Liposomal Doxorubicin in Conjunction with Reirradiation and Local Hyperthermia Treatment in Recurrent Breast Cancer: A Phase I/II Trial Vassilios E. Kouloulias, 1 Costas E. Dardoufas, John R. Kouvaris, Costas S. Gennatas, Aris K. Polyzos, Helen J. Gogas, Panagiotis H. Sandilos, Nikolaos K. Uzunoglu, Elias G. Malas, and Lambros J. Vlahos Radiotherapy Department [V. E. K., C. E. D., J. R. K., P. H. S., L. J. V.] and Department of Surgical Oncology [C. S. G., E. G. M.], Areteion University Hospital, Athens; 1 st Departments of Propedeutic Medicine [A. K. P.] and Medicine [H. J. G.], Laikon Hospital, University of Athens, Athens; and National Technical University of Athens, Department of Electrical and Computer Engineering, Zografou [V. E. K., N. K. U.], Greece ABSTRACT Purpose: This is the first study to evaluate the tolera- bility and activity of liposomal doxorubicin (Caelyx; Scher- ing-Plough Pharmaceuticals) <60 mg/km 2 in patients with locally recurrent breast cancer, when administered in con- junction with reirradiation and local hyperthermia treat- ment. Experimental Design: Fifteen female patients, who had undergone a radical mastectomy and conventional radio- therapy (60 Gy) in the front chest wall, were entered on a multimodal protocol consisting of initial treatment with ra- diotherapy and a monthly infusion of liposomal doxorubicin <60 mg/m 2 in conjunction with local hyperthermia treat- ment. All patients received reirradiation up to a total dose of 30.6 Gy (1.8 Gy/fraction, 5 days a week). To evaluate the drug’s safety, the first 5 patients initially received a dose of 40 mg/m 2 liposomal doxorubicin, which was then escalated to 60 mg/m 2 . The other 10 patients received 60 mg/m 2 for all six cycles of chemotherapy. Hyperthermia (HT) was pro- duced in the region of interest (ROI) using waveguides at a frequency of 433 MHz. The RSS was obtained from the curves representing the change in the ROI’s surface with time for each patient, as fitted by linear regression. Linear regression analysis was used to study the relationship be- tween the time interval from liposomal doxorubicin infusion to HT and the RSS. Results: At doses of <60 mg/m 2 , liposomal doxorubicin was well tolerated, with only mild hematological and non- hematological toxicity. All patients showed an objective measurable response, with 3 patients (20%) demonstrating a clinically complete response. There was a significant corre- lation between the duration of response and Avg Min T 90 > 44°C (r s  0.917, P < 0.0001) and the Mean[Tmin] (r s  0.909, P < 0.0001). The RSS was significantly correlated with the interval between liposomal doxorubicin infusion and HT, as the smaller the time interval, the greater the clinical benefit (r  0.76, P  0.001). Conclusions: The multimodal treatment was effective and well tolerated, producing an objective measurable re- sponse in all patients. Local HT had a significant effect on patients’ response to the drug. The relationship between thermal dose and liposomal action requires further investi- gation. INTRODUCTION Recurrence of breast cancer in the front chest wall after mastectomy and RT 2 poses a major problem, as limited thera- peutic options remain for clinical application. The current and potential role of HT treatment for cancer has already been documented (1). The ESHO has monitored five protocols run- ning in Europe. An odds ratio of 1.37 for survival in favor of combined treatment has been reported for protocol ESHO-1/ Medical Research Council, which examined the role of RT plus HT treatment versus RT alone for the treatment of advanced breast cancer (2). Protocol ESHO-5/Medical Research Council for chest wall recurrence has given an odds ratio of 3.43 for combined treatment (RT + HT; Ref. 2). This role of HT as an adjuvant treatment to RT was also documented by Vernon et al. (3), who reported the results of a large randomized multicenter trial. Among 306 patients, the overall complete response rate for RT alone was 41%, and for combined treatment, it was 59%, giving, after stratification by trial, an odds ratio of 2.3. The greatest effect was observed in patients with recurrent lesions in areas irradiated previously, where further irradiation was limited to low doses. PEGylated liposomal doxorubicin hydrochloride (Caelyx; Schering-Plough Pharmaceuticals), based on the Stealth lipo- some delivery system, is a novel drug formulation with a pro- longed circulation time and preferential extravasation at tumor Received 6/4/01; revised 9/4/01; accepted 10/25/01. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 To whom requests for reprints should be addressed, at EORTC Data Center, Radiotherapy Group, Quality Assurance, Mounier Avenue 83, B1200 Brussels, Belgium. Fax: 0032 27726701; E-mail: vko@eortc.be. 2 The abbreviations used are: RT, radiotherapy; HT, hyperthermia; ESHO, European Society of Hyperthermic Oncology; ROI, region of interest; CCR, clinically complete response; PR, partial response; DFILR, disease-free interval to local relapse; RSS, region of interest’s surface slope; PPE, palmar-plantar erythrodysesthesia. 374 Vol. 8, 374 –382, February 2002 Clinical Cancer Research Research. on September 29, 2021. © 2002 American Association for Cancer clincancerres.aacrjournals.org Downloaded from