Pedro T. Ramirez, MD
Alexander Melamed, MD, MPH
MINIMALLY INVASIVE radical hysterectomy for women with early-stage cervical cancer has been associated with reduced rates of disease-free and overall survival in the phase III LACC randomized noninferiority trial comparing minimally invasive and open abdominal radical hysterectomy. The results were reported by Pedro T. Ramirez, MD, of The University of Texas MD Anderson Cancer Center, and colleagues in The New England Journal of Medicine.1
In addition, in an epidemiologic study using patient data from the National Cancer Database, Alexander Melamed, MD, MPH, of Massachusetts General Hospital and Harvard Medical School, and colleagues showed that women who had minimally invasive procedures had shorter overall survival than did those who had open hysterectomy.2 The results were also in the news, with coverage by major media including The New York Times, TIME, CNN, and NPR.
“The data are compelling, and the conclusions have to be incorporated into patient consultation every single time we are considering minimally invasive radical hysterectomy for a patient with cervical cancer,” David E. Cohn, MD, said in an interview with The ASCO Post.
“The question is whether or not the population in the LACC study is equivalent to the one we see in the United States.”— David E. Cohn, MD
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However, that counseling, Dr. Cohn stressed, “has to include the consideration as to whether the patient in front of you is reflective of the population in the LACC study.” Dr. Cohn is Chief Medical Officer, Arthur G. James Cancer Hospital and Solove Research Institute, and Professor and Director, Division of Gynecologic Oncology, The Ohio State University, Columbus.
Question of Generalizability
IN THE LACC TRIAL, 319 patients with stage IAI, IA2, or IBI cervical cancer were randomly assigned to undergo minimally invasive surgery and 312, open surgery. At 3 years, minimally invasive surgery compared with open surgery was associated with lower rates of disease-free (91.2% vs 97.1%) and overall (93.8% vs 99%) survival.
This was an international study involving a number of different physicians at 33 centers in several countries. “The question is whether or not the population in the LACC study is equivalent to the one we see in the United States. It may not be generalizable across the practice of medicine I see at Ohio State,” Dr. Cohn said.
“When you look at the characteristics of the patients, a very small percentage of them had small tumors,” Dr. Cohn said, making it difficult to draw meaningful conclusions about that specific patient population. In the United States, however, “given the use of screening for cervical precancers and cancers with Pap and human papillomavirus (HPV) testing, we likely pick up cancers at the earlier stages, microscopic-level stages,” Dr. Cohn said. “We might have a higher percentage of our population with smaller tumors.”
While questioning how generalizable the results of the LACC study are, Dr. Cohn noted, “it is not to say that I discount the randomized study. I do believe these data are very important and certainly demonstrate that in the population described, survival is worse with minimally invasive surgery. It just is a question of looking at the individual patient and the individual practice or practitioner and deciding what is the right thing for that patient.”
Practice-Changing or Not?
AN ARTICLE in The New York Times included the following quote from Dr. Ramirez, the LACC study’s lead author: “At MD Anderson, we have completely stopped performing minimally invasive surgery for cervical cancer. Throughout the gynecologic community, we’re seeing a transition back to the predominance of open surgery.”3
Changing the practice of medicine so that “you shall never again do a minimally invasive radical hysterectomy is not the conclusion I draw from that study,” Dr. Cohn said. “But it certainly does lead to a conversation about the risks and expected outcomes with individual patients.”
Amanda N. Fader, MD
In an editorial accompanying these studies in The New England Journal of Medicine, Amanda N. Fader, MD, Director of the Kelly Gynecologic Oncologic Service, Johns Hopkins Medicine, Baltimore, noted that “patients with a tumor size of less than 2 cm did not have worse outcomes with minimally invasive surgery than with open surgery.”4 According to Dr. Fader, although the studies have “dealt a great blow” to minimally invasive radical hysterectomy in cervical cancer treatment, they do not necessarily “signal the death knell.”
Quality of Evidence
THE EPIDEMIOLOGIC study analyzed data from 2,461 women with stage IA2 or IB1 cervical cancer treated with radical hysterectomy between 2010 and 2013, 49.8% of whom underwent minimally invasive surgery. “Over a median follow-up of 45 months, the 4-year mortality was 9.1% among women who underwent minimally invasive surgery and 5.3% among those who underwent open surgery,” the authors reported. A separate analysis, using Surveillance, Epidemiology, and End Results (SEER) data on radical hysterectomy for cervical cancer from 2000 to 2010, showed “the adoption of minimally invasive surgery coincided with a decline in the 4-year relative survival rate of 0.8% per year after 2006.”
