Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer

Timothy M. Zagar, Zeljko Vujaskovic, Silvia Formenti, Hope Rugo, Franco Muggia, Brigid O'Connor, Robert Myerson, Paul Stauffer, I. Chow Hsu, Chris Diederich, William Straube, Mary Keara Boss, Alina Boico, Oana Craciunescu, Paolo Maccarini, David Needham, Nicholas Borys, Kimberly L. Blackwell, Mark W. Dewhirst

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Abstract

Purpose: Unresectable chest wall recurrences of breast cancer (CWR) in heavily pretreated patients are especially difficult to treat. We hypothesised that thermally enhanced drug delivery using low temperature liposomal doxorubicin (LTLD), given with mild local hyperthermia (MLHT), will be safe and effective in this population. Patients and methods: This paper combines the results of two similarly designed phase I trials. Eligible CWR patients had progressed on the chest wall after prior hormone therapy, chemotherapy, and radiotherapy. Patients were to get six cycles of LTLD every 21-35 days, followed immediately by chest wall MLHT for 1 hour at 40-42°C. In the first trial 18 subjects received LTLD at 20, 30, or 40mg/m2; in the second trial, 11 subjects received LTLD at 40 or 50mg/m2. Results: The median age of all 29 patients enrolled was 57 years. Thirteen patients (45%) had distant metastases on enrolment. Patients had received a median dose of 256mg/m 2 of prior anthracyclines and a median dose of 61Gy of prior radiation. The median number of study treatments that subjects completed was four. The maximum tolerated dose was 50mg/m2, with seven subjects (24%) developing reversible grade 3-4 neutropenia and four (14%) reversible grade 3-4 leucopenia. The rate of overall local response was 48% (14/29, 95% CI: 30-66%), with. five patients (17%) achieving complete local responses and nine patients (31%) having partial local responses. Conclusion: LTLD at 50mg/m 2 and MLHT is safe. This combined therapy produces objective responses in heavily pretreated CWR patients. Future work should test thermally enhanced LTLD delivery in a less advanced patient population.

Original languageEnglish
Pages (from-to)285-294
Number of pages10
JournalInternational Journal of Hyperthermia
Volume30
Issue number5
DOIs
StatePublished - Aug 2014

Keywords

  • Hyperthermia
  • Low temperature liposomal doxorubicin
  • Recurrent breast cancer

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    Zagar, T. M., Vujaskovic, Z., Formenti, S., Rugo, H., Muggia, F., O'Connor, B., Myerson, R., Stauffer, P., Hsu, I. C., Diederich, C., Straube, W., Boss, M. K., Boico, A., Craciunescu, O., Maccarini, P., Needham, D., Borys, N., Blackwell, K. L., & Dewhirst, M. W. (2014). Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer. International Journal of Hyperthermia, 30(5), 285-294. https://doi.org/10.3109/02656736.2014.936049