Is it still reasonable to offer MIS hysterectomy? Yes.

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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

Click here to read the con side of the argument: Is it still reasonable to offer MIS hysterectomy? No.

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

"One needs to exmaine the data carefully"
With the published results of the LACC trial, we must consider that there is a possibility that minimally invasive radical hysterectomy does have an inferior oncologic outcome when compared to open hysterectomy and that should be discussed with our patients as part of the consent process. However, one needs to examine the data carefully before completely condemning this procedure for all patients, especially when MIS is associated with significant advantages. One must ask, are any issues with the conduct of the trial that are problematic? Do the results make sense? Are there problems with the design of the clinical trial that cast doubts on the outcomes? Are the inclusion criteria for the trial so broad or one subgroup over-represented so that the results may not apply to everyone included in the trial? Are these international results applicable to practice in the United States? 

Given the relative rarity of cervical cancer and the high demand for MIS in the United States, the LACC trial was conducted internationally and many of the patients were enrolled in countries where medical resources are more limited than they are in the United States. Surgical trials are difficult to conduct as there is significant variability between surgeons, international differences in practice patterns with respect to patient selection for surgery, preoperative imaging, and postoperative therapy. Because no standard preoperative imaging was mandated in this trial, we cannot be assured that there was adequate stratification of risk factors between the groups in the LACC trial even though pathologic factors appeared to be balanced. In this trial there was no central pathology review and data on basic variables such as tumor size were missing in 15% of patients. Further, no specific recommendations for postoperative therapy were mandated by the protocol. This is critical as pelvic radiation has been shown to reduce risk of recurrence by approximately 50% in patients with high-risk tumors and is associated with improved overall survival.⁶ While adjuvant therapy in the form of chemotherapy and radiation were used at similar rates in both the open and laparoscopic arms, we do not know how this correlates with risk factors for recurrence in the two groups or exactly what kind of postoperative therapy was prescribed.³ The preoperative evaluation and postoperative therapy are clearly important when one considers that 27% of recurrences reported in the LACC trial were within 1 year of the surgery, a phenomenon that should be relatively rare after radical hysterectomy for early cervical cancer with negative margins and adequate adjuvant therapy.  

Risk factors can influence the outcome of a trial
One of the most important aspects of a RTC is stratification for risk factors that can influence the outcome of the trial. One concerning aspect of the LACC data is that there was an imbalance in the number of non-cancer-related deaths in the laparoscopic arm unrelated to the surgery, with five deaths in the minimally invasive arm due to causes not related to the cancer or to the surgery, and one additional death due to complications with a second unrelated cancer that prevented adequate adjuvant therapy.³ This is compared to only one death unrelated to cervical cancer in the open group. This death was not otherwise described and we do not know if it was surgically related. Due to the study design, these deaths are included in the DFS and overall survival (OS) calculation. While the differences between the arms with respect to disease recurrence or death from cervical cancer remained after these cases were excluded, this would still suggest that there is some imbalance between the two arms not accounted for in the randomization stratification.

Another striking observation is that the laparoscopic arm actually performed better than any other reported large series of radical hysterectomies.⁷ Thus, the differences between the two groups were not a result of poor performance of the laparoscopic arm, but an over-performance of the open arm. The 3-year disease-specific survival in the MIS arm was 95.6%. However, the 3-year disease specific survival in the open arm was 99.6% in a population where almost half the patients had tumors > 2 cm, half had > 50% cervical invasion, and 13% of patients had positive nodes. The DFS and OS in the open arm are also abnormally high when compared to every other series of abdominal radical hysterectomy.⁷ Because no previous study has demonstrated similar results, one has to consider whether these numbers simply represent a statistical anomaly or are the result of under-reporting of recurrences or deaths due to the challenging logistics of an international trial, casting further doubts on the results of this trial.

Local recurrence risk is a concern with MIS and that was the most significant finding between arms of the LACC trial. Local failure can occur due to inadequate surgical margins or possibly due to tumor contamination of the peritoneal cavity by use of uterine manipulators commonly used during laparoscopic surgery. In the LACC trial, the rate of positive surgical margins between the two arms was comparable. Sub-analysis of the data suggests that patients with larger tumors are clearly at the highest risk of local recurrence, suggesting that there may be a contamination issue with larger tumors. The LACC trial showed a significantly higher risk of local recurrence in patients treated with laparoscopic surgery when their\ tumors were > 2 cm. In both the open and the laparoscopic groups, the local recurrence risk was less than 5%, except in the laparoscopic group with tumors > 2 cm, for whom the rate of local recurrence was almost 15%.

Not a definitive trial
While the results of the LACC trial are concerning, it is not a definitive trial to end the practice of minimally invasive radical hysterectomy in all patients. The DFS and OS differences seen in the LACC trial were secondary endpoints and should be considered exploratory. Just as the US Food and Drug Administration requires two RCTs with a clearly defined primary endpoint for drug approval, we should hold surgical trials to similar standards, thus the LACC trial should prompt a call for another trial to be conducted in the United States or other countries with similar practice patterns with careful attention to oncologic principles and standardized postoperative therapy. Prior to the LACC trial, patient preference for MIS precluded adequate accrual, but the LACC data should rekindle an interest and make such a trial feasible.

An over-reaction to the available data
Moving completely away from minimally invasive radical hysterectomy without a definitive trial is an over-reaction to the available data. The current situation with MIS in cervical cancer is very similar to that in rectal cancer where two non-inferiority trials have been reported with inconclusive results.^8,9 One of these trials was similar to the LACC trial in that the confidence interval for the primary endpoint did not include parity.⁹ However, as previously stated about this trial, “Failure to show non-inferiority cannot be used to imply inferiority.”¹⁰ It seems to be an over-reaction to use data from a single inconclusive trial as a basis for abandoning a procedure that has clear benefits. An unintended consequence of a move away from MIS is that it may decrease the availability of surgery for young patients with cervical cancer. Despite the advantages of surgery, only 9% of women with cervical cancer in the National Inpatient Sample Database from 2008 through 2015 were treated with radical hysterectomy.¹ This likely reflects careful selection of patients for this surgery and suggests that the selection criteria for radical hysterectomy in the United States are particularly stringent, thus the patients treated with surgery here may not be similar to those in the LACC trial. In addition, it has been reported that patients having MIS have a higher body mass index and minimally invasive radical hysterectomy might be offered to patients who might not be candidates for an open radical hysterectomy due to technical challenges of open surgery in women who weigh > 100 Kg.  

The LACC trial should be a call for caution and careful patient selection along with informed consent. This is a reasonable approach until we have more information. While we should inform our patients about the results of this trial when discussing surgery for cervical cancer, it is still reasonable to offer minimally invasive radical hysterectomy, especially to patients with tumors < 2 cm or who have tumors that can be removed prior to surgery.

Disclosures:

The author reports no potential conflicts of interest with regard to this articl

References:

• 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. JMinimInvasiveGynecol. 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. JAMASurg. 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.