FROM THE PEDIATRIC LITERATURE

How Common are Pediatric Feeding Disorders?

March 2021 • Volume XLV, Issue 3

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Feeding disorders in children commonly are seen in both the primary care and pediatric gastroenterology setting. There is no good epidemiologic data about the prevalence of pediatric feeding disorders in children in the United States. Thus, the authors of this study used de-identified data from the Truven Health Analytics MarketScan Commercial Claims and Encounters Database (Ann Arbor, Michigan) for patients with private insurance as well as Arizona and Wisconsin Medicaid data for patients with Medicaid covering the time period from 2009 to 2014. Children between 2 months and 18 years were included in the study, and the authors used 25 International Classification of Diseases (ICD)-9 and ICD-10 codes to identify potential study subjects as there is no specific “feeding disorder” diagnosis code for children. Children who had been diagnosed with one of these codes and not with an eating disorder were included. The authors evaluated all such patients for comorbid conditions, the presence of malnutrition/ failure to thrive, and the presence of a gastrostomy tube. Children were identified as having a complex chronic condition (CCC) based on known ICD codes if they had a medical condition expected to last least 12 months and had at least one organ system involvement which could require pediatric subspecialty care and potential hospitalization.

The presence of feeding disorders increased in all databases during the time period with significantly more children covered by Medicaid having feeding disorders (Arizona, 16.97 per 1000 child-years; 95% CI, 16.84-17.10 and Wisconsin, 21.43 per 1000 child-years; 95% CI, 21.27-21.60) compared to children covered with private insurance (9.38 per 1000 child-years; 95% CI, 9.35-9.40). A lower prevalence of feeding disorders was present in older patients (defined as 12-18 years old), and more males had feeding disorders compared to females throughout the study. Specific patients with CCC (including children with respiratory, gastrointestinal, miscellaneous technology dependency, prematurity/neonatal risk, and organ transplantation) had higher rates of feeding disorders, and the prevalence of feeding disorders in children with a CCC increased throughout the study despite no increase in the number of children with a feeding disorder and without a CCC. Although the prevalence of malnutrition in children with a feeding disorder decreased in all databases throughout the study, children with an associated CCC had a higher prevalence of a malnutrition. The prevalence of gastrostomy tubes decreased in this population throughout the study period, and most children who had both a feeding disorder and a gastrostomy tube also had an associated CCC.

This study demonstrates that pediatric feeding disorders are increasing in children in the United States, and this disorder is commonly associated with the presence of a CCC. Thus, we need early intervention as well as improved long-term treatment options for this population as well as better accuracy in ICD coding in order to track and to care for these children over time.

Kovacic K, Rein L, Szabo A, Kommareddy S, Bhagavatula P, Goday P. Pediatric feeding disorder: a nationwide prevalence study. Journal of Pediatrics 2021; 228: 126-131.

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #208

Bezoars: Recognizing and Managing These Stubborn, Sometimes Hairy, Roadblocks of the Gastrointestinal Tract

March 2021 • Volume XLV, Issue 3
Sonali Palchaudhuri

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A bezoar is a concretion of foreign, indigestible material in the gastrointestinal tract. While bezoars are relatively rare, and often found incidentally, they can be the cause of vague symptoms like nausea and fullness, and lead to complications such as obstructions within the gastrointestinal (GI) tract. This article summarizes the types of bezoars, risk factors for formation, and management.

Introduction

A bezoar is a concretion of foreign, indigestible material in the gastrointestinal tract. While bezoars are relatively rare, and often found incidentally, they can be the cause of vague symptoms like nausea and fullness. The composition defines the bezoar classification, with the most common type being a phytobezoar (plant materials). Other types include trichobezoar (hair), pharmacobezoar (medications), and lactobezoar (milk proteins), though any foreign, indigestible material can be involved in bezoar formation. Bezoars are most commonly reported in the stomach, but can move distally and have the potential to cause small bowel obstruction or ileus. Risk factors for bezoar formation include conditions that lead to poor gastric emptying, reduced gastric acidity, and a psychiatric illnesses that leads to the consumption of indigestible material like hair. There are medical therapies to help dissolve some bezoars, though many require endoscopic or surgical management for fragmentation and removal.

Types of Bezoars

The main types of bezoars are listed in Table 1. The most common type is the phytobezoar, where the bulk of material is made of plant fibers. Plant cell walls include cellulose and lignins as structural components, both which contribute to the fibrous and indigestible nature. Foods high in cellulose include prunes, raisins, celery, leeks, pumpkin, and green beans. Foods high in lignin include flax seeds, root vegetables, wheat bran, edible vegetable and fruit seeds, peas, and peaches.

Another contributor to phytobezoars are tannins, which are astringent compounds that bind to and precipitate proteins. In foods like unripened fruit and red wine, they cause the characteristic mouthpuckering taste. Persimmons have been identified as a particular high-risk food for causing bezoars, due to a persimmon skin tannin (phlobatannin) that has a strong protein binding capacity and coagulates in dilute acid. A persimmon phytobezoar is also known as a diospyrobezoar.1 R. Moriel et al. noted a dramatic increase in incidence in 1982 in Israel, which correlated with an increase in persimmon sales in the country; 68 patients presenting to one of the 12 hospitals during a 6 month period all reported a history of persimmon intake.2 High persimmon consumption is noted in South Korea, Japan, Israel, Spain, Turkey, and Southeastern United States.

The next most commonly reported type of bezoar, though still rare, is a trichobezoar, where the primary component is hair. Human hair is especially resistant to digestion; its smooth surface resists peristalsis, leading to accumulation in the gastric folds. It is most commonly found in the stomach; if it extends into the intestine, the condition is referred to as Rapunzel Syndrome. The bezoar may form after long periods of time, with one case report suggesting a 20-year history of intermittently consuming hair, 1-2 years of abdominal pain, and loss of appetite for 6 months prior to presenting.3

Medication bezoars, known as pharmacobezoars, involve either medications or components of medications accumulating in the GI tract. Medications reported to cause bezoars in case reports4 are listed in Table 2. Usually, pharmacobezoars occur in the setting of other patient risk factors (Table 3), though they have been reported to occur in an otherwise normal GI tract. In one case, a patient with normal GI tract motility presented with a Metamucil bezoar after mixing his usually well-tolerated dose of Metamucil in minimal liquid, resulting in a semi-solid mass that needed to be chewed down.5

A bezoar composed of undigested milk concretions is termed a lactobezoar and is found in young children, primarily infants. Lactobezoars were previously believed to occur only in pre-term infants being fed high-density formulas, however, there are now many cases reported for infants and toddlers involving many other milk products, including breast milk.6 Most common presenting symptoms are abdominal distention and non-bilious emesis, and some patients have a palpable mass. Because symptoms are non-specific and conservative measures may lead to quick resolution, prevalence may be higher than appreciated in the literature.

