This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Niyikiza, C. Articles by Allen, R. H. Search for Related Content PubMed PubMed Citation Articles by Niyikiza, C. Articles by Allen, R. H.

Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285 [C. N., K. N., J. J. R., P. P.]; Cancer Treatment and Research Center (CTRC), University of Texas, San Antonio, Texas 78229 [S. D. B.]; Indiana University School of Medicine, Indianapolis, Indiana 46202 [D. E. S.]; Lilly Research Laboratories, Tularik Inc, South San Francisco, California 94080 [J. M. W.]; University of Colorado Health Sciences Center, Denver, Colorado 80220 [S. P. S., R. H. A.]; University of Newcastle Upon Tyne, Newcastle Upon Tyne, United Kingdom NE4 6BE [A. H. C.]

The purpose of this study was to identify predictive factors for severe toxicity caused by antifolate-chemotherapy using pemetrexed (ALIMTA, LY231514), as a model. Data on potential predictive factors for severe toxicity from pemetrexed were collected from 246 patients treated between 1995 and 1999. Multivariate stepwise regression methods were used to identify markers predictive of severe toxicity. Using a multiple logistic regression model allowed us to quantify the relative risk of developing toxicities and to generate a validated clinical hypothesis on ways to improve the safety profile of pemetrexed. Pretreatment total plasma homocysteine (tHcy) levels significantly predict severe thrombocytopenia and neutropenia with or without associated grade 3/4 diarrhea, mucositis, or infection. Pretreatment methylmalonic acid (MMA) levels significantly and independently predict grade 3/4 diarrhea and mucositis; however, these toxicities are still predicted by tHcy alone. Patients with elevated baseline levels of tHcy alone, or of both tHcy and MMA, were found to have a high risk of severe toxicity that led us to postulate that reducing tHcy would result in a reduction of severe toxicity with no harm to efficacy. This study points out for the first time the importance of pretreatment tHcy levels in predicting severe toxicity associated with an antifolate and sets the stage for a prospective clinical intervention to protect patients from pemetrexed-induced severe toxicity and possibly improve the drug’s efficacy. Antifolates as a class have been associated with sporadic severe myelosuppression with gastrointestinal toxicity. Although infrequent, a combination of such toxicities can carry a high risk of mortality. This phenomenon had been unpredictable until now. Our work shows that by measuring tHcy, one can identify patients that are at risk of toxicity before treatment. Most importantly, decreasing homocysteine levels via vitamin supplementation leads to a better safety profile of pemetrexed and possibly to an improved efficacy.

This article has been cited by other articles:

				Y. Ohe, Y. Ichinose, K. Nakagawa, T. Tamura, K. Kubota, N. Yamamoto, S. Adachi, Y. Nambu, T. Fujimoto, Y. Nishiwaki, et al. Efficacy and Safety of Two Doses of Pemetrexed Supplemented with Folic Acid and Vitamin B12 in Previously Treated Patients with Non-Small Cell Lung Cancer Clin. Cancer Res., July 1, 2008; 14(13): 4206 - 4212. [Abstract] [Full Text] [PDF]

				R. Sharma, J. M. Hoskins, L. P. Rivory, M. Zucknick, R. London, C. Liddle, and S. J. Clarke Thymidylate Synthase and Methylenetetrahydrofolate Reductase Gene Polymorphisms and Toxicity to Capecitabine in Advanced Colorectal Cancer Patients Clin. Cancer Res., February 1, 2008; 14(3): 817 - 825. [Abstract] [Full Text] [PDF]

				T. E. Stinchcombe and M. A. Socinski Considerations for Second-Line Therapy of Non-Small Cell Lung Cancer Oncologist, January 1, 2008; 13(suppl_1): 28 - 36. [Abstract] [Full Text] [PDF]

				S. Chattopadhyay, R. Tamari, S. H. Min, R. Zhao, E. Tsai, and I. D. Goldman Commentary: A Case for Minimizing Folate Supplementation in Clinical Regimens with Pemetrexed Based on the Marked Sensitivity of the Drug to Folate Availability Oncologist, July 1, 2007; 12(7): 808 - 815. [Abstract] [Full Text] [PDF]

				C. H. Takimoto, L. A. Hammond-Thelin, J. E. Latz, L. Forero, M. Beeram, B. Forouzesh, J. de Bono, A. W. Tolcher, A. Patnaik, P. Monroe, et al. Phase I and Pharmacokinetic Study of Pemetrexed with High-Dose Folic Acid Supplementation or Multivitamin Supplementation in Patients with Locally Advanced or Metastatic Cancer Clin. Cancer Res., May 1, 2007; 13(9): 2675 - 2683. [Abstract] [Full Text] [PDF]

				C. G. Azzoli, L. M. Krug, J. Gomez, V. A. Miller, M. G. Kris, M. S. Ginsberg, R. Henry, J. Jones, L. Tyson, M. Dunne, et al. A Phase 1 Study of Pralatrexate in Combination with Paclitaxel or Docetaxel in Patients with Advanced Solid Tumors Clin. Cancer Res., May 1, 2007; 13(9): 2692 - 2698. [Abstract] [Full Text] [PDF]

