Phase III clinical trials of radical hysterectomy with minimal parametrectomy for patients with early-stage cervical cancer: a review

The standard surgery for patients with International Federation Gynecology and Obstetrics (FIGO) stage IB–II cervical cancer is a Piver-Rutledge-Smith class III radical hysterectomy with pelvic lymphadenectomy involving a wide resection of parametrial and paravaginal tissue to control parametrial involvement. However, adverse events can occur such as severe long-term neurogenic bladder due to parametrectomy. This review evaluates ongoing and completed phase III clinical trials of less radical hysterectomy with regard to parametrectomy. The PubMed database, Clinical Trials.gov, and Cochrane Central Register of Controlled Trials were used to extract information on two completed and four ongoing clinical trials. Less radical surgery led to similar oncologic outcomes to standard surgery in two phase III randomized controlled trials (Piver class II vs. class III, and class I vs. class III radical hysterectomy with pelvic lymphadenectomy). Less radical surgery also led to fewer complications, including urologic morbidity; however, more than 50% of patients received radiotherapy following such surgery, and showed higher morbidity rates because their enrolment was due to the presence of a large tumor (>4 cm). Three phase III randomized controlled trials and a phase III nonrandomized confirmatory trial are presently ongoing. Major inclusion criteria include FIGO stage IA, IB, or IIA1, a mainly ≤2-cm tumor, limited depth of stromal invasion, and/or no lymph node metastasis. Surgery for the standard arm is a class II or class III radical hysterectomy, and the experimental surgery is a simple extrafascial hysterectomy or class II radical hysterectomy. Primary endpoints are overall, disease-free, or recurrence-free survival. Although primary endpoints, eligibilities or types of radical hysterectomy differ between trials, if noninferiority in overall, disease-free or recurrence-free survival is observed in any trial, new standard, less radical, curative hysterectomy may be established for early-stage, small-sized, invasive, cervical cancer.

Early-stage cervical cancer; Less radical hysterectomy; Parametrectomy; Tumor size; Phase III clinical trial

[1] Piver MS, Rutledge F, Smith JP. Five classes of extended hysterectomy for women with cervical cancer. Obstetrical & Gynecological Survey. 1975; 30: 220–223.

[2] Kasamatsu T, Onda T, Sawada M, Kato T, Ikeda S, Sasajima Y, et al. Radical hysterectomy for FIGO stage I–IIB adenocarcinoma of the uterine cervix. British Journal of Cancer. 2009; 100: 1400–1405.

[3] Kasamatsu T, Onda T, Sawada M, Kato T, Ikeda S. Radical hysterectomy for FIGO stage IIB cervical cancer: clinicopathological characteristics and prognostic evaluation. Gynecologic Oncology. 2009; 114: 69–74.

[4] Bandy LC, Clarke-Pearson DL, Soper JT, Mutch DG, MacMillan J, Creasman WT. Long-term effects on bladder function following radical hysterectomy with and without postoperative radiation. Gynecologic Oncology. 1987; 26: 160–168.

[5] Scotti RJ, Bergman A, Bhatia NN, Ostergard DR. Urodynamic changes in urethrovesical function after radical hysterectomy. Obstetrics & Gynecology. 1986; 68: 111–120.

[6] Zanolla R, Monzeglio C, Campo B, Ordesi G, Balzarini A, Martino G. Bladder and urethral dysfunction after radical abdominal hysterectomy: rehabilitative treatment. Journal of Surgical Oncology. 1985; 28: 190–194.

[7] Carenza L, Nobili F, Giacobini S. Voiding disorders after radical hysterectomy. Gynecologic Oncology. 1982; 13: 213–219.

[8] Landoni F, Maneo A, Cormio G, Perego P, Milani R, Caruso O, et al. Class II versus class III radical hysterectomy in stage IB–IIA cervical cancer: a prospective randomized study. Gynecologic Oncology. 2001; 80: 3–12.

[9] Landoni F, Maneo A, Zapardiel I, Zanagnolo V, Mangioni C. Class I versus class III radical hysterectomy in stage IB1–IIA cervical cancer. a prospective randomized study. European Journal of Surgical Oncology. 2012; 38: 203–209.

10] Clinical Trials.gov. Explore 421,553 research studies in all 50 states and in 221 countries. 2022. Available at: https://clinicaltrials.gov (Accessed: 18 January 2022).

[11] Japan Registry of Clinical Trials. 2022. Available at: https://jrct. niph.go.jp/ (Accessed: 18 January 2022).

[12] Kunieda F, Kasamatsu T, Arimoto T, Onda T, Toita T, Shibata T, et al. Non-randomized confirmatory trial of modified radical hysterectomy for patients with tumor diameter 2 cm or less FIGO Stage IB1 uterine cervical cancer: Japan clinical oncology group study (JCOG1101). Japanese Journal of Clinical Oncology. 2015; 45: 123–126.

[13] Kato T, Takashima A, Kasamatsu T, Nakamura K, Mizusawa J, Nakanishi T, et al. Clinical tumor diameter and prognosis of patients with FIGO stage IB1 cervical cancer (JCOG0806-A). Gynecologic Oncology. 2015; 137: 34–39.

[14] Sun H, Cao D, Shen K, Yang J, Xiang Y, Feng F, et al. Piver type II vs. type III hysterectomy in the treatment of early-stage cervical cancer: midterm follow-up results of a randomized controlled trial. Frontiers in Oncology. 2018; 8: 568.

[15] Querleu D, Morrow CP. Classification of radical hysterectomy. The Lancet Oncology. 2008; 9: 297–303.

[16] Averette HE, Nguyen HN, Donato DM, Penalver MA, Sevin B, Estape R, et al. Radical hysterectomy for invasive cervical cancer: a 25-year prospective experience with the Miami technique. Cancer. 1993; 71: 1422–1436.

[17] Bergmark K, Avall-Lundqvist E, Dickman PW, Henningsohn L, Steineck G. Vaginal changes and sexuality in women with a history of cervical cancer. New England Journal of Medicine. 1999; 340: 1383–1389.

[18] Zullo MA, Manci N, Angioli R, Muzii L, Panici PB. Vesical dysfunctions after radical hysterectomy for cervical cancer: a critical review. Critical Reviews in Oncology/Hematology. 2003; 48: 287–293.

[19] Ramirez PT, Frumovitz M, Pareja R, Lopez A, Vieira M, Ribeiro R, et al. Minimally invasive versus abdominal radical hysterectomy for cervical cancer. New England Journal of Medicine. 2018; 379: 1895–1904.

[20] Kasamatsu T, Ishikawa M, Murakami N, Okada S, Ikeda S, Kato T, et al. Identifying selection criteria for non-radical hysterectomy in FIGO stage IB cervical cancer. Journal of Obstetrics and Gynaecology Research. 2019; 45: 882–891.

[21] Covens A, Rosen B, Murphy J, Laframboise S, DePetrillo AD, Lickrish G, et al. How important is removal of the parametrium at surgery for carcinoma of the cervix? Gynecologic Oncology. 2002; 84: 145–149.

[22] Derks M, van der Velden J, de Kroon CD, Nijman HW, van Lonkhuijzen LRCW, van der Zee AGJ, et al. Surgical treatment of early-stage cervical cancer: a multi-institution experience in 2124 cases in the Netherlands over a 30-year period. International Journal of Gynecologic Cancer. 2018; 28: 757–763.

[23] National Comprehensive Cancer Network. 2022. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf (Accessed:18 January 2022).