title: Treatment with methylnaltrexone is associated with increased survival in patients with advanced cancer.
abstract: Methylnaltrexone (MNTX), a peripherally acting μ-opioid receptor (MOR) antagonist, is FDA-approved for treatment of opioid-induced constipation (OIC). Preclinical data suggest that MOR activation can play a role in cancer progression and can be a target for anticancer therapy.
  
  
  
  Pooled data from advanced end-stage cancer patients with OIC, despite laxatives, treated in two randomized (phase III and IV), placebo-controlled trials with MNTX were analyzed for overall survival (OS) in an unplanned post hoc analysis. MNTX or placebo was given subcutaneously during the double-blinded phase, which was followed by the open-label phase, allowing MNTX treatment irrespective of initial randomization.
  
  
  
  In two randomized, controlled trials, 229 cancer patients were randomized to MNTX (117, 51%) or placebo (112, 49%). Distribution of patients' characteristics and major tumor types did not significantly differ between arms. Treatment with MNTX compared with placebo [76 days, 95% confidence interval (CI) 43-109 versus 56 days, 95% CI 43-69; P = 0.033] and response (laxation) to treatment compared with no response (118 days, 95% CI 59-177 versus 55 days, 95% CI 40-70; P < 0.001) had a longer median OS, despite 56 (50%) of 112 patients ultimately crossing over from placebo to MNTX. Multivariable analysis demonstrated that response to therapy [hazard ratio (HR) 0.47, 95% CI 0.29-0.76; P = 0.002) and albumin ≥3.5 (HR 0.46, 95% CI 0.30-0.69; P < 0.001) were independent prognostic factors for increased OS. Of interest, there was no difference in OS between MNTX and placebo in 134 patients with advanced illness other than cancer treated in these randomized studies (P = 0.88).
  
  
  
  This unplanned post hoc analysis of two randomized trials demonstrates that treatment with MNTX and, even more so, response to MNTX are associated with increased OS, which supports the preclinical hypothesis that MOR can play a role in cancer progression. Targeting MOR with MNTX warrants further investigation in cancer therapy.
  
  
  
  NCT00401362, NCT00672477.
authors: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston.
authors: F
authors: F
authors: Janku
authors: Salix Pharmaceuticals Inc., Raleigh.
authors: L K
authors: LK
authors: Johnson
authors: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston.
authors: D D
authors: DD
authors: Karp
authors: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston.
authors: J T
authors: JT
authors: Atkins
authors: Department of Medicine, Section of Pulmonary and Critical Care.|Department of Anesthesia and Critical Care, Pritzker School of Medicine, The University of Chicago, Chicago, USA.
authors: P A
authors: PA
authors: Singleton
authors: Department of Anesthesia and Critical Care, Pritzker School of Medicine, The University of Chicago, Chicago, USA jm47@midway.uchicago.edu.
authors: J
authors: J
authors: Moss
mesh_terms: D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid / Q000627:therapeutic use; D003248:Constipation / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D054368:Laxatives / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors
chemical_list: D000701:Analgesics, Opioid; D054368:Laxatives; D000644:Quaternary Ammonium Compounds; D017450:Receptors, Opioid, mu; C032257:methylnaltrexone; D009271:Naltrexone
keywords: cancer; constipation; methylnaltrexone; mu opioid receptor; opioids; survival