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RecruitingNCT04989647CERVANTESUpdated Sep 7, 2023

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

A Phase 3 interventional study of No adjuvant therapy and Adjuvant radiotherapy in Cervical Cancer, sponsored by The Central and Eastern European Gynecologic Oncology Group. Recruiting at 1 site in Czechia. Open to female participants aged 18 Years to 85 Years. Per ClinicalTrials.gov, last updated 2023-09-07.

Sponsored by The Central and Eastern European Gynecologic Oncology Group · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
514
Allocation
Randomized
Ages
18 Years to 85 Years
Sex
Female
01

Study 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%).

Read the detailed description

The role of adjuvant (chemo)radiotherapy in intermediate risk (IR) cervical cancer patients is controversial, supported by single randomised GOG 92 study performed more than 20 years ago. Intermediate-risk group is defined as lymph node negative but with a combination of negative prognostic factors (tumour size >2 cm, lymphovascular space invasion, deep stromal invasion >2/3). Recent retrospective studies showed excellent local control in intermediate risk group patients after radical surgery with no additional adjuvant treatment.

CERVANTES trial is designed to bring level A evidence on the role of adjuvant treatment in IR patients in an international, prospective, randomised study. Patients will be registered into the trial before surgery and randomised after the final pathology report has been received into ARM A, with no additional treatment, and ARM B, receiving adjuvant (chemo)radiotherapy. Quality assurance program will be in place for both, radical surgery and adjuvant treatment.

02

Conditions studied

  • Cervical Cancer

Keywords

  • intermediate risk cervical cancer
  • adjuvant radiotherapy
  • disease free survival
03

Who can participate

Ages eligible
18 Years to 85 Years
Sexes eligible
Female
Accepts healthy volunteers
No

Inclusion criteria

  • Pathologically confirmed invasive cervical cancer
  • FIGO IB1-IIA
  • Squamous cell cancer or HPV-related adenocarcinoma
  • Presence of tumour-related risk factors as follows:

    1. tumour ≥4 cm OR
    2. tumour>2 cm \<4 cm AND lymphovascular space invasion OR
    3. tumour >2 cm \<4 cm AND tumour free distance \<3 mm OR
    4. 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)

Exclusion criteria

Exclusion Criteria:

  • Adenosquamous cancer or adenocarcinoma unusual type (non-HPV related - such as: mucinous, clear cell, mesonephric) or other rare tumour types (those not listed in the inclusion criteria)
  • 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
04

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
514 participants (estimated)

Study arms

  • Experimental
    A: Surgery only

    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

  • Experimental
    B: Surgery + radiothrerapy

    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

  • RadiationNo adjuvant therapy

    Patients will not receive any type of adjuvant therapy.

  • RadiationAdjuvant radiotherapy

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

05

What researchers measure

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.

    Time frame: Analysed 3 years after randomization of the last patient.

Secondary outcomes

  1. Overall survival

    Time frame: Analysed 6 years after randomization of the last patient.

  2. Pelvic disease-free survival

    Time frame: Analysed 3 years after randomization of the last patient.

  3. Health-related quality of life based questionnaire

    The analysis will be made based on EORTC validated questionnaires and developed qualitative CERVANTES questionnaire.

    Time frame: Analysed 3 years after randomization of the last patient.

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

    Time frame: Analysed 3 years after randomization of the last patient.

06

Study locations

1 of 1 sites recruiting
07

References and documents

Publications

  • 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. PubMed 10329031 ↗
  • 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. PubMed 16427212 ↗
  • 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. PubMed 33575846 ↗
  • 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. PubMed 33153125 ↗
  • 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. PubMed 30348519 ↗
  • 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. PubMed 31133601 ↗
  • 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. PubMed 33303568 ↗
  • 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. PubMed 32246761 ↗
  • 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. PubMed 33962994 ↗
  • 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. PubMed 22592722 ↗
  • 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. PubMed 6751268 ↗
  • 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. PubMed 9234917 ↗
  • 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. PubMed 10570432 ↗
  • 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. PubMed 12128131 ↗
  • 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. PubMed 16803494 ↗
  • 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. PubMed 15053068 ↗
  • 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. PubMed 33318656 ↗
  • 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. PubMed 29728273 ↗
  • 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. PubMed 36100282 ↗

Individual participant data

Plan to share: No

08

Registry details

Key details

Study ID
NCT04989647
Lead sponsor
The Central and Eastern European Gynecologic Oncology Group
Responsible party
David Cibula (prof. David Cibula, MD, PhD, General University Hospital, Prague) — Principal investigator
First posted
Aug 4, 2021
Start date
Jun 10, 2022
Primary completion
Dec 2029 (estimated)
Completion
Dec 2032 (estimated)
Last update
Sep 7, 2023

Study contacts

Martina Borcinova, PhD
Contact
martina.borcinova@cervantes-trial.com
+420224969298
Trial Office
Contact
trial.office@cervantes-trial.com
+420224967432
David Cibula, prof.
principal investigator · General University Hospital in Prague, Czech Republic

Oversight

Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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