Familial Nasopharyngeal Carcinoma 6

270 Y. Guo and B. S. Glissonresulting in responses in 5/24 (22%) patients andmedian response duration of 7.5 months (Au et al.1998). Because of the problematic overlapping neurotoxicitywith cisplatin, paclitaxel has been studiedin combination with carboplatin in two trials in thefront-line recurrent setting (Yeo et al. 1998; Tanet al. 1999). Rates of response and median survivalwere similar to that obtained with PF. Severe gradeneutropenia observed in approximately 30% ofpatients was associated with a 28% incidence of neutropenicfever and one toxic death in the trial by Tanet al. (1999). This can be contrasted with a 3% rate ofneutropenic fever observed by Yeo et al. (1998) with alower dose of paclitaxel.Activity in refractory patients was demonstratedin a small study performed by Airoldi et al. (2002). Aresponse rate of 33% and median survival of 9.5months were observed in 12 patients treated withpaclitaxel and carboplatin in the third line setting.For patients who have cisplatin-refractory disease,placlitaxel can be considered; the contribution of carboplatinto response is questionable in that setting.Docetaxel is a semi-synthetic taxane that demonstratedmore potent antineoplastic effect than paclitaxelin preclinical models. Its single agent activity inNPC is not documented to our knowledge. It was initiallystudied in patients with recurrent/metastaticNPC in combination with cisplatin by McCarthy et al.(2002). The trial was closed after accrual of ninepatients when responses had been observed in onlytwo patients. Grade 3–4 neutropenia was seen in allnine patients with three episodes of febrile neutropenia.Toxicity was stated to be manageable. Notably 8of 9 patients were Asian. Similar myelosuppressivetoxicity was observed with the same regimen in thestudy by Chua et al. in Chinese patients (Chua et al.2005). In the initial 15 patients treated at 75 mg/m 2 forboth drugs, febrile neutropenia occurred in 42% ofpatients and resulted in two toxic deaths. The secondcohort of four patients was treated with dose reductionto 60 mg/m 2 with no instances of febrile neutropenia.Response rates and survival in this small trialwere again reminiscent of rates with PF or paclitaxeland carboplatin. This experience with docetaxel inAsian patients with NPC is similar to experience withthe drug in Asian patients with other solid tumors,such as non-small cell lung cancer, suggesting pharmacogenomicdifferences in drug disposition betweenAsians and the predominantly Caucasian populationin the North America or Western Europe. In thesegroups, it is generally well tolerated at 75 mg/m 2 asmonotherapy or in combination with a platin. Thisheld true in a trial with docetaxel 75 mg/m 2 and carboplatinat an area under the curve (AUC) of 6 asneoadjuvant therapy for patients with advanced Nstage NPC treated in North America (Johnson et al.2004). In this trial, the incidence of febrile neutropeniawas 22% and there were no toxic deaths.These data in total suggest that a taxane/platincombination is a reasonable front-line therapy forincurable NPC. The regimen has definite advantageslogistically when compared with P5FU, and is devoidof the mucosal toxicity and HFS of the fluoropyrimidines.Because many patients with recurrent diseasewill have had substantial exposure to cisplatin, carboplatincan be substituted and is preferred withpacliltaxel due to neurotoxicity. Docetaxel, which canbe combined with either cisplatin or carboplatin,should be dosed at no greater than 60 mg/m 2 in Asianpatients, especially if marrow growth factor supportis not given. In view of roughly similar efficacy outcomesto platins combined with either a fluoropyrimidineor a taxane, it is unlikely that a randomizedtrial of these two approaches in the recurrent/metastaticsetting will ever be undertaken.21.2.4Gemcitabine-Based RegimensGemcitabine is an antimetabolite with broad-spectrumantineoplastic activity. Although gemcitabine hasnot been intensively studied in SCCHN of other primarymucosal sites, it is an active drug in the treatmentof NPC as reflected by the monotherapy trialsin Table 21.2 (Foo et al. 2002; Ma et al. 2002; Zhanget al. 2008). The efficacy of gemcitabine/cisplatin issimilar to the other platin-based doublets describedabove with a very reasonable safety profile (Ma et al.2002; Ngan et al. 2002; Jiang et al. 2005). The majorityof patients in all of these trials had been previouslyexposed to cisplatin with or without 5-FU, mostcommonly during definitive-intent treatment, andtime to progression from prior chemotherapy andlines of prior treatment in the various trials is heterogeneous.In the trial reported by Wang, patients wererequired to have progressed while receiving cisplatinand thus the efficacy of gemcitabine/vinorelbine inthat setting is notable (Wang et al. 2006).The triplet regimen of gemcitabine, paclitaxel,and carboplatin followed by maintenance with 5-FUand leucovorin produced a high response rate andprolonged survival in patients who were eitherchemotherapy-naïve or had a minimum 6-month