Familial Nasopharyngeal Carcinoma 6

Neoadjuvant Chemotherapy: Trials and Conclusions 187the incidence of distant failure remained high (>30%).Exploration for a more potent strategy is needed.One logical strategy is to change the sequence ofthe Intergroup 0099 regimen from concurrent–adjuvantto induction–concurrent because the inductionsequence is potent for reduction of failures; substantiallybetter tolerance and patient compliance isoften achievable during this phase. Theoretically,early use of potent combination of cytotoxic drugsat full dose would be more effective for eradicatingmicrometastases. Another possible advantage is thatthis could shrink the primary tumor to give widermargin for irradiation, an advantage that is particularlyneeded for patients with extensive locoregionalinfiltration infiltrating/abutting critical neurologicalstructures.The first study by Rischin et al. (2002) scheduledthree cycles of cisplatin (75 mg/m 2 ) in combinationwith FU and EPI followed by two cycles cisplatin(100 mg/m 2 ) in concurrence with RT at conventionalfractionation. Even though the total radiation doseused was only 60 Gy, excellent 4-year OS rate of 90%,D-FFR of 94%, and LR-FFR of 97% was achieved in35 patients with stages III–IVB by the AJCC 1983 system.However, as only 40% of the series were stage IVwith the current staging AJCC/UICC criteria (2002),more intensive RT is probably needed to maximizethe chance of cure for more advanced group.Thus far, eight Phase II studies on induction–concurrent CRT have been reported in the English literature.Table 14.2 summarizes the patient characteristics,the regimens used, and the treatment outcome. Allexcept that the study by Rischin et al. (2002) aimed ata total radiation dose of 66–70 Gy; six studies usedconventional fractionation, while two studies thatfocused on patients with stage IVA–B disease (Leeet al. 2005c; Yau et al. 2006a) used accelerated fractionation.Incorporation of acceleration was attemptedbecause preliminary results from the NPC-9902 Trial(Lee et al. 2006) and other studies testing acceleratedfractionation plus concurrent–adjuvant CRT (Lin et al.1996; Wolden et al. 2001; Jian et al. 2002) suggestedencouraging results.Different chemotherapy regimens have beentested, all except that by Chan et al. (2004) used cisplatin-basedcombinations for induction chemotherapy,and all except that by Oh et al. (2003) usedcisplatin for concurrent chemotherapy. Incorporationof newer cytotoxic drugs has been attempted, forinstance, paclitaxel (Chan et al. 2004), gemcitabine(GEM) (Yau et al. 2006a), and docetaxel (Hui et al.2009). Cross-series comparison is not possiblebecause of marked variation in patient characteristics,particularly regarding the stage distribution.There are no solid data to suggest, which is morelikely to be the most cost-effective regimen.In the first study from our center (Lee et al. 2005c),we changed the sequence of the Intergroup 0099 regimento give three cycles of cisplatin/FU as inductioninstead of adjuvant chemotherapy. All 49 patientsstudied had stage IVA–B disease with extensivelocoregional infiltration infiltrating/abutting criticalneurological structures. The scheduled dose intensity ofcisplatin and FU were increased to 100 and 5,000 mg/m 2 , respectively, per cycle every 3 weeks (instead of 80and 4,000 mg/m 2 , respectively, per cycle every 4 weeksin the adjuvant schedule of the Intergroup 0099 regimen).This was followed by cisplatin 100 mg/m 2 every3 weeks in concurrence with RT. 3D conformal techniquewas used in this series. A moderate accelerationschedule of 2 Gy per fraction, 6 daily fractions perweek to a total dose of 70 Gy was used. Only 2 cycles ofconcurrent chemotherapy were scheduled unless thepatient has prolongation. Given the grave prognosis ofpatients with such extensive disease, 3-year LR-FFR of77% and OS of 71% was encouraging.Patients did indeed show substantially better toleranceand compliance to induction chemotherapy:98% of patients could complete three cycles of inductionchemotherapy, despite a 20% increase in scheduleddoses, whereas only 55% of patients in theIntergroup 0099 Trial (Al-Sarraf et al. 1998s) completedthree cycles of adjuvant chemotherapy. Only2% of patients had early termination of inductionchemotherapy because of poor response.The induction treatment did not substantiallyjeopardize the tolerance during the concurrent phase,96% of patients could complete the whole course ofRT with a median overall treatment time of 41 days,only 7% failed to complete two cycles of concurrentchemotherapy, and altogether 92% had five or morecycles of chemotherapy.This aggressive treatment did incur a high incidenceof acute toxicities (67% grade 3, 22% grade 4,and 2% grade 5). With the exception of one patientwho died of neutropenic sepsis, the great majorityof toxicities were uneventful and most patientsrecovered rapidly. With a median follow-up of 3.1years, the incidence of late toxicities Grade 3 was22% and Grade 4 was 4%. Hearing loss was the maintoxicity (12 of 13 affected patients). Except for neuroendocrinedysfunction (2%), none of the serieshad radiation-induced neurological damage.However, it must be cautioned that the current fol-