Carboplatin/paclitaxel or carboplatin/vinorelbine followed by accelerated hyperfractionated conformal radiation therapy: report of a prospective phase I dose escalation trial

Purpose: To prospectively determine the maximally tolerated dose (MTD) of conformally delivered RT at 1.6 cGy BID, following C/T or C/N, for unresectable locally advanced lung cancer (IIB-IIIA/B). Materials and Methods: Treatment was induction chemotherapy followed by escalating doses of conformally planned RT. Concurrent boost techniques were used to deliver 1.6 and 1.25 cGy BID to the gross and clinical target volumes, respectively. The median tumor size was 4.1 cm, with a median initial tumor volume of 35cc. Patients were enrolled in cohorts of 7, starting at 73.6 Gy; the first 7 receiving induction C/T, and the second 7 C/N. RT doses escalated in 6.4 Gy intervals to 80 and 86.4 Gy. The C/T and C/N cohorts were considered separately so as to evaluate the impact of the induction regimen on the rate of grade 3 toxicity, and thus the maximum tolerated dose. Results: Between 11/97 and 3/01, 39 patients with median age of 59.2, were enrolled, 61% male, 39% female. Stage breakdown: IIB 1 (3%), IIIA 25 (64%), IIIB 13 (33%). Thirty seven completed induction chemotherapy, 17 partial response, 12 no response, 6 progression, 2 unevaluable. The incidence of RT-induced toxicity is shown in the table for the different patient cohorts. While this is a phase one study, outcomes related to tumor response were also assessed. Following induction chemotherapy and RT, 5 (13%) are radiographic complete responses, and 6 (23%) had partial responses. Median survival is 16.2 months (with a 95% confidence interval from 13.6 to infinity). The one and two year survivals are 67% and 39% respectively. Of the 12 patients that have evidence of tumor regrowth, 6 have a local failure in the high dose volume, 6 a regional failure outside of the high dose volume, and 5 had distant metastatic disease. Conclusion: High dose conformal radiation therapy to 80.0 Gy appears tolerable following either C/T or C/N at a follow-up of 3-24 months. Most significant morbidity appears to be esophageal. Since 2/7 patients that received C/T and 86.4 Gy developed grade 4 toxicity, 80.0 Gy is considered the MTD following C/T. Enrollment at 86.4 Gy in the C/N arm continues and escalation to 92.8 Gy will be considered if 86.4 Gy is tolerable. Supported in part by a grant from Glaxo Smithkline. ∗Incidence of ≥Grade 3 RT ToxicitiesIncidence of ≥Grade 3 RT ToxicitiesDose EscalationCarbo/TaxolCarbo/Navelbine73.6 Gy0/71.7∗Esophagus,80.0 Gy1/7Esophagus,1/7∗Esophagus,86.4 Gy2/7∗Esophagus,, oLung Toxicity (Exceeds MTD)0/3 (Enrolling)∗ Esophagus,o Lung Toxicity Open table in a new tab