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184 A. W. M. Lee14.2Nonrandomized Studies on SequentialInduction ChemotherapyThe effectiveness of induction chemotherapy followedby radiotherapy was first reported in the 1980s.The initial results showed conflicting conclusions.Tannock et al. (1987) using two cycles of cisplatin(60 mg/m 2 ) in combination with BLEO and metrotrexatedemonstrated that high overall response rate(ORR) of 75% could be achieved, but the OS rate in51 patients thus treated (48% at 3-year) was almostidentical to 140 historical controls of similar stagedistribution treated by RT alone (p = 0.8).More promising results were reported by othercenters. In a retrospective review reported by Khouryand Paterson (1987), a high ORR of 86% wasachieved in 14 patients treated with two cycles ofcisplatin-based induction chemotherapy [(3 combinedwith BLEO and 11 with 5-fluorouracil (FU)];furthermore, they showed a substantially higher survivalrate when compared with 52 historical controlstreated by RT alone (86% vs. 35% at 3-year).Among the various cisplatin-based chemotherapyregimens tested, promising response rates havebeen reported using cisplatin (100 mg/m 2 ) in combinationwith FU (Dimery et al. 1993), cisplatin (100 mg/m 2 ) in combination with BLEO and epirubicin (EPI)(Bachouchi et al. 1990), cisplatin (60 mg/m 2 ) incombination with FU, leucovorin, EPI, and mitomycin(Hong et al. 2001).The most widely used regimen prior to definitiveradiation for NPC is cisplatin (100 mg/m 2 ) in combinationwith FU (1,000 mg/m 2 continuous infusionper day for 5 days) every 3-weeks for three cycles. Aprospective study of 47 patients with stage IV disease(as classified by the American Joint Committee onCancer [1983]) showed ORR as high as 93% (21% CRand 73% PR), and a 6-year survival rate of 67%(Dimery et al. 1993).A matched cohort study reported by Geara et al.(1997) showed that 61 patients treated with theabove-mentioned cisplatin/FU induction regimenachieved significantly higher 5-year OS than matchedcontrols treated by radiation alone (69% vs. 48%; p =0.012). The 5-year cumulative incidence of Grade 3 orhigher late toxicities was similar in both groups (5%vs. 8%; p = 0.72). This suggestion of significantimprovement in OS was supported by Hong et al.(1999) comparing 55 patients treated by similar regimenwhen compared with 117 historical controls byRT alone (71% vs. 59% at 5-year; p = 0.04). Both studiesshowed significant reduction of distant metastases(16%–19% vs. 34%; p 0.09).A subsequent study from M.D. Anderson CancerCenter tried to use a combination of docetaxel(80 mg/m 2 ) and carboplatin (to an area under thetime–concentration curve of 6) as induction chemotherapyin 18 patients with T1–2N2–3M0 disease(Johnson et al. 2004). The ORR rate was 89%, butthe CR rate was only 11% and the relapse rate was39% (with a median follow-up of 2 years). Comparedwith the results previously reported by the sameinstitute (Dimery et al. 1993; Geara et al. 1997),it seemed unlikely that this regimen will be superiorto the cisplatin/FU regimen. In addition, neutropeniawas very common: of 53 treatment coursesgiven, 51% incurred Grade 4 and 21% Grade 3neutropenia.14.3Randomized Trials on SequentialInduction ChemotherapyThus far, five randomized trials comparing the efficacyof cisplatin-based induction chemotherapycombined with radiation therapy vs. radiation alonehave been published in the English literature.Table 14.1 summarizes the patient characteristics,the regimens used, and the treatment outcome.The trial by Hareyama et al. (2002) includedpatients of all stages, while the other four trials(Chan et al. 1995; Cvitkovic et al. 1996; Chua et al.1998; Ma et al. 2001) included patients with stagesII–IVB by the current staging systems of AmericanJoint Committee on Cancer and International UnionAgainst Cancer (AJCC/UICC 2002). The histologicaltype in more than 90% of the patients accrued wasthe nonkeratinizing type. Conventional 2D radiationtechnique and conventional fractionation wereused in all trials. The total dose given ranged from65 to 74 Gy.The chemotherapy cycles were scheduled at3-weekly interval in all trials. Four trials focused oninduction chemotherapy, only Chan et al. 1995scheduled four more cycles of adjuvant chemotherapyfollowing completion of RT.