Incorporation of triapine (T) to cisplatin chemoradiation (CRT) for locally advanced cervical and vaginal cancer: Results from NRG-GY006, a phase III randomized trial

Charles A. Leath; Wei Deng; Loren K. Mell; Debra L. Richardson; Joan L. Walker; Laura L. Holman; Jayanthi S. Lea; Sudha R. Amarnath; Luis Javier Santos-Reyes; Rebecca C. Arend; Jyoti Mayadev; Naresh Jegadeesh; Paul DiSilvestro; Hye Sook Chon; Sharad A. Ghamande; Lei Gao; Kevin Albuquerque; Junzo P. Chino; Eric Donnelly; Jonathan M. Feddock; Jessica Lowenstein; Allison M. Quick; Charles M. Kunos; Helen MacKay; Carol Aghajanian; Bradley J. Monk

doi:10.1016/j.ygyno.2025.03.007

Incorporation of triapine (T) to cisplatin chemoradiation (CRT) for locally advanced cervical and vaginal cancer: Results from NRG-GY006, a phase III randomized trial

Charles A. Leath^*, Wei Deng, Loren K. Mell, Debra L. Richardson, Joan L. Walker, Laura L. Holman, Jayanthi S. Lea, Sudha R. Amarnath, Luis Javier Santos-Reyes, Rebecca C. Arend, Jyoti Mayadev, Naresh Jegadeesh, Paul DiSilvestro, Hye Sook Chon, Sharad A. Ghamande, Lei Gao, Kevin Albuquerque, Junzo P. Chino, Eric Donnelly, Jonathan M. FeddockJessica Lowenstein, Allison M. Quick, Charles M. Kunos, Helen MacKay, Carol Aghajanian, Bradley J. Monk

^*Corresponding author for this work

Radiation Oncology

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Background: Cisplatin-based chemoradiation (CRT) plus brachytherapy for locally advanced cervical cancer (LACC) is standard. Intrinsic overexpression of ribonucleotide reductase (RNR) may enhance DNA damage repair from CRT. We report on outcomes of adding RNR inhibitor, triapine (T), to CRT. Methods: NRG-GY006 is an open-label randomized phase III trial. FIGO 2009 LACC (stages IB2, II, IIIB or IVA) without para-aortic nodal involvement or stages II-IV vaginal cancer were eligible. Random assignment to CRT or in combination with thrice-weekly T (CRT + T) occurred. Radiation consisted of either 3D conformal (3DCRT) or image-guided intensity modulated RT (IG-IMRT) followed by intracavitary brachytherapy. Primary endpoint was overall survival (OS). Progression-free survival (PFS) was secondary. Exploratory endpoints included complete metabolic response rate on post treatment PET/CT imaging and comparative toxicity and outcomes for 3DCRT vs. IG-IMRT. Findings: Four-hundred-fifty patients were randomized including 448 eligible (224 in CRT and 224 in CRT + T). Median age was 47 (range 23–85). The majority had cervical cancer (93.3 %) with squamous histology (82 %). 52 % had FIGO stage II disease. Racial/ethnic distribution included non-Hispanic white (53.8 %), black (15.2 %) and Hispanic/Latina (22.5 %). At randomization, IG-IMRT was planned in 74.3 % and HDR brachytherapy in 98.2 %. No differences in Grade 3–5 toxicities were observed: CRT: 52 % and CRT + T: 49 %, with two G5 toxicities (cardiac arrest and acidosis) in the CRT + T arm. The median patient follow-up was 28 months (IQR 15–45). HR for death was 1.018 (95 % CI 0.634–1.635) while HR for progression was 1.021 (95 % CI 0.694–1.501). Interpretation: Triapine added to CRT did not improve OS.

Original language	English (US)
Pages (from-to)	122-133
Number of pages	12
Journal	Gynecologic oncology
Volume	195
DOIs	https://doi.org/10.1016/j.ygyno.2025.03.007
State	Published - Apr 2025

