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

Official title

An International Randomised Trial of Radical Surgery Followed by Adjuvant (Chemo)Radiation Versus no Further Treatment in Patients With Early-stage, Intermediate-risk Cervical Cancer Patients

Overview

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%).

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.

Interventions

• Radiation No adjuvant therapy
  Patients will not receive any type of adjuvant therapy.
• Radiation Adjuvant radiotherapy
  Patients will receive adjuvant treatment composed of either pelvic radiotherapy external beam radiotherapy ± brachytherapy or concomitant chemoradiotherapy (pelvic radiotherapy + chemotherapy).

Primary outcome measures

• Disease-free survival [Time frame: Analysed 3 years after randomization of the last patient.]

Secondary outcome measures (4)

• Overall survival [Time frame: Analysed 6 years after randomization of the last patient.]
• Pelvic disease-free survival [Time frame: Analysed 3 years after randomization of the last patient.]
• Health-related quality of life based questionnaire [Time frame: Analysed 3 years after randomization of the last patient.]
• 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.]

Eligibility criteria

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:

• 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)

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Czechia · 1 center

• General University Hospital in Prague — Prague

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. PMID 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. PMID 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. PMID 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. PMID 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 PMID 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. PMID 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. PMID 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. PMID 32246761

Identifiers

NCT: NCT04989647 · ENGOT-cx16/CEEGOG/CERVANTES

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