Carboplatin plus paclitaxel and sequential radiation followed by consolidation carboplatin and paclitaxel in patients with previously untreated locally advanced NSCLC

Abstract

Chemoradiation is standard treatment for patients with unresectable locally advanced non-small cell lung cancer (NSCLC). However, local and distant relapse rates remain high. It has been postulated that the addition of consolidation chemotherapy might further decrease the systemic relapse rate. We performed this phase II study to evaluate the toxicities and activity of two cycles of paclitaxel and carboplatin administered prior to and following thoracic radiation in patients with locally advanced, inoperable NSCLC. From April to December 1997, 25 patients were entered on study. Twenty-three patients were eligible and received paclitaxel 225 mg/m² intravenously over 3 h followed by carboplatin at an AUC (6) on days 1 and 22. Radiation consisted of 60 Gy given over 6 weeks beginning on day 43. Patients with non-progressive disease received two additional cycles of consolidation carboplatin and paclitaxel. Four of 23 patients progressed during induction chemotherapy. There were seven PR's and 11 had SD after induction chemotherapy. Following radiation, the response changed to 11 PR, four SD, and three had progressive disease. Of the 15 patients eligible to receive consolidation chemotherapy, three were excluded due to a poor performance status. Twelve patients were treated with consolidation chemotherapy with further improvement in two patients (SD to PR, PR to CR). All 12 patients who received consolidation chemotherapy developed grade 3 or 4 neutropenia, including three patients with neutropenic fever. The overall response rate was 52.1%. The median survival, 1-, and 2-year survival was 10.5 months, 45, and 17%, respectively. In conclusion, consolidation chemotherapy was associated with significant hematologic toxicity without an obvious improvement in survival in comparison to other studies utilizing chemoradiation alone.

Introduction

The American Cancer Society estimates that there were 171,000 new cases of lung cancer in 2000 with 156,900 deaths [1]. Seventy-five percent of these patients had non-small cell lung cancer (NSCLC). Surgical resection remains the treatment of choice for patients with stage I, II and selected patients with stage IIIa disease. Unfortunately, only 30% of patients present with potentially resectable disease. Historically, patients with bulky, locally advanced stage IIIa or IIIb NSCLC have been treated with radiation alone with a long-term survival of 3–5% [2]. Chemoradiation has become accepted as the treatment of choice based on a pivotal study by Dillman et al. [3] and supported by studies from three other groups [4], [5] and two meta-analysis [6], [7].

The long-term survival with sequential chemoradiation, while superior to radiation alone, is still only 10–15% [4], [5]. In addition, many questions remain unanswered including what the most effective chemotherapy regimen is and the optimal sequencing of chemotherapy and radiation (sequential, concurrent or some combination of the same). Two randomized trials demonstrated improved survival but increased toxicity with concurrent versus asynchronous chemoradiation [8], [9]. Another strategy to improve survival has been to decrease systemic relapse, which is the most common cause of death in these patients, using consolidation chemotherapy [10]. A phase II Southwest Oncology Group (SWOG) trial demonstrated that concurrent chemoradiotherapy with cisplatin and etoposide followed by consolidation chemotherapy with docetaxel was well tolerated and resulted in a with a median survival of 27 months and 3-year survival of 40% [10].

Carboplatin and paclitaxel is a common chemotherapy combination for metastatic NSCLC and well-tolerated [11]. Its' role has also been explored in locally advanced NSCLC with concurrent chemoradiation in phase II trials [12], [13]. However, its' activity and toxicity when used as induction and consolidation chemotherapy following radiation in locally advanced NSCLC has not yet been reported. It has been postulated that the addition of consolidation chemotherapy might further decrease the systemic relapse rate. We report the results of a phase II trial evaluating the role of carboplatin plus paclitaxel with sequential radiation followed by two additional cycles of consolidation (posterior) chemotherapy for appropriate responding patients with locally advanced NSCLC.