The FDA warning was issued in February 2019 to both the public and physicians. The FDA cautioned that the safety and effectiveness of robotic surgical devices for mastectomy “have not been established” and robots are not approved for the prevention or treatment of breast cancer.
The agency also noted that “diminished long-term survival” was associated with robotic surgery in another women’s cancer, that of hysterectomy for cervical cancer.
The FDA also made a surprising statement. The agency typically approves the robot for surgical use based on 30-day complication rates (compared with standards of care). But it said that going forward it “anticipates” that any evaluation of new use of robots in cancer “would be supported” by cancer outcomes such as progression-free survival and overall survival, which require much longer follow-up.
In short, the FDA hinted that it would change how it regulated medical devices, or at least robots used in women’s cancers. “The FDA takes women’s health very seriously,” said the organization.
Fast forward to 2021, and there are several prospective clinical trials of robot-assisted nipple-sparing mastectomy underway in the United States, including a five-center study sponsored by Intuitive Surgical, the maker of da Vinci robots, the dominant machine on the market. There are also single-center studies at Ohio State and University of Texas Southwestern Medical Center.
However, in each case, the study design either excludes cancer outcomes or does not primarily focus on those measures.
Instead, the primary outcomes are relatively short term and include safety and efficacy measures such as en bloc (in one piece) removal of the breast tissue, conversions to open mastectomy, and the incidence of adverse events during surgery and up to 6 weeks after surgery.
Importantly, none of the studies is a randomized trial; all have single arms.
That’s not what is needed, says breast surgeon Julie A. Margenthaler, MD of Washington University in St. Louis.
“I firmly believe that robotic-assisted mastectomy should only be considered in the context of a well-designed, randomized trial evaluating patient selection, patient safety, surgical complications, and oncologic outcomes with a concomitant cost analysis,” Dr. Margenthaler wrote in an essay published last year in JAMA Surgery.
As with the FDA warning, she cites worse survival with commonly used minimally invasive radical hysterectomy for cervical cancer, saying it “is a stark reminder that the marketing of robotic surgery has its roots in cosmesis and convenience rather than oncologic outcomes.”
In addition, robotic surgery is prohibitively expensive, said Dr. Margenthaler. In fact, cost is her “main criticism regarding robotic-assisted mastectomy.” It costs an additional $6,000 for robot use per procedure, according to a study conducted at a center in Taiwan. “I simply cannot be convinced that this will ever achieve cost-effective or even cost-neutral status,” Dr. Margenthaler wrote.
Not looking at the right outcomes
“They’re not looking at the right outcomes,” said Hooman Noorchashm, MD, PhD, about the current trials in the United States. He is a former surgeon and faculty member at the University of Pennsylvania in Philadelphia, and is now a patient advocate after his wife, Amy Reed, MD, died of uterine cancer in 2017 following a laparoscopic hysterectomy performed with a power morcellator that resulted in the upstaging of an undetected gynecologic cancer.
“You have to look at oncologic outcomes and do randomized, noninferiority trials to demonstrate that those cancer outcomes are at least equivalent to standard of care,” he said in an interview.
The current U.S. trials are “totally inappropriate,” he said.
Are randomized trials forthcoming after this initial set of single-arm trials? This news organization reached out to Intuitive Surgical, maker of the market leader da Vinci robotic surgical equipment to find out.
“Any plans for use of da Vinci Xi surgical system in nipple-sparing mastectomy will be based on these [single-arm] study results as well as other data and evidence,” said a company spokesperson, who did not confirm use of a randomized trial.
What about the FDA? Will the agency change its current approach to approving robots in surgeries for women’s cancers and require – not just anticipate – cancer-related outcomes data? At press time, the FDA did not respond to a request for comment.
Not having a randomized trial with cancer outcomes in any eventual FDA review opens the door for robotic mastectomy to be cleared for use in some mastectomies with short-term, nononcologic data, said Dr. Noorchashm.
Safety concerns with robotic mastectomy
Proponents of robot-assisted nipple-sparing mastectomy, which is coupled with reconstruction to preserve the shape of both the breast and nipple-areola area, suggest that improved patient cosmesis is a significant advantage with the high-tech intervention, said Dr. Margenthaler.
