Familial Nasopharyngeal Carcinoma 6

Concurrent Chemotherapy-Enhanced Radiation: Trials and Conclusions 169ble” because of “protocol violations” and the relativelyhigh percentage of patients having keratinizedlesions (Fu 1998).13.4Singapore, Hong Kong,and Guangzhou TrialsBased solely on the results of Intergroup 0099 study,there was hesitancy in adopting chemoradiationtherapy as the standard of care in the endemic NPCregions of East Asia. Chan et al. (1998) summarizedwell the reservations. First, about a third of thepatients in the Intergroup 0099 trial had WHO Type Ihistology, a subtype that had previously been shownto confer a worse prognosis (Hoppe et al. 1978;Shanmugaratnam et al. 1979); whereas in the Eastover 90% of patients have the endemic non-keratinizingform of NPC (i.e., WHO Types II and III). Second,the radiation technique used was relatively lessaggressive with parapharyngeal boosts (Teo et al.1989a) and brachytherapy (Teo et al. 1989b) beingcommonly administered as adjuncts for selectedpatients in the East. Third, the results observed in theradiotherapy alone arm of the 0099 study appearedinferior to those observed in Singapore (Heng et al.1999) and Hong Kong patients (Lee et al. 1992).Nevertheless, one could not ignore the remarkableresults that the Intergroup 0099 trial had achieved.This resulted in several Phase III trials using theAl-Sarraf regimen being initiated in the endemicregions of East and Southeast Asia. The Singaporegroup conducted a Phase II trial of the Al-Sarraf regimento observe the tolerability of this regimen in anAsian population (TAN et al. 1999). Fifty-seven patientswere treated, 75% received all three cycles of cisplatinduring the radiotherapy phase, and 63% received allthree cycles of adjuvant chemotherapy. The protocolhad acceptable tolerability and the group proceeded toa Phase III trial.13.4.1The Singapore TrialThe Singapore trial, SQNP01 (Wee et al. 2005) wasactivated in September 1997 and accrued 221 patientsover the following 5½ years. The aim of the trial was toconfirm the results of the Intergroup 0099 study andthe applicability of that regimen to the endemic formof NPC. While the trial was essentially modeled afterthe Intergroup 0099 study there were some differences.Patients were staged according to the new AmericanJoint Committee on Cancer/International UnionAgainst Cancer (1997) Staging System (AJCC 1997).That meant that some tumors that would have beenpreviously considered as stage III for the Intergroup0099 trial, would now be labeled stage II disease andwould thus not be considered eligible for this newstudy (e.g., patients with N1 disease). Patients alsohad to have the endemic, non-keratinizing histology(WHO Type II or III) and patients with WHO Type Iwere specifically excluded. Cisplatin was administeredon a divided dose basis of 25 mg/m 2 /day over4 days or at 30/30/40 mg/m 2 /day over 3 days on thefirst, fourth, and seventh weeks of radiation therapy.During the adjuvant phase, cisplatin was similarlygiven on a divided dose of 20 mg/m 2 over 4 days concurrentwith 5-FU, which was given at a dose of1,000 mg/m 2 /day for 4 days.Seventy-nine (71%) of the 111 patients on thechemoradiation therapy arm received all three cyclesof concurrent cisplatin. Six patients on this armreceived less then 62 Gy to their primary tumor. Fiftysevenpercent of patients received all three cycles ofadjuvant chemotherapy and 35 patients (32%) didnot receive any adjuvant treatment. The incidence ofGrade 3 and 4 toxicity was higher in the chemoradiationarm, especially with respect to oropharyngealmucositis, anorexia, emesis, and neutropenia. The2-year distant metastases rate was 30% for the radiationtherapy arm and 13% for the chemoradiotherapyarm. The 3-year disease-free survival (DFS) was alsoimproved from 53% to 72% in the experimental arm.Similarly, the 3-year overall survival was also significantlyimproved from 65% (radiation therapy) to 80%with chemoradiation therapy. (p = 0.0061). Wee (2008)updated the results recently and with a median follow-upof 6.6 years, the distant metastases rate, DFS,and overall survival rates of the chemoradiotherapyarm all remain statistically significantly improvedover the radiotherapy alone arm. The 5-year OS was49% vs. 67% with a hazard ratio of 0.60 and p value of0.0077 – all in favor of combined treatment..13.4.2The Hong Kong TrialsThe Hong Kong Nasopharyngeal Cancer Study Group(HKNPCSG) took a slightly different approach intheir trials. While their primary objective was toconfirm the findings of the Intergroup 0099 study,