CHAPEL HILL, NC-"Local failure in inoperable non-small-cell lung cancer (NSCLC) is high, about 80%-and cure is impossible without local control. The radiotherapy community has not addressed this problem," said Julian C. Rosenman, MD, PhD, professor of radiation oncology at the University of North Carolina (UNC), Chapel Hill. "A 10- cm tumor compared with a 1-mm tumor has a 1-million-fold increase in size, but our response is to reduce dose." For example, he said, a T1c prostate tumor is treated with 75 Gy of radiation, whereas a vastly larger stage IIIa or IIIb NSCLC is typically treated with 60 Gy. Questioning 60 Gy Dr. Rosenman discussed evidence that the 60-Gy dose is insufficient in this patient population, and reported on UNC data suggesting that dose escalation improves survival. The 60- Gy standard, he said, is based on a decades-old Radiation Therapy Oncology Group study (RTOG 73-01) that was conducted before the availability of computed tomography scans and contemporary chemotherapy. This dose has been challenged in four randomized studies but not bested. For example, Johnson and colleagues randomized 319 patients with locally advanced NSCLC to receive vindesine(Drug information on vindesine) (Eldisine) 3 mg/m2, standard thoracic radiotherapy of 60 Gy over a period of 6 weeks, or both vindesine and thoracic radiotherapy (Ann Intern Med 113(1): 33-38, 1990). Median survival time was 8.6 months for radiotherapy alone, 9.4 months for radiotherapy plus vindesine, and 10.1 months for vindesine alone. "The investigators concluded that radiotherapy does not prolong survival over drug therapy, but an alternative interpretation is that 60 Gy is too low a dose for cure and too high for palliation," Dr. Rosenman said. "Most patients today are being treated with 55 to 60 Gy. Perhaps a million patients have been treated at these levels. Shame on us." Dose Pushed to 74 Gy Dr. Rosenman and colleagues examined the radiotherapy dose in UNC study LCCC 9603 for inoperable stage IIIa/IIIb NSCLC patients with a performance status of 0 or 1. Patients were treated with induction carboplatin(Drug information on carboplatin) (Paraplatin) to AUC 6 and paclitaxel(Drug information on paclitaxel) 225 mg/m2, with cycles starting on days 1 and 22. Beginning on day 43, patients received concurrent chemoradiotherapy weekly with carboplatin to AUC 2 and paclitaxel 45 mg/m2, and radiation doses were escalated from 60 to 74 Gy. In 62 patients with NSCLC on carboplatin/ paclitaxel with radiation escalated from 60 to 74 Gy, survival at 1 year was 71%, at 2 years was 50%, at 3 years was 38%, and at 5 years was 29%. Median survival time was 24 months, at a median survivor-followup duration of 43 months. Dr. Rosenman said five other recent studies using 60 Gy reported median survival times of 15.6 to 19 months. He added that the radiation dose in the UNC study was escalated only to 74 Gy because it hit the "DCP-or Doctor Chicken Point" rather than because of adverse effects. Phase III Trial Concurrent chemotherapy with radiotherapy has produced promising responses in NSCLC, perhaps owing to the radiosensitizing effects of chemotherapy. "There are also hints that better local control might improve survival," Dr. Rosenman said. Consequently, he and colleagues set about designing a multi-institutional, phase III trial to compare high-dose vs standard- dose radiotherapy with concurrent chemotherapy in patients with stage IIIa or IIIb NSCLC. Each treatment regimen will be further randomized to amifostine(Drug information on amifostine) (Ethyol) or no amifostine (see Figure 1).The hope is that amifostine will permit more tolerable radiotherapy dose-escalation, which might translate into longer survival.