title: Systematic review to establish the safety profiles for direct and indirect inhibitors of p38 Mitogen-activated protein kinases for treatment of cancer. A systematic review of the literature.
abstract: OBJECTIVE
  To identify potential tolerability issues for a novel selective p38 Mitogen-activated Protein Kinases (p38MAPK) inhibitor, we performed a systematic review of published studies and abstracts reporting safety outcomes for indirect inhibitors of p38MAPK.
  
  
  METHODS
  A systematic review was performed to identify articles and meeting abstracts published between January 1, 1990 and March 31, 2005 that reported safety outcomes in cancer patients. Study, patient, and treatment level data were summarized using descriptive statistics without meta-analyses.
  
  
  RESULTS
  Of 2,408 studies identified in the search, only 174 met eligibility criteria. Most studies (90%) involved thalidomide (or analog); only 12 (8%) studied sorafenib and 5 studied anti-tumor necrosis factor antibodies. In 165 treatment arms, 32% involved thalidomide (or analog) monotherapy and 2.4% involved sorafenib. The tolerability profiles of the two agents differed markedly. The most common Grade 3/4 adverse events experienced on thalidomide monotherapy were venous thrombosis (3.1% of patients), weakness/asthenia/fatigue (3.0%), neutropenia (2.7%), peripheral neuropathy/tingling/numbness (2.4%), somnolence/drowsiness/lethargy (2.4%), constipation (2.1%), and infection (2.0%). In contrast, the most common Grade 3/4 toxicities with sorafenib were diarrhea (4.8%), weakness/asthenia/fatigue (4.0%), hand-foot syndrome (3.2%), and leukopenia (2.4%). For both types of inhibitors, abnormal liver function tests were reported in about 3% of patients.
  
  
  CONCLUSIONS
  The present review summarizes clinical safety information of anti-cancer drugs with indirect or nonspecific p38MAPK inhibitory activity. Based on our analysis, a novel p38MAPK inhibitor should be monitored for similar neurological, gastrointestinal, and cardiovascular symptoms in Phase I clinical trials.
authors.affiliation: United BioSource Corporation (formerly MetaWorks, Inc.), 101 Station Landing, Medford, MA 02155, USA.
authors.forename: J Kay
authors.initials: JK
authors.lastname: Noel
authors.forename: Sheila
authors.initials: S
authors.lastname: Crean
authors.forename: Janet E
authors.initials: JE
authors.lastname: Claflin
authors.forename: Gayatri
authors.initials: G
authors.lastname: Ranganathan
authors.forename: Heather
authors.initials: H
authors.lastname: Linz
authors.forename: Michael
authors.initials: M
authors.lastname: Lahn
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D011725:Pyridines / Q000009:adverse effects* / Q000627:therapeutic use; D000077157:Sorafenib; D013792:Thalidomide / Q000009:adverse effects* / Q000627:therapeutic use; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D013792:Thalidomide; D000077157:Sorafenib; D048051:p38 Mitogen-Activated Protein Kinases