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.

Figure 1

¹⁸F-FDG PET/CT ratio of standard uptake value (SUV) posttherapy-to-pretherapy. A ratio of 0.33 or less (dotted line) significantly discriminates responders and non-responders to radiochemotherapy [5]. The single patient whose ratio did not cross the 0.33 threshold developed relapse at 10 months posttherapy.

Figure 2

Representative cervical cancer ¹⁸F-FDG PET/CT images are shown for baseline and for 3 months after 3-AP radiochemotherapy in a node positive complete metabolic responder [SUV ratio 0.32] (A-B) and in a node-positive incomplete responder [SUV ratio 0.56] (D-E). White circles identify primary and nodal disease (A-B, D-E). Posttherapy biopsy of the uterine cervix showed markedly distorted, enlarged, hyperchromatic and vesicular nuclear changes in keeping with 3-AP radiochemotherapy effect in the partial responder (C). Posttherapy surgical specimens obtained at disease recurrence displayed densely hyalinized tissue with necrosis and cell nests of squamous cancer (F). Cervical cancer cells are stained with hematoxalin and eosin.