title: Gastrointestinal toxicity of vorinostat: reanalysis of phase 1 study results with emphasis on dose-volume effects of pelvic radiotherapy.
abstract: BACKGROUND
  In early-phase studies with targeted therapeutics and radiotherapy, it may be difficult to decide whether an adverse event should be considered a dose-limiting toxicity (DLT) of the investigational systemic agent, as acute normal tissue toxicity is frequently encountered with radiation alone. We have reanalyzed the toxicity data from a recently conducted phase 1 study on vorinostat, a histone deacetylase inhibitor, in combination with pelvic palliative radiotherapy, with emphasis on the dose distribution within the irradiated bowel volume to the development of DLT.
  
  
  RESULTS
  Of 14 eligible patients, three individuals experienced Common Terminology Criteria of Adverse Events grade 3 gastrointestinal and related toxicities, representing a toxicity profile vorinostat has in common with radiotherapy to pelvic target volumes. For each study patient, the relative volumes of small bowel receiving radiation doses between 6 Gy and 30 Gy at 6-Gy intervals (V6-V30) were determined from the treatment-planning computed tomography scans. The single patient that experienced a DLT at the second highest dose level of vorinostat, which was determined as the maximum-tolerated dose, had V6-V30 dose-volume estimates that were considerably higher than any other study patient. This patient may have experienced an adverse radiation dose-volume effect rather than a toxic effect of the investigational drug.
  
  
  CONCLUSIONS
  When reporting early-phase trial results on the tolerability of a systemic targeted therapeutic used as potential radiosensitizing agent, radiation dose-volume effects should be quantified to enable full interpretation of the study toxicity profile.
authors.affiliation: Department of Oncology, Akershus University Hospital, Lørenskog, Norway.
authors.forename: Ase
authors.initials: A
authors.lastname: Bratland
authors.forename: Svein
authors.initials: S
authors.lastname: Dueland
authors.forename: Donal
authors.initials: D
authors.lastname: Hollywood
authors.forename: Kjersti
authors.initials: K
authors.lastname: Flatmark
authors.forename: Anne H
authors.initials: AH
authors.lastname: Ree
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects*; D003131:Combined Modality Therapy / Q000009:adverse effects; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects*; D007414:Intestinal Neoplasms / Q000628:therapy*; D007421:Intestine, Small / Q000528:radiation effects*; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010388:Pelvis / Q000528:radiation effects; D011878:Radiotherapy / Q000009:adverse effects*; D011880:Radiotherapy Planning, Computer-Assisted; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D000077337:Vorinostat