Intermediate Risk Cervical Cancer: Radical Surgery +/- Adjuvant Radiotherapy

NCT04989647 | Recruiting Phase 3 DMC

• 1 other identifier: ENGOT-cx16/CEEGOG/CERVANTES
• Study Type: interventional
• Target: 514
• Locations: 1 country
• Sites: 1

Brief Summary

The objective of the trial is to evaluate if adjuvant (chemo)radiation is associated with a disease-free survival benefit after radical surgery in patients with intermediate risk cervical cancer. The primary endpoint of the study is the disease-free survival from the day of randomisation. A total of 514 patients are required to achieve 80% power on 5% significance level with non-inferiority margin of 5% to test the difference between the ARMs using Cox proportional hazards model. The maximal tolerated margin for non-inferiority in 2-year DFS is 5% (including expected drop-out rate of 10%).

Conditions

Cervical Cancer

Keywords

intermediate risk cervical cancer; adjuvant radiotherapy; disease free survival

Outcome Measures

Primary Outcomes (1)

• Disease-free survival

  Calculated as an interval from the day of randomisation until diagnosis of recurrence: (a) unequivocal finding on imaging by subjective radiological assessment; b) suspicious recurrence on imaging either confirmed by biopsy or supported by other signs (disease progression on imaging or progression of symptoms); (c) physical examination supported by clinical evidence (i.e., symptoms or progression); or (d) death caused by disease or death of unknown cause.

  Analysed 3 years after randomization of the last patient.

Secondary Outcomes (4)

• Overall survival

  Analysed 6 years after randomization of the last patient.

• Pelvic disease-free survival

  Analysed 3 years after randomization of the last patient.

• Health-related quality of life based questionnaire

  Analysed 3 years after randomization of the last patient.

• Treatment-related adverse events based on Common Terminology Criteria for Adverse Events v5.0

  Analysed 3 years after randomization of the last patient.

Study Arms (2)

A: Surgery only

EXPERIMENTAL

Radical hysterectomy, sentinel lymph node biopsy and systematic pelvic lymphadenectomy (PLND)\*. No further treatment will be administered. \*PLND can be avoided in patients with tumours \< 4cm

Radiation: No adjuvant therapy

B: Surgery + radiothrerapy

EXPERIMENTAL

Radical hysterectomy, sentinel lymph node biopsy and systematic pelvic lymphadenectomy (PLND)\*, followed by adjuvant treatment. \*PLND can be avoided in patients with tumours \< 4cm

Radiation: Adjuvant radiotherapy

Interventions

No adjuvant therapy RADIATION

Patients will not receive any type of adjuvant therapy.

A: Surgery only

Adjuvant radiotherapy RADIATION

Patients will receive adjuvant treatment composed of either pelvic radiotherapy external beam radiotherapy ± brachytherapy or concomitant chemoradiotherapy (pelvic radiotherapy + chemotherapy).

B: Surgery + radiothrerapy

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Pathologically confirmed invasive cervical cancer
• FIGO IB1-IIA
• Squamous cell cancer or HPV-related adenocarcinoma
• Presence of tumour-related risk factors as follows:
• tumour ≥4 cm OR
• tumour\>2 cm \<4 cm AND lymphovascular space invasion OR
• tumour \>2 cm \<4 cm AND tumour free distance \<3 mm OR
• tumour \>2 cm \<4 cm AND deep stromal invasion (\>2/3)
• No evidence of suspicious pelvic lymph nodes or distant metastases on imaging (by radiological subjective assessment before surgery and negative pelvic LN on final pathology)
• ECOG performance status 0-1
• Deemed suitable and fit for radical surgery followed by adjuvant radiotherapy
• Negative pregnancy test (if applicable)
• Negative HIV test (only performed in high-risk countries or patients who have moved from those countries within the past 10 years)

You may not qualify if:

• Inconclusive primary site of disease
• Unequivocally positive lymph node by imaging (by radiological subjective assessment)
• FIGO \<IB1 / \>IIA
• Previous pelvic malignancy
• History of second primary cancer outside pelvis if ≤ 3 years complete clinical remission (CCR)
• Previous pelvic radiotherapy
• Neoadjuvant chemotherapy prior surgical treatment
• Low likelihood of patient compliance to the follow-up

Sponsors & Collaborators

• The Central and Eastern European Gynecologic Oncology Group: lead

Study Sites (1)

General University Hospital in Prague

Prague, 12000, Czechia

RECRUITING

Related Publications (19)

• Sedlis A, Bundy BN, Rotman MZ, Lentz SS, Muderspach LI, Zaino RJ. A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology Group Study. Gynecol Oncol. 1999 May;73(2):177-83. doi: 10.1006/gyno.1999.5387.

