Elsevier

European Journal of Cancer

Volume 35, Issue 10, October 1999, Pages 1431-1439
European Journal of Cancer

Original Paper
Efficacy and safety of docetaxel (Taxotere™) in heavily pretreated advanced breast cancer patients: the French compassionate use programme experience

https://doi.org/10.1016/S0959-8049(99)00174-4Get rights and content

Abstract

The aim of this investigation was to assess retrospectively docetaxel safety and efficacy in advanced breast cancer patients in a French compassionate use programme. Patients had received >1 prior chemotherapy regimen for advanced disease, were either anthracycline-resistant (that is progressed within 6 months after anthracycline-based chemotherapy) or had received the maximum cumulative dose. The recommended docetaxel dose was 100 mg/m2/cycle (75 mg/m2 in case of liver function impairment: transaminases >1.5×upper limit of normal (ULN), alkaline phosphatases >3×ULN). Between August 1993 and December 1995, 889 patients were treated in 67 French centres, of whom 870 were evaluable for safety and 825 were evaluable for patient and treatment characteristics and efficacy. 20.5% (of the 825 patients evaluable for baseline characteristics) had poor performance status (PS≥2), 49.3% liver metastasis and 9.6% biological liver dysfunction. 98.4% had been previously treated by anthracyclines, 50.8% had resistant disease and 37.1% had received >2 prior palliative chemotherapy lines. The most frequent severe toxicity, febrile neutropenia (reported in 223/870 (25.6%) patients evaluable for safety), caused 10 deaths, 6 of these being patients with severe liver impairment before inclusion. Fluid retention syndrome and other common non-haematological toxicities were well tolerated. 3.1% (28/889) of all patients and 11.4% of those with liver dysfunction, died from treatment-related causes. The overall response rate in 825 assessable patients was 22.9% (95% confidence interval (CI): 20.2–26.2%). Median time to treatment failure was 4 months (95% CI: 3.6–4.3) and median survival was 9.8 months (95% CI: 8.8–10.7). This report on the largest series of unselected advanced breast cancer patients treated with docetaxel, supports previous phase II studies, confirming docetaxel's utility in patients relapsing after failing anthracycline-containing palliative chemotherapy.

Introduction

Anthracyclines, introduced over 20 years ago, have contributed to the improvement of survival and quality of life of metastatic breast cancer patients [1]. The cyclophosphamide/5-fluorouracil/anthracycline combination was until recently the standard first-line treatment of metastatic disease. However, the median time to progression is generally less than 18 months [1], and median survival has only slightly improved in the last 10 years [2]. In patients relapsing after first-line metastatic treatment with anthracyclines, other standard agents have proven to be poorly active. In recent studies, the overall response rate (ORR) to the second line mitomycin C/vinblastine combination [3] and to vinorelbine 4, 5 was less than 20%.

Docetaxel (Taxotere™; Rhône-Poulenc Rorer, Antony, France), is a recently available anticancer agent of the taxane class. It has shown a high level of activity against advanced breast cancer in several phase II studies. Similar response rates have been observed in first- and second-line metastatic treatment (52–67% and 44–58%, respectively) 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, even in anthracycline-resistant patients 12, 13, 15, or in patients with liver metastases 6, 7, 8, 9, 10, 11, 12, 13, 14, 15. In phase I and II studies, the principal dose-limiting toxicity of docetaxel at 100 mg/m2 per cycle was severe neutropenia, occurring in nearly all cycles. However, it was generally short-lived and rarely complicated by fever or infection. A fluid retention syndrome characterised by peripheral oedema, weight gain and, sometimes, non-malignant serous effusions was related to the cumulative dose of docetaxel administered. During early clinical studies, this syndrome led to the withdrawal from treatment of a number of patients. A 3-to-5-day steroid regimen, starting the day before docetaxel administration, reduces its incidence and severity [16]. The other main non-haematological toxicities are reversible alopecia, sensitive neuropathy, nail disorders and asthenia.

Hepatobiliary extraction is the major route of elimination of docetaxel [17]. In a pharmacokinetics/pharmacodynamics analysis, a 27% decrease in docetaxel clearance was observed in patients with concomitant elevations of transaminases >1.5×the upper limit of normal (ULN) and of alkaline phosphatase >2.5×ULN [18]. Patients presenting these liver dysfunctions and treated at the dose of 100 mg/m2 per cycle are at a higher risk of developing febrile neutropenia, thrombocytopenia and severe stomatitis [19]. Therefore, an initial 25% dose reduction is currently recommended in such patients.

Positive results in the initial clinical studies led Rhône-Poulenc Rorer (RPR) to submit a marketing authorisation dossier for docetaxel to the European Medical Agency on 19 July 1994. From this date, RPR and the French Medical Agency made docetaxel available to practising oncologists through a compassionate use programme, ‘Autorisation Temporaire d'Utilisation’ (ATU), which lasted until the drug was approved by the European Medical Agency on 27 November 1995. The aim of this programme was to provide docetaxel to patients with chemotherapy-resistant advanced breast cancer who could not be entered in ongoing clinical trials with the drug, and for whom no standard salvage treatment was available. In this paper, the serious and unexpected adverse events reported in this patient cohort are reported. In addition, the safety and antitumoral efficacy of docetaxel are further characterised, in these patients who most closely reflect the population actually treated in daily practice.

Section snippets

Patients and methods

Between 8 August 1993 and 19 July 1994, docetaxel was exceptionally supplied by RPR for humanitarian treatment. From 19 July 1994 to 27 November 1995, docetaxel was provided through the ATU programme. Docetaxel continued to be supplied until its effective marketing in France on 31 December 1995. This study reports on all the advanced breast cancer patients treated in France with docetaxel outside clinical trials between 8 August 1993 and 31 December 1995.

RESULTS

From 8 August 1993 to 31 December 1995, 945 patients were registered in the ATU programme. 56 of them did not receive docetaxel treatment so only 889 patients who received at least one cycle of docetaxel were included in this report. 864 of them were registered during the ATU period (between 19 July 1994 and 27 November 1995), whilst 25 patients were treated outside those dates. 19 patients were excluded from the adverse event and efficacy analysis because insufficient data could be collected

Discussion

Given their nature, compassionate use programmes cannot substitute for prospective clinical research. Clinical trials are essential for assessing the efficacy and tolerability of a new drug before and during market availability. Restrictive eligibility criteria in formal clinical trials exclude a significant proportion of advanced breast cancer patients with poor prognosis. Study populations with age restrictions, performance status limitations, normal major organ function, prior treatment

Acknowledgements

The authors wish to thank the following physicians for their participation in the Docetaxel ATU: Ph. Bastit, Centre H. Becquerel, Rue d'Amiens, 76038 Rouen; D. Belpomme, Hôpital Boucicaux, 78 rue de la convention, 75015 Paris; J-P. Bergerat, Hospices Civils, Place de l'hôpital, 67091 Strasbourg; H. Bourgeois, Institut Curie, 26 rue d'Ulm, 75231 Paris; P. Chollet, Centre Jean Perrin, Place Henri Dunand, 63011 Clermont Ferrand Cedex; N. Colbert, Hôpital des Peupliers, 22 rue des Peupliers, 75013

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