A phase II study: docetaxel as first-line chemotherapy for advanced pancreatic adenocarcinoma

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Abstract

The aim of this study was to evaluate the efficacy of docetaxel as first-line chemotherapy in patients with unresectable metastatic or locally advanced pancreatic adenocarcinoma and to further characterise the safety and pharmacokinetic profiles of docetaxel. 43 patients were enrolled into this phase II study. Treatment consisted of a 1-h infusion of docetaxel 100 mg/m2 every 3 weeks without premedication with corticosteroids until progression or unacceptable toxicity occurred. Dose modifications were planned for adverse events. Patients were observed for 1 month after the last docetaxel infusion, to document any late adverse events, with a follow-up every 3 months until death. Response rate and duration were the major efficacy endpoints. Response status was reviewed by an external independent panel. Pharmacokinetic analysis was performed during the first treatment cycle. 40 patients were evaluable for response, and all were evaluable for safety. After independent review, partial response was recorded in 6 patients (overall response rate, 15%; 95% confidence limit (CI), 7.7–29.8%) and stable disease was recorded in 15 patients (38%). The median duration of response was 5.1 months (range: 3.1–7.2). The median pain control time was 4.5 months (range: 0–8) and the median time to performance status worsening was 2.3 months (range: 0–4.5). Most patients 40 (93.0%) received a relative dose intensity of more than 70% of the planned dose. The incidence and severity of adverse events reflected the known safety profile for docetaxel. Docetaxel clearance was reduced in patients with elevated concentrations of hepatic enzymes or bilirubin. Docetaxel is an active agent for unresectable metastatic or locally advanced pancreatic adenocarcinoma.

Introduction

Existing chemotherapeutic options for patients with unresectable metastatic or locally advanced adenocarcinoma of the exocrine pancreas are of limited value. In general, monotherapy with traditional agents such as 5-fluorouracil (5-FU) has resulted in variable response rates (usually less than 10%) and short response durations, and there is scant evidence to suggest that conventional combination therapy offers additional benefit 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. Similarly, modulation of 5-FU with agents such as leucovorin and interferon-α seems to offer little therapeutic advantage over 5-FU alone (although a response rate of 38% was reported recently for the combination of 5-FU, leucovorin, interferon-α-2b and cisplatin) and is associated with considerable toxicity 13, 14, 15, 16, 17, 18.

Despite the discouraging results achieved with existing therapies, trials comparing best supportive care and chemotherapy suggest that chemotherapy does have a positive effect on survival and quality of life 19, 20. Recent research has continued to focus therefore on the development of new active drugs suitable for use as first-line single agents in the treatment of metastatic or locally advanced pancreatic cancer.

One new agent of interest is docetaxel (Taxotere®; Rhône-Poulenc Rorer, Antony, France), a taxoid obtained by hemisynthesis from an inactive precursor extracted from the needles of the European yew, Taxus baccata. Taxoids enhance microtubule assembly and inhibit the depolymerisation of tubulin, thereby promoting the formation of stable, intracellular bundles of microtubules, which disrupt cell replication 21, 22, 23, 24. This mode of action contrasts with those of other spindle poisons in clinical use, such as the vinca alkaloids, which inhibit the polymerisation of tubulin into functional microtubules [25].

This study was performed to evaluate the efficacy of docetaxel as first-line chemotherapy for patients with unresectable metastatic or locally advanced adenocarcinoma of the pancreas, as part of a phase II clinical trial programme. The study also aimed to further characterise the safety and pharmacokinetic profiles of docetaxel in this group of patients.

Section snippets

Eligibility

Men and women aged 18–75 years, with histologically or cytologically proven metastatic or locally advanced pancreatic adenocarcinoma, at least one bidimensionally measurable target lesion, a World Health Organization (WHO) performance status of 0–2, adequate haematological and renal functions, a total bilirubin of ⩽1.25×upper normal limit, aspartate aminotransferase ⩽2×upper normal limit and a life expectancy of at least 12 weeks, were eligible for recruitment into the study.

Specific criteria

Patient disposition and characteristics

All 43 patients (26 males, 17 females) enrolled in the study received at least one docetaxel infusion: 1 patient was not eligible due to active uncontrolled infection at study entry. All patients were evaluable for safety. Baseline elevated concentrations of hepatic enzymes and/or bilirubin above the cut-off defined by the protocol were reported in 5 patients. However, as these abnormalities could be related to the disease, all these patients were included and considered eligible. 3 patients

Discussion

This multicentre, phase II study has shown that docetaxel (100 mg/m2/3 weeks) is an active agent for the treatment of patients with pancreatic adenocarcinoma. Docetaxel produced an encouragingly high response rate of 19% in evaluable patients with metastatic disease and a response rate of 15% in the overall population with a median duration of response of 5.1 (range 3.1–7.2) months. Docetaxel also controlled tumour growth for a median duration of 4.4 months in 6 out of the 9 patients with

Acknowledgements

This work was supported by a grant from Rhône-Poulenc Rorer, Antony, France. We thank Dr R. Pazdur from MD Anderson Cancer Center, Houston, USA, Dr Wils and Dr Schlange from St Laurentius Ziekenhuis, The Netherlands for diagnostic reassessment of our series of cases, René Bruno and Jean-Claude Vergniol for their contributions to the pharmacokinetic analysis and Eric Le Bras for his contribution to the statistical analysis. We thank also the nurses of Unité La Grange, Institut Gustave Roussy,

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