title: Gemcitabine and oxaliplatin or alkylating agents for neuroendocrine tumors: Comparison of efficacy and search for predictive factors guiding treatment choice.
abstract: BACKGROUND
  The alkylating agents (ALKYs) streptozotocin, dacarbazine, and temozolomide currently are the main drugs used in systemic chemotherapy for neuroendocrine tumors (NETs). The promising activity shown by gemcitabine and oxaliplatin (GEMOX) in previous studies prompted this study 1) to confirm the use of GEMOX in a larger population of NET patients, 2) to compare its efficacy with that of ALKYs, and 3) to explore whether the O(6) -methylguanine-DNA methyltransferase (MGMT) status could help in selecting the chemotherapy regimen.
  
  
  METHODS
  One hundred four patients with metastatic NETs (37 pancreatic NETs, 33 gastrointestinal NETs, 23 bronchial NETs, and 11 NETs of other/unknown origin) were treated with GEMOX between 2004 and 2014. Among these patients, 63 also received ALKYs. MGMT promoter gene methylation was assessed via pyrosequencing in 42 patients.
  
  
  RESULTS
  Patients received a median of 6 courses of GEMOX. Twenty-four (23%) had an objective response (OR). The median progression-free survival (PFS) and overall survival were 7.8 and 31.6 months, respectively. In the 63 patients treated with both ALKYs and GEMOX, the ORs (22% and 22%) and the PFSs (7.5 and 7.3 months) were similar. The response was concordant in 53% of the patients. Promoter gene methylation of MGMT was associated with better outcomes with ALKYs (P = .03 for OR and P = .04 for PFS) but not GEMOX.
  
  
  CONCLUSIONS
  GEMOX is effective against NETs; its activity is comparable to that of ALKYs, and it is not influenced by the MGMT status. Our data suggest that GEMOX might be preferred for patients with unmethylated MGMT tumors. Cancer 2015;121:3435-43. © 2015 American Cancer Society.
authors.affiliation: Department of Digestive Oncology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Dussol
authors.affiliation: Lyon Cancer Research Center (National Institute of Health and Medical Research Joint Research Unit 1052), Laennec Faculty, Lyon, France.|Department of Central Anatomy and Pathological Cytology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.|Claude Bernard University Lyon 1, University of Lyon, Villeurbanne, France.
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Joly
authors.affiliation: Lyon Cancer Research Center (National Institute of Health and Medical Research Joint Research Unit 1052), Laennec Faculty, Lyon, France.
authors.forename: Cecile
authors.initials: C
authors.lastname: Vercherat
authors.affiliation: Department of Digestive Oncology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Forestier
authors.affiliation: Lyon Cancer Research Center (National Institute of Health and Medical Research Joint Research Unit 1052), Laennec Faculty, Lyon, France.|Department of Central Anatomy and Pathological Cytology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.|Claude Bernard University Lyon 1, University of Lyon, Villeurbanne, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Hervieu
authors.affiliation: Lyon Cancer Research Center (National Institute of Health and Medical Research Joint Research Unit 1052), Laennec Faculty, Lyon, France.|Department of Central Anatomy and Pathological Cytology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.|Claude Bernard University Lyon 1, University of Lyon, Villeurbanne, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.affiliation: Department of Digestive Oncology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lombard-Bohas
authors.affiliation: Department of Digestive Oncology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.|Lyon Cancer Research Center (National Institute of Health and Medical Research Joint Research Unit 1052), Laennec Faculty, Lyon, France.|Claude Bernard University Lyon 1, University of Lyon, Villeurbanne, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Walter
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000477:Alkylating Agents; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D000077150:Oxaliplatin; D012189:Retrospective Studies; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000477:Alkylating Agents; D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: O6-methylguanine-DNA methyltransferase (MGMT); alkylating agents; gemcitabine and oxaliplatin (GEMOX); neuroendocrine tumors; temozolomide