Familial Nasopharyngeal Carcinoma 6

The Intergroup 0099 Trial for Nasopharyngeal Cancer: History, Perceptions, and Transitions 163was “set up” to fail to reach the levels that radiationtherapy alone could achieve today. Five year OSapproximated 45% for stage III and 30% for stage IV.Five-year disease-free survival approximated 40%for T3 or T4 tumors and 35% for N2 or N3 tumorsand as little as 20% for patients who were unluckyenough to have both T3–4 and N2–3 tumors (Frezzaet al. 1986). In part, this reflected limitations of localcontrol (approximately 70% for T3 and T4 tumors),in part of regional control (approximately 80% forN3 disease) and in part of distant control (approximately70%) (Mesic et al. 1981). But, we truly do notknow how much better results would be withoutthese limitations.12.4Chemotherapy: A Potential AllyAgainst this backdrop, it was appropriate to wonderif the addition of a spatially nontargeted agent, suchas cytotoxic chemotherapy, to radiation therapylikely would be of benefit. To be useful, the additionof chemotherapy would need to (a) be inherentlycancericidal (i.e., it would need to be able to killlocoregional disease that could survive radiationtherapy and/or kill subclinical-size, hematogeneouslyborne emboli of tumor that would otherwise giverise to distant metastases), (b) sensitize tumor to theeffects of radiation therapy (i.e., augment the biologiceffect of radiation therapy to the point thatadditional irradiated tumor cells were killed) or (c)both and it would need to do so without being unacceptablytoxic. And, there was evidence that chemotherapymight be able to do so.By the time that the Intergroup 0099 study waslaunched, there was substantial evidence that chemotherapyproduced a beneficial response inpatients who had metastatic or locoregionally recurrentnasopharyngeal cancer (Al-Kourainy et al.1988; Boussen et al. 1991; Choo and Tannock 1991;Decker et al. 1983). Salutary response rates (approximately20%–25% complete response and 55%–75%total response) were reported. The common denominatorof these chemotherapy trials appeared to becisplatin, often in combination with 5-FU. This logicallyled to a desire to try to combine either cisplatinalone or cisplatin and 5-FU with radiation therapy,giving the chemotherapy before, during, and/or after radiation therapy. Several phase II trials(Atichartakan et al. 1988; Bachouchi et al. 1990;Dimery et al. 1993) began to suggest that chemotherapyand radiation therapy could safely be combinedand further suggested that the concurrentadministration of the two agents was the most effectivestrategy.Furthermore, in vitro, there was evidence of benefitwhen cisplatin was combined with radiationtherapy (Richmond et al. 1977; Douple et al. 1977;Soloway et al. 1979; Szumiel and Niaz 1976).12.4.1Suggestive Evidence of Chemotherapy EffectBut, the most exciting data came from a phase IIRTOG study (RTOG 8117) (Al-Sarraf et al. 1990).Between December 1981 and December 1984, theRTOG conducted a nonrandomized, phase II trial ofconcurrent cisplatin (100 mg/m 2 i.v. bolus administeredevery 3–4 weeks for a total of three courses)and radiation therapy (1.8-2Gy per day 5 days a weekfor a total dose of up to 73.8Gy to the primary tumorsite) in patients who had stage III or IV head andneck cancer. Of the 134 patients enrolled in this trial,28 had nasopharyngeal cancer. One patient had inadequatedata submitted and the published report isbased on the 27 patients who had nasopharyngealcancer (26 of the 27 had stage IV disease) with amedian follow-up of 17.5 months and a rangebetween less than 1 and 95 months. Completeresponse to treatment was observed in 24 of the 27(89%) with 4 of the 24 patients experiencing grade 3or 4 toxicity. All the patients were able to receive atleast 90% of their planned radiation therapy dose;six patients did not receive their third dose of chemotherapybecause of prohibitive toxicity andanother two patients refused their third dose. Withthe typical caveats of the limitations of comparisonwith other historical groups, the authors concluded“superior results are obtained with chemo-radiotherapyas compared with radiotherapy alone inpatients with stage IV” nasopharyngeal cancer. Aprospective phase III trial just for locoregionallyadvanced nasopharyngeal cancer clearly appeared tobe justified and the RTOG, SWOG, and ECOG askedthe American National Cancer Institute for permissionto do so.Design of the prospective trial had to reflect reality.In the United States, there are a limited number ofpatients who are found to have nasopharyngeal cancerannually and the number needed for a prospectivetrial would most likely require the combined