Ribonucleotide Reductase Expression in Cervical Cancer: A Radiation Therapy Oncology Group Translational Science Analysis.
ABSTRACT OBJECTIVE: To evaluate pretherapy ribonucleotide reductase (RNR) expression and its effect on radiochemotherapeutic outcome in women with cervical cancer. METHODS/MATERIALS: Pretherapy RNR M1, M2, and M2b immunohistochemistry was done on cervical cancer specimens retrieved from women treated on Radiation Therapy Oncology Group (RTOG) 0116 and 0128 clinical trials. Enrollees of RTOG 0116 (node-positive stages IA-IVA) received weekly cisplatin (40 mg/m) with amifostine (500 mg) and extended-field radiation then brachytherapy (85 Gy). Enrollees of RTOG 0128 (node-positive or bulky ≥5 cm, stages IB-IIA or stages IIB-IVA) received cisplatin (75 mg/m) on days 1, 23, and 43 and 5-FU (1 g/m for 4 days) during pelvic radiation then brachytherapy (85 Gy), plus celecoxib (400 mg twice daily, day 1 through 1 year). Disease-free survival (DFS) was estimated univariately by the Kaplan-Meier method. Cox proportional hazards models evaluated the impact of RNR immunoreactivity on DFS. RESULTS: Fifty-one tissue samples were analyzed: 13 from RTOG 0116 and 38 from RTOG 0128. M1, M2, and M2b overexpression (3+) frequencies were 2%, 80%, and 47%, respectively. Low-level (0-1+, n = 44/51) expression of the regulatory subunit M1 did not associate with DFS (P = 0.38). High (3+) M2 expression occurred in most (n = 41/51) but without impact alone on DFS (hazard ratio, 0.54; 95% confidence interval, 0.2-1.4; P = 0.20). After adjusting for M2b status, pelvic node-positive women had increased hazard for relapse or death (hazard ratio, 5.5; 95% confidence interval, 2.2-13.8; P = 0.0003). CONCLUSIONS: These results suggest that RNR subunit expression may discriminate cervical cancer phenotype and radiochemotherapy outcome. Future RNR biomarker studies are warranted.
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ABSTRACT: The purpose of this report was to comprehensively describe the activities of the Gynecologic Oncology Working Group within the Radiation Therapy Oncology Group (RTOG). Clinical trials will be reviewed as well as translational science and ancillary activities. During the past 40 years, a myriad of clinical trials have been performed within the RTOG with the aim of improving overall survival (OS) and decreasing morbidity in women with cervical or endometrial cancer. Major study questions have included hyperbaric oxygen, neutron radiotherapy, altered fractionation, hypoxic cell sensitization, chemosensitization, and volume-directed radiotherapy.RTOG 7920 demonstrated improvement in OS in patients with stages IB through IIB cervical carcinoma receiving prophylactic para-aortic irradiation compared to pelvic radiation alone. RTOG 9001 demonstrated that cisplatin and 5-FU chemoradiotherapy to the pelvis for advanced cervix cancer markedly improved OS compared to extended field radiotherapy alone. More recent trials have used radioprotectors, molecular-targeted therapy, and intensity-modulated radiation therapy. Ancillary studies have developed clinical target volume atlases for research protocols and routine clinical use. Worldwide practice patterns have been investigated in cervix, endometrial, and vulvar cancer through the Gynecologic Cancer Intergroup. Translational studies have focused on immunohistochemical markers, changes in gene expression, and miRNA patterns impacting prognosis.The RTOG gynecologic working group has performed clinical trials that have defined the standard of care, improved survival, and added to our understanding of the biology of cervical and endometrial cancers.International Journal of Gynecological Cancer 05/2014; DOI:10.1097/IGC.0000000000000135 · 1.95 Impact Factor
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ABSTRACT: Background: National Cancer Institute phase I #7336 and phase II #8327 clinical trials explored the safety and efficacy of triapine (NSC #663249) added to cisplatin radiochemotherapy in untreated patients with advanced-stage cervical cancer. Triapine inhibits ribonucleotide reductase, the rate-limiting enzyme responsible for DNA-building deoxyribonucleotides, and thereby, enhances radiochemosensitivity by prolonging DNA repair time. Here, we report 3-year efficacy endpoints of pelvic locoregional relapse rate, disease-free, and overall survivals. Methods: Eligible patients with bulky IB–IIIB cervical cancer underwent three-times weekly triapine (25 or 50 mg/m2), once-weekly cisplatin (40 mg/m2), and conventional daily pelvic radiation followed by brachytherapy. A cumulative incidence method estimated pelvic locoregional relapse rates. Disease-free survival was measured from radiochemotherapy start date to the date of first relapse or cancer-related death. Overall survival was measured from radiochemotherapy start date to the date of any-cause death. The Kaplan–Meier method estimated survivals. Findings: Between 2006 and 2011, 24 untreated patients with cervical cancer met criteria for reporting in this study. A median 3.4 years of follow-up time (range, 0.3–7.6 years) has been observed. All had squamous cancers and the majority had either node-positive stage IB–IIA (33%) or stage IIIB (42%) disease. The 3-year pelvic locoregional relapse rate, disease-free survival, and overall survival were 4% [95% confidence interval (CI), 0–20%], 80% (95% CI: 71–89%), and 82% (95% CI: 74–90%), respectively. Interpretation: Triapine radiochemotherapy was safe, active, and effective in patients with untreated advanced-stage cervical cancer, worthy of randomized clinical trial study.Frontiers in Oncology 07/2014; 4:184. DOI:10.3389/fonc.2014.00184
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ABSTRACT: The aim of this study was to evaluate the tolerability and efficacy of poly(ADP-ribose) polymerase (PARP) inhibition by veliparib during cytotoxic topotecan administration with filgrastim or pegfilgrastim neutrophil support in women with persistent or recurrent uterine cervix cancer. This phase I-II trial examined twice-daily oral veliparib (10 mg) given during once-daily intravenous topotecan (0.6 mg/m) on days 1 to 5 of each treatment cycle. Cycles were repeated every 21 days until disease progression or until toxicity prohibited further therapy. Toxicity and objective response rate were primary endpoints. Twenty-seven women were enrolled. Frequently reported grade 3 or higher treatment-related toxicities were anemia (59%), thrombocytopenia (44%), leukopenia (22%), and neutropenia (19%). There were 2 partial responses (7% [90% confidence interval, 1%-22%]). Four patients had a disease progression date more than 6 months after the start of veliparib-topotecan therapy. Patients with low immunohistochemical expression (0-1+) of PARP-1 in their primary uterine cervix cancer were more likely to have a longer progression-free interval (hazard ratio, 0.25; P = 0.02) and survival (hazard ratio, 0.12; P = 0.005) after veliparib-topotecan therapy. Clinical activity of a veliparib-topotecan combination was minimal in women with persistent or recurrent uterine cervix cancer. Women whose uterine cervix cancers express PARP-1 at low levels may benefit preferentially from PARP inhibitors combined with cytotoxic therapies, suggesting further study of PARP expression as an integral triage biomarker.International Journal of Gynecological Cancer 01/2015; 25(3). DOI:10.1097/IGC.0000000000000380 · 1.95 Impact Factor