A phase II study of ifosfamide, 5-fluorouracil and leucovorin in patients with recurrent nasopharyngeal carcinoma previously treated with platinum chemotherapy

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Abstract

The aim of this study was to evaluate the efficacy and toxicity of ifosfamide, 5-fluorouracil (5-FU) and leucovorin (IFL) as a second-line chemotherapy regimen in patients with recurrent undifferentiated nasopharyngeal carcinoma (NPC) previously treated with platinum/5-FU. Between June 1997 and February 1999, 18 patients were entered into the study. 3 patients had loco-regional recurrence, 12 had distant metastases and 3 had both loco-regional recurrence and distant metastases. All patients had previously received platinum/5-FU as adjuvant or palliative treatments. The IFL regimen consisting of ifosfamide 1.2 g/m2 (with mesna), 5-FU 375 mg/m2 and leucovorin 20 mg/m2 for 5 days and was repeated every 21 days. The dose of ifosfamide was escalated to 1.4 and 1.6 g/m2 in subsequent cycles according to the bone marrow toxicity, and the dose of 5-FU to 450 and 525 mg/m2 according to the severity of mucositis. Patients received a median of 3 cycles of IFL (range: 2–6), with a median total ifosfamide dose of 21 g/m2 (range: 13–46) and a median total 5-FU dose of 6.75 g/m2 (range: 4.1–14.7). The median follow-up was 10 months (range: 4–25). 9 patients (50%) achieved a partial response and 1 patient (6%) achieved a complete response, with an overall response rate of 56% (95% confidence interval (CI): 32–80%). For those patients who responded to IFL, 8 had subsequent disease progression on follow-up, with a median response duration of 7.1 months (95% CI: 5.3–8.9). The median time to progression for all patients was 6.5 months (95% CI: 4.2–8.7). 12 patients are still alive with an estimated 1-year survival probability rate of 51%. Treatments were well tolerated, only 1 patient had grade 3 emesis. None of the patients had grade 3/4 anaemia, leucopenia or thrombocytopenia, although IFL was discontinued in 1 patient because of persisting thrombocytopenia. IFL is an effective second-line regimen in patients with recurrent NPC and is well tolerated with mild toxicity. Combining platinum and IFL in chemonaı̈ve patients may further improve the overall response rate and duration and is worth investigating in future trials.

Introduction

Nasopharyngeal carcinoma (NPC) of an undifferentiated type is responsive to a wide range of chemotherapeutic agents, with response rates ranging from 38 to 91% using combination chemotherapy in the setting of loco-regional recurrence and/or distant metastases 1, 2, 3, 4, 5, 6, 7, 8, 9. A higher response rate is commonly observed with the use of platinum-based regimens than with non-platinum-based regimens. Although platinum-based regimens, especially the combination of platinum and 5-fluorouracil (5-FU), have been widely adopted as the first-line chemotherapy regimen in the treatment of recurrent NPC, the choice of a second-line regimen in patients with an unsatisfactory response to platinum or in those previously treated in an adjuvant setting by platinum-based chemotherapy remains unclear. Despite a large number of publications addressing the efficacy of different chemotherapy regimens in NPC, very few reports had specifically studied the efficacy of second-line chemotherapy in patients previously treated with platinum-based regimens.

Ifosfamide is an analogue of cyclophosphamide that possesses a spectrum of toxicities and clinical activity different from that of its parent compound. Significant haemorrhagic cystitis was the dose-limiting factor in phase I trials until the introduction of the uroprotective agent mesna. Activity has been demonstrated for ifosfamide in a variety of tumours, including testicular cancer, sarcoma, lymphoma, lung cancer, paediatric tumours, and gynaecological malignancies. Recent studies also demonstrated an activity of ifosfamide in head and neck cancers 10, 11, 12, 13. However, studies of ifosfamide-based chemotherapy in NPC, have been sparse. 5-FU is also active against a wide range of tumours, and in combination with cisplatin, has a high activity in head and neck cancers including NPC. The cytotoxic effect of 5-FU can be enhanced further by modulation using low-dose leucovorin. In this study, we chose to investigate the combination of ifosfamide, 5-FU and leucovorin as a second-line chemotherapy regimen in patients with advanced recurrent NPC pretreated with platinum/5-FU chemotherapy.

Section snippets

Patient characteristics

Between June 1997 and February 1999, 18 patients with advanced recurrent NPC (loco-regional disease and/or distant metastases) were treated with the study regimen ifosfamide, 5-FU and leucovorin (IFL). The inclusion criteria were: histologically proven NPC (undifferentiated or poorly differentiated carcinoma), completed radical treatment, disease recurrence or progression after previous platinum-based chemotherapy given as part of the primary treatment and/or treatment for recurrence, recurrent

Results

18 patients were recruited into the trial from June 1997 to February 1999 and all were evaluable for toxicity and response. All patients had received previous platinum-based chemotherapy; 3 for neoadjuvant and/or adjuvant treatment, 2 for adjuvant treatment after salvage of earlier recurrences (neck dissection for recurrent neck node in one, and resection of lung metastasis in the other), 2 for both neoadjuvant/adjuvant treatment and recurrence and 11 for recurrence. 13 patients had previously

Discussion

There have been few reports on the use of ifosfamide-based chemotherapy in NPC compared with other head and neck cancers. Liu and colleagues reported using single-agent ifosfamide at a dose of 2 g/m2 for 4 days in 33 patients with recurrent NPC, including 18 chemonaı̈ve patients [14]. 31 patients were evaluable and the overall response rate was 45%, with a complete response rate of 6% and a partial response rate of 39%. Stein and associates combined cisplatin at a dose of 50 mg/m2 with

Acknowledgements

This study was supported by grants from the University of Hong Kong (CRCG Grant No. 10202650/25134/21600/323/01, 10202651/25065/21600/323/01, 337/037/0001, and 335/037/0002) and Asta Medica China Ltd.

References (18)

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