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: Charles A Kunos, Tomas Radivoyevitch, Steven Waggoner, Robert Debernardo, Kristine Zanotti, Kimberly Resnick, Nancy Fusco, Ramon Adams, Raymond Redline, Peter Faulhaber, Afshin Dowlati
• Journal: Gynecologic oncology (Gynecol Oncol) Vol. 130 Issue 1 Pg. 75-80 (Jul 2013) ISSN: 1095-6859 [Electronic] United States
• PMID: 23603372 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Pyridines
• Thiosemicarbazones
• Fluorodeoxyglucose F18
• 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
• Cisplatin

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Brachytherapy
• Chemoradiotherapy
• Cisplatin (administration & dosage, adverse effects)
• Drug Administration Schedule
• Female
• Fluorodeoxyglucose F18
• Humans
• Middle Aged
• Multimodal Imaging (methods)
• Neoplasm Staging
• Positron-Emission Tomography
• Pyridines (administration & dosage, adverse effects)
• Thiosemicarbazones (administration & dosage, adverse effects)
• Tomography, X-Ray Computed
• Uterine Cervical Neoplasms (diagnostic imaging, drug therapy, pathology, radiotherapy)
• Vaginal Neoplasms (diagnostic imaging, drug therapy, pathology, radiotherapy)