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

November 1, 2003

This special “annual highlights” supplement to Oncology News International is acompilation of major advances in the management of lung cancer during 2003, asreported in ONI. Guest editor Dr. Roy Herbst comments on the reports includedherein and discusses advances in the clinical management of lung cancer, with afocus on developments in targeted therapy, new combinations, adjuvant therapy,induction therapy, and what to watch for in 2004.

VANCOUVER, Canada-A trimodal regimen integrating surgicalresection with concurrent chemotherapyand radiation (CT/RT) in non-small-cell lung cancer (NSCLC)continued to show benefits in an updatedanalysis of Intergroup Trial 0139presented at the 10th World Conferenceon Lung Cancer plenary session(abstract PL-4). Kathy Albain, MD,who gave the initial report at ASCO2003 (abstract 2497), presented theupdated results."With further follow-up, the significantdifference in progression-freesurvival is still very solid. There is noweakening of the strength of the dataat this point," said Dr. Albain, of LoyolaUniversity of Chicago's CardinalBernardin Cancer Center.Surgical resection has yielded encouragingresults in patients with stageIIIA NSCLC and pathologically confirmedN2 nodes (pN2), but owing toincreased mortality and morbidityassociated with surgery, CT/RT is thestandard of care. Intergroup Trial 0139was designed to test the value of resectionafter induction CT/RT vs fullcourseCT/RT therapy, in 429 patientswith T1-3, pN2, M0 tumors.All patients had induction chemoradiationwith two cycles of cisplatin(Platinol) and etoposide and daily radiationto 45 Gy, then were randomizedto either surgical resection (surgeryarm) if disease progression hadnot occurred or to uninterrupted radiotherapyto 61 Gy (CT/RT arm),each followed by two more courses ofchemotherapy.The median follow-up in this reportwas 71 months, which representedan additional 8 months beyond the63-month data reported at ASCO. Theanalysis yielded updated disease-freeand overall survival, a new Cox multivariatemodel, and revised patterns offailure in 392 evaluable patients (n =201 surgery arm; n = 191 CT/RT arm).Induction chemotherapy was deliveredper protocol in 95% to 96% ofpatients in both arms. Significantlymore patients in the surgery arm didnot receive consolidation chemotherapy(42% vs 21%), but significantlymore of these patients did receive RTper protocol (97% vs 81%).Toxicities were similar, althoughmore patients died on the surgery arm.The only difference in grade 3-4 toxicitywas more esophagitis in the CT/RTarm (20% vs 9%). Three deaths occurredon the CT/RT arm during orafter consolidation. In the surgery arm,14 patients died (10 of postoperativecomplications). Twelve deaths followedpneumonectomy, 8 of whichwere from acute respiratory distresssyndrome.Updated Survival AnalysisProgression-free survival (PFS) wassignificantly better for patients in thesurgical arm (P = .03). Median PFSwas 13.4 vs 11.8 months, and 3-yearPFS was estimated at 28% vs 19% forsurgery vs CT/RT, respectively. Medianoverall survival was 22 months vs22.3 months, and 3-year survival was37% and 34%, respectively, Dr. Albainreported. "The hazard ratios crosseddue to treatment-related deaths forboth PFS and overall survival, and thelog-rank P value was not significant,"she said.While early survival favors the CT/RT arm, the curves superimpose, thencross, and begin to separate at themedian survival point of 22 months,she said. "By year 3, there is an absolutesurvival benefit of 3% favoring thesurgery arm, for a 10% proportionalrisk reduction. However, confidenceintervals are wide and overlap at thispoint of follow-up. In the surgical arm,more patients are alive without progression(P = .004) and more diedwithout progression (P = .007).""Very little change has occurred inthe outcome end points since theASCO 2003 analysis,|" Dr. Albainnoted. "There is no change in the greaternumber of patients alive withoutprogression [following] surgery, andin the fewer number who died withoutprogression after CT/RT."In the analysis of overall survivalaccording to interim pathologic responsedata, N0 status continued topredict improved outcome whetheror not there was residual primary tumor.Patients who were T0, N0 (pathologicalcomplete response) had a mediansurvival of 36.7 months and a3-year survival of 52%. Patients whowere T0-1, N0 had a median survivalof 36.7 months and a 3-year survivalrate of 53% .CommentaryDiscussant Harvey Pass, MD, professorof surgery and oncology, KarmanosCancer Institute, Detroit, calledIntergroup 0139 "the most anticipatedrandomized trial in lung cancer fora long time. It is a standard for randomizedtrials in induction therapyand serves as a springboard for trialswe need to plan for the future."He said that the study confirmedphase II trials showing that full dosesof cisplatin/etoposide could be deliveredwith radiotherapy and that pathologiccomplete responses could beachieved in 18% of patients. "The mostintriguing part of the trial is that downstagingof N2 disease to N0 will occurin 46% to 48% of patients, and 3-yearsurvival of this group is a phenomenal53%, which is even better than the44% we achieved in SWOG 8805," hesaid. [In SWOG 8805, 126 patientswith pathologically staged IIIA/IIIBdisease received cisplatin plus etoposideconcurrent with radiation therapy,followed by surgical resection.]Dr. Pass said that results in the surgeryarm "reamplified the importanceof nodal clearance on survival." Thefindings do not demonstrate that "everybodyshould get surgery after induction,"but they point to the need todetermine which patients will have nodaldownstaging by any induction method.To accomplish this, Dr. Pass saidpre- and postinduction PET scanningshould be exploited in future trials.Several questions are still unanswered,such as whether the N2 downstagingresults from the radiotherapy,chemotherapy, or combination, andwhat contribution surgery makes tothe outcome. These questions are hardto answer because of the heterogeneityof the N2 population; future studiesshould stratify these patients, Dr.Pass said.