Two researchers at The University of Texas MD Anderson Cancer Center shocked the oncology world in late 2018 when they published the results from separate but related studies showing patients with cervical cancer who underwent an open abdominal radical hysterectomy had lower rates of recurrence of the disease. In addition, overall survival rates were about 10 percent better than women who had minimally invasive surgery.
One study was a randomized-controlled phase III trial led by Pedro Tomas Ramirez, MD, Professor and Director of Minimally Invasive Surgical Research and Education in the Department of Gynecologic Oncology and Reproductive Medicine at MD Anderson. While the other was a retrospective epidemiologic study led by Jose Alejandro Rauh-Hain, MD, MPH, Assistant Professor in the Department of Gynecologic Oncology and Reproductive Medicine and Health Services Research at the Houston facility.
The Ramirez-led clinical trial found that minimally invasive radical hysterectomy was associated with a threefold increase in disease progression when compared with open surgery; an 86 percent rate of disease-free survival at 4.5 years versus 96.5 percent with open surgery; and a 3-year overall survival rate of 91.2 percent versus 97.1 percent with open surgery. Designed for 740 women with early-stage (IA or IB) cervical cancer, the study was halted at 631 patients by the data and safety committee when it was revealed that women undergoing minimally invasive surgery had a worse survival rate 4.5 years following diagnosis(N Engl J Med 2018;379:1895-1904).
The study led by Rauh-Hain was sponsored by NIH and NCI and conducted with researchers from Harvard, Columbia, and Northwestern universities. Data on open versus minimally invasive surgery outcomes from the National Cancer Database registry was analyzed first, followed by a secondary analysis using the NCI Surveillance, Epidemiology and End Results database. The SEER data revealed 4-year mortality risks were 9.1 percent in women who received minimally invasive surgery compared to 5.3 percent for patients who had open surgery. Additionally, the data showed that the advent of the minimally invasive surgery coincided with the beginning of an annual 0.8 percent decline in 4-year relative survival rates between 2006 and 2010 (N Engl J Med 2018;379:1905-1914).
The MD Anderson studies not only refuted all of the retrospective data previously published on surgery and cervical cancer, but the findings also had practice-changing impacts on the field after they appeared in the same November 2018 issue of the New England Journal of Medicine. While some manufacturers of surgical equipment and doctors trained to use the technology disputed the results of the studies, several cancer centers in the U.S. and abroad stopped offering minimally invasive radical hysterectomies based on the findings. MD Anderson had already quit offering the procedure 1 year earlier at the behest of Ramirez and Rauh-Hain.
Meanwhile, their groundbreaking work also has earned the pair of cancer researchers the Runner-Up award in the second annual Excellence in Oncology competition sponsored by the Oncology Times.
“I think it is a great honor to receive this award. And I think that it also highlights the importance of doing surgical trials in oncology, because these were surprising findings. The hope is that now we can continue to deliver the message and keep improving the care of these patients,” Rauh-Hain stated.
“These studies were conducted so that we could potentially change patient care and also change management in our patients. And I think the results of both these works have been impacting, as we have seen exactly that. We're now seeing a change in the standard of care for our patients as a result of all this hard work. So, it is absolutely an honor to receive this recognition,” Ramirez added.
Ramirez, who is also the editor-in-chief of the International Journal of Gynecological Cancer, provided Oncology Times readers with a closer look at the origins, execution, and impact of the landmark MD Anderson studies.
What inspired you to investigate this research question?
“At the time of study initiation and development, there was published evidence from a prospective randomized trial (GOG-LAP2) that minimally invasive surgery was equivalent to open surgery when considering not only perioperative outcomes but also oncologic outcomes (J Clin Oncol 2012;30:695-700). When considering cervical cancer, there were numerable retrospective case series comparing the two surgical approaches, with a primary focus on perioperative outcomes.
“These studies demonstrated that the minimally invasive approach was associated with less blood loss, length of hospital stay, lower postoperative wound-related complications, and faster overall recovery when compared to the open approach. However, there was a significant gap in knowledge as it pertained to oncologic outcomes in the setting of cervical cancer. Although there were a small number of studies comparing cancer-related outcomes, these were often flawed by inadequate sample size, comparisons of different time periods, and much shorter follow-up times in the minimally invasive groups, thus predisposing to shorter time for manifestation of events.
“Therefore, our goal was to embark on a prospective randomized trial comparing the minimally invasive approach versus the open approach when performing radical hysterectomy in patients with early-stage (FIGO 2009 IA2-IB1) cervical cancer. Our goal was to have an adequately powered study, encompassing multiple international institutions.”
What, if anything, surprised you about the results of your research?
“The study was extremely surprising since it demonstrated a higher recurrence rate and higher mortality rates in the minimally invasive radical hysterectomy group when compared to the open approach. This was certainly very moving since this was the only adequately powered prospective trial evaluating this important question and the findings were immediately practice changing.
“Soon after the publication of the trial, the NCCN Cervical Cancer Guidelines were changed to reflect findings from our study with a statement proposing that, given recently presented findings of significantly poorer survival outcomes with the laparoscopic approach compared to the open approach, ‘...women should be carefully counseled about the risks and benefits of the different surgical approaches.’
“One other issue that has also been surprising to me is the tremendous level of cognitive dissonance by practitioners in our field when confronted with the results of our study. Although our study is the only level I trial in the field and published in the most reputable journal in medicine, many in our field refuse to accept a change in practice, even when unable to find valid criticism of any of the study components or design. It has been quite eye-opening to see how clinicians and practitioners are driven by personal intuition and anecdotal evidence, rather than by quality scientific evidence.”
Is there anything about the study others are likely to get wrong?
“There have been several observations regarding the details of the study. One criticism of the study was that it was closed early and thus not completing its full projected accrual. However, it should be noted that the study early closure was due to a call by the data safety monitoring committee because of higher recurrences and higher rates of mortality in the minimally invasive group.
“A second criticism of the study was the fact that most recurrences were primarily found in 14 of the 33 centers involved in the study. One should recognize that most recurrences occurred in these centers, not because of a flaw in surgical technique or expertise, but rather because of the simple nature of the fact that these sites were where most patients were accrued.
“Thirdly, some have suggested that the study did not have an equal balance between the laparoscopic versus robotic approach in the minimally invasive arm. However, the study was not designed to detect a difference between these two surgical approaches and thus not powered for such comparison.
“Lastly, among the most common misconceptions of the study is that, since it showed a very low recurrence rate in tumors <2 cm in both arms, one may deduct that it is safe to perform minimally invasive surgery in patients with low-risk tumors. This is a very concerning misconception, since our study was not designed, nor powered, to detect a difference between minimally invasive surgery and open surgery when performing radical hysterectomy in patients with such low-risk tumors. It is therefore imperative that surgeons do not assume that patients may safely undergo radical hysterectomy when presenting with low-risk tumors.”
What are the clinical implications, if any, of your research?
“The results of our study have led to a major change in our field with many centers currently changing their practice to the open approach when performing a radical hysterectomy. A recent survey conducted in Europe by Chiva and colleagues (through personal communication) evaluated the patterns of practice among gynecologic oncologists members of the European Society of Gynaecological Oncology. In that survey, the authors found that prior to presentation of the data from our study, 65.8 percent of practitioners performed radical hysterectomy by a minimally invasive approach. Subsequent, to the publication of our study, only 27.2 percent are performing the procedure through such approach.
“In our own center at MD Anderson Cancer Center, the Department of Gynecologic Oncology & Reproductive Medicine completely stopped performing minimally invasive radical hysterectomy since October 2017. Numerable other institutions, nationally and internationally, have stopped performing either laparoscopic or robotic radical hysterectomy. In addition, there has been massive media coverage of the results of our study, including numerable articles and references in the media, such as The New York Times, Wall Street Journal, Time Magazine, and CNN. Most importantly, we consider the greatest impact has been increased patient awareness and heightened discussions regarding the findings of our study.”
What further research needs to be done on this topic?
“The most important question to arise from the results of this study is the reason as to the etiology of our findings. In other words, why do patients undergoing minimally invasive radical hysterectomy have a higher rate of recurrences and higher mortality rates?
“It has been postulated that perhaps this may be secondary to the fact that through uterine manipulation one may increase the risk of tumor spillage in these patients. Another postulate is the fact that perhaps the CO2 gas used for insufflation may increase the risk of tumor cell implantation. Further research investigating the actual cause of such higher recurrence rates and mortality should be encouraged.
“Our group is also evaluating differences in the perioperative adverse events, as well as quality-of-life measures between the two arms of the study. In addition, we are also evaluating details of the patients who recurred in each arm of the study with the aim to determine specific risk factors associated with outcomes in each arm of the study.”
Is there anything else you want Oncology Times readers to know about your research?
“This was a collaborative effort that was performed with minimal financial support from industry or collaborative groups. The study was supported primarily by research funds derived from institutional and philanthropic support. [It] exemplifies the feasibility of such efforts, but at the same time calls for increased awareness from collaborative entities and governmental agencies to provide support for surgical research, which, unfortunately, at this time falls far below that from industry supported research.”
Chuck Holt is a contributing writer.
2019 Excellence in Oncology