Other types of bezoars are extremely rare. A lithobezoar is the accumulation of stones in the digestive tract, associated with a history of pica. Individuals with pica have been reported to ingest non-nutritive substances such as clay, dirt, crayons, paint chips, chalk, etc.7 Other materials include parasites (ascaris), fungi (Candida), and ceramics.8

Risk Factors

There are several risk factors predisposing some to bezoar formation (Table 3). Gastric surgery is a key risk factor as procedures may decrease gastric motility through vagotomy or decrease acid production in the stomach, allowing for the collection of undigested material. For procedures involving antrectomy, the loss of pyloric function prevents the appropriate mixing of acid and food, resulting in unhydrolyzed fibers entering the intestine. Bezoars can take months to years to form.9 Case reports have reported bezoars in those having multiple procedures (including gastric banding),10 peptic ulcer surgeries (Billroth I and Billroth II),11 and Roux-en-Y gastric bypass.12,13 Increase in bariatric surgeries has been theorized to contribute to an increased incidence in bezoars.14

Another risk factor is poor movement of food through the GI tract. Gastroparesis and other medical disorders associated with poor motility, like scleroderma, amyloidosis, and hypothyroidism, have been associated with gastric bezoars. Insufficient fluid intake reduces production of mucus in the GI tract. Anatomic abnormalities like gastric outlet obstruction and pyloric stenosis have been associated with bezoars as well, as have other less common causes for obstruction like a duodenal web.15 Poor mastication, often due to dentures or poor dentition, may lead to larger food fragments that are difficult to digest. There is no evidence of acid suppression therapy alone resulting in bezoar formation, though it theoretically may contribute in the setting of other risk factors.

Central to the formation of phytobezoars is fiber consumption. Vegetables and fruits are most often contributory to gastric bezoars due to high cellulose content. As described above, phlobatannin in persimmons are especially difficult to digest, thus leading to the higher prevalence of bezoars in countries with high consumption.

Other types of bezoars are associated with specific risk factors. Trichobezoars are most often associated with trichotillomania (urge to pull one’s hair) and trichotillophagia (urge to eat hair). Medications described above that either disturb motility or provide obstructing material can result in pharmacobezoars. Other disorders in ingestion like pica can lead to the formation of bezoars from other more rare materials.

Prevalence, Clinical Presentation and Complications

Bezoars are relatively rare, with one busy single center reporting an average of 2.5 cases per year.16 The incidence is higher in places with risk factors like persimmon consumption. A single center from Turkey reports 16.5 per year during a four year study.17

Most often, gastric bezoars are found incidentally during endoscopy or on imaging (x-ray or CT) as most bezoars do not cause symptoms. Alternatively, there may be nonspecific symptoms related to retained material in the stomach: early satiety, reduced or loss of appetite, nausea, emesis, all possibly resulting in weight loss from reduced intake.

A case series of patients with Roux-en-Y gastric bypass highlights 16 patients found to have bezoars in different parts of the GI tract: gastric pouch, jejunal limb, anastomotic sites, distal ileum, and ileocecal valve.13 All 16 patients had symptoms, ranging from just nausea to acute abdominal pain with nausea and vomiting.

If the bezoar is applying pressure on the gastric mucosa, it can cause gastric ulcers or bleeding. All types of bezoars may also cause gastric outlet obstruction or, if more distally, intestinal obstruction. Review of 108 case reports of patients with trichobezoars found complications to include ulceration, perforation, intussusception, and pancreatitis in one case, though these are rare and dependent on the size and extent of the trichobezoar.18

Management

The first goal of treatment is removal of the bezoar. Lactobezoars, which are relatively soft, most often improve with withholding oral feedings and gentle gastric lavage. Other bezoars require more aggressive management. The general accepted methods are (1) enzymatic disintegration, (2) endoscopic removal, and (3) surgical removal (Table 4).

Enzymatic Disintegration

Medical management through enzymatic disintegration is most effective on phytobezoars, in which plant fibers are susceptible to dissolution. Even if requiring further therapy with endoscopic maneuvers or surgery, these techniques may soften the bezoar consistency and facilitate further intervention.

The most commonly reported substance used is dark soda (i.e. Coca-Cola, RC Cola, Pepsi), where the acidity from carbonic and phosphoric acid allows for fiber digestion, the sodium bicarbonate acts as a mucolytic, and carbon dioxide bubbles penetrate between fibers to increase the surface area for interaction with acid. The dose often reported is 3L over 24 hours, either though oral intake or nasogastric tube, though this can vary in clinical practice based on tolerance. Use of dark soda is also favorable in that it is cheap, easy to use, and safe. A 2013 systematic review concluded that CocaCola is effective in dissolving gastric phytobezoars 50% of the time; due to the hard consistency of diospyrobezoars, it was only effective 23% in this subcategory and 60.6% for all other phytobezoars.19 Combination with endoscopy resulted in resolution in 91.3% of cases.

The pH of diet sodas are not that much higher and are worth considering, especially in the setting of diabetes. Non-dark sodas have slightly higher pH. Table 5 details pH and carbohydrate content of sodas by brand, for consideration based on availability.

There are a few additive or alternative therapies to consider, especially if the patient cannot tolerate low pH due to the presence of a peptic ulcer or severe GERD. Cellulase at a dose of 3-5 grams in 300-500ml of water over 2-5 days has been utilized in the past, though seen to be inferior to soda.20

Some have seen impact in combination with soda for a more resistant diospyrobezoar in the setting of acid suppression therapy with a proton pump inhibitor.21,22 Papain, an enzyme extracted from the Carica papaya plant was also reported to be used as an alternate therapy. It used to be found in Adolph’s Meat Tenderizer, but is no longer so, and the dose for efficacy is not known, so this has largely fallen out of favor.20 Prokinetic agents, like metoclopramide or erythromycin, may facilitate fragmentation and improve gastric emptying and has been used on occasion.23

Endoscopic Removal

If symptoms or imaging are concerning for a bezoar or remnant material in the stomach, the next step may be endoscopic evaluation and removal. Due to the inherent risk of aspiration from remnant material in the stomach, it is strongly advised to discuss concerns with the endoscopy team and have the patient avoid oral intake for an extended period prior to endoscopy, as determined by the endoscopist. As many bezoars are found incidentally during endoscopy, the endoscopist may attempt removal during the procedure, though in many scenarios, there may not have been the appropriate precautions taken prior to procedure for airway protection to proceed during the endoscopy. In this case, the procedure may be aborted, and the patient may be scheduled for another date with interim attempts for chemical dissolution as appropriate.

