The Birth of Natural Orifice Transluminal Endoscopic Surgery

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In the News ISSUE: SEPTEMBER 2014 | VOLUME: 41:09

The Birth of Natural Orifice Transluminal Endoscopic Surgery Through Sometimes Clandestine Beginnings and Vacillating Enthusiasm, Researchers Continue Steady Quest for Improvement by Victoria Stern

In 1998, a woman presented to Daniel A. Tsin, MD, FACOG, suffering from infertility and intense pelvic pain. Dr. Tsin, a gynecologist specializing in minimally invasive techniques, planned to perform minilaparoscopy to diagnose and treat her problem. During the procedure, Dr. Tsin found endometriosis and a diseased appendix. “We opened the vaginal port to prep the base of the appendix for removal, and took out the appendix through the vagina,” he recalled of his first transvaginal endoscopic appendectomy. Dr. Tsin’s idea to extract organs through the vagina came several months earlier during experiments in the animal lab. “I was trying to overcome the limitations of minilaparoscopy,” said Dr. Tsin, currently the director of minimally invasive surgery at Mount Sinai Hospital of Queens, Astoria, N.Y. “The problem is that it’s impossible to remove an appendix, ovary or gallbladder through 3- to 5-mm ports.” Dr. Tsin saw a solution in culdoscopy, a technique that provides a view of Daniel A. Tsin, MD the pelvic viscera after a culdoscope is inserted through the vagina. However, Dr. Tsin took the technique a step further, combining minilaparoscopy with culdoscopy. He used the vaginal port not only to visualize organs but also to operate on and extract them. Dr. Tsin’s first transvaginal appendectomy in a human patient was a success: The woman had no visible scarring, required almost no pain medications and recovered quickly. Just a few months later, she became pregnant. “The team spirit of collaboration was incredible, and we all recognized we were doing things differently than traditional laparoscopy,” Dr. Tsin recalled. By 1999, Dr. Tsin’s team performed the first transvaginal endoscopic cholecystectomy in humans, using a custom-made 46-cm-long laparoscope with a 30-degree angle view (JSLS 2003;7:171-172), and several months later, Dr. Tsin had completed a small series of three culdolaparoscopic appendectomies and three culdolaparoscopic cholecystectomies. In November 1999, Dr. Tsin presented the results of the first six cases of culdolaparoscopy at the 28th annual meeting of the American Association of Gynecologic Laparoscopists, but his work was largely ignored. “My team and I were aware of the potential future of flexible technology, but the surgical community at the time was not ready for the transvaginal endoscopic approach for cholecystectomy or appendectomy,” Dr. Tsin said. “The surgeons in my hospital were divided. We had a few defenders, but a majority thought we were delirious.”

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On March 8, 2000, Dr. Tsin’s work came under scrutiny and a special committee decided to ban the transvaginal procedures. Dr. Tsin was allowed to continue culdolaparoscopy, but only for gynecologic procedures. Despite this setback, Dr. Tsin had some supporters in the surgical community, including Paul A. Wetter, MD, chairman of the Society of Laparoendoscopic Surgeons, whose encouragement motivated Dr. Tsin to continue his work. Dr. Tsin subsequently published a range of papers in peer-reviewed journals. For instance, in 2001, Dr. Tsin reported on the feasibility of culdolaparoscopy and completed five oophorectomies, four myomectomies, three salpingo-ophorectomies and one salpingectomy using the technique (J Am Assoc Gynecol Laparosc 2001;8:438-441; JSLS 2001;5:69-71). In 2007, when natural orifice transluminal endoscopic surgery (NOTES) was gaining traction in the surgical community, Dr. Tsin published a series on the first 100 minilaparoscopyassisted natural orifice surgeries, noting only one complication related to antibiotics (JSLS 2007;11:24-29). “Finally, by 2007, when NOTES began to take off, people started to recognize my contribution to the field,” Dr. Tsin noted. NOTES Emerges In 1997, while Dr. Tsin was experimenting with culdolaparoscopy, gastroenterologist Anthony N. Kalloo, MD, and six colleagues formed the Apollo Group, an international think tank of gastroenterologists and surgeons from different medical and academic centers. The group included Peter Cotton, MD, Christopher Gostout, MD, Robert Hawes, MD, Sydney Chung, MD, Pankaj Jay Pasricha, MD, and Sergey Kantsevoy, MD, PhD. The members of the Apollo Group wanted to take therapeutic endoscopy to the next level, diagnosing and potentially Anthony Kalloo, treating gastrointestinal disorders through a natural orifice. MD “If you think about the way surgery evolved, it started off as very invasive 100 years ago,” Dr. Kalloo said. “With the advent of laparoscopic surgery, we saw that small incisions were better and patients recovered more quickly. Now, we hoped for endoscopy to go to the next level with no incisions at all.” In 1998, Dr. Kalloo was asked to give a talk at Digestive Disease Week (DDW) regarding the future of endoscopy. “I introduced the concept of breaching the gastric wall to enter the peritoneal cavity and perform surgery,” said Dr. Kalloo, The Moses and Helen Golden Paulson Professor of Gastroenterology and director in the Division of Gastroenterology & Hepatology, Johns Hopkins Hospital, Baltimore. “I believed that the future of endoscopy was beyond the wall, in the peritoneal and chest cavity.” After presenting his novel concept, Dr. Kalloo began experimenting with the natural orifice technique in pigs to determine the feasibility of a transgastric approach to entering the peritoneal cavity for liver biopsy. “When we first tried this approach, it was thrilling,” Dr. Kalloo recalled. “To look at organs in the peritoneal cavity without making an incision across the abdomen was so exciting. We were fearful, however, about how people would respond and we initially did these surgeries in secret.” In the initial feasibility studies, Drs. Kalloo and Kantsevoy successfully entered the peritoneal cavity of a dozen 50-kg pigs through the mouth and obtained liver biopsies. The pigs recovered without any leakage or infection, and the team concluded that the procedure was technically feasible.

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In survival studies, Dr. Kalloo and his colleagues obtained adequate liver biopsy specimens in five pigs. To help bring the infection rate close to zero, they administered IV antibiotics preand postoperatively, cleaned the oral cavity and irrigated the stomach with antibiotic solution. All pigs survived, ate heartily the next day and gained weight. Two weeks later, endoscopy revealed the pigs’ stomachs appeared normal. “I was amazed at how easily I could see organs and get from one point to another,” Dr. Kalloo recalled. “This procedure appeared to be a logical next step in the evolution of minimally invasive techniques.” Dr. Kalloo initially presented the results at DDW in 2000, and published them four years later (Gastrointest Endosc 2004;60:114-117). Beyond the Animal Model The next major step for NOTES was moving from animal models to humans. In 2003, G.V. Rao, MS, MAMS, FRCS, chief of surgical gastroenterology and minimally invasive surgery, and D. Nageshwar Reddy, MD, DM, chief of gastroenterology and therapeutic endoscopy, Asian Institute of Gastroenterology in Hyderabad, India, performed the first transgastric appendectomy in a human, removing the appendix through the mouth. The patient was a young man admitted to the ICU with extensive anterior wall burns. He had developed acute appendicitis. “We realized that the only way to remove his appendix was orally through the stomach,” Dr. Reddy said. The procedure took 1.5 hours under general anesthesia, and the patient did very well, returning home after 48 hours. “Of course, it was a nervous time for us as there was a lot of apprehension about performing the procedure, but this was the only option for the patient,” recalled Dr. Reddy. “We got praised and criticized for our work.” On one hand, there were conservative surgeons and physicians who felt this procedure was too radical, but on the other hand, the duo also received support from the minimally invasive surgeons and gastroenterologists. After his first presentation at the Digestive Disease Week in 2003, Dr. Reddy recalled a prolonged ovation and a lot of curiosity. Drs. Rao and Reddy’s accomplishment was a boon for NOTES. “This advance in humans generated a lot of excitement and pushed the procedure forward,” Dr. Kalloo said.

Guidelines and Challenges Despite the potential for NOTES, Dr. Hawes, president of the American Society for Gastrointestinal Endoscopy (ASGE), and David Rattner, MD, president of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), wanted to ensure that the technique developed in a safe manner. “Dr. Rattner and I were very enthusiastic about NOTES, but also aware it could go badly,” said Dr. Hawes, of the Center for Interventional Endoscopy, Florida Hospital Orlando. “We wanted to avoid the feeding frenzy that occurred in the early days of laparoscopic cholecystectomy, which resulted in unnecessary complications. I thought a similar frenzy might occur with NOTES before the procedure was ready for prime time.” With the intention of advancing NOTES in a responsible fashion, Drs. Hawes and Rattner gathered 14 leaders from ASGE and SAGES in July 2005, and formed Natural Orifice Surgery Consortium for Assessment and Research (NOSCAR). In October of that year, Dr. Hawes published a white paper on NOTES, identifying the barriers to developing the

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technique and outlining guidelines to move forward (Gastrointest Endosc 2006;63:838-839; Surg Endosc 2006;20:329-333). The potential challenges of developing NOTES included gaining safe access to the peritoneal cavity, preventing infection and securing closure of the gastric incision, as well as providing adequate training and developing enabling technologies. Given the success of laparoscopic cholecystectomy, transvaginal cholecystectomy became the primary procedure investigated to further the science of NOTES. NOSCAR declared that anyone performing a NOTES procedure would need approval from an institutional review board. “The purpose was to ensure that people were qualified to use the technique and were answering the questions that would move NOTES forward,” Dr. Hawes said. “We formed a research committee, vetted grant requests and received funding, which allowed researchers to explore the science of NOTES and investigate potential obstacles as well as how to solve them.” For instance, there was initial worry about infection in the peritoneal cavity because as soon as an endoscope comes into contact with the mouth, there are thousands of bacteria; however, research soon quelled these concerns, showing that this infection risk was negligible. Enthusiasm for NOTES started to soar among surgeons and gastroenterologists interested in pursuing the next cutting-edge surgical technique after laparoscopy. As in the early days of laparoscopy, there was an influx of interest and funding from corporations, such as Ethicon, Covidien and Boston Scientific, which helped fuel advances in NOTES research and development. Evolution of NOTES: 2007 to Present After Drs. Rao and Reddy’s initial success in humans and with the guidelines set forth by NOSCAR, physicians worldwide began cautiously testing the feasibility of NOTES for a variety of procedures. In 2007, Jeffrey Ponsky, MD, Department of Surgery, Case Medical Center, Cleveland, published the first NOTES procedure in humans: a percutaneous endoscopic gastrostomy rescue. That year, Jacques Marescaux, MD, from University Louis Pasteur, France, performed the first transvaginal NOTES cholecystectomy (Arch Surg 2007;142:823-826), and shortly after, a team in Brazil and one in Italy did the same technique in a small series of patients (J Laparoendosc Adv Surg Tech A 2008;18:345-351; Surg Endosc 2008;22:542-547). General surgeon Lee Swanstrom, MD, conducted the first human transgastric cholecystectomy (J Surg Oncol 2007;96:678-683). A string of other NOTES firsts occurred, including a transvaginal appendectomy in 2008 (Surg Endosc 2008;22:1343-1347) and a NOTES transanal rectal cancer resection in 2009 (Surg Endosc 2010;24:1205-1210). A 2012 review examined the NOTES landscape from 2007 to 2011, describing 48 studies of various NOTES procedures in humans (Minim Invasive Surg 2012;2012:189296). Field F. Willingham, MD, MPH, director of endoscopy in the Division of Digestive Diseases, Emory University, Atlanta, and his colleagues reported that complication rates varied by procedure and access site. Transvaginal appendectomy, transgastric and transvaginal gastrectomy, and transvaginal splenectomy and incisional hernia repair came with very few complications, whereas transvaginal cholecystectomy (1.5%-25%), transgastric cholecystectomy (18%) and transgastric appendectomy (33.3%) were associated with more complications. The most common NOTES procedure was cholecystectomy (75%) and the most common approach was transvaginal (79%). Additionally, 46% of the procedures were pure NOTES, whereas the other 54% employed hybrid NOTES techniques. Dr. Willingham concluded that NOTES has progressed, but barriers remained that limited its wider acceptance in patients, namely the development of NOTES-specific technologies as

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well as evidence that NOTES offers benefits, beyond cosmesis and reduced pain, over laparoscopic approaches. The Future of NOTES As NOTES evolved, the initial excitement began to wane. Headlines that once asked, “Is NOTES the Next Laparoscopy?” (GSN, June 2007) now pondered, “Natural Orifice Surgery: Is the Thrill Gone?” (GSN, March 2012). Although Drs. Kalloo and Reddy believe that NOTES is ahead of its time, they acknowledge that it has not followed the striking trajectory of laparoscopy. “I think what’s happened is that some people think NOTES is taking a long time and hasn’t done what we expected it to do,” Dr. Kalloo said. “To that, I’d say NOTES is evolving at just the pace it’s supposed to: slowly and surely. Most importantly, NOTES has not come with any significant complications or any deaths.” However, the slow progress of NOTES caused industry’s enthusiasm to fade. “Despite the reduced pain and cosmetic benefits of NOTES, companies began to see that it wouldn’t provide the quantum leap that many had hoped and decided to invest in other techniques, such as single-incision laparoscopy,” said Dr. Hawes. “Without support from industry, it’s been difficult to continue to make progress.” Dr. Hawes believes that for NOTES to take off, it will need a home-run application, like laparoscopic cholecystectomy was for laparoscopic surgery. “My prediction is that transanal colon resection will be the first true NOTES procedure and may propel NOTES back into the limelight,” Dr. Hawes said. Patricia Sylla, MD, FACS, FASCRS, a colorectal surgeon at Massachusetts General Hospital and assistant professor of surgery at Harvard Medical School, Boston, and Antonio M. de Lacy, MD, chief of gastrointestinal surgery at the Hospital Clínic of Barcelona, Spain, pioneered a transanal approach to colorectal surgery. In 2009, Drs. Sylla and de Lacy performed the first NOTES transanal rectal cancer resection successfully on a 76-year-old woman with locally advanced rectal cancer using a transanal endoscopic microsurgery (TEM) platform and laparoscopic assistance (Surg Endosc 2010;24:1205-1210). Dr. Sylla’s interest in a transanal approach to colorectal surgery began in 2007 at a NOSCAR conference in Boston, when she attended a presentation by Mark Whiteford, MD, FACS, FASCRS, on transanal radical sigmoid colectomy in human cadavers using TEM instrumentation (Surg Endosc 2007;21:1870-1874). “No one in the audience really responded, but if you understood the TEM platform, you could see the true potential of this approach,” Dr. Sylla recalled. “I saw this as the future of colorectal surgery.” Back at Massachusetts General, Dr. Sylla experimented with the transanal approach to colorectal surgery on pigs and human cadavers (J Gastrointest Surg 2008;12:1717-1723; Surg Endosc 2010;24:2022-2030; Surg Endosc 2013;27:74-80). However, performing a pure NOTES procedure proved difficult, mostly due to limitations in the available instrumentation. “There are several cases in the literature of pure transanal NOTES colorectal operations, but this has been in very thin patients,” Dr. Sylla noted. “Once we get more innovative, longer and flexible instruments, we will be able to perform more pure transanal NOTES procedures, but a hybrid approach appears to be safest at this time.” Currently, Drs. Sylla and de Lacy have demonstrated the feasibility and preliminary safety of laparoscopy-assisted transanal NOTES total mesorectal excision for rectal cancer in 28 patients (Surg Endosc 2013 Mar. [Epub ahead of print]; Surg Endosc 2013 Apr. [Epub ahead

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of print]; Surg Endosc 2013;27:339-346). Other techniques may have potential to propel NOTES forward. Although not a pure NOTES procedure, some believe that peroral endoscopic myotomy (POEM), a cross between laparoscopic surgery and therapeutic endoscopy, may be the first sentinel application to come out of NOTES, Dr. Willingham said. In 2010, Haruhiro Inoue, MD, a gastroenterologic surgeon, brought POEM to humans, performing the first series to treat esophageal achalasia (Endoscopy 2010;42:265-271). NOTES also may pave the way for hybrid procedures that blend flexible endoscopy with minimally invasive laparoscopic techniques. “Many surgeons don’t have extensive experience with flexible endoscopy and gastroenterologists don’t typically train in laparoscopy,” Dr. Willingham said. “So we are currently examining whether gastroenterologists and surgeons can work together to develop a novel solution when the current approach is not good.” For instance, Dr. Willingham and his colleagues have developed a hybrid laparoscopic and endoscopic approach to removing mass lesions of the foregut, offering a vast improvement over total gastrectomy (GIE 2012;75:905-912). Currently, it’s important to show that a pure or hybrid NOTES procedure offers significant benefits over the standard open or laparoscopic approach to help justify the costs and training associated with investment in a new procedure, Dr. Sylla said. Looking to the future, Dr. Kalloo sees surgery becoming increasingly minimally invasive. “I see a future unfolding in which fewer incisions are the norm,” Dr. Kalloo said. “One hundred years from now, we’ll look back at open and laparoscopic surgery and say how barbaric that was, actually creating a big hole across the abdominal wall to help patients.”

Timeline Of Firsts For NOTES

1998

Transvaginal appendectomy, rigid instruments (J Am Assoc Gynecol Laparosc 2001;8:438-441)

NOTES procedure, swine model (Gastrointest Endosc 2004;60:114-117)

1999 Transvaginal cholecystectomy, rigid instruments (JSLS 2003;7:171-172)

2003

Transgastric appendectomy (Reddy and Rao)

Transvaginal cholecystectomy (Surg Innov 2007;14:279-283)

Transgastric cholecystectomy (J Surg Oncol 2007;96:678-683)

2007 Transanal NOTES radical sigmoidectomy, human cadavers (J Gastroint Surg 2008;12:1717-1723)

POEM, swine model (Endoscopy 2007;39:761-764)

Transvaginal appendectomy 2008

(Surg Endosc 2008;22:1343-1347)

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NOTES peritoneoscopy (Surg Endosc 2008;22:16-20)

Transvaginal donor kidney extraction Transgastric and transvaginal gastrectomy Transvaginal splenectomy 2009

(Surg Innov 2009;16:218-222)

NOTES transanal rectal cancer resection, first human experience, November 2009 (Surg Endosc 2010;24:1205-1210)

Transvaginal incisional hernia repair (Hernia 2010;14:89-91)

2010 POEM In Humans (Endoscopy 2010;42:265-271) POEM, peroral endoscopic myotomy

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