Funding

The authors would like thank all of the patients, and their families, that enrolled on this trial as well as the participating sites and the NRG Oncology Regulatory and Statistical Centers. This study was supported by National Cancer Institute grants to NRG Oncology U10CA180822 (NRG Oncology Statistics and Data Management Center) and U10CA180868 (NRG Oncology Operations), as well as Leath LAPS UG1 CA233330, Mell R01 - 5R01CA255780. The following NRG Oncology member institutions participated in the primary treatment studies: University of Oklahoma Health Sciences Center, University of Texas Southwestern Medical Center, CWRU Case Comprehensive Cancer Center, Puerto Rico Minority Underserved NCORP, University of Alabama at Birmingham/Deep South Research Consortium, UC San Diego Moores Cancer Center, Stroger Hospital of Cook County Minority Underserved NCORP, Women and Infant's Hospital, Moffitt Cancer Center, Georgia Cares Minority Underserved NCORP, Northwestern University, Roswell Park Comprehensive Cancer Center, University of Arkansas for Medical Sciences, Women's Cancer Center of Nevada, University of Cincinnati Cancer Center-UC Medical Center, Thomas Jefferson University Hospital, Banner University Medical Center-Tucson, University of Rochester, Georgia NCI Community Oncology Research Program, Gulf South Minority Underserved NCORP, Indiana University/Melvin and Bren Simon Cancer Center, New Mexico Minority Underserved NCORP, Loyola University Medical Center, University of Minnesota/Masonic Cancer Center, Cooper Hospital University Medical Center, Southeast Clinical Oncology Research Consortium NCORP, Houston Methodist Hospital, University of Colorado Cancer Center, Emory University – Winship Cancer Institute, Odette Cancer Centre – Sunnybrook Health Sciences Centre, University of Kentucky/Markey Cancer Center, Washington University – Siteman Cancer Center, Walter Reed National Military Medical Center, Wake Forest University Health Sciences, Rutgers Cancer Institute of New Jersey, Ochsner NCI Community Oncology Research Program, University of Mississippi Medical Center, Upstate Carolina Consortium Community Oncology Research Program, UC Irvine Health/Chao Family Comprehensive Cancer Center, CommonSpirit Health Research Institute, NCORP of the Carolinas (Prisma Health NCORP), The James Graham Brown Cancer Center at University of Louisville, Mayo Clinic, UPMC Hillman Cancer Center, University of Wisconsin Carbone Cancer Center, ProMedica Flower Hospital, University of Pennsylvania/Abramson Cancer Center, Wisconsin NCI Community Oncology Research Program, Northwestern Medicine Cancer Center Warrenville, Vanderbilt University – Ingram Cancer Center, Mount Sinai Hospital and Nebraska Methodist Hospital. This study was supported by National Cancer Institute grants to NRG Oncology U10CA180822 ( NRG Oncology Statistics and Data Management Center ) and U10CA180868 ( NRG Oncology Operations ), as well as LAPS UG1 CA233330 , Mell R01 - 5R01CA255780 .

Keywords

Chemoradiation
IMRT
Locally advanced cervical cancer
NCT02466971
Novel therapeutics

ASJC Scopus subject areas

Oncology
Obstetrics and Gynecology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ygyno.2025.03.007

Cite this

Leath, C. A., Deng, W., Mell, L. K., Richardson, D. L., Walker, J. L., Holman, L. L., Lea, J. S., Amarnath, S. R., Santos-Reyes, L. J., Arend, R. C., Mayadev, J., Jegadeesh, N., DiSilvestro, P., Chon, H. S., Ghamande, S. A., Gao, L., Albuquerque, K., Chino, J. P., Donnelly, E., ... Monk, B. J. (2025). Incorporation of triapine (T) to cisplatin chemoradiation (CRT) for locally advanced cervical and vaginal cancer: Results from NRG-GY006, a phase III randomized trial. Gynecologic oncology, 195, 122-133. https://doi.org/10.1016/j.ygyno.2025.03.007

@article{b2b94b19e2be41308300924689f85a18,

title = "Incorporation of triapine (T) to cisplatin chemoradiation (CRT) for locally advanced cervical and vaginal cancer: Results from NRG-GY006, a phase III randomized trial",