The authors asserted that minimally invasive radical hysterectomy was broadly adopted in the United States, “despite the paucity of high-quality evidence.” Dr. Cohn commented: “You can make an argument that minimally invasive surgery is not a different operation. It is just a different tool to do the same operation. So, when you look at it that way, how much data do you require to adopt a new technology?”
Initial reports indicated that the length of hospital stay was shorter, patient satisfaction higher, and bleeding lower with minimally invasive surgery. “So, the technology was adopted rapidly,” Dr. Cohn said. “There was no reason to have believed there was not going to be equivalent cancer outcomes compared to traditional open surgery,” he added.
“What is really interesting is that in the LACC study, there was truly no difference in complications between open and minimally invasive surgery,” Dr. Cohn pointed out. There was a difference, however, in the median length of hospital stay (5 vs 3 days).
Unique to Cervical Cancer
PREVIOUS NATIONAL Cancer Database studies that compared minimally invasive and open surgical approaches in patients with early-stage ovarian or endometrial cancer did not show that minimally invasive surgery was associated with inferior survival, which suggests that the observed effect is unique to cervical cancer,” according to the epidemiologic study report. Dr. Cohn agreed that the association between minimally invasive surgery for cervical cancer “should not be generalizable to noncervical gynecologic malignancies.” He pointed out that some previous studies of laparoscopic vs open procedures for endometrial cancer had “demonstrated no difference in overall survival.”
“There might be some specific reasons why laparoscopic or robotic radical hysterectomy for cervical cancer is not generalizable” to noncervical gynecologic malignancies, Dr. Cohn said. “For one, the area of the cervix that is manipulated during the operation itself, where there is an incision that is made around the vagina proximal to the cervix, may potentially be the source of an increased probability of recurrence and death from disease.”
“For patients requiring treatment for early-stage cervical cancer, an explanation of the study data and the implications should absolutely be part of the upfront physician-patient discussion.”— David E. Cohn, MD
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While acknowledging that a limitation of the present study is the inability to explain why minimally invasive surgery was associated with shorter survival, the authors did propose some possible reasons. Among them was the possibility that “uterine manipulators, which are frequently used for retraction and visualization during minimally invasive hysterectomy, may disseminate tumor cells.” Other possibilities listed included “limits to the extent of resection that can be achieved that are inherent to minimally invasive radical hysterectomy,” closer surgical margins with minimally invasive surgery, and more surgical experience with open radical hysterectomy.
Emerging Data
IN NOVEMBER 2018, the Society of Gynecologic Oncology (SGO) issued a statement to its members that began as follows: “Gynecologic oncologists should be aware of the emerging data on minimally invasive surgery for cervical cancer so that a thorough discussion can be undertaken with patients and shared decision making used when choosing the surgical approach for radical hysterectomy.”5
The statement summarized the findings of the studies reported in The New England Journal of Medicine and noted that SGO anticipates “additional data to emerge on this important topic.” A session focused on the surgical approach for radical hysterectomy for cervical cancer is planned for the 2019 SGO Annual Meeting on Women’s Cancer (March 16–19, 2019, Honolulu). ■
DISCLOSURE: Drs. Ramirez, Melamed, and Fader reported no conflicts of interest. Dr. Cohn is a consultant for Oncology Analytics, Inc. and has received institutional funding from Agenus, Ajinomoto, Array BioPharma, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Ergomed, Exelixis, Genentech, GlaxoSmithKline, Gynecologic Oncology Group, ImmunoGen, INC Research, inVentiv Health Clinical, Janssen Research and Development, Ludwig Institute for Cancer Research, Novartis, PRA International, Regeneron Pharmaceuticals, Serono, Stemcentrx, Tesaro, Tracon Pharmaceuticals, AbbVie, Henry Jackson Foundation, Pharma Mar, Sanofi, EMD Serono, Eisai, Pfizer, and Advaxis.
REFERENCES
1. Ramirez PT, Frumovitz M, Pareja R, et al: Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N Engl J Med 379:1895-1904, 2018.
2. Melamed A, Margul DJ, Chen L, et al: Survival after minimally invasive radical hysterectomy for early-stage cervical cancer. N Engl J Med 379:1905-1914, 2018.
3. Grady D: Studies warn against minimally invasive surgery for cervical cancer. The New York Times, October 31, 2018.
4. Fader AN: Surgery in cervical cancer. N Engl J Med 379:1955-1957, 2018.
5. Society of Gynecologic Oncology: Notice to SGO members: Emerging data on the surgical approach for radical hysterectomy in the treatment of women with cervical cancer, November 13, 2018.
