Cervical cancer is among the most frequently diagnosed malignancies and the fourth leading cause of cancer-related death in women, with 570,000 new cases and 311,000 deaths anticipated worldwide in 2019. Despite decades of Pap smear screening, human papillomavirus (HPV) co-testing, and the recent availability of the HPV vaccine, cervical cancer and its precursor, cervical dysplasia, remain a significant public health threat for women worldwide.
In women with early-stage cervical cancer, surgery is indisputably the treatment with the most positive impact on long-term survival. Standard radical hysterectomy and pelvic lymphadenectomy, which are performed through either a transverse or vertical abdominal incision, are associated with the potential for procedural morbidity and patient recovery time. More than a decade ago, however, a new approach to gynecologic cancer surgery was welcomed by surgeons with the Phase III Gynecologic Oncology Group LAP2 trial, a study which demonstrated significant perioperative benefits and almost identical survival outcomes for laparoscopic compared with open hysterectomy in patients with early-stage uterine cancer. Because of outcomes in this and other trials, gynecologic oncologists endeavored to expand the indications for minimally invasive surgery (MIS), including in cervical cancer. Based on subsequent retrospective data touting superior perioperative results and similar oncologic outcomes compared with open approaches, minimally invasive radical hysterectomy was embraced by gynecologic oncology surgeons worldwide for treatment of stage IA2-IB1 cervical cancer.
However, recently, Ramirez and colleagues reported the results of the Laparoscopic Approach in Cervical Cancer (“LACC”) study in the New England Journal of Medicine, the first—and only—Phase III trial addressing the relationship between surgical approach and survival outcomes in early-stage cervical cancer. A total of 631 patients with early-stage squamous cell tumors or adenocarcinomas were randomized to undergo either an open or minimally invasive radical hysterectomy. Midway through this non-inferiority trial, the Data Safety and Monitoring Committee identified a disproportionate number of deaths in the minimally invasive cohort, triggering study closure after an interim analysis revealed inferior disease-free survival at 4.5 years, as well as significantly higher death rates, in the minimally invasive compared to the open hysterectomy cohort. These striking and surprising results were paradigm shifting and raised serious concerns regarding the safety of performing minimally invasive radical hysterectomy.
Critics question the results and ask “why?” and “how?”
Many have questioned how the unanticipated results of the LACC trial could be so incongruous with prior published data. In journal editorials and at national society meetings, minimally invasive enthusiasts and thoughtful gynecologic oncology critics have voiced concerns over perceived trial weaknesses that may limit conclusions. As a surgeon who has studied minimally invasive innovations and performed countless robotic and laparoscopic cancer staging procedures in my career, I was astonished with the LACC trial results, and my voice was among the chorus of critics focused on the trial limitations and urging others that it was premature to sound the death knell for MIS in cervical cancer. I wondered:
- “How can MIS be so dangerous for women with early-stage cervical cancer when we have not observed similar trends in those with early-stage endometrial cancer?”
- “There is no definitive explanation to account for these findings, so what do we make of them?”
- “Why are the LACC trial results seemingly so different than other retrospective studies?”
- “Are the study surgeons using irresponsible techniques or is lack of experience an issue?”
However, after conducting a comprehensive trial analysis and reviewing the many studies that have emerged since the LACC trial publication, my early view on this matter has shifted considerably to one of sober appreciation of these data and an understanding that we could not continue as we had before in our surgical approach to cervical cancer. Herein, I will discuss dilemmas with conducting surgical trials, critically appraise the LACC trial strengths and limitations, review the existing literature on early-stage cervical cancer survival outcomes by surgical approach, and present an argument on why it may be time for the “old” radical hysterectomy technique to become relevant again.
The author reports no potential conflicts of interest with regard to this article.
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