abstract = "Background: Cisplatin-based chemoradiation (CRT) plus brachytherapy for locally advanced cervical cancer (LACC) is standard. Intrinsic overexpression of ribonucleotide reductase (RNR) may enhance DNA damage repair from CRT. We report on outcomes of adding RNR inhibitor, triapine (T), to CRT. Methods: NRG-GY006 is an open-label randomized phase III trial. FIGO 2009 LACC (stages IB2, II, IIIB or IVA) without para-aortic nodal involvement or stages II-IV vaginal cancer were eligible. Random assignment to CRT or in combination with thrice-weekly T (CRT + T) occurred. Radiation consisted of either 3D conformal (3DCRT) or image-guided intensity modulated RT (IG-IMRT) followed by intracavitary brachytherapy. Primary endpoint was overall survival (OS). Progression-free survival (PFS) was secondary. Exploratory endpoints included complete metabolic response rate on post treatment PET/CT imaging and comparative toxicity and outcomes for 3DCRT vs. IG-IMRT. Findings: Four-hundred-fifty patients were randomized including 448 eligible (224 in CRT and 224 in CRT + T). Median age was 47 (range 23–85). The majority had cervical cancer (93.3 \%) with squamous histology (82 \%). 52 \% had FIGO stage II disease. Racial/ethnic distribution included non-Hispanic white (53.8 \%), black (15.2 \%) and Hispanic/Latina (22.5 \%). At randomization, IG-IMRT was planned in 74.3 \% and HDR brachytherapy in 98.2 \%. No differences in Grade 3–5 toxicities were observed: CRT: 52 \% and CRT + T: 49 \%, with two G5 toxicities (cardiac arrest and acidosis) in the CRT + T arm. The median patient follow-up was 28 months (IQR 15–45). HR for death was 1.018 (95 \% CI 0.634–1.635) while HR for progression was 1.021 (95 \% CI 0.694–1.501). Interpretation: Triapine added to CRT did not improve OS.",

keywords = "Chemoradiation, IMRT, Locally advanced cervical cancer, NCT02466971, Novel therapeutics",

author = "Leath, \{Charles A.\} and Wei Deng and Mell, \{Loren K.\} and Richardson, \{Debra L.\} and Walker, \{Joan L.\} and Holman, \{Laura L.\} and Lea, \{Jayanthi S.\} and Amarnath, \{Sudha R.\} and Santos-Reyes, \{Luis Javier\} and Arend, \{Rebecca C.\} and Jyoti Mayadev and Naresh Jegadeesh and Paul DiSilvestro and Chon, \{Hye Sook\} and Ghamande, \{Sharad A.\} and Lei Gao and Kevin Albuquerque and Chino, \{Junzo P.\} and Eric Donnelly and Feddock, \{Jonathan M.\} and Jessica Lowenstein and Quick, \{Allison M.\} and Kunos, \{Charles M.\} and Helen MacKay and Carol Aghajanian and Monk, \{Bradley J.\}",

note = "Publisher Copyright: {\textcopyright} 2025 Elsevier Inc.",

year = "2025",

month = apr,

doi = "10.1016/j.ygyno.2025.03.007",

language = "English (US)",

volume = "195",

pages = "122--133",

journal = "Gynecologic oncology",

issn = "0090-8258",

publisher = "Academic Press Inc.",

}

Leath, CA, Deng, W, Mell, LK, Richardson, DL, Walker, JL, Holman, LL, Lea, JS, Amarnath, SR, Santos-Reyes, LJ, Arend, RC, Mayadev, J, Jegadeesh, N, DiSilvestro, P, Chon, HS, Ghamande, SA, Gao, L, Albuquerque, K, Chino, JP, Donnelly, E, Feddock, JM, Lowenstein, J, Quick, AM, Kunos, CM, MacKay, H, Aghajanian, C & Monk, BJ 2025, 'Incorporation of triapine (T) to cisplatin chemoradiation (CRT) for locally advanced cervical and vaginal cancer: Results from NRG-GY006, a phase III randomized trial', Gynecologic oncology, vol. 195, pp. 122-133. https://doi.org/10.1016/j.ygyno.2025.03.007

TY - JOUR

T1 - Incorporation of triapine (T) to cisplatin chemoradiation (CRT) for locally advanced cervical and vaginal cancer

T2 - Results from NRG-GY006, a phase III randomized trial

AU - Leath, Charles A.

AU - Deng, Wei

AU - Mell, Loren K.

AU - Richardson, Debra L.

AU - Walker, Joan L.

AU - Holman, Laura L.

AU - Lea, Jayanthi S.

AU - Amarnath, Sudha R.

AU - Santos-Reyes, Luis Javier

AU - Arend, Rebecca C.

AU - Mayadev, Jyoti

AU - Jegadeesh, Naresh

AU - DiSilvestro, Paul

AU - Chon, Hye Sook

AU - Ghamande, Sharad A.

AU - Gao, Lei

AU - Albuquerque, Kevin

AU - Chino, Junzo P.

AU - Donnelly, Eric

AU - Feddock, Jonathan M.

AU - Lowenstein, Jessica

AU - Quick, Allison M.

AU - Kunos, Charles M.

AU - MacKay, Helen

AU - Aghajanian, Carol

AU - Monk, Bradley J.

