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Randomized Phase II Trial of Triapine-Cisplatin-Radiotherapy for Locally Advanced Stage Uterine Cervix or Vaginal Cancers.

ABSTRACT: Uterine cervix or vaginal cancers have inherent overactivity of ribonucleotide reductase (RNR), making these cancers rational targets for therapy based on interruption of cisplatin-radiotherapy-induced DNA damage repair. We conducted a pilot, open-label randomized phase II trial to evaluate the efficacy and safety of cisplatin-radiotherapy with or without triapine, a small molecule with RNR-inhibitory activity, in patients with advanced-stage uterine cervix or vaginal cancers (NCT01835171), as a lead in to a randomized phase III study (NCT02466971). A total of 26 women were randomly assigned to receive 6 weeks of daily radiotherapy followed by brachytherapy (80 Gy) and once-weekly cisplatin (40 mg m-2)-with or without three-times weekly intravenous triapine (25 mg m-2)-in one 56-days cycle. Primary end points were metabolic complete response by positron emission tomography and safety. Additional end points included the rate of clinical response, rate of methemoglobinemia, and progression-free survival. The addition of triapine to cisplatin-radiotherapy improved the rate of metabolic complete response from 69 to 92% (P = 0.32) and raised the 3-year progression-free survival estimate from 77 to 92% (hazard ratio for progression, 0.30; P = 0.27). The most frequent grade 3 or 4 adverse events in either treatment group included reversible leukopenia, neutropenia, fatigue, or electrolyte abnormalities. No significant differences were seen between the two groups in the rate of adverse events. Symptomatic methemoglobinemia was not encountered after triapine infusion. In conclusion, the addition of triapine to cisplatin-radiotherapy improved the rate of metabolic complete response in patients with advanced-stage uterine cervix or vaginal cancers without significant toxicity. A phase III trial adequately powered to evaluate progression-free and overall survival is underway (NCT02466971).

SUBMITTER: Kunos CA

PROVIDER: S-EPMC6803528 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Randomized Phase II Trial of Triapine-Cisplatin-Radiotherapy for Locally Advanced Stage Uterine Cervix or Vaginal Cancers.

Kunos Charles A CA Andrews Stephen J SJ Moore Kathleen N KN Chon Hye Sook HS Ivy S Percy SP

Frontiers in oncology 20191015

Uterine cervix or vaginal cancers have inherent overactivity of ribonucleotide reductase (RNR), making these cancers rational targets for therapy based on interruption of cisplatin-radiotherapy-induced DNA damage repair. We conducted a pilot, open-label randomized phase II trial to evaluate the efficacy and safety of cisplatin-radiotherapy with or without triapine, a small molecule with RNR-inhibitory activity, in patients with advanced-stage uterine cervix or vaginal cancers (NCT01835171), as a ...[more]

