Randomized Study of CODE Versus Alternating CAV/EP for Extensive-Stage Small-Cell Lung Cancer: An Intergroup Study of the National Cancer Institute of Canada clinical Trials Group and the Southwest Oncology Group

Reviewers: Li Liu, MD
Source: Journal of Clinical Oncology, Volume 17, No 8 (August):2300-2308, 1999

Background

Despite decades of intensive investigation using various combinations of chemotherapy, the outcome of patients with extensive-stage small cell lung cancer (ESCLC) remains poor. . Even so small-cell lung cancer is a highly responsive tumor sensitive to a broad spectrum of cytotoxic agents. Numerous dose escalation and dose-intensity trials with various antineoplastic agents have been attempted. However, to date, higher complete remission rates have not translated into better survival. This is a report of a randomized intergroup trial to compare an intensive chemotherapy regimen plus irradiation versus standard chemotherapy for the treatment of ESCLC.

Methods

Eligibility criterion included age younger than 68, performance status of 0 to 2, and freedom from brain metastases. Patients were randomized to either cisplatin, vincristine, doxorubicin, and etoposide (CODE) or alternating cyclophosphamide, doxorubicin, vincristine/etoposide and cisplatin (CAV/EP). Patients on the CODE arm who achieved a complete response (CR) or a partial response (PR) at the primary site and a CR at all known metastatic sites were to receive both consolidative thoracic irradiation (TI) and prophylactic cranial irradiation (PCI). PCI was given to patients with CR to the CAV/EP regimen, whereas TI was optional.

Results

A total of 109 on the CAV/EP arm and 110 on the CODE arm were eligible for analysis. More than 70% of all patients received the intended protocol chemotherapy on both arms.

• Toxicity of the CODE was more severe than that of the CAV/EP, nine of 110 patients on the CODE arm died during chemotherapy, whereas 1/109 patients died on the CAV/EP arm.
• Despite higher response rates observed on CODE arm than CAV/EP arm (87% vs. 70%, p=.006), progression-free survival and overall survival showed no difference between the two arms.

Discussion

Due to the high treatment-related fatality rate in the CODE arm, the study was terminated before the intended sample size was reduced. Dose-intense chemotherapy again showed no benefit in survival for patients with ESCLC despite higher response rates compared with standard chemotherapy. Future success in improving outcome of ESCLC may rely on better understanding of the underlying biology of this malignancy and the development of new therapeutic agents.