Liposomal doxorubicin in conjunction with reirradiation and local hyperthermia treatment in recurrent breast cancer: a phase I/II trial.

PURPOSE: This is the first study to evaluate the tolerability and activity of liposomal doxorubicin (Caelyx; Schering-Plough Pharmaceuticals) < or =60 mg/km(2) in patients with locally recurrent breast cancer, when administered in conjunction with reirradiation and local hyperthermia treatment. EXPERIMENTAL
DESIGN: Fifteen female patients, who had undergone a radical mastectomy and conventional radiotherapy (60 Gy) in the front chest wall, were entered on a multimodal protocol consisting of initial treatment with radiotherapy and a monthly infusion of liposomal doxorubicin < or =60 mg/m(2) in conjunction with local hyperthermia treatment. 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 produced 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 between the time interval from liposomal doxorubicin infusion to HT and the RSS.
RESULTS: At doses of < or =60 mg/m(2), liposomal doxorubicin was well tolerated, with only mild hematological and nonhematological toxicity. All patients showed an objective measurable response, with 3 patients (20%) demonstrating a clinically complete response. There was a significant correlation between the duration of response and Avg Min T(90) > 44 degrees 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 response 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 investigation.