There are a few common endoscopic techniques for managing a bezoar. For phytobezoars that are amenable to fragmentation, a polypectomy snare (a wire loop that is used for the removal of polyps) or endoscopic forceps can be used to break the bezoar into smaller pieces. Lavage with soda or cellulase may aid in the fragmentation of the bezoar prior to endoscopy. Small pieces may pass through the GI tract. For remaining pieces or larger pieces that could not be fragmented, one option is to collect the material with a Roth net and remove it with the endoscope.

Less common techniques have been reported. A proposed technique is to use a bezoaratum, a specialized device that involves a snare connected to a handle for easier lithotripsy of the bezoar.24 For a particularly firm, calcified bezoar in the rectum that was refractory to routine endoscopic removal, a team used cholangioscopy-guided electric hydraulic lithotripsy (EL) to fracture the bezoar enough for piecemeal removal with Roth Net.25

Surgical Removal

For bezoars that cannot be fragmented and endoscopically removed, or are too difficult to access endoscopically, surgery may be necessary. Trichobezoars are especially resistant to fragmentation; in one review, endoscopy was attempted in 40 of 108 cases, and only 2 (5%) were successful; the rest required surgery.18 Depending on location, the bezoar may be amenable to being milked passed the ileocecal valve, from where it may be able to pass naturally through the rectum. Most are surgically excised, either through traditional open laparotomy or less invasive laparoscopic approach when possible. Complications from the bezoar like ulcerations and signs of necrosis may require segmental resection.26

Secondary Prevention

The second goal of management after removal is prevention of recurrence by identifying and addressing risk factors. If there are comorbidities concerning for gastric dysmotility, the patient will likely benefit from a gastroparesis diet of small frequent meals, reduced whole fiber, and emphasis on liquids. Handouts for patient education are available online.27,28 For phytobezoars, they may benefit from reducing the amount of causative fibrous foods, especially persimmons if found to have a diospyrobezoar. For pharmacobezoars, causative medications may have alternative therapies and dose adjustments to consider. Those with trichobezoars may benefit from psychiatric assessment.

CONCLUSION

Given their rarity, many clinicians may never encounter a patient with a bezoar. Yet it is prudent to be aware of predisposing factors and consider bezoars in the differential diagnosis of nonspecific GI complaints. For primary care physicians, the key is to trial methods for enzymatic disintegration, if appropriate, consider endoscopic evaluation, and be aware that many require surgical management. Long-term management after a bezoar is diagnosed requires addressing predisposing factors as possible.

References

  1. Iwamuro M, Okada H, Matsueda K, et al. Review of the diagnosis and management of gastrointestinal bezoars. World J Gastrointest Endosc. 2015;7(4):336-345.
  2. Moriel EZ, Ayalon A, Eid A, et al. An unusually high incidence of gastrointestinal obstruction by persimmon bezoars in Israeli patients after ulcer surgery. Gastroenterology. 1983;84(4):752-755.
  3. Jain A, Agrawal A, Tripathi AK, et al. Trichobezoar without a clear manifestation of trichotillomania. J Fam Med Prim Care. 2020;9:2566- 2568.
  4. Taylor JR, Streetman DS, Castle SS. Medication bezoars: a literature review and report of a case. Ann Pharmacother. 1998;32(9):940-946.
  5. Frohna WJ. Metamucil bezoar: an unusual cause of small bowel obstruction. Am J Emerg Med. 1992;10(4):393-395.
  6. DuBose TM 5th, Southgate WM, Hill JG. Lactobezoars: a patient series and literature review. Clin Pediatr (Phila). 2001;40(11):603-606.
  7. Narayanan SK, Akbar Sherif VS, Babu PR, et al. Intestinal obstruction secondary to a colonic lithobezoar. J Pediatr Surg. 2008;43(7):e9-10.
  8. Paschos KA, Chatzigeorgiadis A. Pathophysiological and clinical aspects of the diagnosis and treatment of bezoars. Ann Gastroenterol. 2019;32(3):224-232.
  9. Ben-Porat T, Dagan S, Goldenshluger A, et al. Gastrointestinal phytobezoar following bariatric surgery: Systematic review. Surg Obes Relat Dis. 2016;12:1747-1754.
  10. White NB, Gibbs KE, Goodwin A, Obstruction due to Bezoar in Elderly Patients: Risk Factors and Treatment Results Gastric bezoar complicating laparoscopic adjustable gastric banding, and review of literature. Obes Surg. 2003;13(6):948-950.
  11. Altintoprak F, Gemici E, Yildiz YA, Obstruction due to Bezoar in Elderly Patients: Risk Factors and Treatment Results Intestinal Obstruction due to Bezoar in Elderly Patients: Risk Factors and Treatment Results. Emerg Med Int. 2019;3647356.
  12. Pinto D, Carrodeguas L, Soto F, et al. Gastric bezoar after laparoscopic Roux-en-Y gastric bypass. Obes Surg. 2006;16(3):365-368.
  13. Antonio C, Morales M, Gonzalez M, et al. Ileal bezoar causing bowel obstruction mimicking an internal hernia in a patient with Roux‑en‑Y gastric bypass. 2020; 13: 1111-1115.
  14. Ben-Porat T, Sherf Dagan S, Goldenshluger A, et al. Gastrointestinal phytobezoar following bariatric surgery: Systematic review. Surg Obes Relat Dis. 2016;12(9):1747-1754.
  15. Arora G, Choudary R, Karnavat BS. Gastroduodenal Bezoar with Duodenal Web: A Rare Association. J Indian Assoc Pediatr Surg. 2020;25(3):189-190.
  16. Mihai C, Mihai B, Drug V, et al. Gastric bezoars – diagnostic and therapeutic challenges. J Gastrointestin Liver Dis. 2013;224(1):111.
  17. Gokbulut V, Kaplan M, Kacar S, et al. Bezoar in upper gastrointestinal endoscopy: A single center experience. Turk J Gastroenterol. 2020;31(2):85-90.
  18. Gorter RR, Kneepkens CMF, Mattens ECJL, et al. Management of trichobezoar: case report and literature review. Pediatr Surg Int. 2010;26(5):457-463.
  19. Ladas SD, Kamberoglou D, Karamanolis G, et al. Systematic review: Coca-Cola can effectively dissolve gastric phytobezoars as a first-line treatment. Aliment Pharmacol Ther. 2013;37(2):169-173.
  20. Iwamuro M, Okada H, Matsueda K, et al. Review of the diagnosis and management of gastrointestinal bezoars. World J Gastrointest Endosc. 2015;7(4):336.
  21. Chun J, Pochapin M. Gastric Diospyrobezoar Dissolution with Ingestion of Diet Sodaand Cellulase Enzyme Supplement. ACG Case Reports J. 2017;4:1-3.
  22. Gök, A, Sonmez, RE, Kantarci, TR, et al. Discussing treatment strategies for acute mechanical intestinal obstruction caused by phytobezoar: A single-center retrospective study. Turkish J Trauma Emerg Surg. 2019;25(5):503-509.
  23. Iwamuro M, Tanaka S, Shiode J, et al. Clinical characteristics and treatment outcomes of nineteen Japanese patients with gastrointestinal bezoars. Intern Med. 2014;53(11):1099-1105.
  24. Kurt M, Posul E, Yilmaz B, et al. Endoscopic removal of gastric bezoars: an easy technique. Gastrointest Endosc. 2014;80(5):895-896.
  25. Shi L, Lin S, Yao J, Li F. A novel endoscopic method for removal of giant calcified stool bezoar by cholangioscopy-guided electric hydraulic lithotripsy. Gastrointest Endosc. 2019;90(3):531-532.
  26. Katsurahara M, Yamada R, Inoue H, et al. Gastrointestinal: A case of small bowel obstruction caused by a bezoar, preoperatively found by double-balloon enteroscopy. J Gastroenterol Hepatol. 2019;34(6):962.
  27. University of Virginia. GI Nutrition Patient Education Handouts. https:// med.virginia.edu/ginutrition/patient-education/. Accessed January 5, 2021.
  28. Cleveland Clinic. Diet for Gastroparesis: Health Information for Patients and the Community. https://my.clevelandclinic.org/-/scassets/files/org/ digestive/gastroparesis-clinic/diet-for-gastroparesis. Accessed January 5, 2021.