PY - 2025/4

Y1 - 2025/4

N2 - Background: Cisplatin-based chemoradiation (CRT) plus brachytherapy for locally advanced cervical cancer (LACC) is standard. Intrinsic overexpression of ribonucleotide reductase (RNR) may enhance DNA damage repair from CRT. We report on outcomes of adding RNR inhibitor, triapine (T), to CRT. Methods: NRG-GY006 is an open-label randomized phase III trial. FIGO 2009 LACC (stages IB2, II, IIIB or IVA) without para-aortic nodal involvement or stages II-IV vaginal cancer were eligible. Random assignment to CRT or in combination with thrice-weekly T (CRT + T) occurred. Radiation consisted of either 3D conformal (3DCRT) or image-guided intensity modulated RT (IG-IMRT) followed by intracavitary brachytherapy. Primary endpoint was overall survival (OS). Progression-free survival (PFS) was secondary. Exploratory endpoints included complete metabolic response rate on post treatment PET/CT imaging and comparative toxicity and outcomes for 3DCRT vs. IG-IMRT. Findings: Four-hundred-fifty patients were randomized including 448 eligible (224 in CRT and 224 in CRT + T). Median age was 47 (range 23–85). The majority had cervical cancer (93.3 %) with squamous histology (82 %). 52 % had FIGO stage II disease. Racial/ethnic distribution included non-Hispanic white (53.8 %), black (15.2 %) and Hispanic/Latina (22.5 %). At randomization, IG-IMRT was planned in 74.3 % and HDR brachytherapy in 98.2 %. No differences in Grade 3–5 toxicities were observed: CRT: 52 % and CRT + T: 49 %, with two G5 toxicities (cardiac arrest and acidosis) in the CRT + T arm. The median patient follow-up was 28 months (IQR 15–45). HR for death was 1.018 (95 % CI 0.634–1.635) while HR for progression was 1.021 (95 % CI 0.694–1.501). Interpretation: Triapine added to CRT did not improve OS.

AB - Background: Cisplatin-based chemoradiation (CRT) plus brachytherapy for locally advanced cervical cancer (LACC) is standard. Intrinsic overexpression of ribonucleotide reductase (RNR) may enhance DNA damage repair from CRT. We report on outcomes of adding RNR inhibitor, triapine (T), to CRT. Methods: NRG-GY006 is an open-label randomized phase III trial. FIGO 2009 LACC (stages IB2, II, IIIB or IVA) without para-aortic nodal involvement or stages II-IV vaginal cancer were eligible. Random assignment to CRT or in combination with thrice-weekly T (CRT + T) occurred. Radiation consisted of either 3D conformal (3DCRT) or image-guided intensity modulated RT (IG-IMRT) followed by intracavitary brachytherapy. Primary endpoint was overall survival (OS). Progression-free survival (PFS) was secondary. Exploratory endpoints included complete metabolic response rate on post treatment PET/CT imaging and comparative toxicity and outcomes for 3DCRT vs. IG-IMRT. Findings: Four-hundred-fifty patients were randomized including 448 eligible (224 in CRT and 224 in CRT + T). Median age was 47 (range 23–85). The majority had cervical cancer (93.3 %) with squamous histology (82 %). 52 % had FIGO stage II disease. Racial/ethnic distribution included non-Hispanic white (53.8 %), black (15.2 %) and Hispanic/Latina (22.5 %). At randomization, IG-IMRT was planned in 74.3 % and HDR brachytherapy in 98.2 %. No differences in Grade 3–5 toxicities were observed: CRT: 52 % and CRT + T: 49 %, with two G5 toxicities (cardiac arrest and acidosis) in the CRT + T arm. The median patient follow-up was 28 months (IQR 15–45). HR for death was 1.018 (95 % CI 0.634–1.635) while HR for progression was 1.021 (95 % CI 0.694–1.501). Interpretation: Triapine added to CRT did not improve OS.

KW - Chemoradiation

KW - IMRT

KW - Locally advanced cervical cancer

KW - NCT02466971

KW - Novel therapeutics

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U2 - 10.1016/j.ygyno.2025.03.007

DO - 10.1016/j.ygyno.2025.03.007

M3 - Article

C2 - 40101606

AN - SCOPUS:105000064240

SN - 0090-8258

VL - 195

SP - 122

EP - 133

JO - Gynecologic oncology

JF - Gynecologic oncology

ER -

Incorporation of triapine (T) to cisplatin chemoradiation (CRT) for locally advanced cervical and vaginal cancer: Results from NRG-GY006, a phase III randomized trial

Abstract

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UN SDGs

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