Will Future Progress in Non–Small-Cell Lung Cancer Be Step by Step … or by Leaps and Bounds?

“We cannot sit and wait for the promise of tomorrow so long as stepwise progress can be made with the tools at hand today.” In terms of lung cancer therapy, these words of Dr Howard Skipper from 1979 seem to apply just as much today as they did a quarter of a century ago. Before 1980, the standard of care for locally advanced/unresectable non– small-cell lung cancer (LA-NSCLC) was definitive radiation therapy (RT) alone. However, the 5-year survival rate was disappointingly low, at only 5%. The treatment paradigm began to shift after a landmark trial by the Cancer and Leukemia Group B (CALGB 84-33) demonstrated that induction chemotherapy (with two cycles of cisplatin and vinblastine) followed by RT significantly improved survival compared with RT alone. Yet, the results with sequential chemotherapy followed by RT in CALGB 84-33 seemed too good to be true. There was almost a “triple jump” improvement in the 5-year survival from 6% with RT alone to 17% with sequential therapies. Indeed, two subsequent randomized trials utilizing the same regimen as CALGB 84-33 (with substantially more patients) demonstrated more modest long-term survival rates of 8% to 10%. The next incremental gain in LA-NSCLC came from the use of concurrent rather than sequential chemotherapy and RT. In 1999, Furuse et al reported in the Journal of Clinical Oncology the results of a randomized trial with 320 patients, comparing sequential chemotherapy (mitomycin, vindesine, and cisplatin) followed by RT (56 Gy) versus concurrent chemoradiotherapy. They found a statistically significant improvement in 5-year survival of 16% for concurrent chemoradiotherapy compared with 9% for sequential therapies (P .01). In another randomized trial with more than 600 patients, Radiation Therapy Oncology Group (RTOG) trial 94-10, Curran et al reported remarkably similar superior results of once-a-day RT (63 Gy) concurrent with chemotherapy over the same therapies delivered sequentially. Zatloukal et al also performed a randomized phase II trial favoring concurrent therapy. Patterns of failure data suggest that the benefit of concurrent chemoradiotherapy is due to a synergistic effect that leads to an improvement in local, rather than distant, control. In this issue of the Journal, Fournel et al add yet another study corroborating the clinical benefit of concurrent over sequential chemoradiotherapy. In this phase III trial, 212 patients were randomly assigned between induction chemotherapy with cisplatin and vinorelbine followed by RT (66 Gy), compared with the same RT concurrent with cisplatin and etoposide followed by consolidation therapy with cisplatin and vinorelbine. While not statistically significant, they report potentially clinically meaningful differences in the median and 4-year survival rates, favoring the concurrent arm (16.3 v 14.5 months and 21% v 14%, respectively). The key reason for the borderline result was the lack of adequate statistical power in this study to reject the null hypothesis. According to their study design, with a calculated sample size of 210 patients, Fournel et al only had the ability to detect an improvement in 2-year survival from 20% in the sequential arm to 35% in the concurrent arm. This relative improvement of 75% was simply too high a bar, too great a leap, and did not follow the general rule of “stepwise” improvements that one would expect in this setting. Moreover, unlike RTOG 94-10, this trial was confounded by the addition of consolidation chemotherapy in the experimental arm. Fortunately, this was not the first trial on this subject, or some may have incorrectly concluded that concurrent therapy is no better than sequential treatments. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 25 SEPTEMBER 1 2005