Abstract
This phase II study determined response rate of patients with locally advanced or metastatic head and neck cancer treated with pemetrexed disodium, a new multitargeted antifolate that inhibits thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase. 35 patients with local or metastatic relapse of squamous cell carcinoma of the head and neck (31 male, 4 female; median age 53 years) were treated with pemetrexed 500 mg m2administered as a 10-minute infusion on day 1 of a 21-day cycle. Patients received 1 to 8 cycles of therapy. 9 patients (26.5%) had an objective response, with a median response duration of 5.6 months (range 2.9–20 months). 15 (44.1%) had stable disease, and 8 (23.5%) had progressive disease. 2 patients were not assessable for response. Median overall survival was 6.4 months (range 0.7–28.1 months; 95% CI: 3.9–7.7 months). 24 patients (68.6%) experienced grade 3/4 neutropenia, with febrile neutropenia in 4 (11.4%). Grade 3/4 anaemia and thrombocytopenia occurred in 11 (34.3%) and 6 (17.1%) patients, respectively. The most frequent non-haematological toxicity was grade 3/4 mucositis (17.1%; 6 patients). In conclusion, pemetrexed is active in squamous cell carcinoma of the head and neck. Although substantial haematological toxicities were experienced by patients, subsequent studies have shown that these toxicities can be proactively managed by folic acid and vitamin B12supplementation. © 2001 Cancer Research Campaign www.bjcancer.com
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Alati, T, Worzalla, JF, Shih, C, Bewley, JR, Lewis, S, Moran, RG & Grindey, GB (1996). Augmentation of the therapeutic activity of lometrexol – (6-R) 5,10-dideazatetrahydrofolate- by oral folic acid. Cancer Res, 56, 2331–2335.
Anon (1990). A phase III randomised trial of cisplatinum, methotrextate, cisplatinum + methotrexate and cisplatinum + 5-FU in end stage squamous carcinoma of the head and neck. Liverpool Head and Neck Oncology Group. Br J Cancer 61: 311–315 [erratum appears in (1990). Br J Cancer, 62, 171]
Bunn, P, Paoletti, P, Niyikiza, C, Rusthoven, J, Nelson, K, Hanauske, A, Stabler, S, Calvert, H & Allen, R (2001). Vitamin B12 and Folate reduce toxicity of Alimta (pemetrexed disodium, LY231514, MTA), a novel antifolate/antimetabolite. Proceedings of ASCO, A300, (Abstr.)
Calvert, AH & Walling, JM (1998). Clinical studies with MTA. Br J Cancer, 78, 35–40.
Chen, VJ, Bewley, JR, Andis, SL, Schultz, RM, Iverson, PW, Shih, C, Mendelsohn, LG, Seitz, DE & Tonkinson, JL (1999). Cellular pharmacology of MTA: a correlation of MTA-induced cellular toxicity and in vitro enzyme inhibition with its effect on intracellular folate and nucleoside triphosphate pools in CCRF-CEM cells. Semin Oncol, 26, 48–54.
Clavel, M, Vermorken, JB, Cognetti, F, Capperaere, P, de Mulder, PH, Schornagel, JH, Tueni, EA, Verweij, J, Wildiers, J & Clerico, M (1994). Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol, 5, 521–526.
Dimery, IW & Hong, WK (1993). Overview of combined modality therapies for head and neck cancer. J Natl Cancer Inst, 85, 95–111.
Fleming, ID, Cooper, JS & Henson, DE (1997). AJJC Cancer Staging Manual, 5th ed.. American Joint Committee on Cancer, Lippincott-Raven Publishers: Philadelphia, PA
Forastiere, AA, Metch, B, Schuller, DE, Ensley, JF, Hutchins, LF, Trizzi, P, Kish, JA, McClure, S, Van Feldt, E & Williamson, SK (1992). Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol, 10, 1245–1251.
Jacobs, C, Meyers, F, Hendrickson, C, Kohler, M & Carter, S (1983). A randomized phase III study of cisplatin with or without methotrexate for recurrent squamous cell carcinoma of the head and neck. A Northern California Oncology Group study. Cancer, 52, 1563–1569.
John, W, Picus, J, Blanke, C, Clark, J, Shulman, LN, Thorton, D, Rowinsky, E & Loehrer, PJ Sr (2000). Activity of multitargeted antifolate (pemetrexed disodium, LY231514) in patients with advanced colorectal carcinoma: results from a phase II study. Cancer, 88, 1807–1813.
Landis, SH, Murray, T, Bolden, S & Wingo, PA (1999). Cancer statistics, 1999. CA Cancer J Clin, 49, 8–31.
Mandema, J, Verotta, D & Sheiner, L (1992). Building population pharmacokinetic-pharmacodynamic models. I. Models for covariate effects. J. Pharmacokin. Biopharm, 20, 5111–5128.
Mendelsohn, LG, Gates, SB, Habeck, LL, Shackelford, KA, Worzalla, J, Shih, C & Grindey, GB (1996). The role of dietary folate in modulation of folate receptor expression, folylpolyglutamate synthetase activity and the efficacy and toxicity of lometrexol. Adv Enzyme Regul, 36, 365–381.
