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      Triapine Radiochemotherapy in Advanced Stage Cervical Cancer

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          Abstract

          Clinical ribonucleotide reductase (RNR) inhibitors have reinvigorated enthusiasm for radiochemotherapy treatment of patients with regionally advanced stage cervical cancers. About two-thirds of patients outlive their cervical cancer ( 1), even though up to half of their tumors retain residual microscopic disease ( 2). The National Cancer Institute Cancer Therapy Evaluation Program conducted two prospective trials of triapine–cisplatin–radiation to improve upon this finding by precisely targeting cervical cancer’s overactive RNR. Triapine’s potent inactivation of RNR arrests cells at the G1/S cell cycle restriction checkpoint and enhances cisplatin–radiation cytotoxicity. In this article, we provide perspective on challenges encountered in and future potential of clinical development of a triapine–cisplatin–radiation combination for patients with regionally advanced cervical cancer. New trial results and review presented here suggest that a triapine–cisplatin–radiation combination may offer molecular cell cycle target control to maximize damage in cancers and to minimize injury to normal cells. A randomized trial now accrues patients with regionally advanced stage cervical cancer to evaluate triapine’s contribution to clinical benefit after cisplatin–radiation ( clinicaltrials.gov, NCT02466971).

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          Most cited references41

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          A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage.

          The p53 gene is frequently inactivated in human cancers. Here we have isolated a p53-inducible gene, p53R2, by using differential display to examine messenger RNAs in a cancer-derived human cell line carrying a highly regulated wild-type p53 expression system. p53R2 contains a p53-binding sequence in intron 1 and encodes a 351-amino-acid peptide with striking similarity to the ribonucleotide reductase small subunit (R2), which is important in DNA synthesis during cell division. Expression of p53R2, but not R2, was induced by ultraviolet and gamma-irradiation and adriamycin treatment in a wild-type p53-dependent manner. Induction of p53R2 in p53-deficient cells caused G2/M arrest and prevented cells from death in response to adriamycin. Inhibition of endogenous p53R2 expression in cells that have an intact p53-dependent DNA damage checkpoint reduced ribonucleotide reductase activity, DNA repair and cell survival after exposure to various genotoxins. Our results indicate that p53R2 encodes a ribonucleotide reductase that is directly involved in the p53 checkpoint for repair of damaged DNA. The discovery of p53R2 clarifies a relationship between a ribonucleotide reductase activity involved in repair of damaged DNA and tumour suppression by p53.
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            A phase III randomized trial of postoperative pelvic irradiation in Stage IB cervical carcinoma with poor prognostic features: follow-up of a gynecologic oncology group study.

            To investigate, in a phase III randomized trial, whether postoperative external-beam irradiation to the standard pelvic field improves the recurrence-free interval and overall survival (OS) in women with Stage IB cervical cancers with negative lymph nodes and certain poor prognostic features treated by radical hysterectomy and pelvic lymphadenectomy. Eligible patients had Stage IB cervical cancer with negative lymph nodes but with 2 or more of the following features: more than one third (deep) stromal invasion, capillary lymphatic space involvement, and tumor diameter of 4 cm or more. The study group included 277 patients: 137 randomized to pelvic irradiation (RT) and 140 randomized to observation (OBS). The planned pelvic dose was from 46 Gy in 23 fractions to 50.4 Gy in 28 fractions. Of the 67 recurrences, 24 were in the RT arm and 43 were in the OBS arm. The RT arm showed a statistically significant (46%) reduction in risk of recurrence (hazard ratio [HR] = 0.54, 90% confidence interval [CI] = 0.35 to 0.81, p = 0.007) and a statistically significant reduction in risk of progression or death (HR = 0.58, 90% CI = 0.40 to 0.85, p = 0.009). With RT, 8.8% of patients (3 of 34) with adenosquamous or adenocarcinoma tumors recurred vs. 44.0% (11 of 25) in OBS. Fewer recurrences were seen with RT in patients with adenocarcinoma or adenosquamous histologies relative to others (HR for RT by histology interaction = 0.23, 90% CI = 0.07 to 0.74, p = 0.019). After an extensive follow-up period, 67 deaths have occurred: 27 RT patients and 40 OBS patients. The improvement in overall survival (HR = 0.70, 90% CI = 0.45 to 1.05, p = 0.074) with RT did not reach statistical significance. Pelvic radiotherapy after radical surgery significantly reduces the risk of recurrence and prolongs progression-free survival in women with Stage IB cervical cancer. RT appears to be particularly beneficial for patients with adenocarcinoma or adenosquamous histologies. Circumstances that may have influenced the overall survival differences are considered.
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              Consensus recommendations for the use of 18F-FDG PET as an indicator of therapeutic response in patients in National Cancer Institute Trials.

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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                07 May 2018
                2018
                : 8
                : 149
                Affiliations
                Cancer Therapy Evaluation Program, National Cancer Institute , Bethesda, MD, United States
                Author notes

                Edited by: Elena Ratner, Yale University, United States

                Reviewed by: Pietro Valerio Foti, Università degli Studi di Catania, Italy; Connie Irene Diakos, University of Sydney, Australia

                *Correspondence: Charles A. Kunos, charles.kunos@ 123456nih.gov

                Specialty section: This article was submitted to Women’s Cancer, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2018.00149
                5949312
                29868473
                1e2f3c65-3d90-441c-b667-2ee26dae0eba
                Copyright © 2018 Kunos and Ivy.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 27 February 2018
                : 23 April 2018
                Page count
                Figures: 2, Tables: 2, Equations: 0, References: 47, Pages: 7, Words: 5248
                Funding
                Funded by: National Cancer Institute 10.13039/100000054
                Funded by: Cancer Therapy Evaluation Program
                Funded by: Division of Cancer Treatment and Diagnosis
                Categories
                Oncology
                Perspective

                Oncology & Radiotherapy
                triapine,cervical cancer,uterine cervix cancer,vaginal cancer,radiation therapy,cisplatin

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