				S. Malempati, H. S. Nicholson, J. M. Reid, S. M. Blaney, A. M. Ingle, M. Krailo, L. C. Stork, A. S. Melemed, R. McGovern, S. Safgren, et al. Phase I Trial and Pharmacokinetic Study of Pemetrexed in Children With Refractory Solid Tumors: The Children's Oncology Group J. Clin. Oncol., April 20, 2007; 25(12): 1505 - 1511. [Abstract] [Full Text] [PDF]

				S. Chattopadhyay, R. G. Moran, and I. D. Goldman Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications Mol. Cancer Ther., February 1, 2007; 6(2): 404 - 417. [Abstract] [Full Text] [PDF]

				E. K. Rowinsky, M. Beeram, L. A. Hammond, G. Schwartz, J. De Bono, B. Forouzesh, Q. Chu, J. E. Latz, S. Hong, W. John, et al. A Phase I and Pharmacokinetic Study of Pemetrexed Plus Irinotecan in Patients with Advanced Solid Malignancies Clin. Cancer Res., January 15, 2007; 13(2): 532 - 539. [Abstract] [Full Text] [PDF]

				M. A. Socinski, C. Weissman, L. L. Hart, J. T. Beck, J. K. Choksi, J. P. Hanson, D. Prager, M. J. Monberg, Z. Ye, and C. K. Obasaju Randomized Phase II Trial of Pemetrexed Combined With Either Cisplatin or Carboplatin in Untreated Extensive-Stage Small-Cell Lung Cancer J. Clin. Oncol., October 20, 2006; 24(30): 4840 - 4847. [Abstract] [Full Text] [PDF]

				C. H. Takimoto and A. C. Mita Design, Conduct, and Interpretation of Organ Impairment Studies in Oncology Patients J. Clin. Oncol., July 20, 2006; 24(21): 3509 - 3510. [Full Text] [PDF]

				A. C. Mita, C. J. Sweeney, S. D. Baker, A. Goetz, L. A. Hammond, A. Patnaik, A. W. Tolcher, M. Villalona-Calero, A. Sandler, T. Chaudhuri, et al. Phase I and Pharmacokinetic Study of Pemetrexed Administered Every 3 Weeks to Advanced Cancer Patients With Normal and Impaired Renal Function J. Clin. Oncol., February 1, 2006; 24(4): 552 - 562. [Abstract] [Full Text] [PDF]

				C. X. Ma, P. Steen, K. M. Rowland, R. D. Niedringhaus, T. R. Fitch, J. W. Kugler, D. W. Hillman, E. A. Perez, J. N. Ingle, and A. A. Adjei A phase II trial of a combination of pemetrexed and gemcitabine in patients with metastatic breast cancer: an NCCTG study Ann. Onc., February 1, 2006; 17(2): 226 - 231. [Abstract] [Full Text] [PDF]

				H. L. Gomez, S. L. Santillana, C. S. Vallejos, R. Velarde, J. Sanchez, X. Wang, N. L. Bauer, R. D. Hockett, V. J. Chen, C. Niyikiza, et al. A Phase II Trial of Pemetrexed in Advanced Breast Cancer: Clinical Response and Association with Molecular Target Expression Clin. Cancer Res., February 1, 2006; 12(3): 832 - 838. [Abstract] [Full Text] [PDF]

				C. J. Sweeney, C. H. Takimoto, J. E. Latz, S. D. Baker, D. J. Murry, J. H. Krull, K. Fife, L. Battiato, A. Cleverly, A. K. Chaudhary, et al. Two Drug Interaction Studies Evaluating the Pharmacokinetics and Toxicity of Pemetrexed When Coadministered with Aspirin or Ibuprofen in Patients with Advanced Cancer Clin. Cancer Res., January 15, 2006; 12(2): 536 - 542. [Abstract] [Full Text] [PDF]

				A. H. Calvert Fishing for New Drugs J. Clin. Oncol., November 1, 2005; 23(31): 7780 - 7782. [Full Text] [PDF]

				H. Oettle, D. Richards, R. K. Ramanathan, J. L. van Laethem, M. Peeters, M. Fuchs, A. Zimmermann, W. John, D. Von Hoff, M. Arning, et al. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer Ann. Onc., October 1, 2005; 16(10): 1639 - 1645. [Abstract] [Full Text] [PDF]

				K. Robien Folate During Antifolate Chemotherapy: What We Know... and Do Not Know Nutr Clin Pract, August 1, 2005; 20(4): 411 - 422. [Abstract] [Full Text] [PDF]

				G. Beutel, H. Glen, P. Schoffski, J. Chick, S. Gill, J. Cassidy, and C. Twelves Phase I Study of OSI-7904L, a Novel Liposomal Thymidylate Synthase Inhibitor in Patients with Refractory Solid Tumors Clin. Cancer Res., August 1, 2005; 11(15): 5487 - 5495. [Abstract] [Full Text] [PDF]