  PMID: 10329031 BACKGROUND

• Rotman M, Sedlis A, Piedmonte MR, Bundy B, Lentz SS, Muderspach LI, Zaino RJ. 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. Int J Radiat Oncol Biol Phys. 2006 May 1;65(1):169-76. doi: 10.1016/j.ijrobp.2005.10.019. Epub 2006 Jan 19.

  PMID: 16427212 BACKGROUND

• Scharl S, Becher C, Gerken M, Scharl A, Anapolski M, Ignatov A, Inwald EC, Ortmann O, Kolbl O, Klinkhammer-Schalke M, Papathemelis T. Is there a benefit for adjuvant radio(chemo)therapy in early cervical cancer? Results from a population-based study. Arch Gynecol Obstet. 2021 Sep;304(3):759-771. doi: 10.1007/s00404-021-05989-w. Epub 2021 Feb 11.

  PMID: 33575846 BACKGROUND

• Kim SI, Kim TH, Lee M, Kim HS, Chung HH, Lee TS, Jeon HW, Kim JW, Park NH, Song YS. Impact of Adjuvant Radiotherapy on Survival Outcomes in Intermediate-Risk, Early-Stage Cervical Cancer: Analyses Regarding Surgical Approach of Radical Hysterectomy. J Clin Med. 2020 Nov 3;9(11):3545. doi: 10.3390/jcm9113545.

  PMID: 33153125 BACKGROUND

• Cibula D, Abu-Rustum NR, Fischerova D, Pather S, Lavigne K, Slama J, Alektiar K, Ming-Yin L, Kocian R, Germanova A, Fruhauf F, Dostalek L, Dusek L, Narayan K. Surgical treatment of "intermediate risk" lymph node negative cervical cancer patients without adjuvant radiotherapy-A retrospective cohort study and review of the literature. Gynecol Oncol. 2018 Dec;151(3):438-443. doi: 10.1016/j.ygyno.2018.10.018. Epub 2018 Oct 20.

  PMID: 30348519 BACKGROUND

• van der Velden J, Mom CH, van Lonkhuijzen L, Tjiong MY, Westerveld H, Fons G. Analysis of isolated loco-regional recurrence rate in intermediate risk early cervical cancer after a type C2 radical hysterectomy without adjuvant radiotherapy. Int J Gynecol Cancer. 2019 Jun 2;29(5):874-878. doi: 10.1136/ijgc-2019-000445.

  PMID: 31133601 BACKGROUND

• Cao L, Wen H, Feng Z, Han X, Zhu J, Wu X. Role of adjuvant therapy after radical hysterectomy in intermediate-risk, early-stage cervical cancer. Int J Gynecol Cancer. 2021 Jan;31(1):52-58. doi: 10.1136/ijgc-2020-001974. Epub 2020 Dec 10.

  PMID: 33303568 BACKGROUND

• Akilli H, Tohma YA, Bulut AN, Karakas LA, Haberal AN, Kuscu UE, Ayhan A. Comparison of no adjuvant treatment and radiotherapy in early-stage cervical carcinoma with intermediate risk factors. Int J Gynaecol Obstet. 2020 Jun;149(3):298-302. doi: 10.1002/ijgo.13147. Epub 2020 Apr 22.

  PMID: 32246761 BACKGROUND

• Nasioudis D, Latif NA, Giuntoli Ii RL, Haggerty AF, Cory L, Kim SH, Morgan MA, Ko EM. Role of adjuvant radiation therapy after radical hysterectomy in patients with stage IB cervical carcinoma and intermediate risk factors. Int J Gynecol Cancer. 2021 Jun;31(6):829-834. doi: 10.1136/ijgc-2021-002489. Epub 2021 May 6.

  PMID: 33962994 BACKGROUND

• Rogers L, Siu SS, Luesley D, Bryant A, Dickinson HO. Radiotherapy and chemoradiation after surgery for early cervical cancer. Cochrane Database Syst Rev. 2012 May 16;2012(5):CD007583. doi: 10.1002/14651858.CD007583.pub3.

  PMID: 22592722 BACKGROUND

• Bilek K, Ebeling K, Leitsmann H, Seidel G. Radical pelvic surgery versus radical surgery plus radiotherapy for stage Ib carcinoma of the cervix uteri. Preliminary results of a prospective randomized clinical study. Arch Geschwulstforsch. 1982 May;52(3):223-9.

