title: Targeted combined anti-inflammatory and angiostatic therapy in advanced melanoma: a randomized phase II trial.
abstract: An angiostatic approach was used to assess the impact of anti-inflammatory therapy in combination with metronomic low-dose chemotherapy. A randomized multi-institutional phase II trial was designed to select metronomic chemotherapy (arm A: trofosfamide 50 mg orally three times daily, day 1+) or combined anti-inflammatory/angiostatic treatment (arm B: trofosfamide as above mentioned plus rofecoxib 25 mg orally, day 1+, and pioglitazone 60 mg orally, day 1+) for further evaluation. A total of 76 patients, mostly (>60%) refractory to at least one previous chemotherapy with maximum tolerated doses, and progression of metastatic melanoma were included. The estimated progression-free survival (PFS) rates at one year were 0% for metronomic chemotherapy (A), but 9% for additional anti-inflammatory therapy (B). Vice versa the hazard ratio for the intent-to-treat analysis of A versus B was 1.9 (P=0.008). By Cox analysis, the impact of anti-inflammatory therapy on PFS achieved significance (P=0.016) as well as C-reactive protein response on overall survival (P=0.045). WHO grade 3 (no grade 4) toxicities were reported in arm A/B in 19 and 28%, respectively. In conclusion, control of tumour-associated inflammatory processes (C-reactive protein response) is associated with longer PFS than achieved with metronomic chemotherapy alone in metastatic melanoma.
authors.affiliation: Department of Hematology/Oncology, University Hospital Regensburg, Regensburg, Germany. albrecht.reichle@klinik.uni-regensburg.de
authors.forename: Albrecht
authors.initials: A
authors.lastname: Reichle
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogt
authors.forename: Brigitte
authors.initials: B
authors.lastname: Coras
authors.forename: Peter
authors.initials: P
authors.lastname: Terheyden
authors.forename: Klaus
authors.initials: K
authors.lastname: Neuber
authors.forename: Uwe
authors.initials: U
authors.lastname: Trefzer
authors.forename: Erwin
authors.initials: E
authors.lastname: Schultz
authors.forename: Anna
authors.initials: A
authors.lastname: Berand
authors.forename: E B
authors.initials: EB
authors.lastname: Bröcker
authors.forename: Michael
authors.initials: M
authors.lastname: Landthaler
authors.forename: Reinhard
authors.initials: R
authors.lastname: Andreesen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D002097:C-Reactive Protein / Q000032:analysis; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007783:Lactones / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary; D008875:Middle Aged; D000077205:Pioglitazone; D016879:Salvage Therapy; D013450:Sulfones / Q000008:administration & dosage / Q000627:therapeutic use*; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007783:Lactones; D013450:Sulfones; D045162:Thiazolidinediones; C116926:rofecoxib; D003520:Cyclophosphamide; D002097:C-Reactive Protein; C003726:trofosfamide; D000077205:Pioglitazone