title: Complications of hyperglycaemia with PI3K-AKT-mTOR inhibitors in patients with advanced solid tumours on Phase I clinical trials.
abstract: BACKGROUND
  PI3K-AKT-mTOR inhibitors (PAMi) are promising anticancer treatments. Hyperglycaemia is a mechanism-based toxicity of these agents and is becoming increasingly important with their use in larger numbers of patients.
  
  
  METHODS
  Retrospective case-control study comparing incidence and severity of hyperglycaemia (all grades) between a case group of 387 patients treated on 18 phase I clinical trials with PAMi (78 patients with PI3Ki, 138 with mTORi, 144 with AKTi and 27 with PI3K/mTORi) and a control group of 109 patients treated on 10 phase I clinical trials with agents not directly targeting the PAM pathway. Diabetic patients were excluded in both groups.
  
  
  RESULTS
  The incidence of hyperglycaemia was not significantly different between cases and controls (86.6% vs 80.7%, respectively, P=0.129). However, high grade (grade 3-4) hyperglycaemia was more frequent in the PAMi group than in controls (6.7% vs 0%, respectively, P=0.005). The incidence of grade 3-4 hyperglycaemia was greater with AKT and multikinase inhibitors compared with other PAMi (P<0.001). All patients with high-grade hyperglycaemia received antihyperglycemic treatment and none developed severe metabolic complications (diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic state). High-grade hyperglycaemia was the cause of permanent PAMi discontinuation in nine patients.
  
  
  CONCLUSIONS
  PI3K-AKT-mTOR inhibitors are associated with small (6.7%) but statistically significant increased risk of high-grade hyperglycaemia compared with non-PAM targeting agents. However, PAMi-induced hyperglycaemia was not found to be associated with severe metabolic complications in this non-diabetic population of patients with advanced cancers.
authors.affiliation: Drug Development Unit, The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK.|Investigative Clinical Oncology (INCO), Fondazione del Piemonte per l'Oncologia-Institute for Cancer Research and Treatment of Candiolo, Turin, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Geuna
authors.affiliation: Drug Development Unit, The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Roda
authors.affiliation: Drug Development Unit, The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Rafii
authors.affiliation: Drug Development Unit, The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: B
authors.initials: B
authors.lastname: Jimenez
authors.affiliation: Drug Development Unit, The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Capelan
authors.affiliation: Drug Development Unit, The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: K
authors.initials: K
authors.lastname: Rihawi
authors.affiliation: Investigative Clinical Oncology (INCO), Fondazione del Piemonte per l'Oncologia-Institute for Cancer Research and Treatment of Candiolo, Turin, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Montemurro
authors.affiliation: Drug Development Unit, The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: T A
authors.initials: TA
authors.lastname: Yap
authors.affiliation: Drug Development Unit, The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: S B
authors.initials: SB
authors.lastname: Kaye
authors.affiliation: Drug Development Unit, The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: J S
authors.initials: JS
authors.lastname: De Bono
authors.affiliation: Drug Development Unit, The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: L R
authors.initials: LR
authors.lastname: Molife
authors.affiliation: Drug Development Unit, The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: U
authors.initials: U
authors.lastname: Banerji
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001786:Blood Glucose / Q000187:drug effects; D016022:Case-Control Studies; D017321:Clinical Trials, Phase I as Topic; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000453:epidemiology* / Q000209:etiology*; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D012189:Retrospective Studies; D012307:Risk Factors; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases