Randomized Trial of Radiation Therapy With or Without Chemotherapy for Endometrial Cancer (PORTEC-3)

• ClinicalTrials.gov Identifier: NCT00411138
• Recruitment Status: Active, not recruiting
• First Posted: December 13, 2006
• Last Update Posted: October 11, 2023
• Sponsor: Leiden University
• Collaborators: Cancer Research UK; Australia New Zealand Gynaecological Oncology Group; NCIC Clinical Trials Group; Mario Negri Institute for Pharmacological Research; UNICANCER
• Information provided by (Responsible Party): Carien Creutzberg, Leiden University

Tracking Information

• First Submitted Date: December 11, 2006
• First Posted Date: December 13, 2006
• Last Update Posted Date: October 11, 2023
• Actual Study Start Date: November 23, 2006
• Actual Primary Completion Date: November 29, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 12, 2018)

• Overall survival [ Time Frame: 5 years ]
  co-primary endpoint
• Failure-free survival [ Time Frame: 5 years ]
  co-primary endpoint

Original Primary Outcome Measures (submitted: December 11, 2006)

• Overall survival at 5 years
• Failure-free survival at 5 years

Current Secondary Outcome Measures (submitted: February 12, 2018)

• Quality of life by QLQ-C30 v3.0 [ Time Frame: 5 years ]
  Health-related overall quality of life and patient-reported symptom measures
• Severe treatment-related morbidity [ Time Frame: 5 years ]
  Acute serious events and SAE and late grade 3-4 complications
• Vaginal or pelvic relapse [ Time Frame: 5 years ]
  Both vaginal or pelvic relapse as first failure and total vaginal or pelvic relapse
• Distant metastases [ Time Frame: 5 years ]
  Both distant relapse as first failure and total distant relapse

Original Secondary Outcome Measures (submitted: December 11, 2006)

• Quality of life by QLQ-C30 v3.0
• Severe treatment-related morbidity
• Rate of vaginal or pelvic relapse
• Rate of distant metastases

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Randomized Trial of Radiation Therapy With or Without Chemotherapy for Endometrial Cancer
• Official Title: Randomized Phase III Trial Comparing Concurrent Chemoradiation and Adjuvant Chemotherapy With Pelvic Radiation Alone in High Risk and Advanced Stage Endometrial Carcinoma: PORTEC-3

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as cisplatin, paclitaxel, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving chemotherapy and radiation therapy after surgery may kill any tumor cells that remain after surgery. It is not yet known whether giving chemotherapy together with radiation therapy is more effective than giving radiation therapy alone in treating endometrial cancer.

PURPOSE: This randomized phase III trial is studying chemotherapy and radiation therapy to see how well they work compared with radiation therapy alone in treating patients with high-risk, stage I, stage II, or stage III endometrial cancer.

Detailed Description

OBJECTIVES:

Primary

• Compare the overall survival and failure-free survival of patients with high-risk stage IB-III endometrial carcinoma treated with concurrent chemoradiotherapy followed by adjuvant chemotherapy vs pelvic radiotherapy alone.

Secondary

• Compare the rates of pelvic and distant recurrence, severe (grades 3 and 4) treatment-related toxicity, and quality of life of patients treated with these regimens.

OUTLINE:

This is a multicenter, prospective, open-label, randomized, controlled study. Patients are stratified according to participating group (DGOG vs UK NCRI vs NCIC CTG vs MaNGO vs Unicancer), type of surgery (total abdominal hysterectomy and bilateral salpingo-oophorectomy [TAH-BSO] vs TAH-BSO plus lymphadenectomy vs laparoscopic hysterectomy [TLH-BSO] vs TLH-BSO plus lymphadenectomy), stage (IA vs IB vs II vs III), and histological type (endometrioid carcinoma vs serous or clear cell carcinoma). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive external-beam pelvic radiotherapy 5 days a week for up to 6 weeks, combined with cisplatin IV days 1 and 22. Patients with cervical involvement undergo vaginal brachytherapy boost. At least 3 weeks after completion of chemoradiotherapy, patients undergo adjuvant chemotherapy comprising paclitaxel IV and carboplatin IV on day 1. Adjuvant chemotherapy repeats every 3 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients undergo external-beam pelvic radiotherapy (and vaginal brachytherapy alone in case of cervical involvement) as in arm I.

Quality of life is assessed at baseline, completion of radiotherapy, completion of chemotherapy, at 6 months, and then once a year for 5 years.

After completion of study therapy, patients are followed periodically for up to 10 years.

PROJECTED ACCRUAL: A total of 670 patients will be accrued for this study.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Endometrial Cancer

Intervention

• Radiation: Radiation Therapy
  External beam pelvic radiotherapy (48.6 Gy in 1.8 Gy fractions) Vaginal brachytherapy boost in case of cervical involvement
  Other Names:

  • RT
  • 3D conformal radiotherapy
  • IMRT
  • brachytherapy
• Drug: cisplatin
  cisplatin 50 mg/m2 i.v., 2 cycles during radiotherapy, 3 wks interval
  Other Name: Cisplatine
• Drug: carboplatin
  carboplatin AUC 5, 4 cycles after completion of radiotherapy, 3 wks interval
  Other Names:

  • Carboplatine
  • Carbotaxol
• Drug: Paclitaxel
  paclitaxel 175 mg/m2, 4 cycles after completion of radiotherapy, 3 wks interval
  Other Names:

  • Taxol
  • Taxolcarbo

Study Arms

• Active Comparator: Radiation Therapy
  Pelvic Radiotherapy alone
  Intervention: Radiation: Radiation Therapy
• Experimental: Radiation Therapy and Chemotherapy
  Pelvic Radiation plus 2 concurrent cycles cisplatin followed by 4 adjuvant cycles carboplatin and paclitaxel
  Interventions:

  • Radiation: Radiation Therapy
  • Drug: cisplatin
  • Drug: carboplatin
  • Drug: Paclitaxel

