From Pages to Practice
Many physicians may be surprised to learn that the first laparoscopic appendectomy was performed in 1980 by a gynecologist. Since then, minimally invasive surgery has come a long way in all fields, including gynecology, as we attempt to push the boundaries of technology. The assumption is that minimally invasive surgery is better for the patient than open surgery whenever safely possible. Studies have shown that most minimally invasive approaches are associated with less pain, shorter hospital stays, and quicker return to daily activities. The safety of minimally invasive surgery has been demonstrated for colorectal cancer, prostate cancer, and uterine cancer, and as a result, it has become the standard of care for patients with these diseases. Extrapolating a similar conclusion for cervical cancer would seem obvious. However, when evaluating a new technique in oncologic surgery, both functional and oncologic outcomes are important to measure.
Although several retrospective and cohort studies support the use of laparoscopy for early stage cervical cancer, no randomized-control trials have been conducted to confirm this assumption. Nonetheless, practice has changed in favor of a minimally invasive approach for early stage cervical cancer to avoid the morbidity associated with open surgery. Two studies in this week’s issue of NEJM call into question the equivalence of long-term oncologic outcomes associated with minimally invasive and open radical hysterectomy in patients with early cervical cancer.
The Laparoscopic Approach in Cervical Cancer (LACC) trial by Ramirez et al. is the first phase 3 randomized trial to compare oncologic outcomes associated with minimally invasive versus open radical hysterectomy for treatment of early cervical cancer. The study included patients with Stage IA1 or IB1 cervical cancer (including squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma) at 33 centers worldwide. What is unique about the trial is that each participating site was required to submit outcomes from ten minimally invasive (laparoscopic or robotic) radical hysterectomies and two unedited videos of the procedure to ensure quality of the surgeon’s technique. The primary outcome was disease-free survival and secondary outcomes included recurrence and overall survival rates.
The investigators aimed to recruit 740 patients to provide sufficient statistical power. However, the study was stopped early by the Data and Safety Monitoring Committee after 631 patients were enrolled due to an imbalance in deaths between the two groups. Patient characteristics were similar in the two groups, including histologic subtype, grade, tumor size, lympho-vascular invasion, parametrial involvement, lymph node involvement, and use of adjuvant therapy (although not standardized). At the time of the analysis, the probability of disease-free survival at 4.5 years was 96.5% in the open-surgery group versus 86.0% in the minimally invasive group. This difference did not meet the prespecified noninferiority margin. Compared with open hysterectomy, minimally invasive surgery was also associated with lower disease-free survival at 3 years, (hazard ratio, 3.74; 95% CI, 1.63–8.58), even after adjusting for multiple confounding factors, as well as lower overall survival (HR, 6.00; 95% CI,1.48–20.3), and higher local-regional recurrence (HR, 4.26; 95% CI, 1.44-12.6).
In a large observational cohort study, Melamed et al. reported similar findings based on an inverse probability of treatment analysis among women who underwent radical hysterectomy for stage IA2 or IB1 cervical cancer during 2010–2013 (using data from the National Cancer Registry). They also performed an interrupted time-series analysis among women who underwent radical hysterectomy for cervical cancer during 2000–2010 (using the Surveillance, Epidemiology, and End Results [SEER] database). About 50% of women underwent minimally invasive hysterectomy. Four-year mortality was higher in women who underwent the minimally invasive approach than in women who underwent open surgery (9.1% vs. 5.3% for open surgery; HR, 1.65; 95% CI, 1.22–2.22; P=0.002 by the log-rank test). The interrupted time-series analysis supported this finding by showing that transition to minimally invasive surgery coincided with a decline in four-year relative survival of 0.8% per year after 2006.
So why is minimally invasive surgery associated with worse disease-free survival and overall survival than open surgery? How is cervical cancer different than colorectal cancer or its anatomically close cousin, uterine cancer? Does cervical cancer behave differently than other cancers? Was something unaccounted for in the study designs? Is minimally invasive surgery for cervical cancer technically harder and therefore more difficult to achieve a complete resection?
In an accompanying editorial, Amanda Fader, MD addresses these questions. She notes that in the LACC trial, all cancer recurrences occurred in only 14 of the 33 participating centers, calling into question unique patient or surgical factors, despite quality control of the surgical technique. Fader also postulates that use of uterine or cervical manipulators and carbon dioxide gas in minimally invasive radical hysterectomy encouraged tumor spread. However, data on manipulator use was not reported in either study, and this effect would more likely cause abdominal metastases than the locoregional recurrences that were more common in the trial. Despite these and other study design flaws and the fact that the trial was stopped early, the power was adequate to provide confidence in the result.
Will these study results change practice? “Not necessarily, but this approach has been dealt a great blow,” says Fader. She adds, “Though the data are alarming, select patient subgroups may still benefit from a less invasive approach…Until further details are known, however, surgeons should proceed cautiously, counsel their patients regarding these collective study results, and assess each woman’s individual risks and benefits for minimally invasive versus open radical hysterectomy.”