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FRONTIERS IN ENDOSCOPY, SERIES #71

Endoscopic Treatment of Symptomatic Zenker’s Diverticula

March 2021 • Volume XLV, Issue 3
Eric Tatro,John C. Fang,Douglas G. Adler,Neil Sharma

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Introduction

Originally described by Ludlow in 1767,1 and then with a case series collected by Zenker et al. in 1877,2 after whom the entity was named, a Zenker’s diverticulum (ZD) is a pharyngeal pouch in which the mucosa extends through Killian’s triangle, the oblique inferior pharyngeal constrictor muscle and the transverse cricopharyngeal muscle, usually occurring in older patients.3 A pathological combination of increased intraluminal pressure in the oropharynx, inadequate relaxation of the cricopharyngeus, and incomplete upper esophageal sphincter (UES) relaxation is thought to lead to this outpouching of the dorsal pharyngoesophageal wall.4 Our understanding of and treatments for this entity have evolved substantially over nearly 200 years. Endoscopic techniques were described as early as 1917 by Mosher with cricomyotomy.5 This was followed by the use of a rigid transoral endoscope by Dohlman and Mattson in 1960.6 Collard et al. first described the use of an endoscopic stapling device for Zenker’s repair in 1993,7 and since then, surgical and flexible endoscopic methods for ZD repair have become the mainstay in treatment of this entity. This article will review modern treatments for ZD, with an emphasis on endoscopic approaches.

Zenker’s repair in 1993,7 and since then, surgical and flexible endoscopic methods for ZD repair have become the mainstay in treatment of this entity. This article will review modern treatments for ZD, with an emphasis on endoscopic approaches.

ZD Repair: Surgical Techniques

Surgical approaches for repair of ZD include Dolman’s procedure, division of the septum between the esophagus and the diverticulum pouch, cricopharyngeal myotomy alone or in combination with either suspension, inversion, or excision of the pouch.1 The open surgical technique is accomplished under general or selective spinal anesthesia with transcervical access. Exposure of the ZD is made by dividing the platysma, retracting the sternocleidomastoid and carotid sheath laterally and thyroid gland medially. Myotomy is first performed on the cricopharyngeus followed by a variety of procedures—removal of the diverticulum (diverticulectomy), the diverticulum is retracted and suspended (diverticulopexy), or the diverticulum is inverted into the esophageal lumen and oversewn (diverticulum invagination).8,9 Minimally invasive options have largely replaced open surgical techniques with endoscopic therapies as the mainstay of treatment of ZD repair.

ZD Repair: Endoscopic Techniques

Endoscopic repair methods include surgical-type options e.g., stapling, harmonic scalpel, in addition to cap-assisted or flexible endoscopic techniques: carbon dioxide laser diverticulostomy with argon plasma anticoagulation, needle and hook knife, bipolar forceps, endoscopic scissoring, and submucosal septum division among others.10

When performing the endoscopic myotomy, the technical goal is to achieve an endoscopic muscular dissection (EMD) of the cricopharyngeus sufficient to improve symptoms, while avoiding perforation (or treating it endoscopically if it develops).

A key to proficiency and durable outcomes of endoscopic methods is an understanding of the anatomic landmarks of the oropharynx and esophageal introitus. Additionally, knowledge of the layers beneath the mucosa – submucosa, cricopharyngeus muscle, buccopharyngeal fascia, retropharyngeal space, alar fascia, and the danger space just above the prevertebral fascia – will allow for a more complete resection of the cricopharyngeus which decreases recurrence rates (Figure 1).

