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Journal of Clinical Oncology, Vol 22, No 2 (January 15), 2004: pp. 377-378 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.247
In Reply:Department of Radiation Oncology, Taichung Veterans General Hospital, Taiwan We would like to thank Dr Licitra et al for their comments on chemotherapy infusion procedure as described in our report [1]. Indeed, the cisplatin and fluorouracil (FU) admixture was prepared, and the pump was refilled daily. We chose the combination of cisplatin and FU because both chemotherapeutic agents have a radiosensitizer effect. FU is a cell cycle-specific antimetabolite with a very short elimination half-life. It is expected to have a better effect when delivered by continuous infusion than by bolus injection. Cisplatin can sensitize hypoxic cells to radiation by increasing DNA susceptibility to radiation damage and inhibit the repair of radiation-induced damage. It was found that cisplatin must be present at the time of irradiation as well as shortly after irradiation. In our experience, continuous infusion of cisplatin causes significantly less nausea/vomiting than short-term infusion. We also believed that the most important function of concurrent chemoradiotherapy (CCRT) is to increase the interaction time between two modalities. Thus, we favored delivery of both drugs by continuous infusion, simultaneously with radiation. In a pilot study of CCRT for stage IV nasopharyngeal carcinoma (NPC) [2], we used double intravenous lines. However, it is not convenient. In a phase II trial [3], we changed concurrent chemotherapy to a conventional schedule (ie, cisplatin 75 mg/m2, 2 hours infusion at day 1, followed by FU 400 mg/m2/d, for 96-hour continuous infusion). The compliance to this most acceptable schedule was relatively poor for the first 49 enrolled patients. Three patients interrupted CCRT prematurely after 15, 25, and 55.5 Gy. Three patients interrupted the radiotherapy for 1 to 4.5 weeks, and two patients refused the second cycle of concurrent chemotherapy. Then, we tried the concurrent chemotherapeutic agents in a single-infusion solution for the last 14 patients; we observed good tolerance with similar tumor response. Consequently, we adopted this schedule in our phase III trial [1]. Adverse reaction and anticancer activity are two major concerns of admixtures delivery in clinical practice. During more than 10 years experience, we did not observe any color or turbidity changes, or in-dwelling catheter blockage. Although one report showed evidence of substantial loss of cisplatin in the mixture of cisplatin and FU [4], the cisplatin + FU or cisplatin + FU + leucovorin mixtures were shown to be effective in either concurrent/neoadjuvant/adjuvant chemotherapy for advanced NPC, or primary chemotherapy for disseminated disease [1,3,5-8]. These results support the idea that, except for free forms of each drug in the mixture, a putative platinum-FU adduct is still effective as a cytotoxic agent [9], or may act as a radioenhancer. In comparison with different administration schedules of concurrent chemotherapy for NPC (cisplatin 100 mg/m2, every 3 weeks [10]; cisplatin 40 mg/m2 weekly [11]; or cisplatin 60 mg/m2, day 1, followed by FU 600 mg/m2/d, 5-day continuous infusion [12]), our mixture in a single-infusion pump seemed to be at least as efficacious as or superior to the other protocols with fewer side effects. In addition, our infusion procedure is the most convenient in clinical practice and can be given as an outpatient procedure. The basic mechanism of drug mixture interaction with radiation is unclear, and deserves to be investigated in the future. 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. Lin JC, Jan JS, Hsu CY: Pilot study of concurrent chemotherapy and radiotherapy for stage IV nasopharyngeal cancer. Am J Clin Oncol 20:6-10, 1997[CrossRef][Medline] 3. Lin JC, Chen KY, Jan JS, et al: Partially hyperfractionated accelerated radiotherapy and concurrent chemotherapy for advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 36:1127-1136, 1996[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. Lin JC, Jan JS, Hsu CY: Outpatient weekly chemotherapy in patients with nasopharyngeal carcinoma and distant metastasis. Cancer 83:635-640, 1998[CrossRef][Medline] 6. Chi KW, Chan WK, Cooper DL, et al: A phase II study of outpatient chemotherapy with cisplatin, 5-fluorouracil, and leucovorin in nasopharyngeal carcinoma. Cancer 73:247-252, 1994[CrossRef][Medline] 7. 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] 8. Lin JC, Jan JS, Chen KY, et al: Outpatient weekly 24-hour infusional adjuvant chemotherapy of cisplatin, 5-fluorouracil, and leucovorin for high-risk nasopharyngeal carcinoma. Head Neck 25:438-450, 2003[CrossRef][Medline] 9. Davidson JP, Faber PJ, Fischer RG, et al: "Platinum-pyrimidine blues" and related complexes: A new class of potent antitumor agents. Cancer Chemother Rep 59:287-300, 1975[Medline]
10. 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
11. Chan ATC, Teo PML, Ngan RK, et al: Concurrent chemotherapy-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: Progression-free survival analysis of a phase III randomized trial. J Clin Oncol 20:2038-2044, 2002 12. Cheng SH, Jian JJM, Tsai SYC, et al: Prognostic features and treatment outcome in locoregionally advanced nasopharyngeal carcinoma following concurrent chemotherapy and radiotherapy. Int J Radiat Oncol Biol Phys 41:755-762, 1998[CrossRef][Medline]
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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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