Publications *

• Jameson MG, McNamara J, Bailey M, Metcalfe PE, Holloway LC, Foo K, Do V, Mileshkin L, Creutzberg CL, Khaw P. Results of the Australasian (Trans-Tasman Oncology Group) radiotherapy benchmarking exercise in preparation for participation in the PORTEC-3 trial. J Med Imaging Radiat Oncol. 2016 Aug;60(4):554-9. doi: 10.1111/1754-9485.12447. Epub 2016 Apr 5.
• ANZGOG and PORTEC Group; Blinman P, Mileshkin L, Khaw P, Goss G, Johnson C, Capp A, Brooks S, Wain G, Kolodziej I, Veillard AS, O'Connell R, Creutzberg CL, Stockler MR. Patients' and clinicians' preferences for adjuvant chemotherapy in endometrial cancer: an ANZGOG substudy of the PORTEC-3 intergroup randomised trial. Br J Cancer. 2016 Nov 8;115(10):1179-1185. doi: 10.1038/bjc.2016.323. Epub 2016 Oct 20.
• de Boer SM, Wortman BG, Bosse T, Powell ME, Singh N, Hollema H, Wilson G, Chowdhury MN, Mileshkin L, Pyman J, Katsaros D, Carinelli S, Fyles A, McLachlin CM, Haie-Meder C, Duvillard P, Nout RA, Verhoeven-Adema KW, Putter H, Creutzberg CL, Smit VTHBM; for PORTEC Study Group. Clinical consequences of upfront pathology review in the randomised PORTEC-3 trial for high-risk endometrial cancer. Ann Oncol. 2018 Feb 1;29(2):424-430. doi: 10.1093/annonc/mdx753.
• de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C, Ottevanger PB, Ledermann JA, Khaw P, Colombo A, Fyles A, Baron MH, Kitchener HC, Nijman HW, Kruitwagen RF, Nout RA, Verhoeven-Adema KW, Smit VT, Putter H, Creutzberg CL; PORTEC study group. Toxicity and quality of life after adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2016 Aug;17(8):1114-1126. doi: 10.1016/S1470-2045(16)30120-6. Epub 2016 Jul 7.
• de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C, Ottevanger PB, Ledermann JA, Khaw P, Colombo A, Fyles A, Baron MH, Jurgenliemk-Schulz IM, Kitchener HC, Nijman HW, Wilson G, Brooks S, Carinelli S, Provencher D, Hanzen C, Lutgens LCHW, Smit VTHBM, Singh N, Do V, D'Amico R, Nout RA, Feeney A, Verhoeven-Adema KW, Putter H, Creutzberg CL; PORTEC study group. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Mar;19(3):295-309. doi: 10.1016/S1470-2045(18)30079-2. Epub 2018 Feb 12. Erratum In: Lancet Oncol. 2018 Apr;19(4):e184.
• de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C, Ottevanger PB, Ledermann JA, Khaw P, D'Amico R, Fyles A, Baron MH, Jurgenliemk-Schulz IM, Kitchener HC, Nijman HW, Wilson G, Brooks S, Gribaudo S, Provencher D, Hanzen C, Kruitwagen RF, Smit VTHBM, Singh N, Do V, Lissoni A, Nout RA, Feeney A, Verhoeven-Adema KW, Putter H, Creutzberg CL; PORTEC Study Group. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019 Sep;20(9):1273-1285. doi: 10.1016/S1470-2045(19)30395-X. Epub 2019 Jul 22. Erratum In: Lancet Oncol. 2019 Sep;20(9):e468.
• Post CCB, de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C, Ottevanger NPB, Ledermann JA, Khaw P, D'Amico R, Fyles A, Baron MH, Kitchener HC, Nijman HW, Lutgens LCHW, Brooks S, Jurgenliemk-Schulz IM, Feeney A, Goss G, Fossati R, Ghatage P, Leary A, Do V, Lissoni AA, McCormack M, Nout RA, Verhoeven-Adema KW, Smit VTHBM, Putter H, Creutzberg CL. Long-Term Toxicity and Health-Related Quality of Life After Adjuvant Chemoradiation Therapy or Radiation Therapy Alone for High-Risk Endometrial Cancer in the Randomized PORTEC-3 Trial. Int J Radiat Oncol Biol Phys. 2021 Mar 15;109(4):975-986. doi: 10.1016/j.ijrobp.2020.10.030. Epub 2020 Oct 28.
• Leon-Castillo A, de Boer SM, Powell ME, Mileshkin LR, Mackay HJ, Leary A, Nijman HW, Singh N, Pollock PM, Bessette P, Fyles A, Haie-Meder C, Smit VTHBM, Edmondson RJ, Putter H, Kitchener HC, Crosbie EJ, de Bruyn M, Nout RA, Horeweg N, Creutzberg CL, Bosse T; TransPORTEC consortium. Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit From Adjuvant Therapy. J Clin Oncol. 2020 Oct 10;38(29):3388-3397. doi: 10.1200/JCO.20.00549. Epub 2020 Aug 4.
• Post CCB, Stelloo E, Smit VTHBM, Ruano D, Tops CM, Vermij L, Rutten TA, Jurgenliemk-Schulz IM, Lutgens LCHW, Jobsen JJ, Nout RA, Crosbie EJ, Powell ME, Mileshkin L, Leary A, Bessette P, Putter H, de Boer SM, Horeweg N, Nielsen M, Wezel TV, Bosse T, Creutzberg CL. Prevalence and Prognosis of Lynch Syndrome and Sporadic Mismatch Repair Deficiency in Endometrial Cancer. J Natl Cancer Inst. 2021 Sep 4;113(9):1212-1220. doi: 10.1093/jnci/djab029.
• Wortman BG, Post CCB, Powell ME, Khaw P, Fyles A, D'Amico R, Haie-Meder C, Jurgenliemk-Schulz IM, McCormack M, Do V, Katsaros D, Bessette P, Baron MH, Nout RA, Whitmarsh K, Mileshkin L, Lutgens LCHW, Kitchener HC, Brooks S, Nijman HW, Astreinidou E, Putter H, Creutzberg CL, de Boer SM. Radiation Therapy Techniques and Treatment-Related Toxicity in the PORTEC-3 Trial: Comparison of 3-Dimensional Conformal Radiation Therapy Versus Intensity-Modulated Radiation Therapy. Int J Radiat Oncol Biol Phys. 2022 Feb 1;112(2):390-399. doi: 10.1016/j.ijrobp.2021.09.042. Epub 2021 Oct 2.
• Khaw P, Do V, Lim K, Cunninghame J, Dixon J, Vassie J, Bailey M, Johnson C, Kahl K, Gordon C, Cook O, Foo K, Fyles A, Powell M, Haie-Meder C, D'Amico R, Bessette P, Mileshkin L, Creutzberg CL, Moore A. Radiotherapy Quality Assurance in the PORTEC-3 (TROG 08.04) Trial. Clin Oncol (R Coll Radiol). 2022 Mar;34(3):198-204. doi: 10.1016/j.clon.2021.11.015. Epub 2021 Dec 11.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: April 11, 2012): 670
• Original Enrollment (submitted: December 11, 2006): 800
• Estimated Study Completion Date: December 31, 2024
• Actual Primary Completion Date: November 29, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically confirmed endometrial carcinoma, with one of the following postoperative FIGO 2009 stages and grade:

  1. stage IA with invasion, grade 3 with documented LVSI
  2. stage IB grade 3
  3. stage II
  4. stage IIIA or IIIC; or IIIB if parametrial invasion only
  5. stage IA (with invasion), IB, II, or III with serous or clear cell histology
• WHO-performance status 0-2
• WBC ≥ 3.0 x 109/L.
• Platelets ≥ 100 x 109/L.
• Bilirubin ≤ 1.5 x UNL
• ASAT/ALAT ≤ 2.5 x UNL
• Written informed consent

Exclusion criteria:

• Uterine sarcoma (including carcinosarcoma)
• Previous malignancy (except for non-melanomatous skin cancer) < 10 yrs
• Previous pelvic radiotherapy
• Hormonal therapy or chemotherapy for this tumor
• Macroscopic stage II for which Wertheim type hysterectomy (eligible if stage II grade 3 or stage III at pathology)
• Prior diagnosis of Crohn's disease or ulcerative colitis
• Residual macroscopic tumor after surgery
• Creatinine clearance ≤ 60 ml/min (Cockroft) or ≤ 50 ml/min (EDTA clearance, or measured creatinine clearance)
• Impaired cardiac function, prohibiting the infusion of large amounts of fluid during cisplatin therapy
• Peripheral Neuropathy > or = grade 2
• Hearing impairment > or = grade 3, or born deaf

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years to 90 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT00411138
• Other Study ID Numbers: CDR0000521447; P06.031; CKTO-2006-04 ( Other Grant/Funding Number: Dutch Cancer Society ); ISRCTN14387080 ( Registry Identifier: International Standard Randomised Controlled Trial Number ); P06.031-PORTEC-3 ( Other Identifier: Leiden University Medical Center ); 2007-004917-33 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Sharing of data will be an option after publication of long-term outcomes and after submission of a research plan with is approved by the with international TMG
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Anticipated in 218

• Current Responsible Party: Carien Creutzberg, Leiden University
• Original Responsible Party: Not Provided
• Current Study Sponsor: Leiden University
• Original Study Sponsor: Leiden University Medical Center

Collaborators

• Cancer Research UK
• Australia New Zealand Gynaecological Oncology Group
• NCIC Clinical Trials Group
• Mario Negri Institute for Pharmacological Research
• UNICANCER

Investigators

• Study Chair: Carien L. Creutzberg, MD, PhD; Leiden University Medical Center

• PRS Account: Leiden University Medical Center
• Verification Date: October 2023