  PMID: 6751268 BACKGROUND

• Schorge JO, Molpus KL, Koelliker D, Nikrui N, Goodman A, Fuller AF Jr. Stage IB and IIA cervical cancer with negative lymph nodes: the role of adjuvant radiotherapy after radical hysterectomy. Gynecol Oncol. 1997 Jul;66(1):31-5. doi: 10.1006/gyno.1997.4691.

  PMID: 9234917 BACKGROUND

• Kridelka FJ, Berg DO, Neuman M, Edwards LS, Robertson G, Grant PT, Hacker NF. Adjuvant small field pelvic radiation for patients with high risk, stage IB lymph node negative cervix carcinoma after radical hysterectomy and pelvic lymph node dissection. A pilot study. Cancer. 1999 Nov 15;86(10):2059-65.

  PMID: 10570432 BACKGROUND

• Hong JH, Tsai CS, Lai CH, Chang TC, Wang CC, Lee SP, Tseng CJ, Hsueh S. Postoperative low-pelvic irradiation for stage I-IIA cervical cancer patients with risk factors other than pelvic lymph node metastasis. Int J Radiat Oncol Biol Phys. 2002 Aug 1;53(5):1284-90. doi: 10.1016/s0360-3016(02)02831-6.

  PMID: 12128131 BACKGROUND

• Pieterse QD, Trimbos JB, Dijkman A, Creutzberg CL, Gaarenstroom KN, Peters AA, Kenter GG. Postoperative radiation therapy improves prognosis in patients with adverse risk factors in localized, early-stage cervical cancer: a retrospective comparative study. Int J Gynecol Cancer. 2006 May-Jun;16(3):1112-8. doi: 10.1111/j.1525-1438.2006.00600.x.

  PMID: 16803494 BACKGROUND

• Chen SW, Liang JA, Yang SN, Lin FJ. Early stage cervical cancer with negative pelvic lymph nodes: pattern of failure and complication following radical hysterectomy and adjuvant radiotherapy. Eur J Gynaecol Oncol. 2004;25(1):81-6.

  PMID: 15053068 BACKGROUND

• Cibula D, Slama J, Dostalek L, Fischerova D, Germanova A, Fruhauf F, Dundr P, Nemejcova K, Jarkovsky J, Sebestova S, Burgetova A, Borcinova M, Kocian R. Tumour-free distance: a novel prognostic marker in patients with early-stage cervical cancer treated by primary surgery. Br J Cancer. 2021 Mar;124(6):1121-1129. doi: 10.1038/s41416-020-01204-w. Epub 2020 Dec 14.

  PMID: 33318656 BACKGROUND

• Cibula D, Potter R, Planchamp F, Avall-Lundqvist E, Fischerova D, Haie Meder C, Kohler C, Landoni F, Lax S, Lindegaard JC, Mahantshetty U, Mathevet P, McCluggage WG, McCormack M, Naik R, Nout R, Pignata S, Ponce J, Querleu D, Raspagliesi F, Rodolakis A, Tamussino K, Wimberger P, Raspollini MR. The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology guidelines for the management of patients with cervical cancer. Radiother Oncol. 2018 Jun;127(3):404-416. doi: 10.1016/j.radonc.2018.03.003. Epub 2018 May 1.

  PMID: 29728273 BACKGROUND

• Cibula D, Borcinova M, Kocian R, Feltl D, Argalacsova S, Dvorak P, Fischerova D, Dundr P, Jarkovsky J, Hoschlova E, Slama J, Scambia G. CERVANTES: an international randomized trial of radical surgery followed by adjuvant (chemo) radiation versus no further treatment in patients with early-stage, intermediate-risk cervical cancer (CEEGOG-CX-05; ENGOT-CX16). Int J Gynecol Cancer. 2022 Oct 3;32(10):1327-1331. doi: 10.1136/ijgc-2022-003918.

  PMID: 36100282 DERIVED

MeSH Terms

Conditions

Uterine Cervical Neoplasms

Interventions

Radiotherapy, Adjuvant

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Intervention Hierarchy (Ancestors)

Combined Modality Therapy; Therapeutics; Radiotherapy

Study Officials

• David Cibula, prof.

  General University Hospital in Prague, Czech Republic

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Martina Borcinova, PhD

CONTACT

+420224969298; martina.borcinova@cervantes-trial.com

Trial Office

CONTACT

+420224967432; trial.office@cervantes-trial.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: prof. David Cibula, MD, PhD

Study Record Dates

• First Submitted: July 29, 2021
• First Posted: August 4, 2021
• Study Start: June 10, 2022
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2032
• Last Updated: September 7, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

CZ (1)