Regarding which technique is the most commonly performed, one study examined over 600 flexible endoscopic ZD repairs and found the most common instrument reported for the myotomy was needle knife (59.6%) followed by argon plasma coagulation (25.7%). Forceps coagulation, hook knife, among other methods comprised the remaining 14.7%.11 Although there is sufficient evidence to consider endoscopic myotomy as a safe and effective method of ZD repair, there is currently no consensus on which technique or instrument is superior in regard to outcomes, and several different methods may be equally viable.12

In order to enhance the view of the operative field and reduce collateral injury to tissue surrounding the myotomy site, endoscopic accessories are often used in combination with the needle-knife technique. A nasogastric (NG), orogastric (OG) tube, or even biliary guidewire by itself can be placed in order to identify the true lumen of the esophagus and protect the anterior esophageal wall from thermal or mechanical injury during ZD repair. These objects also help the endoscopist to have a very clear reference point for the esophageal lumen when performing the myotomy. Clear mucosectomy caps, which are utilized broadly in endoscopic procedures to depress mucosal folds and improve visualization, have been described in ZD repair to enhance the view of the septum and diverticulum. Another accessory used to enhance the endoscopist’s view and protect the diverticular walls from injury is the “soft diverticuloscope”. This is a specially crafted overtube which goes over the endoscope and has two flaps which straddle the diverticular septum, providing stability during the procedure while avoiding the risk of trauma from a rigid endoscope.5,13,14,15

Flexible Endoscopic Myotomy Techniques Hook Knife Technique

The Hook knife (Olympus endotherapy, Tokyo, Japan) has a 5mm rotatable, hook-shaped knife tip that allows for variable dissection orientations with the ability to pull tissue prior to cutting it. After visualization of the diverticulum and septum, the myotomy technique with the Hook knife is as follows: The hook is locked in the 12 o’clock position, and then the incision is performed from the superior aspect of the bridge moving inferiorly, allowing the hook to pull the muscle fibers prior to cutting them. Through-the-scope (TTS) endoscopic clips are placed on either side of the inferior portion of the myotomy site for prophylaxis against bleeding and micro-perforation.16

Stag Beetle Knife (SB Knife) Technique

The Stag beetle knife (SB knife, Sumitomo Bakelite, Tokyo, Japan) is a scissor-like instrument developed for ESD and often used for myotomy in ZD repair. The Stag beetle (SB) knife junior has a similar design and rotational mechanism with slightly smaller dimensions (3.5mm x 4.5mm). The instrument is electrically insulated in a manner which allows the current to be focused on the electrodes at the edges of the blade, and the curved upward knife tips also serve to prevent inadvertent tissue damage and reduce perforation risk.17 The myotomy incision is initiated at the center of the diverticulum septum, and can progress both across the septum and deeper through the muscle fibers and the knife is rotated circumferentially, simultaneously cutting and coagulating, to perform the submucosal dissection and myotomy in the desired tissue plane while avoiding deeper tissue injury. One advantage of this knife is its ability to also function as a hemostatic device.18 (Figure 2)

Needle-knife Technique

The needle-knife is the most commonly used instrument for ZD repair, owing to the low cost and widespread availability of this device. (Figure 3) The tip of the instrument is placed at the center of the septum where either coagulation, blended, or alternating current is used depending on the preference of the operator. The incision is often made craniocaudally, exposing the transverse cricopharyngeus muscles. Care should be taken to avoid a myotomy which exceeds 10mm from the inferior portion of the diverticulum, as this is associated with a higher risk of perforation. If intra-procedural bleeding develops, argon plasma coagulation (APC) is often then applied to ensure hemostasis.5,19,20

Outcomes: Endoscopy vs. Surgery in ZD Repair

Albers et al. performed a meta-analysis of 11 retrospective cohort studies comparing outcomes in endoscopic vs. surgical repair of ZD. Endoscopic treatment was found to be superior to surgical repair in regard to reduced operative time, shorter length of hospitalization, and faster time to diet introduction. Surgical repair was found to be superior with regard to the risk of recurrence of symptoms compared to those treated endoscopically.21

Antonello et al. described a series of 25 patients who underwent flexible endoscopic repair for ZD. This study compared two treatment groups. The first group had experienced symptom recurrence after having surgical and/or endoscopic stapling previously vs. a treatment naïve group. The methods of myotomy used included needle knife (n=6), hook knife (n=9), and SB knife (n=15). After a mean follow-up of 17 months, no significant difference was found between the two groups with regards to symptom improvement, complications, or adverse events.22

Leong et al. performed a meta-analysis of 15 retrospective studies of patients who underwent endoscopic stapling for ZD repair. Of the 585 patients, 540 (92.3%) were successfully stapled. By the first post-op day, 92% of those who underwent stapling were able to resume oral intake, 87% were discharged on post-op day 2, and greater than 90% had greatly improved symptoms.23

Mittal et al. performed a retrospective, multicenter study examining 161 patients who underwent endoscopic myotomy for ZD. No significant difference was found in technical or clinical success (defined by patients experiencing improvement and/or resolution of their symptoms) between various knives utilized in the cohort. Clinical success was the highest among patients whose repairs were performed via hook knife (n= 43, 96.7%) followed by needle knife (n= 33, 76.6%), and then insulated (IT) tip knife (n=33, 47.1%).24

Brueckner et al. described a case series of 46 patients who underwent ZD repair with only the Hook knife technique with a similar success rate of 95%. This study reported a higher recurrence rate of 30%.25 Similarly, Christiaens et al. also published a series of 21 patients receiving ZD repair strictly with Hook knife myotomy; their reported recurrence rate was lower at 9.5%.26

Repici et al. also reported a series of 32 patients who underwent ZD repair using the hook-knife ESD technique. After a mean follow-up of 23.87 months, the authors reported an overall success rate 90.6%, with four patients reporting ongoing dysphagia. Of these four, three were found to have a residual Zenker’s bridge and achieved clinical success with a second treatment of the same endoscopic technique. The last patient declined further treatment due to advanced age.27

Jain et al. reviewed the outcomes from 23 original studies including 997 patients who underwent flexible endoscopic diverticulotomy (FED) for ZD. The follow-up between the studies varied widely from 7 to 43 months. The authors found the composite technical success rate of the procedures to be 99.4% with a clinical success rate of 87.9%. The composite rate for symptom recurrence after long-term follow-up was 13.6%, but 61.8% of these patients experienced symptom relief after repeat endoscopic intervention. The authors also reported differences in clinical outcomes between FED with diverticuloscope (FEDD) vs. FED with cap (FEDC). Technical outcomes in both groups were near 100%. The clinical success rates, defined by symptom improvement and/or resolution, differed significantly. Clinical success rates in the FEDC group were higher (86.8% vs 75.4%), and the FEDC group had nearly half the risk of symptom recurrence vs. the FEDD group (9.5 vs 16.5%).28

