Randomized Study of Code Versus Alternating CAV/EP for Extensive-Stage Small-Cell Lung Cancer

Reviewers: John Han-Chih Chang, MD
Source: Journal of Clinical Oncology 1999; Volume 17: pages 2300 - 2308

Background

Small-cell lung cancer (SCLCa) is found to be "extensive stage" (ES) in nearly two-thirds of the cases. A recent trial demonstrated long-term survival (over 5 years) in some patients treated with accelerated hyperfractionated radiation therapy (RT) who had a complete response to induction chemotherapy.1 Chemotherapy (ChT) regimens used have included a combination of cyclophosphamide, doxorubicin and vincristine (CAV) or etoposide and cisplatin (EP). Recently, a pilot study from Vancouver, Canada demonstrated some promising results with an intensive weekly regimen of cisplatin, vincristine, doxorubicin and etoposide (CODE) coupled with thoracic RT (TRT).2,3 This report is from a collaborative effort of the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) and the Southwest Oncology Group (SWOG), who evaluated the efficacy of the CODE regimen in a randomized fashion against standard ChT.

Summary/Discussion/Conclusion

Two hundred and nineteen patients were randomized to either CODE (drugs given in a weekly or q2week fashion) over the course of 9 weeks versus 3 cycles of CAV alternating with 3 cycles of EP over a course of 18 weeks. The patients receiving CODE were given TRT and prophylactic cranial irradiation (PCI), if they obtained a complete response. The utilization of RT for patients in the CAV/EP arm was left to the discretion of the treating physician. The TRT dose was 30 Gy in 3Gy/day fractionations. Granulocyte colony-stimulating factor (G-CSF) was not utilized prophylactically, but was given for neutopenic fever and to those who had treatment delays due to leukopenia.

Patient characteristics appeared well balanced except for the number of patients who had multiple sites of involvement (72.5% versus 80% for the CAV/EP and CODE arms, respectively). This may have biased the outcome data in favor of the CAV/EP arm.

In both arms, 3/4th of the patients completed all the specified treatment. The actual dose delivered was higher for each ChT agent in the CODE arm versus the CAV/EP arm.

TRT was given to more patients in the CODE arm than CAV/EP arm (41% versus 27%, respectively). PCI was also given more frequently in the CODE arm (39% versus 26% in the standard ChT arm) Initial response rate was 87% in the CODE arm versus 70% in the CAV/EP arm. There was no difference in the number of complete responses (20 - 25%) between the two arms. The overall survival rate was reported as just less than 20% at 2 years for both groups. This is similar to most of the modern series of ES SCLCa.

Quality of life measures were taken on 81 of the patients treated. These appeared to be more favorable in patients treated with the CAV/EP regimen versus CODE during weeks 10 - 15 of treatment corresponding to the timing of the TRT. Thus quality of life seemed to be related to the acute side effects of radiation therapy, which resolve with time. The fact that there is no difference after week 16 attests to that fact.

Along with dose intensity and increased frequency of RT came increased toxicity. Nine (8.2%) patients had treatment related deaths (6 were infectious related sequelae) in the CODE arm, while only 1 in the CAV/EP arm died of treatment related causes. This may have negated any survival benefit that CODE may have had.

This international trial has demonstrated that the dose intensive regimen of CODE has significant toxicity with no survival advantage when compared to standard ChT for ES SCLCa. The addition of prophylactic G-CSF may have reduced the toxicity, since most toxicity was related to infection. For the near future this dose intensive regimen of CODE should only be considered as part of clinical trials in ES SCLCa.