PMID: 31681600

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Project description:ImportanceThe evidence for concurrent chemoradiotherapy (CT-RT) in International Federation of Gynecology and Obstetrics (FIGO) stage IIIB squamous cell carcinoma of the uterine cervix is not robust. This study reports the final results of a randomized clinical trial of concurrent cisplatin-based CT-RT and radiotherapy alone (RT) in women with FIGO stage IIIB squamous cell carcinoma of the uterine cervix.ObjectiveTo investigate the benefit of concurrent CT-RT in FIGO stage IIIB squamous cell carcinoma of the uterine cervix.Design, setting, and participantsThis phase 3 open-label randomized clinical trial accrued 850 women in Mumbai, India, between July 7, 2003, and September 22, 2011. Of 2121 screened, 850 women with FIGO stage IIIB squamous cell carcinoma of the uterine cervix suitable for concurrent cisplatin chemotherapy were randomly assigned to CT-RT and RT using block randomization (1:1). The data were updated for a minimum follow-up period of 5 years until December 2016. The final analyses were performed in February and March 2017. This single-institution study was conducted at a tertiary cancer center setting.InterventionsRandomization to receive RT (RT arm), comprising a combination of external beam RT (50 Gy in 25 fractions over 5 weeks) and brachytherapy, or to receive in addition to the same RT concurrent weekly cisplatin chemotherapy (40 mg/m2 per week) (CT-RT arm).Main outcomes and measuresThe primary end point was 5-year disease-free survival (DFS), defined as the time between the date of randomization and the date of any recurrence or death (whichever occurred first) in the intent-to-treat population.ResultsThis trial included 424 women assigned to CT-RT (mean [SD] age, 49.4 [7.9] years) and 426 women assigned to RT (mean [SD] age, 49.3 [7.9] years). At a median follow-up of 88 months (interquartile range, 61.3-113.1 months), there were 222 recurrences and 213 deaths in the CT-RT arm and 252 recurrences and 243 deaths in the RT arm. The 5-year DFS was significantly higher in the CT-RT arm (52.3%; 95% CI, 52.2%-52.4%) compared with the RT arm (43.8%; 95% CI, 43.7%-43.9%), with a hazard ratio for relapse or death of 0.81 (95% CI, 0.68-0.98) (P = .03). Similarly, the 5-year overall survival (OS) was significantly higher in the CT-RT arm (54.0%; 95% CI, 53.9%-54.1%) compared with the RT arm (46.0%; 95% CI, 45.9%-46.1%), with a hazard ratio for death of 0.82 (95% CI, 0.68-0.98; P = .04). After adjusting for prognostic factors, CT-RT continued to be significantly superior to RT for DFS and OS. There was a higher incidence of acute hematological adverse effects in the CT-RT arm.Conclusions and relevanceChemoradiotherapy using weekly cisplatin results in significantly better DFS and OS compared with RT in women with stage IIIB squamous cell carcinoma of the uterine cervix. This study provides level 1 evidence in the largest clinical trial reported so far in favor of concurrent weekly cisplatin chemotherapy in this setting.Trial registrationclinicaltrials.gov Identifier: NCT00193791.

Project description:BackgroundDynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may provide biomarkers of the outcome of locally-advanced cervical carcinoma (LACC). There is, however, no agreement on how DCE-MR recordings should be analyzed. Previously, we have analyzed DCE-MRI data of LACC using non-model-based strategies. In the current study, we analyzed DCE-MRI data of LACC using the Tofts pharmacokinetic model, and the biomarkers derived from this analysis were compared with those derived from the non-model-based analyses.MethodsEighty LACC patients given cisplatin-based chemoradiotherapy with curative intent were included in the study. Treatment outcome was recorded as disease-free survival (DFS) and overall survival (OS). DCE-MRI series were analyzed voxelwise to produce Ktrans and ve frequency distributions, and ROC analysis was used to identify the parameters of the frequency distributions having the greatest potential as biomarkers. The prognostic power of these parameters was compared with that of the non-model-based parameters LETV (low-enhancing tumor volume) and TVIS (tumor volume with increasing signal).ResultsPoor DFS and OS were associated with low values of Ktrans, whereas there was no association between treatment outcome and ve. The Ktrans parameters having the greatest prognostic value were p35-Ktrans (the Ktrans value at the 35 percentile of a frequency distribution) and RV-Ktrans (the tumor subvolume with Ktrans values below 0.13?min-?1). Multivariate analysis including clinical parameters and p35-Ktrans or RV-Ktrans revealed that RV-Ktrans was the only independent prognostic factor of DFS and OS. There were significant correlations between RV-Ktrans and LETV and between RV-Ktrans and TVIS, and the prognostic power of RV-Ktrans was similar to that of LETV and TVIS.ConclusionsBiomarkers of the outcome of LACC can be provided by analyzing DCE-MRI series using the Tofts pharmacokinetic model. However, these biomarkers do not appear to have greater prognostic value than biomarkers determined by non-model-based analyses.

Dataset Information

Randomized Phase II Trial of Triapine-Cisplatin-Radiotherapy for Locally Advanced Stage Uterine Cervix or Vaginal Cancers.

Publications

Randomized Phase II Trial of Triapine-Cisplatin-Radiotherapy for Locally Advanced Stage Uterine Cervix or Vaginal Cancers.

Similar Datasets

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