Familial Nasopharyngeal Carcinoma 6

172 J. Weedisease-free survival rates of 89.5% and 83.3%,respectively (Lin et al. 1997). This spurred the team onto embark on a Phase III trial (Lin et al. 2003). This trialaccrued 284 patients between December 1993 and April1999. Patients were staged according to the 1988 AJCC/TNM staging system (AJCC 1988) and were eligible ifthey had stage III or IV and M0 disease. Radiotherapyto a dose of 70–74 Gy in 7–8 weeks was administered inboth arms. Chemotherapy consisted of cisplatin at20 mg/m 2 /day and 5-FU at 400 mg/m 2 /day as a 96-hinfusion for 4 days on weeks 1 and 5 of radiotherapy inthe experimental arm. Nine patients did not receive thesecond cycle of chemotherapy and another nine hadtheir chemotherapy delayed by >1 week. The toxicity inthe chemoradiotherapy arm was more severe than thatof the radiotherapy alone arm, but was less than that ofthe chemoradiotherapy arm of Intergroup 0099 trial.The 5-year overall survival rate was significantlyimproved from 54.2% in the radiotherapy alone armto 72.3% in the chemoradiation therapy arm(p = 0.0022). Similarly, the 5-year progression-freesurvival rates were 71.6% for the chemoradiationgroup when compared with 53.0% for the radiationonlygroup (p = 0.0012). Chemoradiation therapy hadalso appeared to improve local-regional control anddistant control, although the differences just failed toachieve statistical significance.13.5.4The Hong Kong Queen Mary Hospital TrialThe Queen Mary group launched a 2 × 2 factorial studybased on the hypothesis that concurrent chemotherapywould improve local control and that adjuvant chemotherapywould tackle microscopic distant metastases.Patients were first randomized to receive radiationtherapy alone or concurrent chemoradiation therapyand then a second randomization after completion ofradiation therapy or chemoradiation therapy to determineif adjuvant chemotherapy would or would not begiven. The drug used during the radiation phase wasthe 5-FU prodrug UFT (uracil and tegafur in a 4:1 molarratio) at a dose of 200 mg three times a day, 7 days aweek for the duration of radiation therapy. Previousstudies had shown that UFT can simulate continuousinfusion 5-FU and enhance the antineoplastic effect of5-FU while reducing the side effects attributed to 5-FUcatabolism (Taguchi 1997). Although there was not alot of data about the use of UFT in NPC when the studywas first conceived, 5-FU was well known to have chemotherapeuticeffects on NPC and was also known tohave radiosensitization properties. Oral administrationalso made UFT an attractive alternative to cisplatinradiosensitization. During the adjuvant phase, an alternatingregimen of cisplatin-5-FU (PF) and VBM (vincristine,bleomycin, and methotrexate) was given every3 weeks for a total of six cycles. Both combinations(Al-Kourainy et al. 1988, Hill et al. 1987) are knownto have activity in NPC and the group was following theprinciples of the Goldie Coldman hypothesis (Goldieand Coldman 1979) and aimed to reduce the developmentof drug resistance and toxicity of individual chemotherapeuticagents, as well as to maximize theadditive effects of different effective cytotoxic drugs.Patients accrued had Ho’s staging T3 or N2–3 or N1with LN >4 cm. The primary tumor received at least68 Gy and selected patients received a 10 Gy boost.Between May 1995 and October 2001, a total of 222patients were recruited of whom 219 were included inthe final analysis. The preliminary results were publishedin 2004 (Kwong et al. 2004) and the final 7-yearresults were presented at ASCO in 2008 (Kwong et al.2008). Concurrent chemoradiation therapy using UFTsignificantly reduced distant metastases and diseasefailure. The 7-year distant metastases-free survivalwas 68.6% (radiation) vs. 82.9% (chemoradiation)(p = 0.014) and the 7-year failure-free survival was52.4% (radiation) vs. 66.6% (chemoradiation)(p = 0.016). The 7-year disease-specific survival was68.9% (radiation) vs. 78.6% (chemoradiation), butthis just missed statistical significance (p = 0.057).Local control was not improved with concurrentchemoradiation therapy. None of these parameterswere improved with adjuvant chemotherapy. Thegroup postulated that a potential action of concurrentUFT could be the antiangiogenic effect from its metronomicscheduling resulting in a reduction in distantmetastases. One potential reason why adjuvant chemotherapydid not work in this study could be attributedto alternating the chemotherapy drug such thattheir relative dose intensity was compromised.13.5.5The Thai NoninferiorityTrial of Cisplatin vs. CarboplatinThe Thai group (Chitapanarux et al. 2007) randomized206 locally advanced NPC tumors to receiveeither cisplatin or carboplatin concurrent with radiotherapyin their Phase III non-inferiority trial. In thecisplatin arm, 59% of patients completed concurrentchemoradiotherapy and 42% completed three cycles