Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL®/CAELYX®) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group

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Abstract

CAELYX®/DOXIL®, pegylated liposomal doxorubicin, has shown antitumour activity and reduced toxicity compared with standard doxorubicin in other tumour types. In this prospective randomised trial, 94 eligible patients with advanced soft-tissue sarcoma (STS) were treated, 50 with CAELYX® (50 mg/m2 by a 1 h intravenous (i.v.) infusion every 4 weeks) and 44 with doxorubicin (75 mg/m2 by an i.v. bolus every 3 weeks). Histological subtypes were evenly matched, 33% were leiomyosarcoma (CAELYX®: 18; doxorubicin: 13). Primary disease sites were well matched. CAELYX® was significantly less myelosuppressive, only 3 (6%) patients had grade 3 and 4 neutropenia, versus 33 (77%) on doxorubicin; febrile neutropenia occurred in 7 (16%) patients given doxorubicin, but only 1 (2%) given CAELYX®. 37 (86%) patients on doxorubicin had grade 2–3 alopecia, but only 3 (6%) on CAELYX®, and the major toxicity with CAELYX® was to the skin. Palmar-plantar erythrodysesthesia with CAELYX® was grade 1: 4 (8%) patients, grade 2: 11 (22%) patients, grade 3: 9 (18%) patients and grade 4: 1 (2%) patient. Other non-haematological grade 3 and 4 toxicities were rare. Confirmed responses were observed with both agents: CAELYX®: complete response (CR) 1 (uterine), partial response (PR) 4 (response rate (RR) 10%); and doxorubicin: CR 1, PR 3 (RR of 9%); with the best response being stable disease (NC) in 16 and 18 patients, respectively. The reason for the low response rate is unknown, but it may be due partly to a high proportion of gastrointestinal stromal tumours. In conclusion, CAELYX® has equivalent activity to doxorubicin in STS with an improved toxicity profile and should be considered for further investigation in combination with other agents such as ifosfamide.

Introduction

Chemotherapy of adult soft-tissue sarcoma (STS) is presently unsatisfactory with only two agents reliably demonstrating significant activity, i.e. doxorubicin [1] and ifosfamide [2]. There appears to be a dose–response relationship for both agents, but randomised trials have so far failed to show a benefit for dose intensification using haemopoietic growth factors support [3]. Similarly, a three-way randomised trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) did not show a significant benefit in terms of progression-free or overall survival for combination chemotherapy with respect to single agent doxorubicin [4]. For this reason, single agent doxorubicin has been taken as the most logical comparator for studies involving new agents in the treatment of these tumours 1, 5.

Doxorubicin treatment is limited by bone marrow suppression and cumulative cardiotoxicity. A new form of doxorubicin has been developed in which the drug is encapsulated in liposomes which have been modified by the addition of polyethylene glycol (PEG) [6]. These sterically hindered STEALTH® liposomes, when carrying doxorubicin, are known as CAELYX® or DOXIL®. They have the advantage over unmodified liposomes that they are less readily eliminated by the reticuloendothelial system resulting in a long circulation half-life of approximately 50 h in man. Extravasation of liposomes through the relatively leaky tumour vasculature into the tumour interstitial spaces results in a level of targeting of the drug to the tumour relative to normal tissue which has been observed in animal models [7] leading to activity in refractory human tumours 8, 9. Although accumulation of the drug in the tumour is of potential value, there is also accumulation in the skin necessitating a greater dose interval than is usual for doxorubicin, e.g. 4 weeks [10].

Phase I trials of CAELYX® have shown reduced alopecia and myelosuppression compared with conventional doxorubicin and also a reduction in cardiotoxicity 9, 10. Skin toxicity and to a lesser extent bone marrow suppression was dose limiting. The skin toxicity consists of reddening and pain in the palms of the hands, soles of the feet, skin creases and pressure points and has been termed palmar-plantar erythrodysesthesia (PPE). Phase II studies have been carried out using a range of doses and dosing intervals. Treatment every 3 weeks resulted in unacceptable levels of skin toxicity but, with a 4 week interval, doses in the range 40–60 mg/m2 can be given [10]. Antitumour activity has been reported in refractory ovarian cancer and Kaposi's sarcoma 8, 9.

In this study, patients with advanced or metastatic adult STS were randomised to receive either CAELYX® 50 mg/m2 every 4 weeks by intravenous (i.v.) infusion or doxorubicin 75 mg/m2 by i.v. bolus injection every 3 weeks. The end-points of the study were response rate, response duration and toxicity.

Section snippets

Eligibility

Patients had to meet the following inclusion criteria: (1) histologically confirmed diagnosis of one of the following sarcoma types — malignant fibrous histiocytoma, liposarcoma, rhabdomyosarcoma, synovial sarcoma, malignant paraganglioma, fibrosarcoma, leiomyosarcoma, including haemangiopericytoma, neurogenic sarcoma, unclassified sarcoma, miscellaneous sarcoma including mixed mesodermal tumours of the uterus; (2) no prior chemotherapy; (3) at least one bidimensionally measurable lesion of

Patients

The demographic details are shown in Table 1. Patients are well matched for age, performance status and prior therapy. In total, 95 patients were entered into the study (Fig. 1). Two patients randomised to doxorubicin did not receive treatment as part of the study. One was ineligible due to lack of regulatory approval in that country at the time, owing to an administrative oversight, and one refused treatment after randomisation. The analysis has been conducted according to intention to treat.

Discussion

As expected, CAELYX® demonstrated antitumour activity in this population of patients with advanced adult STS, with reduced toxicity compared with standard i.v. bolus doxorubicin with the exception of skin toxicity, which was more severe. This is in keeping with reports from phase II trials in other tumour types 9, 12. The level of antitumour activity was similar in the two arms. Previously reported single arm phase II studies in sarcoma have produced variable results, but indicated some

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