Familial Nasopharyngeal Carcinoma 6

Drug Therapy for Nasopharyngeal Carcinoma: Cytotoxic and Targeted Therapy 151and concurrent weekly low-dose cisplatin for sevencycles. For the territory as a whole, the introductionof concurrent chemoradiation has contributed to theimproved clinical outcome of patients with locoregionallyadvanced NPC over the last decade. In areport by the Hong Kong NPC Study Group (Leeet al. 2005), the survival rates for NPC have improvedsignificantly during the period from 2000 to 2006,compared with historic series reported in the 1970–1980s (Teo et al. 1989; Lee et al. 1992; Hong et al.2000; Cooper et al. 1998). In the contemporary setting,the 5-year overall and progression-free rates forstage III–IVB NPC are expected to be 66% and 53%,respectively (Lee et al. 2005).11.2.3NeoadjuvantNeoadjuvant chemotherapy with platinum-basedregimens has been used in clinical practice since theearly 1980s in Hong Kong, for the treatment of bulkyprimary tumors where adequate radiation dose andcoverage cannot be given without a significant risk ofdamaging the vital structures, such as the optic nerveor brainstem (Teo et al. 1989). Of all the phase IIIstudies published to date, none has conclusivelyreported a survival benefit of neoadjuvant chemotherapyover radiotherapy alone (Roussy 1996; Maet al. 1998; Chua et al. 1998; Hareyama et al. 2002). Ina pooled analysis of two previously reported negativestudies conducted in Hong Kong (Chua et al. 1998)and China (Ma et al. 1998), an absolute 12.9% improvementin overall survival favoring the neoadjuvant armwas reported at 5-year follow-up (Chua et al. 2005).Since the adoption of concurrent chemoradiationas a standard of care for locoregionally advancedNPC, researchers at the Prince of Wales Hospital evaluatedthe strategy of combining neoadjuvant therapywith taxane-based regimens with chemoradiation. Ina phase II study, the addition of two cycles of carboplatinand paclitaxel were tolerated when given beforechemoradiation (Chan et al. 2004). This strategy wassubsequently evaluated against chemoradiation withweekly low-dose cisplatin in a randomized phase IIstudy of 60 patients (Hui et al. 2009). The 3-year overallsurvival for patients who had neoadjuvant cisplatinand taxotere was 94.1%, compared with 67.7% forthose who had chemoradiation alone (hazard ratio =0.24; 95% confidence interval, CI, 0.078–0.73; p =0.012) (Hui et al. 2009). This strategy is promisingand warrants further evaluation in the setting of awell-powered phase III study.11.2.4AdjuvantBased on the U. S. Intergroup protocol, which firstdemonstrated the superiority of adding 3-weeklyhigh-dose cisplatin during radiotherapy followed bythree cycles of cisplatin and 5-fluorouracil(Al-Sarraf et al. 1998), adjuvant chemotherapy hasbeen used routinely in locoregionally advanced NPCin some Asian centers. However, none of the phase IIIstudies published to date have demonstrated a survivalbenefit of adjuvant chemotherapy over chemoradiationalone (Rossi et al. 1988; Chan et al. 1995;Chi et al. 2002). Similarly, a meta-analysis reportedby the MAC–NPC Collaborative group, based on thedata derived from 1,753 individual participants fromeight clinical trials, did not find any survival benefitwith adjuvant chemotherapy (Baujat et al. 2006).Poor patient compliance has been thought to contributeto this lack of benefit, as up to 15% of patientsdid not receive any planned adjuvant chemotherapyin phase III trials owing to patient refusal or toxicity(Al-Sarraf et al. 1998; Wee et al. 2005).11.3Cytotoxic Chemotherapy11.3.1Platinum-Based ChemotherapyCisplatin and its analogs, carboplatin and oxaliplatin,are alkylating-like agents, which interfere withDNA repair by forming DNA crosslinks and adducts.In preclinical studies on NPC cell lines, cisplatincan enhance cell killing from radiation (Wang et al.2002), induce apoptosis (Cheung et al. 2005) andsensenescent-like growth arrest in the CNE-1 cells(an EBV-negative NPC cell line) (Wang et al. 1998).A preclinical study in NPC cell lines also suggestedthat the synergistic effect of cisplatin on radiationwas best observed when cisplatin was administeredbefore radiation (Wang et al. 2002).Cisplatin is the first-generation platinum that wasfirst used in NPC in Hong Kong during the early1980s for neoadjuvant and palliative indications(Teo et al. 1989). Successive generations of phase IIstudies have focused on optimizing the clinicalresponse to cisplatin, by combining it with one ormore classes of chemotherapy such as the anthracyclines,antimetabolites, alkylating agents, microtubuleinhibitors, and cytotoxic antibiotics. The