Jian-Sheng Jan

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.

Detection of Epstein-Barr Virus DNA in the Peripheral-Blood Cells of Patients With Nasopharyngeal Carcinoma: Relationship to Distant Metastasis and Survival

PURPOSE Nasopharyngeal carcinoma (NPC) has been proved to be an Epstein-Barr virus (EBV)-associated cancer. By use of nested polymerase chain reactions (PCRs), we examined whether the presence of EBV DNA in the peripheral-blood cells (PBC) can serve as a prognostic indicator for NPC. PATIENTS AND METHODS Peripheral blood from 124 patients with NPC who had no evidence of distant metastasis and 114 healthy volunteers with serologically positive findings for EBV infection was collected prospectively. Plasma and erythrocytes were separated. DNA was extracted from PBCs and analyzed by a nested PCR using primers specific to Epstein-Barr virus nuclear antigen 1 (EBNA-1). All patients were treated by radiotherapy with or without chemotherapy. Clinical parameters and status of EBNA-1 in PBCs were used for survival analysis using the Kaplan-Meier method and the Cox proportional hazards model. RESULTS Positive rates of EBNA-1 DNA in PBCs of NPC patients and healthy volunteers are 71% and 14%, respectively (P =.001). No significant difference was observed with regard to the clinical characteristics of patients who were EBNA-1-positive (n = 88) and those who were EBNA-1-negative (n = 36). After a median follow-up period of 38 months (range, 24 to 56 months), 29 of 88 EBNA-1-positive patients and only one of 36 EBNA-1-negative patients developed distant metastases (P =.00015). Kaplan-Meier estimates of overall survival (P =.0010), metastasis-free survival (P =.0004), and progression-free survival (P =.0004) were significantly lower for the patients in the EBNA-1-positive group than for those in the EBNA-1-negative group. Multivariate Cox analysis confirmed the same results. CONCLUSION The presence of EBNA-1 DNA in PBCs is a novel, important risk factor for patients with NPC that indicates a significantly higher risk of developing distant metastasis as well as a lower survival rate.

Plasma EBV DNA clearance rate as a novel prognostic marker for metastatic/recurrent nasopharyngeal carcinoma.

Purpose: To investigate the prognostic effect of the concentrations and clearance rates of plasma EBV DNA in metastatic/recurrent nasopharyngeal carcinoma (NPC). Experimental Design: Thirty relapsed and four previously nontreated metastatic NPC patients were treated according to the consensus guidelines of the head and neck cancer team in our hospital (i.v. chemotherapy first, followed by local irradiation boost and oral maintenance chemotherapy where applicable). Multiple plasma samples were collected during the first month of chemotherapy. Circulating EBV DNA concentrations were measured by a real-time quantitative PCR. The half-life values (t1/2) of plasma EBV DNA clearance were calculated. The associations between clinical outcome and plasma EBV DNA assays were analyzed. Results: Tumor response evaluated after 12 weeks of treatment showed 14 complete responses (41.2%), 12 partial responses (35.3%), 7 stable diseases (20.6%), and 1 progression disease (2.9%). The plasma EBV DNA concentrations have no significant effects on outcome prediction. The t1/2 of plasma EBV DNA clearance ranged from 1.85 to 28.29 days (median, 3.99). Patients with a short t1/2 of plasma EBV DNA clearance have significantly higher complete response rate and overall survival than those with long t1/2. Multivariate analysis revealed a significant effect of the t1/2 of plasma EBV DNA clearance on survival. Conclusions: The clearance rates of plasma EBV DNA during the first month of chemotherapy can predict tumor response and patient survival. Early change of chemotherapy regimen may be considered for patients with slow plasma EBV DNA clearance rate. Clin Cancer Res; 16(3); 1016–24

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.

Evaluation of cytokeratin-19 mRNA as a tumor marker in the peripheral blood of nasopharyngeal carcinoma patients receiving concurrent chemoradiotherapy

The reverse transcriptase‐polymerase chain reaction (RT‐PCR) technique is a tool capable of detecting minute quantities of circulating tumor cell‐derived transcripts. Nasopharyngeal carcinoma (NPC) is a rapidly growing tumor of epithelial origin and high metastatic potential. The aim of our study is to investigate the clinical value of circulating cytokeratin‐19 (CK‐19) mRNA detection in NPC patients. Between June 1997 and March 1999, 57 previously untreated, advanced NPC patients without distant metastasis were uniformly treated by concurrent chemoradiotherapy. Peripheral blood samples were collected prospectively before treatment and subjected to a nested RT‐PCR assay. Measures were taken to prevent contamination and pseudogene interference. PCR products of positive results were verified by restriction enzyme Hae II and direct sequencing. Under our nested RT‐PCR experimental conditions, 33.3% (19/57) clinically nonmetastatic NPC patients had CK‐19 mRNA in their blood. The positive detection rates of CK‐19 mRNA in the peripheral blood for different stages were 20.0% for stage II, 31.6% stage III and 43.5% stage IV (p = 0.1335). After a median follow‐up time of 35 months, 2 patients had recurrences of their primary tumors and 14 developed distant metastases without locoregional recurrence. Nine of 19 (47.4%) CK‐19 mRNA‐positive patients and 5 of 38 (13.2%) CK‐19 mRNA‐negative patients developed distant metastasis (p = 0.00826). The 3‐year metastasis‐free survival rates were 49.9% for patients with detectable CK‐19 and 85.9% for those with undetectable CK‐19 (p = 0.0089, log‐rank test). Our data suggest that the presence of CK‐19 mRNA in the peripheral blood may be a potential marker of micrometastasis for NPC.

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.