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Journal of Clinical Oncology, Vol 22, No 2 (January 15), 2004: pp. 377 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.219
Cisplatin and Fluorouracil Concurrent to Radiotherapy in Nasopharyngeal Cancer: Is the Schedule Compatible?Medical Oncology, Head and Neck Department, and the Preclinical Chemotherapy and Pharmacology Unit, Istituto Nazionale Tumori, Milan, Italy To the Editor: The recent phase III study reported by J.C. Lin et al [1], which was performed to compare concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma, concluded that chemoradiotherapy was superior to radiotherapy alone. Chemotherapy consisted of cisplatin 20 mg/m2/d and fluorouracil 400 mg/m2/d, both as a 96-hour continuous infusion in an outpatient setting for two cycles, during weeks 1 and 5 of concurrent radiotherapy. Apparently, in this study, an unusual procedure was used to deliver chemotherapy—cisplatin was mixed with fluorouracil in normal saline using an ambulatory pump to allow a 96-hour continuous infusion. The authors state that the adopted schedule was previously evaluated in terms of safety and activity. However, they refer to two studies in which the combination of the two drugs was administered as a 24-hour infusion [2,3]. Cisplatin is a well-known reactive electrophilic agent that is expected to react with a variety of electron-rich nucleophiles. In particular, nucleophilic centers in purines and pyrimidines (eg, ring nitrogen of the bases) are reactive to platinum compounds, resulting in covalent adducts. Indeed, there is evidence of substantial loss of cisplatin in the mixture of cisplatin and fluorouracil [4]. This observation raises important issues concerning the pharmacodynamic basis of the reported combination. It would suggest that the improved efficacy of this schedule, combined with radiotherapy, could be related to the low dose of remaining free cisplatin sufficient to modulate the response to radiotherapy, and/or to the radiosensitizing effect of fluorouracil alone. An alternative explanation is that a putative platinum-fluorouracil adduct is still effective as a cytotoxic agent. Although platinum-modified pyrimidines have been described as active agents, these complexes are poorly characterized [5]. Unexpectedly, a less severe grade 3 to 4 toxicity of leukopenia is reported, in comparison with monochemotherapy with cisplatin at 100 mg/m2 as used in the Intergroup study [6]. This observation is unusual for the concurrent administration of a polychemotherapy regimen at the total dosages herein reported, thus more resembling that of a low-dose radiosensitizing schedule. Whatever the underlying mechanism of an (inter-)action of the two drugs, the administration modality does not allow a controlled delivery of well-defined molecular species. With such limitations, the study hardly contributes to identifying the optimal schedule of chemotherapy to be concurrently delivered with radiation therapy in nasopharyngeal carcinoma, neither in terms of efficacy nor toxicity. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Lin JC, Jan JS, Hsu CY, et al: Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: Positive effect on overall and progression-free survival. J Clin Oncol 21:631-637, 2003 2. Chi KW, Chan WK, Shu CH, et al: Elimination of dose limiting toxicities of cisplatin, 5-fluorouracil, and leucovorin using a weekly 24-hour infusion schedule for the treatment of patients with nasopharyngeal carcinoma. Cancer 76:2186-2192, 1995[CrossRef][Medline] 3. Lin JC, Jan JS, Hsu CY: Outpatient weekly chemotherapy in patients with nasopharyngeal carcinoma and distant metastasis. Cancer 83:635-640, 1998[CrossRef][Medline] 4. Stewart CF, Fleming RA: Compatibility of cisplatin and fluorouracil in 0.9% sodium chloride injection. Am J Hosp Pharm 47:1373-1377, 1990[Abstract] 5. Davidson JP, Faber PJ, Fischer RG: "Platinum-pyrimidine blues" and related complexes: A new class of potent antitumor agents. Cancer Chemother Rep 59:287-300, 1975[Medline]
6. Al-Sarraf M, LeBlanc M, Giri PGS, et al: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 16:1310-1317, 1998 Related Article
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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