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Surgery After CT/RT in NSCLC: Benefits Upheld With Longer Follow-up of Intergroup 0139

Surgery After CT/RT in NSCLC: Benefits Upheld With Longer Follow-up of Intergroup 0139

VANCOUVER, Canada- A trimodal regimen integrating surgical resection with concurrent chemotherapy and radiation (CT/RT) in non- small-cell lung cancer (NSCLC) continued to show benefits in an updated analysis of Intergroup Trial 0139 presented at the 10th World Conference on Lung Cancer plenary session (abstract PL-4). Kathy Albain, MD, who gave the initial report at ASCO 2003 (abstract 2497), presented the updated results. "With further follow-up, the significant difference in progression-free survival is still very solid. There is no weakening of the strength of the data at this point," said Dr. Albain, of Loyola University of Chicago's Cardinal Bernardin Cancer Center. Surgical resection has yielded encouraging results in patients with stage IIIA NSCLC and pathologically confirmed N2 nodes (pN2), but owing to increased mortality and morbidity associated with surgery, CT/RT is the standard of care. Intergroup Trial 0139 was designed to test the value of resection after induction CT/RT vs fullcourse CT/RT therapy, in 429 patients with T1-3, pN2, M0 tumors. All patients had induction chemoradiation with two cycles of cisplatin (Platinol) and etoposide and daily radiation to 45 Gy, then were randomized to either surgical resection (surgery arm) if disease progression had not occurred or to uninterrupted radiotherapy to 61 Gy (CT/RT arm), each followed by two more courses of chemotherapy. The median follow-up in this report was 71 months, which represented an additional 8 months beyond the 63-month data reported at ASCO. The analysis yielded updated disease-free and overall survival, a new Cox multivariate model, and revised patterns of failure in 392 evaluable patients (n = 201 surgery arm; n = 191 CT/RT arm). Induction chemotherapy was delivered per protocol in 95% to 96% of patients in both arms. Significantly more patients in the surgery arm did not receive consolidation chemotherapy (42% vs 21%), but significantly more of these patients did receive RT per protocol (97% vs 81%). Toxicities were similar, although more patients died on the surgery arm. The only difference in grade 3-4 toxicity was more esophagitis in the CT/RT arm (20% vs 9%). Three deaths occurred on the CT/RT arm during or after consolidation. In the surgery arm, 14 patients died (10 of postoperative complications). Twelve deaths followed pneumonectomy, 8 of which were from acute respiratory distress syndrome. Updated Survival Analysis Progression-free survival (PFS) was significantly better for patients in the surgical arm (P = .03). Median PFS was 13.4 vs 11.8 months, and 3-year PFS was estimated at 28% vs 19% for surgery vs CT/RT, respectively. Median overall survival was 22 months vs 22.3 months, and 3-year survival was 37% and 34%, respectively, Dr. Albain reported. "The hazard ratios crossed due to treatment-related deaths for both PFS and overall survival, and the log-rank P value was not significant," she said. While early survival favors the CT/ RT arm, the curves superimpose, then cross, and begin to separate at the median survival point of 22 months, she said. "By year 3, there is an absolute survival benefit of 3% favoring the surgery arm, for a 10% proportional risk reduction. However, confidence intervals are wide and overlap at this point of follow-up. In the surgical arm, more patients are alive without progression (P = .004) and more died without progression (P = .007)." "Very little change has occurred in the outcome end points since the ASCO 2003 analysis,|" Dr. Albain noted. "There is no change in the greater number of patients alive without progression [following] surgery, and in the fewer number who died without progression after CT/RT." In the analysis of overall survival according to interim pathologic response data, N0 status continued to predict improved outcome whether or not there was residual primary tumor. Patients who were T0, N0 (pathological complete response) had a median survival of 36.7 months and a 3-year survival of 52%. Patients who were T0-1, N0 had a median survival of 36.7 months and a 3-year survival rate of 53% . Commentary Discussant Harvey Pass, MD, professor of surgery and oncology, Karmanos Cancer Institute, Detroit, called Intergroup 0139 "the most anticipated randomized trial in lung cancer for a long time. It is a standard for randomized trials in induction therapy and serves as a springboard for trials we need to plan for the future." He said that the study confirmed phase II trials showing that full doses of cisplatin/etoposide could be delivered with radiotherapy and that pathologic complete responses could be achieved in 18% of patients. "The most intriguing part of the trial is that downstaging of N2 disease to N0 will occur in 46% to 48% of patients, and 3-year survival of this group is a phenomenal 53%, which is even better than the 44% we achieved in SWOG 8805," he said. [In SWOG 8805, 126 patients with pathologically staged IIIA/IIIB disease received cisplatin plus etoposide concurrent with radiation therapy, followed by surgical resection.] Dr. Pass said that results in the surgery arm "reamplified the importance of nodal clearance on survival." The findings do not demonstrate that "everybody should get surgery after induction," but they point to the need to determine which patients will have nodal downstaging by any induction method. To accomplish this, Dr. Pass said pre- and postinduction PET scanning should be exploited in future trials. Several questions are still unanswered, such as whether the N2 downstaging results from the radiotherapy, chemotherapy, or combination, and what contribution surgery makes to the outcome. These questions are hard to answer because of the heterogeneity of the N2 population; future studies should stratify these patients, Dr. Pass said.

 
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