, et al. A Randomized Phase II Study Comparing Nivolumab With Carboplatin-Pemetrexed for Patients With EGFR Mutation- Positive Nonsquamous Non-Small-Cell Lung Cancer Who Acquire Resistance to Tyrosine Kinase Inhibitors Not Due to a Secondary T790M Mutation: Rationale and Protocol Design for the WJOG8515L Study. Clin Lung Cancer 2017;18:719-723.10.1016/j.cllc.2017.05.012Search in Google Scholar
6. Park CK, Oh IJ, Kim KS, Choi YD, Jang TW, Kim YS, et al. Randomized Phase III Study of Docetaxel Plus Cisplatin Versus Pemetrexed Plus Cisplatin as First-line Treatment of Nonsquamous Non-Small-cell Lung Cancer: A TRAIL Trial. Clin Lung Cancer 2017;18:e289-e296.10.1016/j.cllc.2017.01.002Search in Google Scholar
7. Cheng Y, Murakami H, Yang PC, He J, Nakagawa K, Kang JH, et al. Randomized Phase II Trial of Gefitinib With and Without Pemetrexed as First-Line Therapy in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations. J Clin Oncol 2016;34:3258-66.10.1200/JCO.2016.66.9218Search in Google Scholar
8. Niyikiza C, Baker SD, Seitz DE, Walling JM, Nelson K, Rusthoven JJ, et al. Homocysteine and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy. Mol Cancer Ther 2002;1:545-52.Search in Google Scholar
9. Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13:176-81.10.1016/S1053-4296(03)00031-6Search in Google Scholar
10. McLeod HL, Cassidy J, Powrie RH, Priest DG, Zorbas MA, Synold TW, et al. Pharmacokinetic and pharmacodynamic evaluation of the glycinamide ribonucleotide formyltransferase inhibitor AG2034. Clin Cancer Res 2000;6:2677-84.Search in Google Scholar
11. Manegold C. Pemetrexed: its promise in treating non-small-cell lung cancer. Oncology (Williston Park) 2004;18:43-8.Search in Google Scholar
12. Fossella FV. Pemetrexed for treatment of advanced non-small cell lung cancer. Semin Oncol 2004;31:100-5.10.1053/j.seminoncol.2003.12.001Search in Google Scholar PubMed
13. Zhu Y, Xing P, Wang S, Ma D, Mu Y, Li X, et al. Evaluation of calculating carboplatin dosage in carboplatin-pemetrexed therapy as the first-line therapy for Chinese patients with advanced lung adenocarcinoma. Thorac Cancer 2018;9:400- 407.10.1111/1759-7714.12594Search in Google Scholar PubMed PubMed Central
14. Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt W, Zabeck H, Kollmeier J, et al. Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study. Ann Oncol 2013;24:986-92.10.1093/annonc/mds578Search in Google Scholar PubMed
15. Kim HS, Lee GW, Kim JH, Kim HY, Kwon JH, Song HH, et al. A phase II study of pemetrexed and carboplatin as a salvage therapy for platinum-pretreated patients with non-small cell lung cancer. Lung Cancer 2010;70:71-6.10.1016/j.lungcan.2009.12.015Search in Google Scholar PubMed
16. Castagneto B, Botta M, Aitini E, Spigno F, Degiovanni D, Alabiso O, et al. Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM). Ann Oncol 2008;19:370-3.10.1093/annonc/mdm501Search in Google Scholar PubMed
17. Brechot JM, Morère JF. Update of pemetrexed in thoracic oncology. Bull Cancer 2007;94 Spec No Actualites:S139-41.Search in Google Scholar
18. Schlei Z, Tan W, Faber MG, Chen H, Meagher A, Dy GK. 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. Clin Lung Cancer 2018;19:467-475.10.1016/j.cllc.2018.05.017Search in Google Scholar PubMed
19. Bironzo P, Scagliotti GV. Pemetrexed, Vitamin B12, and Thoracic Tumors: The Times, They Are A-Changin’. Clin Lung Cancer 2018;19:461-463.10.1016/j.cllc.2018.07.007Search in Google Scholar PubMed
20 Tsuda Y, Kitamura A, Nishimura N, Yagi N, Takayama S, Okafuji K, et al. Safety of pemetrexed according to the duration of vitamin B12 and folic acid supplementation prior to the first dose of pemetrexed. Gan To Kagaku Ryoho 2015;42:471-5.Search in Google Scholar
21. Tanaka H, Horiike A, Sakatani T, Saito R, Yanagitani N, Kudo K, et al. Plasma homocysteine levels and hematological toxicity in NSCLC patients after the first cycle of pemetrexed under folate supplementation. Anticancer Drugs 2015;26:573-8.10.1097/CAD.0000000000000220Search in Google Scholar PubMed
22. Baoshan C, Yu Z, Sen C, Wenqi Y, Yu X, Wen M, et al. Correlation of peripheral blood homocysteine, vitamin B12 and folic acid levels with pemetrexed induced blood toxicity. Chinese journal of laboratory diagnosiS 2011;15:2085-2087.Search in Google Scholar
© 2019 Zhi Chang et al., published by De Gruyter Open
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