Primary Analysis of the Phase II Component of a Phase I/II Dose Intensification Study Using Three-Dimensional Conformal Radiation Therapy and Concurrent Chemotherapy for Patients With Inoperable Non–Small-Cell Lung Cancer: RTOG 0117

Jeffrey D. Bradley,Journal of Clinical Oncology, Vol 28, No 14 (May 10), 2010: pp. 2475-2480
Phase I of Radiation Therapy Oncology Group (RTOG) 0117 determined that 74 Gy was the maximum-tolerated dose with concurrent weekly carboplatin/paclitaxel chemotherapy for inoperable non–small-cell lung cancer (NSCLC). Phase II results are reported here. Patients with unresectable stages I-III NSCLC were eligible. Chemotherapy consisted of weekly paclitaxel at 50 mg/m2 and carboplatin at area under the curve 2 mg/m2. The radiation dose was 74 Gy given in 37 fractions. Radiation therapy volumes included those of the gross tumor and involved nodes. The volume of lung at or exceeding 20 Gy (V20) was mandated to be ≤ 30%.

Results Of the combined phase I/II enrollment, a total of 55 patients received 74 Gy, of whom 53 were evaluable. The median follow-up was 19.3 months for all patients and 25.4 months for those still alive. The median survival for all patients was 25.9 months. The percentage surviving at least 12 months was 75.5%. The median overall survival (OS) and progression-free survival (PFS) times for stage III patients (n = 44) were 21.6 months and 10.8 months, respectively. OS and PFS rates at 12 months were 72.7% and 50.0%, respectively. Twelve patients experienced grade ≥ 3 lung toxicity (two patients had grade 5 lung toxicity).

Over the past several years, three other groups have prospectively tested the tolerability and efficacy of 74 Gy given with weekly paclitaxel and carboplatin chemotherapy. All three groups independently reached a similar conclusion: 74 Gy is likely the MTD in this setting. The North Central Cancer Treatment Group (NCCTG) has reported prospective phase I results for 13 patients treated to 70, 74, or 78 Gy. In their study, 70 and 74 Gy were well tolerated and 78 Gy was not. With a median follow-up of 28 months for the 13 patients on NCCTG N0028, the median survival time was 37 months. The Cancer and Leukemia Group B (CALGB) has also reported results of a randomized phase II comparison of two different chemotherapy regimens given with 74 Gy.Patients either received induction paclitaxel and carboplatin for two cycles followed by the same weekly chemotherapy or they received induction carboplatin and gemcitabine followed by twice weekly gemcitabine during RT. The trial enrolled 69 patients and had a median follow-up of 16.4 months at last report. The median survival was 24.2 months on the paclitaxel/carboplain arm. The gemcitibine arm was closed early because 13% of the patients had grade 5 pulmonary events. On the basis of these two trials as well as RTOG 0117, the NCCTG and the CALGB have joined efforts with the RTOG to support RTOG 0617 as an intergroup trial.

North Carolina investigators have reported the results of four sequential prospective phase I/II studies to assess the safety and feasibility of high-dose (74-90 Gy) three-dimensional conformal radiation treatment in the setting of concurrent weekly carboplatin and paclitaxel chemotherapy.These investigators also delivered two cycles of carboplatin and paclitaxel neoadjuvantly before concurrent chemoradiotherapy. In total, 112 patients were accrued, with a median follow-up of 4.9 years for surviving patients. The median survival was 24 months. The 1-, 3-, and 5-year OS rates were 69%, 36%, and 24%, respectively. The relatively longer follow-up duration of this population provides information about late complication risks.

Various studies have combined chemotherapy with radiation in various combinations. The RTOG 92-04 trial compared induction chemotherapy with concurrent chemoradiation as a standard dose or hyperfractionation, the 5-year overall and median survival rate was 13% and 16.4 months in Arm 1 compared with 16% and 15.5 months for Arm 2, respectively.  Various other studies are also noted below

CLGB/ECOG Trial for unresectable Stage III NSCL. All patients receive induction chemotherapy with vinblastine/cisplatin for 5 weeks then XRT alone (60Gy) or XRT+C (carboplatin 100mg/M2/w). Results showed same median survival (13.4 mos) and survival curves as noted

Years
Clamon. J Clin Onc 1999;17:4

Another recent review of chemoradiation (Pisters. SWOG S9504. Proc ASCO 2000) made the following comparisons:

ChemoRadiation for Inoperable Lung Cancer

Induction Carboplatin/Paclitaxel followed by Concurrent Carboplatin/Paclitaxel and Dose-Escalating Conformal Thoracic Radiation Therapy in Unresectable Stage IIIA/B Nonsmall Cell Lung Carcinoma

Cancer 89:534-42, 2000

Mark A. Socinski, M.D.

Twenty-nine patients with unresectable Stage III NSCLC were included. Patients received 2 cycles of induction carboplatin (AUC 6) and paclitaxel (225 mg/m²/3 hours) every 21 days. On Day 43, concurrent TCRT and weekly (x6) carboplatin (AUC 2) and paclitaxel (45 mg/m²/3 hours) was initiated. The TCRT dose was escalated from 60 to 74 Gy in 4 cohorts. The response rate to induction carboplatin/paclitaxel was 52%. Three patients (10%) experienced disease progression during the induction phase. No dose-limiting toxicity was seen during the escalation of the TCRT dose from 60 to 74 Gy. The major toxicity was esophagitis, with 18% of patients developing Radiation Therapy Oncology Group Grade 3 esophagitis. The overall response rate was 70% (1 complete response and 18 partial responses). Survival rates at 1 and 2 years were 69% and 45%, with a median survival of 21 months. The 1-year progression free survival probability was 41% (95% confidence interval, 23-59%).

TCRT was initiated on Day 43 concurrent with weekly paclitaxel and carboplatin as noted above. Patients underwent a planning CT scan after the second cycle of chemotherapy. The lungs, esophagus, heart (left ventricle), spinal cord, primary tumor, and radiographically positive lymph nodes were contoured. The prechemotherapy CT scan then was registered spatially with the planning CT scan, and the initial treatment was designed from it. The macroscopic tumor volume (GTV) included the primary tumor and any radiographically positive lymph nodes (all lymph nodes > 1.0 cm). The clinical target volume (CTV) included the GTV, the entire uninvolved mediastinum, and a 1.0-2.0 cm margin around the GTV; then, 50 Gy were delivered to this prechemotherapy CTV. Respiratory variation (planning target volume [PTV]) was taken into account only in the sense that the superior and inferior field margins usually were extended to 2 cm. The boost volumes included only the GTV and a 1.0-2.0 cm margin. The spinal cord dose was limited to 48 Gy (including the dose under the blocks), and the total left ventricle dose was limited to 40 Gy. The treatment was given with a standard daily fractionation of 2.0 Gy per fraction 5 days per week.