title: Radiochemotherapy plus 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in advanced-stage cervical and vaginal cancers.
abstract: OBJECTIVE
  Cervical and vaginal cancers have virally-mediated or mutated defects in DNA damage repair responses, making these cancers sensible targets for ribonucleotide reductase inhibition during radiochemotherapy.
  
  
  METHODS
  We conducted a phase II study evaluating 3× weekly 2-hour intravenous 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, 25 mg/m(2)) co-administered with 1× weekly intravenous cisplatin (40 mg/m(2)) and daily pelvic radiation (45 Gy) in women with stage I(B2)-IV(B) cervical (n=22) or stage II-IV vaginal (n=3) cancers. Brachytherapy followed (40 Gy). Toxicity was monitored by common terminology criteria for adverse events (version 3.0). The primary end point of response was assessed by 3-month posttherapy 2-[(18)F] fluoro-2-deoxy-d-glucose positron emission tomography (PET/CT) and clinical examination.
  
  
  RESULTS
  3-AP radiochemotherapy achieved clinical responses in 24 (96% [95% confidence interval: 80-99%]) of 25 patients (median follow-up 20 months, range 2-35 months). 23 (96% [95% confidence interval: 80-99%]) of 24 patients had 3-month posttherapy PET/CT scans that recorded metabolic activity in the cervix or vagina equal or less than that of the cardiac blood pool, suggesting complete metabolic responses. The most frequent 3-AP radiochemotherapy-related adverse events included fatigue, nausea, diarrhea, and reversible hematological and electrolyte abnormalities.
  
  
  CONCLUSIONS
  The addition of 3-AP to cisplatin radiochemotherapy was tolerable and produced high rates of clinical and metabolic responses in women with cervical and vaginal cancers. Future randomized phase II and III clinical trials of 3-AP radiochemotherapy are warranted.
authors.affiliation: Department of Radiation Oncology, CASE Comprehensive Cancer Center, University Hospitals Case Medical Center and Case Western Reserve University School of Medicine, Cleveland, OH 44106, United States. kunosc@summahealth.org
authors.forename: Charles A
authors.initials: CA
authors.lastname: Kunos
authors.forename: Tomas
authors.initials: T
authors.lastname: Radivoyevitch
authors.forename: Steven
authors.initials: S
authors.lastname: Waggoner
authors.forename: Robert
authors.initials: R
authors.lastname: Debernardo
authors.forename: Kristine
authors.initials: K
authors.lastname: Zanotti
authors.forename: Kimberly
authors.initials: K
authors.lastname: Resnick
authors.forename: Nancy
authors.initials: N
authors.lastname: Fusco
authors.forename: Ramon
authors.initials: R
authors.lastname: Adams
authors.forename: Raymond
authors.initials: R
authors.lastname: Redline
authors.forename: Peter
authors.initials: P
authors.lastname: Faulhaber
authors.forename: Afshin
authors.initials: A
authors.lastname: Dowlati
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001918:Brachytherapy; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008875:Middle Aged; D064847:Multimodal Imaging / Q000379:methods; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects; D013882:Thiosemicarbazones / Q000008:administration & dosage / Q000009:adverse effects; D014057:Tomography, X-Ray Computed; D002583:Uterine Cervical Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D014625:Vaginal Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*
chemical_list: D011725:Pyridines; D013882:Thiosemicarbazones; D019788:Fluorodeoxyglucose F18; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; D002945:Cisplatin