title: 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.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Radiation Oncology, University of North Carolina Hospital , Chapel Hill , North Carolina .
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Zagar
authors.forename: Zeljko
authors.initials: Z
authors.lastname: Vujaskovic
authors.forename: Silvia
authors.initials: S
authors.lastname: Formenti
authors.forename: Hope
authors.initials: H
authors.lastname: Rugo
authors.forename: Franco
authors.initials: F
authors.lastname: Muggia
authors.forename: Brigid
authors.initials: B
authors.lastname: O'Connor
authors.forename: Robert
authors.initials: R
authors.lastname: Myerson
authors.forename: Paul
authors.initials: P
authors.lastname: Stauffer
authors.forename: I-Chow
authors.initials: IC
authors.lastname: Hsu
authors.forename: Chris
authors.initials: C
authors.lastname: Diederich
authors.forename: William
authors.initials: W
authors.lastname: Straube
authors.forename: Mary-Keara
authors.initials: MK
authors.lastname: Boss
authors.forename: Alina
authors.initials: A
authors.lastname: Boico
authors.forename: Oana
authors.initials: O
authors.lastname: Craciunescu
authors.forename: Paolo
authors.initials: P
authors.lastname: Maccarini
authors.forename: David
authors.initials: D
authors.lastname: Needham
authors.forename: Nicholas
authors.initials: N
authors.lastname: Borys
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Blackwell
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000628:therapy*; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000097:blood / Q000628:therapy*; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000628:therapy*; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D013696:Temperature; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Hyperthermia; low temperature liposomal doxorubicin; recurrent breast cancer