Phase II study of pegylated liposomal doxorubicin (Caelyx™) as induction chemotherapy for patients with squamous cell cancer of the head and neck

Abstract

A phase II trial of pegylated liposomal doxorubicin (Caelyx™) as induction chemotherapy was conducted in 20 patients with treatment-naı̈ve squamous cell cancer of the head and neck (SCCHN). 10 patients received two cycles of Caelyx™ (40 mg/m²) every 3 weeks before starting radical radiotherapy (RT). Subsequently, consecutive groups of 3 patients received a third escalating dose of Caelyx™ (10, 15 and 20 mg/m²) 3 days before RT. 9 of 18 (50%, 95% confidence intervals (CI): 26–74%) evaluable patients responded to Caelyx™, with 11 responses in 26 (42%, 95% CI: 24–62%) evaluable sites (three complete responses (12%), eight partial responses (31%)). There was no grade 3/4 haematological, mucosal or cardiac toxicity. Nausea and vomiting were minimal. There were no drug-related RT delays. Local RT-induced toxicity was not increased. Caelyx™ has significant activity against SCCHN and warrants further investigation in this disease. In view of its tumour targeting properties and activity at moderate doses, it may be useful in concomitant chemoradiotherapy strategies for SCCHN.

Introduction

The poor prognosis of patients with locally advanced squamous cell cancer of the head and neck (SCCHN) who are treated with surgery, radiotherapy (RT) or combinations of these treatments has prompted the search for more effective approaches incorporating cytotoxic chemotherapy into multimodality strategies 1, 2. Two recent overview analyses have demonstrated that the addition of chemotherapy to radical RT improves survival. Most benefit accrues from concomitant chemoradiotherapy (CCRT), with a survival advantage of 8–12% 3, 4. Published data support the activity of anthracycline-based chemotherapy in treating patients with head and neck cancer 5, 6, 7, 8, although the majority of patients in those studies had locally recurrent or metastatic disease and had received prior therapy. Response rates of 12–13% have been reported for single agent epirubicin in patients with relapsed disease 7, 8. Doxorubicin has been incorporated in combination regimens, although the presence of other active agents has obscured the contribution of doxorubicin to the therapeutic effect 5, 6.

It has been suggested that pegylated liposomes might enhance the therapeutic efficacy of cytotoxic agents in combination with RT [9]. Cytotoxic agents entrapped in pegylated liposomes have improved pharmacokinetics 10, 11, increased tumour localisation 9, 10, 11, 12, 13, 14, 15, 16, enhanced therapeutic efficacy 9, 17, 18, 19, 20, 21 and attenuated toxicity profiles 15, 17, 21 when compared with the corresponding unencapsulated agent in preclinical studies. We have recently demonstrated that radiolabelled pegylated liposomes localise to locally advanced head and neck tumours in patients [22] and that Caelyx™ is active against head and neck cancer xenograft tumours in nude mice, both as definitive therapy [21] and at lower doses in conjunction with RT [9]. In addition, pegylated liposomal doxorubicin (Caelyx™, ALZA Corporation, USA) has been subjected to a Phase I evaluation in patients with recurrent or metastatic SCCHN and a response rate of 33% was reported [23].

Therefore, as an extension of this work, we have conducted a trial of Caelyx™ in patients with SCCHN. For this initial study, it was decided to use induction, rather than concomitant, chemotherapy for two reasons. First, there were concerns about the risk of liposomal drug deposition in normal tissues exacerbating the toxicity of RT. Second, in our institution there is an interval of approximately 6 weeks between diagnosis and commencement of RT during which treatment planning occurs. This interval offers the opportunity to deliver two cycles of induction chemotherapy without delaying the start of radical RT. Therefore, it was decided that this study design represented a pragmatic means of achieving the following aims: (i) to assess the response of inoperable locally advanced treatment-naı̈ve SCCHN to 2 cycles of Caelyx™ (40 mg/m² every 3 weeks) administered as induction treatment; (ii) to evaluate the ability to deliver a radical course of hyperfractionated RT after induction treatment with Caelyx™.