Radical hysterectomy is the preferred method of treatment for early cervical cancer, especially in younger women. Surgery for cervical cancer often eliminates the need for radiation, which is associated with premature ovarian failure, chronic bowel and bladder toxicity, and poor sexual function. With improvements in surgical equipment and techniques, radical hysterectomy can now be performed either by laparoscopy or robotic-assisted minimally invasive techniques. Minimally invasive surgery (MIS) allows faster recovery, shorter hospital stays, decreased peri-operative morbidity including less blood loss, lower wound infection rates, less fever, lower rates of sepsis, lower risk of deep venous embolism, and less risk of post-operative ileus.1 It is likely that MIS can also avoid the known morbidity of open surgery, such as ventral hernia formation and the 10-fold increase in bowel obstruction due to adhesions associated with open hysterectomy. 2
LACC trial controversy
While MIS has many benefits, the recently reported LACC trial has created controversy with respect to oncologic safety of the minimally invasive approach to radical hysterectomy in cervical cancer.3 The primary endpoint of this international, randomized controlled trial (RCT) was a 7.2% non-inferiority disease-free survival (DFS) boundary at 4.5 years. The design of this trial with this boundary comes a priori with the expectation that we are willing to accept up to a 7.2% difference in DFS in return for the advantages of MIS. The LACC trial was inconclusive with respect to the primary endpoint as the DFS confidence interval in the trial crossed the non-inferiority boundary.4 However, in the LACC trial, there was a decrease in DFS, with an increase in local recurrence risk and overall cervical cancer mortality associated with MIS. Despite the fact that this trial was inconclusive for the primary endpoint, many of the narratives, and even the abstract of the article itself, do not make this obvious. Instead, the adverse secondary endpoints have been highlighted and some institutions have declared a moratorium on minimally invasive radical hysterectomy as a result.5
While randomized RCTs should be the highest level of evidence for treatment of our patients, we must be careful in interpreting these data. All clinical trials, including RCTs, have pitfalls and can be prone to over-interpretation. Because we set the risk of a Type I error at 0.05, we accept that 1:20 RCTs will demonstrate false-positive results. More importantly, we often erroneously hold secondary endpoints to the same degree of certainty that we hold the primary outcome of a trial, forgetting that these secondary endpoints should be hypothesis-generating. This is certainly true for the LACC trial about which significant concern has been expressed over secondary endpoints that were not prespecified in the original statistical plan. In this trial, the confidence intervals for DFS, local recurrence, and recurrence due to cervical cancer did not cross parity. However, because these endpoints were not prespecified or corrected for multiple comparisons, they were not assigned a P value when the LACC trial was reported.3
The author reports no potential conflicts of interest with regard to this articl
- Piedimonte S, Czuzoj-Shulman N, Gotlieb W, Abenhaim Ha. Robotic radical hysterectomy for cervical cancer; a population-based study of adoption and immediate postoperative outcomes in the US. J Minim Invasive Gynecol. 2019; Mar-Apr;26(3):551-557.
- Monk BJ, Berman ML, Montz FJ. Adhesions after extensive gynecologic surgery: clinical significance, etiology, and prevention. Am J Obstet Gynecol. 1994;170:1396-403.
- Ramirez PT, Frumovitz M, Pareja R, Lopez A, Vieira M, Ribeiro R, et al. Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N Engl J Med. 2018;379:1895-1904.
- Acuna SA, Dossa F, Baxter NN. Frequency of misinterpretation of inconclusive noninferiority trials: the case of the laparoscopic vs open resection for rectal cancer trials. JAMA Surg. 2019 Jan 1;154(1):90-92.
- Ong M. Conversation with The Cancer Letter. Ramirez: We no longer offer minimally invasive radical hysterectomy at MD Anderson. In: The Cancer Letter. Washington, DC; 2018.
- 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;73: 177-183.
- Wang YZ, Deng L, Xu HC, Zhang Y, Liang ZQ. Laparoscopy versus laparotomy for the management of early stage cervical cancer. BMC Cancer. 2015;15:928.
- Fleshman J, Branda M, Sargent DJ, Boller AM, George V, Abbas M, et al. Effect of laparoscopic-assisted resection vs open resection of stage ii or iii rectal cancer on pathologic outcomes: the ACOSOG Z6051 randomized clinical trial. JAMA. 2015;314:1346-1355.
- Stevenson AR, Solomon MJ, Lumley JW, Hewett P, Clouston AD, Gebski VJ, et al. Effect of laparoscopic-assisted resection vs open resection on pathological outcomes in rectal cancer: The ALaCaRT randomized clinical trial. JAMA. 2015;314:1356-1363.
- Stevenson AR. The future for laparoscopic rectal cancer surgery. Br J Surg. 2017;104: 643-645.