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, 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

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 40 mg/m2; in the second trial, 11 subjects received LTLD at 40 or 50 mg/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 256 mg/m2 of prior anthracyclines and a median dose of 61 Gy of prior radiation. The median number of study treatments that subjects completed was four. The maximum tolerated dose was 50 mg/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 50 mg/m2 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.

Trial registration: ClinicalTrials.gov NCT00346229 NCT00826085.

Keywords: Hyperthermia; low temperature liposomal doxorubicin; recurrent breast cancer.

Figures

Figure 1.
Figure 1.
Pharmacokinetic profiles for cycles 1 and 2 at each dose level for doxorubicin and its cardiotoxic metabolite, doxorubicinol. The half-life of the drug was the same for cycle 1 and cycle 2 and was not dependent upon doxorubicin dose.
Figure 2.
Figure 2.
Evaluation of treatment course for a patient who achieved a complete response. (A) Photo of thermometry placement, and (B) position of the 18 × 10 cm applicator over the lesion. This lesion was treated in a single field using this applicator. The 25% isoSAR line encompassed the tumour region. (C) Appearance of the involved region prior to initiation of treatment. The margins of the tumour are easily seen by the red colour against the normal skin. (D) Appearance of the tumour area prior to cycle 3. The patient had achieved a partial response by this time point. (E) Thermographic camera image of chest well shows temperature distribution on the surface of the tumour region, prior to therapy. (F) Thermographic image of the chest wall prior to cycle 4 shows reduced surface temperature compared with baseline. (G) Thermographic images of the chest wall prior to cycle 5. By this time, the temperature of the involved region had reduced by 1 °C. This was most likely the result of reduced perfusion and metabolism, associated with tumour regression. This patient went on to achieve a complete response (not shown).

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Source: PubMed

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