Familial Nasopharyngeal Carcinoma 6

The Intergroup 0099 Trial for Nasopharyngeal Cancer: History, Perceptions, and Transitions 165concurrent chemoradiotherapy and 55% were able totolerate all three planned courses of subsequent adjuvantchemotherapy. While it must be recognized thatp-values are not proof and that any one trial can producemisleading results, in the absence of data tocontradict the findings of 0099, the trial needs to beviewed as the defining data that changed the paradigmof treatment of locoregionally advancednasopharyngeal carcinoma from radiation therapyalone to combined radiation therapy and chemotherapy.As a proof of the principle that chemotherapycould augment the effectiveness of radiationtherapy (at least radiation therapy of the quality thatcould be delivered in the late 1980s – early 1990s), thetrial justified exploration of other combinations inthe treatment of nasopharyngeal cancer and, byextension of the principle, the treatment of othermalignancies.12.5.2Intergroup 0099: The LimitationsHowever, the trial did not answer many questions. Bydesign, it could not address the relative importance/contribution of the concurrent application of cisplatinchemotherapy with radiation therapy vs. thesequential provision of two drug adjuvant chemotherapyafter radiation therapy. Furthermore, theleadership of SWOG made the decision not to performany subgroup analyses and therefore there is nopublically accessible 0099-related data from whichhypotheses about the relative merits of the treatmentin different cohorts of patients (e.g., T-category,N-category, histologic grade, age, etc.) could bederived.We are also left to ponder the potential influenceof the 2½ D radiation therapy technique that wasused in the trial. Did chemotherapy merely compensatefor inadequate radiation therapy? Would routineMRI assessment of the extent of tumor have mattered?Would coverage of tumors that spread into theparapharyngeal regions have improved and PFS withit? Would CT-based simulation, 3D conformal, orintensity-modulated radiation therapy have influencedthe results? As radiation therapy does a betterjob of eliminating tumor in a greater proportion ofpatients, does the presumably added benefit of chemotherapybecome more or less important?Similarly, what was the influence of the specificmanner in which chemotherapy was administered inthe trial? Would other schedules (weekly, daily) haveimproved or worsened the outcome? Would the inclusionof other drugs that work by different mechanisms,such as bleomycin or tirapazamine, havemattered? Could 5-FU have been omitted? Would theradiation therapy coverage of tumors have been betterif chemotherapy was used in a neo-adjuvant fashionbefore irradiation, or would the added toxicityhave precluded subsequent concurrent chemoradiationin an unacceptable number of patients?These remaining questions form the frameworkof the following chapters. 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