Radiochemotherapy plus 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in advanced-stage cervical and vaginal cancers

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 x weekly 2-hour intravenous 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, 25 mg/m(2)) co-administered with I x weekly intravenous cisplatin (40 mg/m2) and daily pelvic radiation (45 Gy) in women with stage I-B2-IVB 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-[F-18] fluoro-2-deoxy-o-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. (C) 2013 Elsevier Inc. All rights reserved.