Chen-Yi Hsu

Phase III Study of Concurrent Chemoradiotherapy Versus Radiotherapy Alone for Advanced Nasopharyngeal Carcinoma: Positive Effect on Overall and Progression-Free Survival

PURPOSE Nasopharyngeal carcinoma (NPC) is a radiosensitive and chemosensitive tumor. This randomized phase III trial compared concurrent chemoradiotherapy (CCRT) versus radiotherapy (RT) alone in patients with advanced NPC. PATIENTS AND METHODS From December 1993 to April 1999, 284 patients with 1992 American Joint Committee on Cancer stage III to IV (M0) NPC were randomly allocated into two arms. Similar dosage and fractionation of RT was administered in both arms. The investigational arm received two cycles of concurrent chemotherapy with cisplatin 20 mg/m(2)/d plus fluorouracil 400 mg/m(2)/d by 96-hour continuous infusion during the weeks 1 and 5 of RT. Survival analysis was estimated by the Kaplan-Meier method and compared by the log-rank test. RESULTS Baseline patient characteristics were comparable in both arms. After a median follow-up of 65 months, 26.2% (37 of 141) and 46.2% (66 of 143) of patients developed tumor relapse in the CCRT and RT-alone groups, respectively. The 5-year overall survival rates were 72.3% for the CCRT arm and 54.2% for the RT-only arm (P =.0022). The 5-year progression-free survival rates were 71.6% for the CCRT group compared with 53.0% for the RT-only group (P =.0012). Although significantly more toxicity was noted in the CCRT arm, including leukopenia and emesis, compliance with the combined treatment was good. The second cycle of concurrent chemotherapy was refused by nine patients and was delayed for > or = 1 week for another nine patients. There were no treatment-related deaths in either arm. CONCLUSION We conclude that CCRT is superior to RT alone for patients with advanced NPC in endemic areas.

Partially hyperfractionated accelerated radiotherapy and concurrent chemotherapy for advanced nasopharyngeal carcinoma

PURPOSE A newly designed concomitant chemoradiotherapy was undertaken to assess the feasibility and efficacy for advanced nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS Sixty-three patients with biopsy-proven NPC were entered in this Phase II trial from March 1992 to November 1993. Most patients present with Stage IV disease (93.4%) and poorly differentiated epidermoid carcinoma or undifferentiated carcinoma were the major pathologic type. Radiotherapy was delivered using a telecobalt unit and 10 MV x-rays and by altered fractionation (72-74 Gy/45 fractions/6 weeks). Chemotherapy with cisplatin 75 mg/m2, 2 h infusion at day 1, followed by 5-FU 400 mg/m2/day, continously infused for 4 days was given concurrently during the first and fifth weeks of radiotherapy. RESULTS The major toxicity was mucositis (61% belong to Grade 3, 31% to Grade 2). Weight loss, leucopenia, and skin reaction were frequently encountered. Three patients withdrew from treatment at 15, 25, and 55.5 Gy, three patients interrupted the radiotherapy for 1-4.5 weeks, and two patients refused the second cycle of concomitant chemotherapy due to toxicities. The initial tumor response showed 100% overall response rate, with 90.5% complete response. After a median follow-up time of 38 months, five patients failed at the primary and/or neck (four recurrent and one persistent), and 14 patients developed distant metastases alone. The 3-year primary disease-free, regional disease-free, distant disease-free, and overall survival rates are 89.1, 92.8, 74.3, and 73.6%, respectively. The late complication rate is acceptable so far. CONCLUSIONS Our data indicates that concurrent chemoradiotherapy for advanced NPC is both feasible and effective, with acceptable toxicities. Distant metastases are the major site of treatment failure. Postradiation adjuvant chemotherapy to eradicate subclinical distant metastasis should be further studied.

Outpatient weekly neoadjuvant chemotherapy followed by radiotherapy for advanced nasopharyngeal carcinoma: high complete response and low toxicity rates

Nasopharyngeal carcinoma (NPC) is a radiosensitive and chemosensitive tumour. The aim of this prospective study is to evaluate the toxicity and efficacy of an outpatient weekly neoadjuvant chemotherapy (NeoCT) plus radiotherapy for advanced NPC. From November 1998 to August 2001, 90 NPC patients meeting the following criteria were treated: (1) neck node >6 cm; (2) supraclavicular node metastasis; (3) skull base destruction/intracranial invasion plus multiple nodes metastasis; (4) multiple neck nodes metastasis with one of nodal size >4 cm; or (5) elevated serum LDH level. The NeoCT consists of cisplatin 60 mg m−2, alternating with 5-fluorouracil 2500 mg m−2 plus leucovorin 250 mg m−2 (P–FL) by an outpatient weekly schedule for a total of 10 weeks. Local radiotherapy ⩾70 Gy by conventional fractionation was delivered within 1 week after NeoCT. Patient compliance was rather good. Grade 3–4 toxicity of NeoCT included leucopaenia (7.8%), anaemia (18.9%), thrombocytopaenia (3.3%), nausea/vomiting (4.4%), and weight loss (1.1%). Response evaluated after NeoCT showed 73.3% complete response (CR) rate of primary tumour, 71.1% CR rate of neck nodes, and an overall CR rate of 57.8%. In all, 88 out of 90 patients received rebiopsy of primary tumour and 55 patients (62.5%) revealed pathological CR. After a median follow-up time of 24 months, one persistent disease and 18 relapses were noted. The 2-year nasopharynx disease-free, neck disease-free, distant disease-free, overall, and progression-free survival rates are 98.9, 95.9, 80.0, 92.1, and 77.5%, respectively. Preliminary data of the current study show that P–FL NeoCT plus radiotherapy is a low-toxic regimen with promising results on very advanced NPC patients and merits to be investigated in phase III trials.

