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

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%).

Sex

Female

Minimum age

18 Years

Maximum age

85 Years

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:

* 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

• BACKGROUNDSedlis 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
• BACKGROUNDRotman 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
• BACKGROUNDScharl 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
• BACKGROUNDKim 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
• BACKGROUNDCibula 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
• BACKGROUNDvan 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.