Morgan, SL, Baggott, JE, Vaughn, WH, Young, PK, Austin, JV, Krumdieck, CL & Alarcon, GS (1990). The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum, 33, 9–18.
Niyikiza, C, Baker, SD, Johnson, R, Walling, J, Thornton, D, Seitz, D & Allen, R (1998). MTA (LY231514): relationship of vitamin metabolite profile, drug exposure, and other patient characteristics to toxicity. Ann Oncol, 9, 609P (Abstr)
O’Dwyer, PJ, Nelson, K & Thornton, DE (1999). Overview of phase II trials of MTA in solid tumors. Semin Oncol, 26, 99–104.
Postmus, PE & Green, MR (1999). Overview of MTA in the treatment of non-small cell lung cancer. Semin Oncol, 26, 31–36.
Pivot, X, Niyikiza, C, Poissonnet, G, Dassonville, O, Bensadoun, RJ, Thyss, A, Demard, F, Kayitalire, L & Schneider, M (2000). Multivariate analysis of prognostic factors in local recurrent and metastatic head and neck cancer: implication for clinical trials. Proc Am Soc Clin Oncol, 19, 414 (Abst 1634)
Recondo, G, Armand, JP, Tellez-Bernal, E, Domenge, C, Nelehradek, M, De Vathaire, F, Wibault, P, Richard, JM & Cvitkovic, E (1991). Recurrent and/or metastatic head and neck squamous cell carcinoma: a clinical, univariate and multivariate analysis of response and survival with cisplatin-based chemotherapy. Laryngoscope, 101, 494–501.
Rinaldi, DA, Kuhn, JG, Burris, HA, Dorr, FA, Rodriguez, G, Eckhardt, SG, Jones, S, Woodworth, JR, Baker, S, Langley, C, Mascorro, D, Abrahams, T & Von Hoff, DD (1999). A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation. Cancer Chemother Pharmacol, 44, 372–380.
Rusthoven, J, Eisenhauer, E, Butts, C, Gregg, R, Dancey, J, Fisher, B & Iglesias, J (1999). Multitargeted antifolate LY231514 as first-line chemotherapy for patients with advanced non-small-cell lung cancer: a phase II study. J Clin Oncol, 17, 1194–1199.
Schornagel, JH, Verweij, J, de Mulder, PH, Cognetti, F, Vermorken, JB, Cappelaere P Armand, JP, Wildiers, J, de Graff, A & Clavel, M (1995). Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck: a European Organization for Research and Treatment of Cancer Head and Neck Cancer Cooperative Group study. J Clin Oncol, 13, 1649–1655.
Shih, C, Chen, VJ, Gossett, LS, Gates, SB, MacKellar, WC, Habeck, LL, Shackelford, KA, Mendelsohn, LG, Soose, DT, Patel, VF, Andis, SL, Bewley, JR, Rayl, EA, Moroson, BA, Beardsley, GP, Kohler, W, Ratnam, M & Schultz, RM (1997). LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res, 57, 1116–1123.
Smith, GK, Amyx, H, Boytos, CM, Duch, DS, Ferone, R & Wilson, HR (1995). Enhanced antitumor activity for the thymidylate synthase inhibitor 1843U89 through decreased host toxicity with oral folic acid. Cancer Res, 55, 6117–6125.
Vogl, SE, Schoenfeld, DA, Kaplan, BH, Lerner, HJ, Engstrom, PF & Horton, J (1985). A randomized prospective comparison of methotrexate with a combination of methotrexate, bleomycin, and cisplatin in head and neck cancer. Cancer, 56, 432–442.
Vokes, EE, Weichselbaum, RR, Lippman, SM & Hong, WK (1993). Head and neck cancer [see comments]. N Engl J Med, 328, 184–194.
World Health Organization (2000). The World Health Report 2000. Health Systems: Improving Performance,
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Pivot, X., Raymond, E., Laguerre, B. et al. Pemetrexed disodium in recurrent locally advanced or metastatic squamous cell carcinoma of the head and neck. Br J Cancer 85, 649–655 (2001). https://doi.org/10.1054/bjoc.2001.2010
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1054/bjoc.2001.2010
Keywords
This article is cited by
-
Clinical benefit of nanoparticle albumin-bound-paclitaxel in recurrent/metastatic head and neck squamous cell carcinoma resistant to cremophor-based paclitaxel or docetaxel
Medical Oncology (2017)
-
Tumorrezidive der Kopf-Hals-Region nach Primärtherapie
Der Onkologe (2014)
-
A phase II study of pralatrexate with vitamin B12 and folic acid supplementation for previously treated recurrent and/or metastatic head and neck squamous cell cancer
Investigational New Drugs (2014)
-
Open-label, single-arm phase II study of pemetrexed in the treatment of patients with recurrent or metastatic nasopharyngeal carcinoma who have had prior platinum-based chemotherapy
Cancer Chemotherapy and Pharmacology (2012)
-
Current Treatment Options for Metastatic Head and Neck Cancer
Current Treatment Options in Oncology (2012)