Outpatient weekly 24‐hour infusional adjuvant chemotherapy of cisplatin, 5‐fluorouracil, and leucovorin for high‐risk nasopharyngeal carcinoma

Distant metastasis rather than locoregional recurrence is the major site of failure after adequate radiotherapy in nasopharyngeal carcinoma (NPC). The aim of this study is to evaluate the toxicity and survival of outpatient weekly 24‐hour infusion adjuvant chemotherapy for NPC patients with high‐risk of distant failure.

Pilot study of concurrent chemotherapy and radiotherapy for stage IV nasopharyngeal cancer.

Nasopharyngeal carcinoma (NPC) is a more radio- and chemosensitive tumor than all other head and neck cancers. Between September 1991 and December 1992, a total of 19 patients (13 men and six women; median age, 44 years) with AJCC stage IV NPC were entered into a pilot study of concurrent chemoradiotherapy. Pathology showed either poorly differentiated epidermoid carcinoma or undifferentiated carcinoma. Radiotherapy was delivered using a telecobalt unit and 10-MV x-rays and by conventional fractionation (1.8-2.0 Gy/fraction, 5 fractions/week). The total doses delivered were 70-75 Gy to the primary tumor and neck positive region, and 50-55 Gy to the neck negative area. Chemotherapy with cisplatin (10 mg/m2/day, days 1-5) and 5-fluorouracil (500 mg/m2/day, continuously infused for 5 days) was administered concurrently during weeks 1 and 5 of radiotherapy. The major toxicities were mucositis (42% had grade III and 58% grade II) and leukopenia (nadir white blood cells <3,000/mm3 in eight of 19). Although four patients required a delay in their second cycle of concurrent chemotherapy or had their radiotherapy interrupted for 1 week, all 19 patients completed the planned treatment and achieved a 100% complete response rate. After a median follow-up period of 42 months, one patient suffered from neck recurrence plus distant metastasis, and three patients developed distant metastases alone. The 3-year overall and disease-free survival rates are 89.5% and 83.3%, respectively. Our data indicated that concurrent chemoradiotherapy for advanced NPC is both feasible and effective, with acceptable toxicities. A phase III randomized trial to compare the efficacy of concurrent chemoradiotherapy and radiotherapy alone deserves to be studied further.

Neoadjuvant Chemotherapy for Advanced Nasopharyngeal Carcinoma

Between October 1990 and November 1991, a total of 16 male patients with advanced nasopharyngeal carcinoma were treated by neoadjuvant chemotherapy before conventional radiotherapy. They belonged to the AJCC stage IV with multiple bulky neck nodes metastases. The chemotherapy consisted of bleomycin, epirubicin, and cisplatin. Six patients completed 3 cycles, 9 patients finished 2 cycles, and 1 patient received 1 cycle of chemotherapy. Seven of the 16 patients (44%) were in complete response, and 50% (8/16) achieved partial response. The overall response rate was 94%. The major toxicities consisted of leucopenia (12/37 cycles had grade III-IV), nausea/vomiting, alopecia. Aplastic marrow developed in 1 patient, and one died of bleomycin-induced pneumonitis. Subsequent radiation therapy was well tolerated. After a minimal follow-up time of 24 months, the 2-year actuarial survival rate was 56%. Although we confirmed the impressively high response rate of this regimen, the toxicities were high and most patients failed at distant site(s). The efficacy of neoadjuvant chemotherapy for advanced nasopharyngeal carcinoma is doubtful and should be further studied in prospective randomized trials.

High rate of clinical complete response to weekly outpatient neoadjuvant chemotherapy in oral carcinoma patients using a new regimen of cisplatin, 5‐fluorouracil, and bleomycin alternating with methotrexate and epirubicin

A Phase II trial was initiated to evaluate the response to and toxicity of a new regimen of weekly outpatient neoadjuvant chemotherapy in patients with oral carcinoma.

Preliminary report of outpatient weekly adjuvant chemotherapy for high-risk nasopharyngeal carcinoma.

Distant metastasis has become the most frequent failure site-more so than locoregional relapse-after adequate radiotherapy in nasopharyngeal carcinoma (NPC). A prospective study was initiated to test the role of postradiation adjuvant chemotherapy using a weekly schedule for selected patients with high-risk NPC (N3, T4N2b-2c, and N2b-2c, with one of nodal size > 4 cm, or residual disease after radiotherapy). Through July 1993 to August 1994, a total of 20 patients were entered into the study: 16 men and four women, with a median age of 49 years and age range of 27-75 years. Pathology showed WHO type I:II:III = 2:13:5. Previous treatment consisted of concurrent chemoradiotherapy (16 patients), radiotherapy alone (two), and neoadjuvant chemotherapy followed by radiotherapy (two). Postradiation adjuvant chemotherapy was usually started 2 months after radiotherapy, using a weekly FP schedule (5-fluorouracil 1,250 mg/m2 + cisplatin 25 mg/m2, mixed in 100 ml saline, 24 h continuous i.v. infusion) for 18 weeks. The treatment of five patients was at 5, 6, 10, 14, and 15 weeks because of leukopenia-induced mortality, sudden death unrelated to adjuvant chemotherapy, a patients refusal, and distant metastasis (the last two cases) during adjuvant chemotherapy. The major toxicity was leukopenia (grade I, 20%; grade II, 45%; grade III, 15%; and grade IV, 10%). Ten patients (50%) developed distant metastasis after a median follow-up time of 20 months. Our preliminary data indicate that postradiation adjuvant chemotherapy with a weekly FP regimen at our dosage is not recommended for high-risk NPC.