title: Efficacy and safety of continuous low-irradiance photodynamic therapy in the treatment of chest wall progression of breast cancer.
abstract: BACKGROUND
  Photodynamic therapy (PDT) is a binary therapy using a drug and high-energy light source. PDT is approved for several premalignant and malignant conditions. Recent in-vitro and animal data suggest that enhanced tumor-specific cytotoxicity can be achieved with far less collateral damage to normal surrounding tissues if PDT is administered continuously at a lower dose rate for extended periods of time. Based on these promising preclinical data, we conducted a Phase I clinical trial of continuous low-irradiance photodynamic therapy (CLIPT) using 630 nm laser energy and intravenously administered porforin sodium as the photosensitizer. We determined the maximum tolerated dose (MTD) of CLIPT on skin and tumor response in subjects with cutaneous and subcutaneous metastatic nodules who had failed radiation and surgery.
  
  
  METHODS
  Patients with cutaneous and/or subcutaneous metastatic nodules that had failed radiation and surgery were offered enrollment into the trial. The initial study design planned for sequential cohorts of six subjects to be treated at increasing laser intensity, starting at 100 J/cm(2) administered continuously over 24 h (10(-2) dose rate compared with standard PDT). Dose-limiting toxicity was defined as partial or full-thickness necrosis of the surrounding tumor-free, previously irradiated skin. The MTD was defined as the highest laser energy at which ≤33% of subjects experienced the dose-limiting toxicity. Subjects received intravenous porfirmer sodium 0.8 mg/kg 48 h before commencing CLIPT. Response rates and quality of life measures were assessed.
  
  
  RESULTS
  Nine subjects were enrolled with chest wall progression of breast cancer following mastectomy. All had failed prior surgery and electron-beam radiation therapy. The initial two subjects were treated at 100 J/cm(2) and developed partial thickness skin necrosis. Dose reduction was therefore instituted, and the next cohort was treated at 50 J/cm(2). None of the subsequent seven subjects suffered partial or full thickness necrosis, thus establishing the MTD at 50 J/cm(2) over 24 h (0.5 mW irradiance). Six of the nine subjects (67%) had either a complete or partial clinical response. Of note, two subjects had significant regression of tumor nodules distant from the treatment field. Of the eight subjects whose terminal deoxynucleotidyl transferase dUTP nick end labeling assay results were available, 8 (100%) demonstrated histologic response to treatment as evidenced by either tumor apoptosis or regression. Quality of life measures were improved following treatment-particularly bleeding and pain from the tumor nodules.
  
  
  CONCLUSIONS
  The MTD of CLIPT was established at 50 J/cm(2) administered continuously over 24 h. These preliminary data suggest CLIPT may be an effective, low-morbidity therapeutic modality in the treatment of cutaneous and subcutaneous metastases of breast cancer following mastectomy. Further evaluation in a larger cohort is warranted to better assess efficacy and optimize the intervention.
authors.affiliation: Department of Surgery, Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts. Electronic address: samorrison@partners.org.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Morrison
authors.affiliation: Rogers Sciences, Inc, Southbridge, Massachusetts.
authors.forename: Sam L
authors.initials: SL
authors.lastname: Hill
authors.affiliation: Department of Surgery, Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts; Department of Dermatology, Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Rogers
authors.affiliation: Department of Surgery, Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Graham
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000556:secondary / Q000601:surgery; D017323:Dihematoporphyrin Ether / Q000627:therapeutic use*; D018450:Disease Progression; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D007834:Lasers; D008408:Mastectomy; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D010778:Photochemotherapy / Q000009:adverse effects / Q000379:methods*; D017319:Photosensitizing Agents / Q000627:therapeutic use; D011832:Radiation Injuries / Q000517:prevention & control*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000556:secondary / Q000601:surgery; D050151:Subcutaneous Fat / Q000473:pathology / Q000528:radiation effects; D035441:Thoracic Wall / Q000473:pathology* / Q000528:radiation effects
chemical_list: D017319:Photosensitizing Agents; D017323:Dihematoporphyrin Ether
keywords: Chest wall recurrence of breast cancer; Continuous low irradiance photodynamic therapy; Photodynamic therapy; Photofrin