				K. Puto and J. S Garey Pemetrexed Therapy for Malignant Pleural Mesothelioma Ann. Pharmacother., April 1, 2005; 39(4): 678 - 683. [Abstract] [Full Text] [PDF]

				S. Dubey and J. H. Schiller Three Emerging New Drugs for NSCLC: Pemetrexed, Bortezomib, and Cetuximab Oncologist, April 1, 2005; 10(4): 282 - 291. [Abstract] [Full Text] [PDF]

				M. Hazarika, R. M. White Jr., B. P. Booth, Y.-C. Wang, D. Y. Lee Ham, C. Y. Liang, A. Rahman, J. V.S. Gobburu, N. Li, R. Sridhara, et al. Pemetrexed in Malignant Pleural Mesothelioma Clin. Cancer Res., February 1, 2005; 11(3): 982 - 992. [Abstract] [Full Text] [PDF]

				G. V. Scagliotti, C. Kortsik, G. G. Dark, A. Price, C. Manegold, R. Rosell, M. O'Brien, P. M. Peterson, D. Castellano, G. Selvaggi, et al. Pemetrexed Combined with Oxaliplatin or Carboplatin as First-Line Treatment in Advanced Non-Small Cell Lung Cancer: A Multicenter, Randomized, Phase II Trial Clin. Cancer Res., January 15, 2005; 11(2): 690 - 696. [Abstract] [Full Text] [PDF]

				M. Pistolesi and J. Rusthoven Malignant Pleural Mesothelioma: Update, Current Management, and Newer Therapeutic Strategies Chest, October 1, 2004; 126(4): 1318 - 1329. [Abstract] [Full Text] [PDF]

				M. Hazarika, R. M. White, J. R. Johnson, and R. Pazdur FDA Drug Approval Summaries: Pemetrexed (Alimta(R)) Oncologist, September 1, 2004; 9(5): 482 - 488. [Abstract] [Full Text] [PDF]

				C. Monnerat, T. Le Chevalier, K. Kelly, C. K. Obasaju, J. Brahmer, S. Novello, T. Nakamura, A. M. Liepa, L. Bozec, P. A. Bunn Jr, et al. Phase II Study of Pemetrexed-Gemcitabine Combination in Patients with Advanced-Stage Non-Small Cell Lung Cancer Clin. Cancer Res., August 15, 2004; 10(16): 5439 - 5446. [Abstract] [Full Text] [PDF]

				J. L. Misset, E. Gamelin, M. Campone, S. Delaloge, J. E. Latz, L. Bozec, and P. Fumoleau Phase I and pharmacokinetic study of the multitargeted antifolate pemetrexed in combination with oxaliplatin in patients with advanced solid tumors Ann. Onc., July 1, 2004; 15(7): 1123 - 1129. [Abstract] [Full Text] [PDF]

				A. A. Adjei Pemetrexed (ALIMTA), A Novel Multitargeted Antineoplastic Agent Clin. Cancer Res., June 15, 2004; 10(12): 4276S - 4280S. [Abstract] [Full Text] [PDF]

				R. Zhao and I. D. Goldman Enter Alimta(R): A New Generation Antifolate Oncologist, June 1, 2004; 9(3): 242 - 244. [Full Text] [PDF]

				K. Uchida, K. Hayashi, K. Kawakami, S. Schneider, J. M. Yochim, H. Kuramochi, K. Takasaki, K. D. Danenberg, and P. V. Danenberg Loss of Heterozygosity at the Thymidylate Synthase (TS) Locus on Chromosome 18 Affects Tumor Response and Survival in Individuals Heterozygous for a 28-bp Polymorphism in the TS Gene Clin. Cancer Res., January 15, 2004; 10(2): 433 - 439. [Abstract] [Full Text] [PDF]

				H. Refsum, A. D. Smith, P. M. Ueland, E. Nexo, R. Clarke, J. McPartlin, C. Johnston, F. Engbaek, J. Schneede, C. McPartlin, et al. Facts and Recommendations about Total Homocysteine Determinations: An Expert Opinion Clin. Chem., January 1, 2004; 50(1): 3 - 32. [Abstract] [Full Text] [PDF]

				E. Bajetta, L. Celio, R. Buzzoni, L. Ferrari, A. Marchiano, A. Martinetti, R. Longarini, C. Becerra, C. Ilardi, and W. John Phase II study of pemetrexed disodium (Alimta(R)) administered with oral folic acid in patients with advanced gastric cancer Ann. Onc., October 1, 2003; 14(10): 1543 - 1548. [Abstract] [Full Text] [PDF]

				N. J. Vogelzang, J. J. Rusthoven, J. Symanowski, C. Denham, E. Kaukel, P. Ruffie, U. Gatzemeier, M. Boyer, S. Emri, C. Manegold, et al. Phase III Study of Pemetrexed in Combination With Cisplatin Versus Cisplatin Alone in Patients With Malignant Pleural Mesothelioma J. Clin. Oncol., July 15, 2003; 21(14): 2636 - 2644. [Abstract] [Full Text] [PDF]