21.1 Introduction

The initial concept of natural orifice transluminal endoscopic surgery (NOTES) was to pass a flexible endoscope through the gut wall and perform surgical procedures in the peritoneal cavity or mediastinum. While this concept has not yet come to full fruition, the movement should be credited with accelerating the progression of therapeutic endoscopy. Therapeutic endoscopy has a long tradition extending from polypectomy in the 60s to endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy, stone extraction, and stent placement through hemostasis and luminal stenting. We have now entered an era of endoluminal therapy which includes treatment of gastrointestinal reflux disease (GERD), en bloc resection of early gastrointestinal cancers, obesity management, and full-thickness resection of tumors of the gut wall. The next progression is cooperative laparoscopic and endoscopic techniques (CLET). With CLET, the disciplines of minimally invasive surgery (MIS) and therapeutic endoscopy have come together to solve common problems and this has given birth to hybrid procedures; laparoscopy-assisted endoscopy and endoscopy-assisted laparoscopic surgery. This progression from standard therapeutic endoscopy through CLET will eventually culminate in a more complete realization of NOTES. It was in fact the NOTES movement that brought together therapeutic endoscopists and minimally invasive surgeons. The experience gained from this cooperation of disciplines combined with lessons learned by working through the progression of endoluminal and hybrid procedures promises to offer less invasive treatments which will hopefully lower costs and improve outcomes. The purpose of this chapter is to provide an overview of these new techniques and to provide a window into the future of therapeutic endoscopy. While attempts will be made to provide the indications, complications, and training required to perform these procedures, it must be understood that these new therapeutic domains are rapidly evolving and outcomes today will likely be different in the near future.

21.2 History of NOTES

The idea of natural orifice surgery (NOS) was conceived by Sergei Kantsevoy and Tony Kalloo in the late 1990s. While working with the Apollo Group, they introduced the concept of passing a flexible endoscope through a natural orifice and accessing the mediastinum or peritoneal cavity using the gut as a window (like the skin). The first report of their work was presented to the Society for Surgery of the Alimentary Tract (SSAT) during Digestive Disease Week (DDW) in 2000 and involved transgastric peritoneoscopy. ¹ However, it was their report 2 years later at DDW describing a NOTES gastrojejunostomy in a survival swine model that really caught the attention of the MIS world. ² The excitement (and concern) prompted the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) and the American Society for Gastrointestinal Endoscopy (ASGE) to form a committee to oversee the responsible development of NOTES. This societal cooperation resulted in an annual meeting devoted to updating the progress of NOTES, a White Paper presenting a roadmap for the responsible development of NOTES ³ and research support to solve the obstacles to the clinical implementation of NOTES procedures. As time progressed, it became clear that flexible endoscopes and existing accessories were inadequate to implement the types of procedures that Kalloo and Kantsevoy initially conceived. Therapeutic gastroenterologists were unable to enter the operating room (OR) and were not credentialed to do surgical procedures. Surgeons, except for a chosen few, did not have the endoscopic skills to perform surgical procedures with the flexible endoscope. Minimally invasive surgeons wanted to continue to use their familiar rigid platforms and ventured into transvaginal cholecystectomy and single-port laparoscopic surgery as potentially less invasive approaches to standard laparoscopic surgery. Enthusiasm among gastroenterologists, surgeons, and industry waned and the NOTES movement lost its focus.

The idea of doing surgical procedures with the flexible endoscope through a natural orifice was resurrected by Haru Inoue when he advanced two concepts originally developed within the Apollo Group. The first concept was introduced by Chris Gostout and his group at the Mayo Clinic. Dr. Gostout’s team was trying to solve the riddle of safe and easy en bloc resection. As part of this work, they developed the concept of “submucosal tunneling” to create a working area within the submucosal space. ⁴ , ⁵ , ⁶ , ⁷ They modified concepts developed by the Japanese for endoscopic submucosal dissection (ESD) and became proponents of using balloons to expand the submucosal space. During this time, Jay Pasricha conceived of the second concept, the idea of using Dr. Gostout’s tunneling technique to perform an endoscopic myotomy as a treatment for achalasia. ⁸ It was the brilliance of Dr. Inoue, relying on his extensive experience in ESD and laparoscopic Heller’s myotomy, that enabled him to perform the first per oral endoscopic myotomy (POEM) for the treatment of achalasia. ⁹ , ¹⁰ It was the introduction of POEM into clinical practice that initiated the concept of submucosal surgery. With the advent of POEM, it has proven the safety of making a small mucosal incision, working within the submucosal space and achieving safe and effective closure by placing clips on the mucosal incision. This has now led to a procedure called submucosal tunneling endoscopic resection (STER) which is being applied to small gastrointestinal stromal tumors (GISTs). GISTs arise from the muscularis propria and thus endoscopic resection usually results in entry into the peritoneal cavity or mediastinum. A desire to remove GISTs and early gastric cancers is what is primarily responsible for the development of laparoscopic–endoscopic and endoscopic–laparoscopic hybrid procedures. Endoscopic submucosal surgery and hybrid laparoscopic–endoscopic procedures represent the critical bridges between therapeutic endoscopy and NOTES.

21.3 Submucosal Surgery

POEM is covered more thoroughly in other areas within this textbook. Briefly, the procedure involves making a small submucosal injection in the esophageal wall followed by a vertical mucosal incision (▶Fig. 21.1; Video 21.1). The entry point is either anterior or posterior depending on the preference of the endoscopist and whether the patient has had prior treatment. Once the space is entered, a step-by-step dissection of the submucosal fibers is performed using various ESD instruments. This dissection is extended a few centimeters into the cardia. When the dissection is complete, the endoscope is withdrawn to a point a few centimeters distal to the mucosal incision and the myotomy is begun. There is not a uniform standard and some endoscopists perform a selective myotomy involving only the inner circular muscle layer while others purposely cut through both circular and longitudinal fibers. There are no comparative studies between these two techniques. Once the myotomy is extended into the cardia, the scope is withdrawn and the mucosal incision is closed by a series of clips. Decisions about whom to treat and the length of the myotomy are now being determined by the results of high-resolution manometry and categorizing the patient according to the Chicago Classification. ¹¹ , ¹² Large single-and multicenter studies have now been reported and randomized trials comparing POEM with Heller’s myotomy and pneumatic dilation are nearly complete and will soon be reported. Many consider POEM to be the first natural orifice surgery. Two important concepts emerging from the POEM experience which are relevant to the advancement of therapeutic endoscopy are the safety and efficacy of working within the submucosal space and that safe and effective closure of “tunnels” can be achieved by simple closure of the mucosal incision.

Endoscopic resection of submucosal tumors came about as an extension of POEM. It is primarily applied to GISTs in the esophagus and stomach (▶Fig. 21.2). The technique is initiated in the same manner as POEM. At a certain distance from the submucosal tumor, a submucosal injection followed by a mucosal incision into the submucosal space is made. The endoscopist then tunnels down to the lesion and works within the submucosal space to dissect, isolate, and resect the tumor. The tumor is withdrawn through the tunnel and the mucosal incision is closed with clips. In the course of this procedure, entry into the mediastinum or peritoneal cavity can occur. For the mediastinum, as long as CO₂ is being used, escape of gas from the endoscope is usually not problematic. In the case of gastric GISTs, placement of a Veress needle may be required to evacuate CO₂from the peritoneal cavity. The importance of STER is that it allows resection of submucosal tumors while preserving the stomach wall. It reinforces the safety of working within the submucosal space and has now led to exploration of endoscopic pyloromyotomy for the treatment of gastroparesis. ¹³ The potential for submucosal surgery is vast, and in addition to POEM and pyloromyotomy includes the smooth muscle biopsy in gut motility disorders, drug delivery, pacemaker, and neural stimulation procedures (Video 21.2).

21.4 Back to NOTES

The era of NOTES began in earnest when SAGES and the ASGE combined forces and formed a joint committee to oversee the responsible development of NOTES. The first and most important contribution of that committee was the publication of the first White Paper published jointly in Gastrointestinal Endoscopy and Surgical Endoscopy in 2006. ³ An important component of the White Paper was a list of obstacles that the committee felt needed to be addressed in order for NOTES to become a clinical reality (▶Table 21.1). At the first International Summit in NOTES in 2006, working groups were formed to make recommendation on research required to overcome these obstacles.

A number of proposals were made and tested to achieve safe access to the peritoneal cavity. These included a simple incision with a needle knife–like instrument, utilizing a percutaneous endoscopic gastrostomy tube technique as well as tunneling as described under submucosal surgery section of this chapter. In the end, no single technique came to the fore.

From the beginning, there was considerable concern about safe and effective gastric closure. Some felt that the ESD experience of perforation closure with hemoclips could be translated to a NOTES closure. Most felt, however, that clips were insufficiently robust and durable to reach the very high threshold for secure closure established by surgical suturing. Investigators largely agreed that the ideal closure is the time-tested, full-thickness suturing which is well established in surgical practice. There is now an available endoscopic full-thickness suturing system (OverStitch, Apollo Endosurgery, Austin, Texas).

While there is a product for endoscopic suturing that potentially solves the issue of secure closure, there is no suturing system with the size and maneuverability to do fine suturing within the peritoneal cavity. Most NOTES contributors, especially minimally invasive surgeons, felt that it will be necessary to build a multitasking platform with articulating arms in order to meet the need of intraperitoneal suturing.

Surgeons were extremely concerned about spatial orientation. The “in-line” imaging provided by a flexible endoscope is completely different than the “overview” perspective provided by an umbilical camera. There is insufficient experience to determine whether this is a real issue or not but many feel that sophisticated platforms capable of doing surgical procedures in the peritoneal cavity will require separation of the optics from the end-effector functions.

One of the most intriguing obstacles to the full implementation of NOTES is the idea that it will require a multitasking platform. Minimally invasive surgeons are extremely reluctant to give up the ability to have two “arms” and have the ability to triangulate. Much of the early work in this area tested flexible direct drive systems. Olympus began testing a system they called EndoSamurai (Olympus Corporation, Tokyo). The Carl Stortz company, unveiled the Anubiscope (Karl Storz, Tuttlingen, Germany). Boston Scientific (Natick, Massachusetts) did early testing of a flexible articulating platform they called the direct drive endoscopic system (DDES) as well. All these systems, in their original form, have been abandoned. It is now felt that computer interface, motor-driven robotic systems hold the greatest promise in therapeutic endoscopy and NOTES. There are numerous companies now working on such systems but none are currently approved for use in humans and are commercially available.

A critical component of surgical practice is the management of intraoperative “issues” to avoid becoming complications. Hemostasis, closure of inadvertent perforation, and proper energy delivery to avoid excessive collateral tissue damage are all important components of surgical practice. The same “issues” could occur during NOTES procedures and techniques and instruments need to be available to solve these emergent issues. There is not yet a full array of laparoscopic-type instruments available on a flexible platform. Intraperitoneal suturing is not possible and a ubiquitous instrument, used in most laparoscopic surgeries, the harmonic scalpel (or a comparable technology) is not yet available in a flexible platform.

There was concern that NOTES might cause unforeseen physiologic events. It was always assumed that endoscopic systems would need to use CO₂ rather than room air when working in the peritoneal cavity and that a pneumoperitoneum would need to be maintained. However, it was not known whether intraperitoneal pressure requirements for NOTES would be higher or lower when compared to standard laparoscopic surgery. It was also not known whether transintestinal entry would lead to greater or lesser amounts of postoperative adhesions. In the course of NOTES research, no unanticipated or unique physiologic events have been encountered.

The final obstacle was training. In reality, although there has been much discussion, this issue has not been resolved or fully addressed. It is assumed that a degree of cross-training would be required; minimally invasive surgeons would require significant amount of training in flexible endoscopy and gastroenterologists would require a certain amount of general surgical training as well as some laparoscopic experience. It was hypothesized that NOTES would lead to a hybrid specialty—someone specializing in minimally invasive therapy irrespective of the specific instrument(s) required. There was general consensus that such hybrid training would not lead to board certification in both surgery and internal medicine. In the end, although not all agree, it is most likely that the majority of minimally invasive therapists of the future will come from the surgical ranks with flexible endoscopic training coming either from specialized surgical programs or specialized advanced endoscopy training centers.

Assessment depends on how physicians define the procedure. Several thousand cases of hybrid transvaginal procedures are documented in the literature including cholecystectomy, nephrectomy, and vertical sleeve gastrectomy, ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ but usually the procedure is performed with rigid instruments and often with transcutaneous laparoscopic ports. Most physicians involved with NOTES feel that POEM represents the first clinically applied NOTES procedure. It is performed through a natural orifice with a flexible instrument and mimics a surgical procedure. In this context, STER could also be considered a NOTES procedure.

Currently, the most promising pure NOTES procedure is transanal colon resection. This was introduced by Swanstom in 2007 when his group described transanal sigmoid resection in a human cadaver model. ¹⁹ Transanal access for colon resection has now been proven safe and feasible in both swine and fresh human cadaver models. ²⁰ , ²¹ As in all NOTES procedures, limitations imposed by lack of optimal instrumentation had to be overcome. Instrument needs for transanal procedures has been solved in part by the availability of transanal endoscopic microsurgery (TEM) platforms. ²² Once the technique for transanal colon resection was established, it was necessary to determine if oncologic principles could be maintained if the resection was performed for cancer. The capability of performing an adequate oncologic resection was confirmed by Rieder in 2011 when he randomized male cadavers to either laparoscopic or transanal sigmoid resection for simulated cancers at 25 cm. ²³ Adequate proximal margins (transanal approach required laparoscopic assistance) were achieved with both techniques and lymph node yields were similar. The first hybrid NOTES transanal total mesorectal excision (TME) for rectal cancer was reported in 2010 by Sylla and Lacy. ²⁴ The number of transanal TME cases is growing exponentially and trials are now ongoing to determine its safety and efficacy. ²⁵