That’s because most robotic mastectomies performed to date (almost exclusively in Europe and Asia) have employed a 3- to 5-cm vertical incision located behind the lateral breast fold, allowing the scar to be hidden under the patient’s arm.
But therein also lies a safety concern, she asserted.
The “oncologic integrity” of the specimen on extraction is in question in some cases, she wrote, because of “such a small opening.”
Dr. Noorchashm agreed: “It all comes down to trying to get a large specimen out of a small incision.”
Traditional open mastectomy optimally yields the en bloc removal of a tumor – in one whole piece – to avoid fragmenting the cancerous tissue and possibly leaving residual disease behind. These undesirable events are associated with a higher risk for recurrence and treatment failure, he explained.
Thus, there is a need for a randomized trial with longer-term oncologic outcomes that compares the new approach with traditional open mastectomy, argued both Dr. Margenthaler and Dr. Noorchashm.
In defense of single-arm trials
“Oncologic safety is what we are concerned about and what we would like to study,” said Ko Un (Clara) Park, MD, a breast surgeon at The Ohio State University in Columbus.
Dr. Park is leading a single-center, single-arm pilot study of robotic nipple-sparing mastectomy enrolling up to 20 women with early-stage breast cancer or inherited genetic risk factors (but no cancer diagnosis). The trial, sponsored by a Pelotonia Idea Grant and Ohio State, recently enrolled its first patient.
The study’s primary outcomes include the feasibility of removal of the breast tissue en bloc; however, none of the outcomes are classic oncologic metrics such as progression-free survival.
The en bloc removal outcome is in direct response to the FDA’s concerns about minimally invasive cancer surgeries in women, Dr. Park said in an interview. The pilot trial has an investigational device exemption (IDE) granted by the FDA.
“The reason why we can’t just open a randomized controlled study (of robot versus open) and measure oncologic outcomes like recurrence-free survival is because, before we get to that point, we have to make sure” basic safety issues are addressed and established, she explained.
But Dr. Noorchashm said that argument is missing the larger, more important point: “They are still doing an oncologic procedure – you are still obliged to do noninferiority [randomized] testing with respect to cancer outcomes.”
Dr. Park sounded a different note: “We are doing it as safely as we can do it.”
Prophylactic use is also a cancer surgery
Intuitive’s five-center trial does not include en bloc removal of the breast gland as a primary outcome. Instead, the two primary outcomes are conversions to open mastectomy (efficacy measure) and the incidence of adverse events during surgery to 42 days after surgery (safety measure).
The company’s trial does not include any women with breast cancer, but is limited to women at increased risk for breast cancer and seeking prophylactic nipple-sparing mastectomy surgery.
Enrollment in the 145-patient single-arm trial began in the last few months and has a primary completion date of December 2022. It also has an IDE from the FDA.
“I do think that things like this need to be done with caution,” said Katherine Kopkash, MD, an investigator in the Intuitive trial and a breast surgeon at NorthShore University HealthSystem in Evanston, Ill., referring to the trial’s FDA exemption.
Dr. Kopkash said in an interview that the researchers in the multisite, single-arm Intuitive trial will also track oncologic outcomes, but the trial description at clinicaltrials.gov does not indicate that.
Both Dr. Kopkash and Dr. Park cited the high-profile missteps that took place in 2018 at Monmouth County Medical Center in Long Branch, N.J., during what was described as the first-ever use of robotic nipple-sparing mastectomy for invasive cancer in the United States, as reported by Medscape Medical News. However, neither the center or surgeon, Stephen Chagares, MD, requested or received an IDE from the FDA, and use of robotic mastectomy was halted after two cases.
It’s conceivable that Intuitive will seek out FDA clearance for use of its da Vinci system in robotic nipple-sparing mastectomy with data in a prophylactic setting and then expand the pool of patients, argued Dr. Noorchashm.
“Even if you introduce a new technology ... for a narrow subset of patients, the application of it eventually occurs on a ‘sliding scale,’ ” he said.
The former surgeon gave an example: The first device used in gastric bypass surgery was cleared for use in 2001 by the FDA for adults who were “severely morbidly obese.” But by the late 2000s, the operation was also being performed on people with lower body mass indexes who hadn’t exhausted traditional weight loss procedures. “It was very lucrative,” Dr. Noorchashm said about the surgery.