title: A phase II pilot trial of concurrent biochemotherapy with cisplatin, vinblastine, temozolomide, interleukin 2, and IFN-alpha 2B in patients with metastatic melanoma.
abstract: OBJECTIVE
  In an effort to reduce the frequency of central nervous system (CNS) progression in patients with metastatic melanoma with ongoing systemic response to biochemotherapy, we modified our standard concurrent biochemotherapy regimen by replacing dacarbazine (DTIC) with oral temozolomide.
  
  
  METHODS
  Patients received cisplatin, vinblastine, and temozolomide (20 mg/m(2) cisplatin and 1.2 mg/m(2) vinblastine i.v., days 1-4; 150 mg/m(2) p.o. temozolomide, days 1-4) concurrent with interleukin 2 (9 MIU/m(2)/day) by continuous i.v. infusion on days 1-4 and IFN-alpha (5 MU/m(2)/day) on days 1-5, 8, 10, and 12. Prophylactic antibiotics and a maximum of four cycles were administered. Routine granulocyte-colony stimulating factor and aggressive antiemetics were also provided. Tumor staging included torso computed tomography scans and brain magnetic resonance imaging pretreatment, after cycle 4 and then every 3 months for 2 years. Torso computed tomography scans were also performed after cycle 2.
  
  
  RESULTS
  A total of 147 treatment cycles were administered to 48 patients. No patients had received prior chemotherapy or interleukin 2; however, 19 (40%) had received prior adjuvant IFN-alpha. Significant toxicities included 2 deaths from cardiac events (pericarditis al tamponade and posttreatment myocardial infarction with associated ventricular arrhythmia) and 3 gastrointestinal serious adverse events (pancreatitis, appendicitis, and upper GI bleed). No other nonhematological grade 4 toxicities were observed. Tumor responses were seen in 22 of 47 evaluable patients (relative risk, 47%) with 7 complete responses (15%). Response durations ranged from 1 to 29+ months with 1 currently ongoing. Median survival was 7.5 months. The CNS was the initial site of progression in 2 responding patients. An additional 6 responding patients developed CNS progression within 3 months of systemic progression. Initial CNS progression was significantly less frequent what was seen with the prior DTIC-based biochemotherapy regimen (2 of 22 versus 12 of 19; P = 0.001).
  
  
  CONCLUSIONS
  This regimen appears to be active and reasonably well tolerated in patients with metastatic melanoma. Although the substitution of temozolomide for DTIC reduced the incidence of initial CNS progression, this effect did not appear to result in an improved overall outcome.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. matkins@caregroup.harvard.edu
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
authors.forename: Jared A
authors.initials: JA
authors.lastname: Gollob
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.forename: Linda
authors.initials: L
authors.lastname: Tutin
authors.forename: Patricia
authors.initials: P
authors.lastname: Sorokin
authors.forename: Robert A
authors.initials: RA
authors.lastname: Parker
authors.forename: James W
authors.initials: JW
authors.lastname: Mier
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D018572:Disease-Free Survival; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary; D008875:Middle Aged; D010865:Pilot Projects; D011994:Recombinant Proteins; D000077204:Temozolomide; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007376:Interleukin-2; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D014747:Vinblastine; D003606:Dacarbazine; D002945:Cisplatin; D000077204:Temozolomide