title: Whole blood stem cell reinfusion and escalated dose melphalan in castration-resistant prostate cancer: a phase 1 study.
abstract: OBJECTIVE
  Nontaxane-based chemotherapeutic options in castrate-resistant prostate cancer (CRPC) are limited despite the long natural history of the disease. We carried out a phase 1 dose-escalation study of the alkylating agent melphalan with autologous stem cell transplantation, comparing rapid changes in circulating tumor cells (CTC) and prostate-specific antigen (PSA) as a measure of response.
  
  
  METHODS
  Cohorts of individuals with advanced CRPC received high-dose intravenous melphalan, and autologous blood was returned to patients during treatment. The efficacy endpoints were the PSA reduction rate, CTC response, survival parameters, toxicity and whether reinduction of endocrine sensitivity occurred.
  
  
  RESULTS
  Twenty-four patients were recruited. Dose escalation was feasible with the highest dose cohort being reached. Of 23 individuals evaluable for response, 16 had a PSA response of more than 30%; of 11 patients with soft tissue disease, 4 achieved a partial response and 7 had stable disease. Patients with CTC counts that decreased to less than 5 within 2 weeks from the start of therapy had a longer overall survival (30.6 months vs. 15.3 months, P = 0.03) Treatment was associated with myelosuppression and frequent hospitalizations. In 20 patients after the study, hormone therapy was reintroduced when PSA increased again; response rates were high.
  
  
  CONCLUSIONS
  Autologous transplantation following high-dose alkylating agent chemotherapy induces responses but proved toxic, although dose escalation proved possible. The possibility of using CTCs to identify responders at two weeks may be used to justify such an intensive approach. Many individuals went on to further respond to both docetaxel and hormonal therapy.
authors.affiliation: Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Shamash
authors.forename: Jimmy
authors.initials: J
authors.lastname: Jacob
authors.forename: Samir
authors.initials: S
authors.lastname: Agrawal
authors.forename: Thomas
authors.initials: T
authors.lastname: Powles
authors.forename: Katherine
authors.initials: K
authors.lastname: Mutsvangwa
authors.forename: Peter
authors.initials: P
authors.lastname: Wilson
authors.forename: Justin
authors.initials: J
authors.lastname: Stebbing
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D015331:Cohort Studies; D003131:Combined Modality Therapy; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D009360:Neoplastic Cells, Circulating / Q000187:drug effects; D009919:Orchiectomy; D036102:Peripheral Blood Stem Cell Transplantation; D011467:Prostate / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D017430:Prostate-Specific Antigen; D008558:Melphalan