RESUMEN
BACKGROUND: Occasional complete responses have been reported in patients with squamous-cell carcinoma of the esophagus treated with carboplatin, and the inferior outcomes seen in early studies might have been the result of underdosing using BSA calculations. Docetaxel was reported to have single-agent activity in squamous-cell carcinoma of the esophagus, with a 50% response rate in a pilot study performed in South Africa. Thus, ECOG investigated the potential role of combination carboplatin using AUC-based dosing and docetaxel in patients with squamous-cell carcinoma of the esophagus. PATIENTS AND METHODS: ECOG 2298 was a multicenter, international, phase II clinical study of docetaxel and carboplatin in patients with histologically confirmed, measurable squamous-cell carcinoma of the esophagus. Docetaxel 75 mg/m(2) was infused over 1 hour on day 1 of each cycle. The carboplatin dose was calculated to an AUC of 6 and infused over 15-30 minutes immediately after the docetaxel. The regimen was repeated every 3 weeks for a total of 6 cycles or until disease progression occurred or unacceptable toxicity developed. RESULTS: A total of 32 patients were accrued, mostly men (78%) with a median age of 64 (range, 41-86). Half the patients were black and half were white. Five patients were not evaluable due to protocol violations. Of the remaining 27 patients, one (3%) achieved a complete clinical response. Four others (13%) achieved partial responses. Thirteen (41%) had stable disease and 9 (28%) had progression of disease. Overall objective response rate was 15.6% (95% CI 5.9% to 36%). The most common grade 3 and 4 toxicities were leukopenia (25/32=78%) and neutropenia (27/32=84%). Most nonhematologic toxicities were infrequent and ≤ grade 3; however, two patients experienced grade 5 toxicities; one died of bowel obstruction and another died of infection with grade 4 neutropenia. CONCLUSIONS: The high toxicity and poor efficacy shown in this study suggest that the combination of carboplatin and docetaxel in squamous-cell carcinoma of the esophagus should not be investigated further. Newer agents need to be investigated in this malignancy.
RESUMEN
INTRODUCTION: Topoisomerase inhibitors are active agents in small cell lung cancer (SCLC), and preclinical models indicate that sequential administration of a topoisomerase I inhibitor followed by a topoisomerase II inhibitor can result in enhanced cytotoxicity. PATIENTS AND METHODS: In this phase II study, patients with extensive SCLC were treated with two sequential topoisomerase-based regimens: irinotecan (150 mg/m(2))/oxaliplatin (85 mg/m(2)) [regimen A] on day 1 followed by etoposide (100 mg/m(2)×3)/carboplatin (AUC 6) [regimen B] on day 15. Regimen A was repeated 3 weeks later. The primary objective was objective response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and exploratory correlative analysis of the tumor expression of the excision repair cross complementing (ERCC1) and topoisomerase II-α. Patients received a maximum of 5 cycles of sequential therapy of regimen AâB. RESULTS: The overall response rate was 96%, the 6-month PFS was 76.9%, the median PFS was 8.95 months, and OS was 12.9 months in 26 evaluable patients. Grade 4 neutropenia (23%) and thrombocytopenia (58%) were observed with regimen B; and grade 2/3 nausea-vomiting (54%) and diarrhea (46%) with regimen A. Seven patients required dose reductions in regimen A and 19 patients in regimen B. The dose intensity, delivered during the first three cycles was 89%. No significant correlations were observed between the tumor expression of the ERCC1 and topoisomerase II-α and clinical outcomes (PFS or OS). CONCLUSIONS: Although cross-study comparisons are difficult to make, our data suggests that sequential topoisomerase-targeting regimens may enhance the efficacy of chemotherapy in newly diagnosed SCLC patients (Clinical Trial Registration Number, 9 NCT00240097; Clinical Trials.gov number, NCT00240097).
