Affiliation of author: Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Womens Hospital, and Harvard Medical School, Boston, MA.
Correspondence to: Bruce E. Johnson, MD, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Rm. D1234, Boston, MA 02445 (e-mail: bejohnson{at}partners.org).
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 nonsmall-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 ratio = 0.89, 95% confidence interval = 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 = 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 = 0.87; P = .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; www.nci.nih.gov/clinicaltrials [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 cisplatin-based 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 etoposidecisplatin 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 two other regimens (etoposide and cisplatin or mitomycin, ifosfamide, and cisplatin) (6). Only 69% of the patients in the MVP group were able to complete the three planned cycles of treatment; the remainder did not complete adjuvant chemotherapy because of toxicity (n = 66), because they requested that chemotherapy treatment be stopped (n = 44), or because they refused to start treatment after being randomly assigned to the chemotherapy group (n = 48) (1). It should be possible to increase the proportion of patients completing treatment in future trials by selecting appropriate chemotherapy regimens that are better tolerated so patients can both initiate and continue their treatment. Reports of combination chemotherapy trials for patients with advanced NSCLC have provided information on the number of cycles of chemotherapy that can be administered and the reasons for discontinuing chemotherapy (79). Although most patients stop chemotherapy because of cancer progression, data on the number and percentage of patients able to tolerate chemotherapy in the absence of disease progression may help in selecting future adjuvant regimens that can be safely administered and well tolerated. Further research completed after the MVP chemotherapy was selected for the ALPI trial has documented that other regimens give similar patient outcomes with different toxicities compared with the MVP regimen in the ALPI trial (79). The information on grades 3 and 4 toxicity and patient outcome on these trials may now prompt selection of different chemotherapy combinations to be used in future adjuvant chemotherapy trials. Careful attention should be paid to the number of cycles that can be delivered to a patient following surgical resection and the efficacy of the chemotherapy so that this information can be used for planning adjuvant chemotherapy treatment.
Interpretation of the ALPI trial results is potentially complicated because some patients were treated with chest radiotherapy. For example, 90 patients in the adjuvant chemotherapy arm and 69 patients in the control arm died in the first year after resection. The authors provided incomplete information on these early deaths, and I am concerned that some of these patients might have died of complications related to chest radiotherapy. Causes of these early deaths may be important when evaluating the survival curves presented in Fig. 2 of Scagliotti et al. (1). The survival curves show higher mortality during the first year in the adjuvant treatment arm than in the control arm, similar mortality in the two arms in years 24, and lower mortality in the adjuvant treatment arm than in the control arm after year 4 (1). The increased mortality in the first year points out the importance of ascertaining the causes of death in the first 612 months in adjuvant chemotherapy trials to help interpret the efficacy and toxicity of the adjuvant chemotherapy. I encourage groups reporting results of such adjuvant chemotherapy trials to attempt to capture this information, particularly for the patients whose treatment includes chest radiotherapy. Results of a meta-analysis of patients who participated in adjuvant chest radiotherapy trials suggest that patients with stage I or II NSCLC treated with chest radiotherapy do not survive as long as patients randomly assigned to no chest radiotherapy, suggesting an adverse impact of adding this therapy (10). Therefore, it will be helpful to report the causes of the early deaths (i.e., within the first 612 months after starting treatment) in patients by stage and by whether the patients were treated with chest radiotherapy.
The information reviewed here suggests that it will be important for future trial designs to select appropriate stages for study, select appropriate regimens that can be tolerated after surgical resection, and identify the cause of deaths in the trials, if possible. Results of the unplanned subset analyses by stage suggest that patients with stage II NSCLC could be excellent candidates for further adjuvant chemotherapy studies (1). In addition, Kato et al. (2) reported that among 979 patients with resected stage I adenocarcinoma of the lung who were randomly assigned to receive either oral tegafururacil (UFT) chemotherapy or observation, the patients with stage IA adenocarcinoma of the lung treated with UFT did not live longer than the patients assigned to observation. Patients with stage IB adenocarcinoma treated with UFT had a 5-year survival of 85%, whereas patients assigned to the observation arm had a 5-year survival of 74%. It will be helpful for ALPI trialists and future investigators to provide the outcomes for patients with stages IA or IB NSCLC. Patients with stage IA may not be appropriate candidates for reasonably sized adjuvant trials because of their low rates of relapse and death from lung cancer.
As has been the case for adjuvant trials in breast and colon cancer, it will be important to select appropriate disease stages, drugs, and treatment durations and to allow adequate amounts of time to pass before assessing patient outcomes (11,12). The results of the ALPI trial and other recent trials (13) should prompt future investigations of patients with resected stages IB or II NSCLC. The findings of the ALPI trial (1) and the Eastern Cooperative Oncology Group trial (5) reinforce that adjuvant chemotherapy does not benefit patients with stage III disease when chest radiotherapy is part of the treatment. Nonetheless, the ALPI investigators are to be commended for completing a trial of this size in this patient population, which has generated important information for interpreting the potential impact of adjuvant chemotherapy for patients with resected NSCLC that has reinforced previous findings, and which should generate further information in these patient populations. The report of this, the first of the large trials to be completed in this decade, brings to mind the comment of Winston Churchill, "This is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning."
REFERENCES
1 Scagliotti GV, Fossati R, Torri V, Crinò L, Giaccone G, Silvano G, et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell lung cancer. J Natl Cancer Inst 2003;95:145361.
2 Kato H, Tsuboi M, Ohta M, Hata E, Tsubota N, Hamajima N, et al. In: Grunberg SM, editor. A randomized phase III trial of adjuvant chemotherapy with UFT for completely resected pathological stage I (T1N0M0, T2N0M0) adenocarcinoma of the lung. Annual Meeting of the American Society of Clinical Oncology (ASCO); 2003 May 31-Jun 3; Chicago. Alexandria (VA): ASCO; 2003;22:621.
3 Le Chevalier T. In: Grunberg SM, editor. Results of the randomized international adjuvant lung cancer trial (IALT) cisplatin-based chemotherapy (CT) versus no CT in 1867 patients with resected non-small cell lung cancer. Annual Meeting of the American Society of Clinical Oncology (ASCO); 2003 May 31-Jun 3; Chicago. Alexandria (VA): ASCO; 2003;22:2.
4 Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995;311:899909.
5 Keller SM, Adak S, Wagner H, Herskovic A, Komaki R, Brooks BJ, et al. A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. Eastern Cooperative Oncology Group. N Engl J Med 2000;343:121722.
6 Crino L, Clerici M, Figoli F, Carlini P, Ceci G, Cortesi E, et al. Chemotherapy of advanced non-small-cell lung cancer: a comparison of three active regimens. A randomized trial of the Italian Oncology Group for Clinical Research (G.O.I.R.C.). Ann Oncol 1995;6:34753.[Abstract]
7 Kelly K, Crowley J, Bunn PA Jr, Presant CA, Grevstad PK, Moinpour CM, et al. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 2001;19:32108.
8 Scagliotti GV, De Marinis F, Rinaldi M, Crino L, Gridelli C, Ricci S, et al. Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol 2002;20:428591.
9 Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:928.
10 Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet 1998;352:25763.[CrossRef][ISI][Medline]
11 Legare RD, Strenger R. Adjuvant therapy in breast cancer. Obstet Gynecol Clin North Am 2002;29:2018, ix.[ISI][Medline]
12 Saltz LB, Minsky B. Adjuvant therapy of cancers of the colon and rectum. Surg Clin North Am 2002;82:103558.[ISI][Medline]
This article has been cited by other articles in HighWire Press-hosted journals:
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |