Adjuvant Chemotherapy for Non-Small-Cell Lung Cancer: The End of the Beginning

B. E. Johnson
2003 Journal of the National Cancer Institute  
In this issue of the Journal, Scagliotti and colleagues (1) present results from the Adjuvant Lung Project Italy (ALPI) trial, the largest study yet reported of adjuvant chemotherapy in patients with resected non-small-cell lung cancer (NSCLC). They report that there was no difference in survival between patients who received adjuvant chemotherapy and those who did not. Although patients treated with adjuvant chemotherapy had longer progression-free survival than the untreated patients (hazard
more » ... atio ‫ס‬ 0.89, 95% confidence interval ‫ס‬ 0.76 to 1.03), that finding was not statistically significant. The interpretation of this result is made even more important by the results of two randomized studies (2,3) of adjuvant chemotherapy that were reported at the American Society of Clinical Oncology meeting in 2003. Both studies (2,3) showed a survival advantage for patients with surgically resected early-stage lung cancer who were treated with chemotherapy compared with patients who underwent observation alone. There are several things to consider when comparing the findings of the ALPI trial with those of the adjuvant studies that have been published, reported in abstract form, or are currently ongoing: the number of patients treated on the trial, stage of the lung cancer, the chemotherapy regimen selected, and administration of chest radiotherapy for some patients participating in the studies. Scagliotti et al. (1) are to be commended for assembling a multidisciplinary international group that enrolled more than 1200 lung cancer patients on the ALPI trial in 5 years. It is a challenge to enroll patients in an adjuvant trial in which one arm is observation while the other is combination chemotherapy, particularly when all of the patients are recovering from a thoracotomy for the resection of their lung cancer. The ALPI trial was appropriately powered to see an increase in 5-year survival from 50% to 57%. The number of patients who participated in this randomized trial was similar to the number of patients (n ‫ס‬ 1394) reported on in a meta-analysis of eight randomized trials of cisplatin-based adjuvant chemotherapy following surgical resection of NSCLC (4). Scagliotti et al. (1) enrolled patients with stages I, II, or IIIA NSCLC into the ALPI trial. The stage distribution in the ALPI trial corresponded to that in the meta-analysis of randomized cisplatin-based adjuvant chemotherapy trials described in (4). That meta-analysis reported that the 706 patients treated with adjuvant chemotherapy had a 5% survival advantage 5 years following surgical resection compared with the 688 resected patients observed without adjuvant chemotherapy (hazard ratio ‫ס‬ 0.87; P ‫ס‬ .08). There are some potentially important aspects of the design of the ALPI trial that may have had an impact on patient outcome. First, the number of patients with stages IA or IB enrolled in the ALPI trial was not provided. This information would be helpful for interpreting the outcomes in this study because patients with surgically resected stage IA NSCLC are least likely to relapse within 5 years after resection. Consequently, patients with stage IA NSCLC have been excluded from other adjuvant studies (i.e., the BR 10 and CLB-9633 trials; [click on NCI Clinical Trials Search Form (Basic)]). Therefore, the potential benefit from adjuvant chemotherapy reported for the ALPI trial may be difficult to assess without knowing the number of patients with stage IA NSCLC. Second, patients with stage II or IIIA NSCLC were included in the ALPI trial, so chest radiotherapy was incorporated into the treatment of some of the patients. However, the meta-analysis (4) reported that patients with resected NSCLC who had a survival benefit from adjuvant cisplatinbased chemotherapy did not have chest radiotherapy administered as part of their treatment. In addition, results of a randomized trial (5) of 488 patients with resected stage II or IIIA NSCLC treated with chest radiotherapy that became available after the ALPI trial was designed indicated that there was no difference in outcome between patients treated with and without four cycles of etoposide-cisplatin chemotherapy. The 1995 meta-analysis (4) also reported no survival benefit for 332 patients with NSCLC treated with adjuvant chemotherapy plus chest radiotherapy following surgery compared with 336 patients treated with surgery plus chest radiotherapy. The inclusion of patients treated with chest radiotherapy in the ALPI trial may have decreased the probability of seeing a difference between the two groups of patients. Scagliotti et al. (1) did not provide information on the number of patients treated with chest radiotherapy by disease stage, which would allow the evaluation of the impact of such treatment on the outcome; this information should be included in reports of future adjuvant trials. The type of chemotherapy used in the ALPI trial may have an impact on the ability to administer the drugs in the adjuvant setting following a thoracotomy and on the toxicity and the efficacy of the chemotherapy. The study was designed in 1995 before multiple large studies of stage IIIB and stage IV NSCLC had been completed and reported. Scagliotti et al. (1) selected a chemotherapy regimen (mitomycin, vindesine, and cisplatin [MVP]) that had been studied by their group and that they had previously shown to be associated with the longest median survival and with similar grade 3 and 4 toxicities compared with
doi:10.1093/jnci/djg077 pmid:14519741 fatcat:y7lnor3f4nclvpfzplj4frsdk4