Familial Nasopharyngeal Carcinoma 6

304 E. Ozyar and I. Ayanand 127 (96.3%) out of 132 patients treated with preradiationchemotherapy responded either completelyor partially to 2–4 cycles of various combinations ofchemotherapy. The univariate and multivariate analysisdemonstrated statistically significant differencesfor LRFS (92% vs. 65%), LRRFS (85% vs. 65%), andDFS (72% vs. 51%), but not for OS rates, betweenpatients who were treated with combined chemoradiationtherapy to radiation therapy and who weretreated with radiation alone (Ozyar et al. 2006).Although some retrospective studies demonstratedthe superiority of preradiation chemotherapyon survival, such conclusion has not been confirmed.Results on local and locoregional control are veryheterogenous and there is no consensus on theresponse evaluation. Nevertheless, improved local orlocoregional control rates with combined modalitytreatments have been achieved in most retrospectiveseries demonstrated in Table 23.1. The RCN study hascollected the largest data of pediatric NPC. The datarevealed the benefit of chemotherapy on LRFS, LRRS,and DFS, but the conclusive data on the impact ofchemotherapy on survival, drug doses, combinations,and scheduling with RT has to be collected from prospectivecooperative group studies.As mentioned earlier, only two published prospectivemultiinstitutional studies are available on themanagement of pediatric NPC. In GPOH Study NPC-91 from Germany, 58 high-risk patients less than 25years of age were treated with three cycles of preradiationchemotherapy combination of methotrexate,cisplatin, and 5-FU followed by radiation therapy.After irradiation, all the patients were treated withrecombinant IFN-b for 6 months. The rationale forpostradiation immunotherapy was: suppressedimmunological response in patients with NPC atdiagnosis, the strong role of EBV infection in thepathogenesis of disease, antiangiogenic effect ofinterferon, and a 10%–15% response to IFN-b as asingle agent in patients with recurrent NPC. Excellentresults have been achieved from this study with 91%DFS and 95% OS rates. Among 58 high-risk patients,one patient showed tumor progression during chemotherapy,and another patient had only one cycle oftreatment because of acute cardiotoxicity. Distantand local recurrences were reported in three and onepatients, respectively. It was concluded that the combinationof preradiation chemotherapy, relativelylow cumulative radiotherapy dose (59.4 Gy to primarysite, 45 Gy for neck area), and postradiationinterferon improved the outcome of children andadolescents with high-risk NPC. The study group haslaunched out a new treatment protocol with theintent to investigate the role of concurrent chemoradiotherapywith cisplatin followed by 6 months treatmentof interferon after three cycles of preradiationcisplatin and 5-FU.The second prospective multiinstitutional study(i.e., POG 9486) from the U.S., where 16 high-riskpatients less than 22 years of age were treated withfour cycles of preradiation chemotherapy consistedof methotrexate, cisplatin, and 5-FU followed byradiotherapy. Only one patient had progression duringpreradiation chemotherapy and the overallresponse rate to four cycles of induction chemotherapywas 93.7%. The overall 4-year EFS and OS rateswere 77% and 75%, respectively. All treatment failuresoccurred in systemic sites in spite of the four cycles ofpreradiation chemotherapy. It was reported that theseverity of mucositis and the need for nutritional supportwas greater than expected, and it was mainlyrelated to methotrexate. In their new protocol, thesame study group will explore the use of less toxicpreradiation chemotherapy with cisplatin and 5-FU,followed by concurrent chemoradiotherapy. The circulatingEBV-DNA levels will also be measured toevaluate the prognostic significance in an attempt tocreate risk-adapted, less toxic but effective therapies.The results from these two trials indicated thatincorporation of chemotherapy improved the outcomeand allowed radiation dose reduction to 60 Gyin chemo-responsive patients, thus, approving theprevious suggestions. The other important result wasthat the OS and the DFS rates of patients in GPOHstudy was superior to that of POG study, althoughpatients in the POG study had one more cycle of similarchemotherapy and a slightly higher dose ofradiotherapy. The difference may be explained by theincorporation of immunotherapy with interferon inGPOH study and/or the severe toxicity of four cyclesof preradiation chemotherapy used in POG study,which might have reduced the dose intensity and/orcaused delay of radiotherapy.In view of the results of these retrospective andprospective nonrandomized studies, early inductionwith chemotherapy improved the outcome of childhoodand adolescence NPC by increasing the locoregionalcontrol and to some extent, the systemiccontrol. Induction chemotherapy has allowed radiationdose reduction to 60 Gy. Further reductions maybe possible in good responders to chemotherapy, asit was demonstrated that these patients have superiorsurvival and that initial response to inductionchemotherapy is a strong predictor of the outcome.