Minimally-Invasive Radical Hysterectomy for Cancer of the Cervix: The Perspective of the Society of Gynecologic Oncology of Canada (GOC)

A randomized controlled trial1Ramirez PT Frumovitz M Pareja R et al.Minimally invasive versus abdominal radical hysterectomy for cervical cancer.N Engl J Med. 2018; 379: 1895-1904Crossref PubMed Scopus (937) Google Scholar and a two-part cancer registry study,2Melamed A Margul DJ Chen L et al.Survival after minimally invasive radical hysterectomy for early-stage cervical cancer.N Engl J Med. 2018; 379: 1905-1914Crossref PubMed Scopus (407) Google Scholar published in the New England Journal of Medicine, report increased recurrence and mortality rates with the use of minimally invasive (MIS) radical hysterectomy as compared to laparotomy for women with cancer of the cervix. These results have important implications that could lead to changes in practice in the surgical treatment of cancer of the cervix. Based on the findings in these two studies, careful scientific investigation is necessary to evaluate which biological, technical, or surgical factors may explain the observed deleterious effect of MIS in cervical cancer that have not been observed in randomized trials in other solid tumours, such as endometrial3Walker JL Piedimonte MR Spirtos NM et al.Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2 Study.J Clin Oncol. 2012; 30: 695-700Crossref PubMed Scopus (502) Google Scholar gastric,4Kim YW Yoon HM Yun YH et al.Long-term outcomes of laparoscopy-assisted distal gastrectomy for early gastric cancer: result of a randomized controlled trial (COACT 0302).Surg Endosc. 2013; 27: 4267-4276Crossref PubMed Scopus (102) Google Scholar and colorectal cancer.5Bonjer HJ Deijen CL Abis GA A randomized trial of laparoscopic versus open surgery for rectal cancer.N Engl J Med. 2015; 372: 1324-1332Crossref PubMed Scopus (833) Google Scholar, 6Kitano S Inomata M Mizusawa J et al.Survival outcomes following laparoscopic versus open D3 dissection for stage II or III colon cancer (JCOG0404): a phase 3, randomised controlled trial.Lancet Gastroenterol Hepatol. 2017; 2: 261-268Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 7Jeong SY Park JW Nam BH et al.Open versus laparoscopic surgery for mid-rectal or low-rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): survival outcomes of an open-label, non-inferiority, randomised controlled trial.Lancet Oncol. 2014; 15: 767-774Abstract Full Text Full Text PDF PubMed Scopus (588) Google Scholar Once the factors driving worse outcomes are better understood, practice guidelines can be updated to enhance the care of patients with cancer of the cervix in Canada. The Laparoscopic Approach to Cervical Cancer trial (LACC) is a randomized international multicentre study including 631 patients with stage IA1-IB1, randomized either to MIS (319 patients, 84.4% by laparoscopy and 15.6% by robotic surgery) or laparotomy (312 patients).1Ramirez PT Frumovitz M Pareja R et al.Minimally invasive versus abdominal radical hysterectomy for cervical cancer.N Engl J Med. 2018; 379: 1895-1904Crossref PubMed Scopus (937) Google Scholar Three-year disease-free survival was 91.2% in the MIS group compared to 97.1% in the open surgery group (HR 3.74; 95% CI 1.63–8.58), and the overall three-year survival was 93.8% in the MIS group and 99.0% in the open surgery group (HR 6.00; 95% CI 1.77–20.30). Although the survival in the open surgery group was higher than expected, the observed differences between the two groups are significant and concerning. As a result, the Society of Gynecologic Oncology of Canada (GOC) recommends withholding the routine use of MIS for radical hysterectomy in patients with cancer of the cervix. That being said, the study was performed in different areas of the world (Argentina, Australia, Brazil, Bulgaria, Canada [one centre], China, Colombia, India, Italy, Korea, Mexico, Peru, and United States) with well-established differences in incidence and outcome of cervical cancer.8International Agency for Research on Cancer. Estimated age-standardized incidence rates (World) in 2018, cervix uteri, female, all ages [graphic]. https://bit.ly/2L7UQze. Accessed on December 10, 2018.Google Scholar It is unknown if these differences would apply to the Canadian context. Another important question raised by the study is whether different MIS techniques may have influenced outcomes, such as the use of intrauterine manipulators, the type of colpotomy (intraperitoneal vs. extraperitoneal), and the possible risk of intraperitoneal spread of cancer cells during specimen extraction. The second study provided data from two large cancer registries.2Melamed A Margul DJ Chen L et al.Survival after minimally invasive radical hysterectomy for early-stage cervical cancer.N Engl J Med. 2018; 379: 1905-1914Crossref PubMed Scopus (407) Google Scholar The first part evaluated 2461 patients with stage IA2-IB1 cervical cancer from the National Cancer Database between 2010 and 2013 who underwent minimally invasive radical hysterectomy (1225 patients, 79.8% by robotics) and who underwent open radical hysterectomy (1236 patients). The four-year survival was 90.9% in the MIS group and 94.7% in the open group (HR, 1.65; 95% CI 1.22–2.22). This is a retrospective registry cohort study in which there were differences in risk factors between the MIS and open surgery groups on the final surgical pathology specimen (Table). These pathologic risk factors are strongly associated with survival and may have influenced the results, and no statistical analysis is provided.TableRisk factors in MIS and Open Surgery GroupsIA2-IB1 (2010-2013)MIS(n=1225)Open Surgery(n=1236)4-year survival90,9%94,7%Positive lymph nodes10.7%8.9%Parametrial involvement11%9.5%Positive margins5%4.4%Presence of lymph vascularspace involvement31.9%28%MIS: minimally invasive surgery. Open table in a new tab MIS: minimally invasive surgery. The second part of this study evaluated the Surveillance, Epidemiology, and End Results (SEER) database for trends in 4-year relative survival rates in the U.S. (interrupted time-series analysis) and showed an increase in all-cause mortality over the years 2010 to 2016, coinciding with the increase in MIS uptake. The time trend analysis does not appear to use age-standardized survival, so it is possible that their analysis may be confounded by increasing age at diagnosis. Although we do not have this type of data available in Canada, net cancer age-standardized cervical cancer survival has not declined over the past two decades.9Statistics Canada. Deaths and age-specific mortality rates (Table 13-10-0392-01). https://www150.statcan.gc.ca/t1/tbl1/en/tv.action?pid=1310039201. Accessed on December 10, 2018.Google Scholar In these two studies, survival rates are worse when radical hysterectomy is performed by MIS compared to those of open procedures to treat early-stage cervical cancer. This difference cannot be ignored and could be specific to the biology of cervical cancer, or to specific technical aspects of the procedure leading to peritoneal contamination of tumours cells. Strategies proposed to decrease the risk of contamination include placing a suture on the unaffected cervix at the beginning of surgery for easy retrieval and if possible to cover the tumour, using a vaginal vault cup without intrauterine manipulator, performing a colpotomy circumferentially intra-abdominally (rather than across the vagina) or via the vaginal route, and using specimen extraction techniques that mitigate intra-abdominal spillage.10Peeters F Vaknin Z Lau S et al.Technical modifications in the robotic assisted surgical approach for gynecologic operations.J Robotic Surg. 2010; 4: 253-257Crossref PubMed Scopus (12) Google Scholar The survival difference in tumours greater than 2 cm is clear in the LACC trial, but the trial was not powered to evaluate oncologic outcomes in low-risk cervical cancers with tumours smaller than 2 cm, or in surgeries performed by robotic-assisted laparoscopy. Although not designed to answer the same question, CX.5 (SHAPE trial11A Randomized Phase III Trial Comparing Radical Hysterectomy and Pelvic Node Dissection vs Simple Hysterectomy and Pelvic Node Dissection in Patients With Low-Risk Early Stage Cervical Cancer (SHAPE). https://clinicaltrials.gov/ct2/show/NCT01658930. Accessed on December 10, 2018.Google Scholar) may provide some informative data on the outcomes of patients with smaller tumours, most of whom were treated with MIS. In addition, a recent large Korean national database study on 6335 patients who underwent radical hysterectomy between 2011 and 2014 either by laparoscopy (n=3100) or laparotomy (n=3235) showed better survival in the laparoscopy group (HR=0.74; 95% CI 0.64–0.85), but no information on stage distribution or tumour size was provided.12Kim JH Kim K Park SJ et al.Comparative effectiveness of abdominal versus laparoscopic radical hysterectomy for cervical cancer in the postdissemination era.Cancer Res Treat. 2018; (Epub 11 September 2018)Google Scholar In view of the results of these two important studies, it is imperative to proceed with caution when counselling women with early stage cervical cancer about the approach to radical hysterectomy. In all circumstances, the information should be discussed thoroughly with patients.

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