Vogelsang et al. described long-term outcomes in a series of 31 patients who underwent myotomy with the needle-knife technique for ZD. Of the 31 patients, four had previously underwent ZD repair unsuccessfully via argon beam coagulation (mean number of treatments=2.8). All of the patients had initial symptomatic relief, with 10 requiring repeat treatment due to recurrence of symptoms after a mean of 5.3 months. After a mean follow-up 26 months, 84% experienced long-term symptom relief to varying degrees, with 61% experiencing relief of symptoms after a single treatment.29

Adverse Events

Perbtani et al. published a retrospective analysis of adverse events in the 678 total patients from the 19 published case series from 1995 to 2015 who underwent flexible endoscopic ZD repair. Of the 678 patients, adverse events were reported in 80 (11.8%). These were, in descending order of frequency, micro-perforations (7.7%), infection (1.8%), bleeding (1.3%), macro-perforations (0.6%), and death (0.1%).5 However, reported rates of adverse events vary. Leong et al.’s metaanalysis of 15 retrospective case series of a total of 585 patients who underwent endoscopic stapling, demonstrated an overall perforation rate of 4.8%, and a mortality rate of 0.2%.17

Regarding adverse events with specific endoscopic knife utilization, Rouquette et al. reported an overall adverse event rate of 8.3% (2/24 with mild intra-procedural bleeding) in 24 patients treated with hook-knife myotomy. No perforations or post-procedural bleeding complications were reported.10 Adverse events reported in patients treated with the needle -knife technique for EMD vary substantially. Costamagna et al. reported an adverse event rate of 32% in those undergoing cap-assisted needle-knife myotomy, with 18% (5/28 patients) having perforations which were managed conservatively. Conversely, in the same study, 11 patients underwent diverticuloscopeassisted needle-knife myotomy with zero reported complications.8 In a series of 31 patients who underwent needle-knife myotomy, Vogelsang et al. described a minor complication rate (e.g., subcutaneous or mediastinal emphysema) of 23% and no major complications.23

In Rouquette et al.’s case series of 24 patients with ZD repair performed strictly with the Hook knife technique, the authors reported an overall adverse event rate of 8.3% (2/24) due to intraprocedural bleeding. There were no perforations or post-procedural events reported. Fever and/ or mild pain was reported in 37.5% of patients, which was managed conservatively.10 Repici et al. reported a series of 32 patients who also underwent ZD repair with hook-knife myotomy. The adverse event rate was reported at 6.25% (2/32), with one patient having intra-procedural bleeding treated successfully with APC, and one with cervical emphysema managed without additional procedures but via medical management (nasogastric tube, total parenteral nutrition, intravenous proton pump inhibitor, and antibiotics). 21

Crawley et al. recently published a metaanalysis examining adverse events in rigid vs. flexible endoscopic ZD repair in 2019 examining a total of 115 studies. The authors found bleeding (20% vs. 4%) and recurrence of symptoms (4% vs. 0%) to be significantly higher in flexible vs. rigid endoscopy techniques. Of note, the flexible endoscopic studies were more likely to report bleeding as an adverse event. Adverse events associated with rigid endoscopy were dental injury (1%) and vocal fold palsy (0.3%). Differences in rates of mortality, infection and perforation were not found to be statistically significant between the two groups.30

Conclusion

Endoscopic treatment of ZD appears to be safe and effective. There are currently no randomized controlled trials comparing outcomes among patients who have undergone endoscopic vs. surgical ZD repair. Although there are several studies comparing short-term outcomes between endoscopic and surgical techniques ZD, long-term outcome data is still lacking. Among the various flexible endoscopic techniques available, there is insufficient data to conclude that one method is superior to another. Nevertheless, the data that is available is sufficient to conclude that flexible endoscopic ZD repair should be considered first-line due to its minimally-invasive nature, effectiveness, and acceptable safety profile in a predominately elderly patient population.

References

  1. Ludlow A. A case of obstructed deglutition, from a preternatural dilatation of and bag formed in the pharynx. Med Soc Phys 1767;3:35-101.
  2. Zenker FA, Von Ziemssen H. Krankheiten des oesophagus (Diseases of the esophagus). In: Von Ziemssen H, editor. Handbuch der speciellenpathologie und therapie (Handbook of special pathology and therapy),vol 7 (suppl). Leipzig: FCW Vogel; 1877. p. 1-87.
  3. van Eeden S, Lloyd RV, Tranter RM. Comparison of the endoscopic stapling technique with more established procedures for pharyngeal pouches: results and patient satisfaction survey. J Laryngol Otol 1999;113: 237–240.
  4. Bizzotto A, Iacopini F, Landi R, Costamagna G. Zenker’s diverticulum: exploring treatment options. Acta Otorhinolaryngol Ital. 2013;33(4):219-229.
  5. Mosher HP. Webs and pouches of the esophagus, their diagnosis and treatment. Surg Gynecol Obstet 1917;25:175-87.
  6. Dohlman G, Mattsson 0. The endoscopic operation for hypopharyngeal diverticula. Arch Otolaryngol 1960; 71: 744-52.
  7. Collard JM, Otte JB, Kestens PJ. Endoscopic stapling technique of esophagodiverticulostomy for Zenker’s diverticulum. Ann Thorac Surg 1993; 56: 573–576
  8. Bonavina L, Bona D, Abraham M, et al. Long-term results of endosurgical and open surgical approach for Zenker diverticulum. World J Gastroenterol 2007;13:2586-9.
  9. Simić A, Radovanović N, Stojakov D, et al. Surgical experience of the national institution in the treatment of Zenker’s diverticula. Acta Chir Iugosl 2009;56:25-33.
  10. Ishaq S, Hassan C, Antonello A, Tanner K, Bellisario C, Battaglia G, Anderloni A, Correale L, Sharma P, Baron TH, Repici A. Flexible endoscopic treatment for Zenker’s diverticulum: a systematic review and meta-analysis. Gastrointest Endosc. 2016 Jun;83(6):1076-1089.e5.
  11. Perbtani Y, Suarez A, Wagh MS. Techniques and efficacy of flexible endoscopictherapy of Zenker’s diverticulum. World J Gastrointest Endosc. 2015 Mar 16;7(3):206-12. doi: 10.4253/ wjge.v7.i3.206.
  12. Sakai P. Endoscopic myotomy of Zenker’s diverticulum: lessons from 3 decades of experience. Gastrointest Endosc 2016; 83: 774-775.
  13. Evrard S, Le Moine O, Hassid S, Devière J. Zenker’s diverticulum:a new endoscopic treatment with a soft diverticuloscope. Gastrointest Endosc 2003; 58: 116-12.
  14. Costamagna G, Iacopini F, Tringali A, Marchese M, Spada C, Familiari P, Mutignani M, Bella A. Flexible endoscopic Zenker’s diverticulotomy: cap-assisted technique vs. diverticuloscope assisted technique. Endoscopy 2007; 39: 146-152
  15. Rabenstein T, May A, Michel J, Manner H, Pech O, Gossner L, Ell C. Argon plasma coagulation for flexible endoscopic Zenker’s diverticulotomy. Endoscopy 2007; 39: 141-145.
  16. Rouquette O, Abergel A, Mulliez A, Poincloux L. Usefulness of the Hook knife in flexible endoscopic myotomy for Zenker’s diverticulum. World J Gastrointest Endosc. 2017 Aug 16;9(8):411-416.
  17. Oka S, Tanaka S, Takata S, Kanao H, Chayama K. Usefulness and safety of SB knife Jr in endoscopic submucosal dissection for colorectal tumors. Dig Endosc. 2012 May;24 Suppl 1:90-5.
  18. Goelder SK, Brueckner J, Messmann H. Endoscopic treatment of Zenker’s diverticulum with the stag beetle knife (sb knife) – feasibility and follow-up. Scand J Gastroenterol. 2016 Oct;51(10):1155-8.
  19. Hondo FY, Maluf-Filho F, Giordano-Nappi JH, Neves CZ, Cecconello I, Sakai P. Endoscopic treatment of Zenker’s diverticulum by harmonic scalpel. Gastrointest Endosc 2011; 74:666-671
  20. Huberty V, El Bacha S, Blero D, Le Moine O, Hassid S, Devière J. Endoscopic treatment for Zenker’s diverticulum: long-term results (with video). Gastrointest Endosc 2013; 77: 701-707
  21. Albers DV, Kondo A, Bernardo WM, et al. Endoscopic versus surgical approach in the treatment of Zenker’s diverticulum: systematic review and meta-analysis. Endosc Int Open. 2016;4(6):E678-E686.
  22. Antonello A, Ishaq S, Zanatta L, Cesarotto M, Costantini M, Battaglia G. The role of flexible endotherapy for the treatment of recurrent Zenker’s diverticula after surgery and endoscopic stapling. Surg Endosc. 2016 Jun;30(6):2351-7.
  23. Leong SC, Wilkie MD, Webb CJ. Endoscopic stapling of Zenker’s diverticulum: establishing national baselines for auditing clinical outcomes in the United Kingdom. Eur Arch Otorhinolaryngol2012; 269: 1877-1884
  24. Mittal C, Diehl D, Draganov P, Jamil L, Khalid A, Khara H, Khullar V, Law R, Lo S, Mathew A, Mirakhor E, Sedarat A, Sharma N, Sharzehi S, Tavvakoli A, Thaker A, Thosani N, Yang D, Zelt C, Wagh MS. PRACTICE PATTERNS, TECHNIQUES, AND OUTCOMES OF FLEXIBLE ENDOSCOPIC MYOTOMY FOR ZENKER’S DIVERTICULUM: RETROSPECTIVE, MULTI-CENTER STUDY. Endoscopy. 2020 Jul 14.
  25. Brueckner J, Schneider A, Messmann H, Gölder SK. Longterm symptomatic control of Zenker diverticulum by flexible endoscopic mucomyotomy with the hook knife and predisposing factors for clinical recurrence. Scand J Gastroenterol 2016; 51: 666-671
  26. Christiaens P, De Roock W, Van Olmen A, Moons V, D’Haens G.Treatment of Zenker’s diverticulum through a flexible endoscope with a transparent oblique-end hood attached to the tip and a monopolar forceps. Endoscopy 2007; 39: 137-140.
  27. Repici A, Pagano N, Romeo F, Danese S, Arosio M, Rando G, Strangio G, Carlino A, Malesci A. Endoscopic flexible treatment of Zenker’s diverticulum: a modification of the needleknife technique. Endoscopy. 2010 Jul;42(7):532-5.
  28. Jain D, Sharma A, Shah M, Patel U, Thosani N, Singhal S. Efficacy and Safety of Flexible Endoscopic Management of Zenker’s Diverticulum. J ClinGastroenterol. 2018 May/ Jun;52(5):369-385.
  29. Vogelsang A, Preiss C, Neuhaus H, Schumacher B. Endotherapy of Zenker’s diverticulum using the needle-knife technique: long-term follow-up. Endoscopy 2007; 39: 131-136.
  30. Crawley B, Dehom S, Tamares S, Marghalani A, Ongkasuwan J, Reder L, Ivey C, Amin M, Fritz M, Pitman M, TulunayUgur O, Weissbrod P. Adverse Events after Rigid and Flexible Endoscopic Repair of Zenker’s Diverticula: A Systematic Review and Meta-analysis. Otolaryngol Head Neck Surg. 2019 Sep;161(3):388-400

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #207

March is Colorectal Cancer Awareness Month – What Clinicians Need to Know in 2021

February 2021 • Volume XLV, Issue 2
Lindsey Bierle,Cynthia Yoshida

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March is National Colorectal Cancer (CRC) Awareness Month. Annually in March, hospital systems, media outlets, and community partners look to gastroenterologists to promote CRC awareness, to advocate for policy change, and to educate the public about the importance of screening, early detection, and prevention. The goal of this article is to provide an update on what’s new in the arena of CRC to support your efforts to get the word out about CRC. Specifically, we will review: 1) the recent increase in early onset colorectal cancer, 2) new guidelines to begin screening at age 45 in average risk adults, 3) when to start screening patients who have a first degree relative with CRC or an advanced polyp, 4) dietary and lifestyle changes to decrease CRC risk, and 5) resources with practical information about CRC screening tests to provide to your colleagues, patients, and community.

Introduction

National Colorectal Cancer Awareness Month was first established in 2000 by a Presidential Proclamation signed by President Bill Clinton.1 Annually in March, hospital systems, media outlets, and community partners look to gastroenterologists to promote colorectal cancer (CRC) awareness, to advocate for policy change, and to educate the public about the importance of screening, early detection and prevention.

