High incidence of pulmonary toxicity of weekly docetaxel and gemcitabine in patients with non-small cell lung cancer: results of a dose-finding study

Abstract

Purpose: To determine the maximum tolerated doses (MTD) and the dose-limiting toxicities (DLTs) of the weekly administration of docetaxel and gemcitabine as first-line treatment in patients with advanced non-small cell lung cancer (NSCLC). Patients and methods: Chemotherapy-naı̈ve patients with histologically or cytologically confirmed unresectable stage III_B or IV NSCLC were enrolled onto the study. Escalated doses of gemcitabine (starting dose 700 mg/m² per week) and docetaxel (starting dose 30 mg/m² per week) were given on a weekly basis for three consecutive weeks in cycles of 4 weeks. Results: Twenty-six patients received a total of 94 chemotherapy cycles. At the doses of docetaxel 40 mg/m² per week and gemcitabine 1000 mg/m² per week, the MTD had not yet been reached. However, the study was prematurely closed because of a high incidence of severe pulmonary adverse events. Six (23%) patients developed fever and pulmonary dysfunction (severe dyspnea, hypoxia in association with diffuse interstitial pneumonitis), which was fatal in two of them. No risk factors were identified contributing to these pulmonary adverse events; four patients had a low absolute number of peripheral blood CD4+ lymphocytes. Grade 3/4 neutropenia occurred in five (19%) patients and grade 3/4 anemia in two (8%). Conclusion: The weekly administration of gemcitabine and docetaxel in patients with advanced NSCLC is associated with a high incidence of severe pulmonary toxicity, which does not seem to be dose-related. The regimen cannot be used outside a clinical protocol.

Introduction

The development of an effective non-cisplatin (CDDP)-containing regimen is of paramount importance in the treatment of patients with non-small cell lung cancer (NSCLC), given the increased toxicity of CDDP and the small, although significant, survival benefit with CDDP-based regimens [1]. During the last decade several new anticancer agents have been developed. Most of them (paclitaxel, docetaxel, vinorelbine, gemcitabine, irinotecan) have shown considerable activity against NSCLC [2]. The combination of two such agents, in two phase III studies, has been shown to be equally effective but more tolerable in comparison with a CDDP-based regimen [3], [4].

Docetaxel and gemcitabine represent good candidates for combination chemotherapy in NSCLC since they have different mechanisms of action and non-overlapping toxicities [2], [5]. In a phase II study, the combination of gemcitabine (given on days 1 and 8) plus docetaxel (given on day 8) (DG regimen) was well tolerated and resulted in a 37.5% objective response rate and a median survival of 13 months [6]; the toxicity of DG regimen was acceptable with grades 3–4 neutropenia occurring in 8% of the patients, grade 3/4 diarrhea in 6% and grade 2/3 asthenia in 20%. Subsequently, in a large multicenter randomized trial we compared the efficacy and toxicity of the DG regimen with that of docetaxel/cisplatin (DC regimen) [3]. That study revealed that there was no difference between the two regimens in terms of response rate, duration of response, time to tumor progression and overall survival. However, the DG regimen was associated with a more favorable toxicity profile than the DC combination since the incidence of grade 3/4 neutropenia, grade 3/4 nausea/vomiting and grade 3/4 diarrhea was significantly lower. In addition, the DG regimen could be administered on an outpatient basis whereas the DC regimen required a prolonged inpatient stay or overnight admission to the hospital for hydration. Similar results have also been reported by other investigators [4].

Recently, several clinical studies have shown a lower incidence of treatment-related side effects, particularly of hematologic toxicity, with the weekly administration of taxanes as compared with the conventional administration every 3 weeks [7], [8], [9]. The decreased hematologic toxicity of taxanes given on a weekly basis favors their combination with other agents. Another anticipated benefit is that the prolonged or increased exposure of neoplastic cells to the taxanes, which are phase-specific agents, may result in increased cytotoxic activity.

Based on these considerations, we conducted a phase I trial to determine the maximum tolerated doses (MTDs) and the dose-limiting toxicities (DLTs) of the weekly administration of docetaxel and gemcitabine as first-line treatment in patients with advanced NSCLC.