Colorectal cancer is the third most common cancer in the United States and the second leading cause of cancer death in men and women combined. In 2021, the American Cancer Society (ACS) projects there will be 149,500 new CRC cases and 52,980 deaths from the disease.2 Lifetime risk of developing CRC is approximately 1 in 23 (4.4%) in men and 1 in 25 (4.1%) in women. CRC incidence is 20% higher in Blacks compared to non-Hispanic whites (NHW) and this disparity is predominantly due to decreased access to healthcare/screening and increased risk factors.3 The cause of CRC is unknown, but certain risk factors are strongly linked to development of the disease (see Table 1).4

The majority of CRCs arise from precursor polyps which progress to adenocarcinoma over many years. Molecular carcinogenesis pathways include chromosomal instability, microsatellite instability, and CpG island methylator phenotype. The evolution from polyp to cancer is a slow process, on average requiring over 10 years.5,6

Screening saves lives. CRC is preventable if pre-cancerous polyps can be detected and removed before they become malignant. Survival rates approach 90% for those diagnosed with localized disease7 , highlighting the utility of early detection through screening. Although CRC is the second leading cause of cancer deaths in the United States, mortality rates have declined by 53% from 1970-2016 largely due to consistent increases in screening.3 Between 2003 and 2007, the Centers for Disease Control (CDC) reported nearly 66,000 fewer CRC diagnoses and 32,000 fewer deaths, half of which were attributed to improved screening rates.8 Yet despite these gains in screening, there is still work to be done as confirmed by these sobering facts:

  • 38 million Americans over age 50 are not getting recommended CRC screening.
  • Only two-thirds (67.3%) of age eligible Americans are up to date with CRC screening.
  • Although providers encourage on-time health maintenance, adults between age 50-64 are the least likely to be screened.9
  • Screening rates vary geographically – across the U.S. screening prevalence was lowest in New Mexico (58.5%) and highest in Maine (75.9%).10
  • Rural communities, low income/uninsured and certain racial/ethnic groups including Hispanic, American Indian/Native Alaskan, and Asian/ Pacific Islander are those with the greatest disparity.9
  • There has been an alarming rise in CRC among young adults under the age of 50.11 As a result, the United States Preventive Services Task Force recently submitted a draft recommendation to decrease the screening age to 45 years old for average risk adults.12

In an effort to increase screening rates and to save more lives, the ACS, CDC, and the National Colorectal Cancer Roundtable (NCCRT) expanded their “80% by 2018” initiative to the current “80% in Every Community” – a goal to screen 80% of age-eligible adults in every community.13 This campaign urges us all to reflect upon how we can promote CRC awareness in all of the “communities” we are connected to.

2020 was a devastating year due to the global COVID-19 pandemic, which led to the deaths of millions of people. COVID-19 also negatively affected CRC screening. Following the declaration of the COVID-19 national emergency, U.S. CRC screening rates abruptly dropped 86%.14 Komodo Health analyzed their nationwide database and found that during spring 2020, colonoscopy procedures declined by 89%, resulting in 32% fewer new CRC diagnoses.15 COVID-19 also exacerbated disparities. People lost their livelihoods and in turn their health insurance; as a result, they no longer had disposable income to contribute to preventive healthcare. The Epic Health Research Network estimates that between March – June 2020, 95,000 colon cancer screenings were missed, a staggering 64% fewer screenings as compared to prior years.14 A recent modeling study predicts that this sizable deficit of missed screenings will lead to nearly 4,500 more CRC deaths over the next decade as a result of the pandemic.16 This March especially, we will need to augment our efforts to increase CRC screening education and awareness in an effort to make up this substantial loss.

The goal of this article is to provide an update on what’s new in the arena of CRC and to provide links to resources to support your efforts in getting the word out about CRC and ultimately help you to save lives. Specifically, we will review:

The recent increase in early onset colorectal cancer
New guidelines to begin screening at age 45 in average risk adults
When to start screening patients who have a first degree relative with CRC or an advanced polyp
Dietary and lifestyle changes to decrease CRC risk, and
Resources with practical information about CRC screening tests that you can provide to your colleagues, patients, community.

Increasing Incidence of Colorectal Cancer in Adults Under 50

Even superheroes are vulnerable to colon cancer. Chadwick Boseman was diagnosed with stage 3 colon cancer in 2016 at age 39, the year he made his debut as Black Panther in Captain America: Civil War. 17 He privately fought the disease for four years and tragically lost his battle in August 2020 at the age of 43.18

Nearly 18,000 young people under the age of 50 will be diagnosed with early onset colorectal cancer (EOCRC) this year. Tragically, 49 young people will be diagnosed with EOCRC every day and 10 young people per day will die from the disease.3 Over the last five decades, CRC incidence and mortality have declined in older adults in large part due to an increased uptake of screening, most notably colonoscopy and polypectomy. Recently, the overall incidence has plateaued or even slightly risen due to an alarming increase in the number of young adults under the age of 50 who are diagnosed with the disease. The incidence of EOCRC has been rising since the mid-1970s with as much as 3% annual increases in the last five years. Colorectal cancer is the second leading cause of cancer death in young men under age 50.11

EOCRC patients have a significantly higher prevalence of distal tumors in the left colon and rectum and are more likely to present with symptoms such as rectal bleeding. Tumors are more likely to have high microsatellite instability and, unlike tumors in older patients, they are less likely to have BRAF mutations. EOCRC displays more aggressive histopathologic features and patients are more likely to have larger tumors and metastatic disease at presentation.19 Additionally, EOCRC patients often experience delays in diagnosis. A study of rectal cancer patients found that the median time to diagnosis was four times longer in patients under age 50 as compared to those over age 50 (217 versus 30 days, respectively).20 Both providers and patients tended to attribute alarm symptoms such as rectal bleeding or constipation to minor problems like hemorrhoids and did not consider or recognize that they could be due to CRC in young patients.

The etiology of the rise in EOCRC is unknown. Although genetic conditions are more common in EOCRC, similar to CRC in older patients, the majority of EOCRC cases are sporadic. Increases in EOCRC have also been documented in Europe, Asia, Australia, New Zealand, and Canada, with the uptrend beginning in the mid-1990s. Younger generations carry the increased CRC risk with them as they age in what is known as the birth cohort effect. This generational increase in disease suggests an environmental etiology.21 Recent evidence portends diets rich in red and processed meats, high-fructose corn syrup, and heavy alcohol consumption may be partly responsible for the escalating number of cases perhaps due to enhanced inflammation and effects on the gut microbiome. Environmental toxins such as pesticides and chemicals in air, water, food, and soil are also being studied.22

Numerous research studies are currently underway to determine the cause of EOCRC. Today, an important way we can all help to combat this deadly disease in young people is by increasing awareness. Spread the word about the early warning signs of colon cancer in young adults – symptoms such as rectal bleeding and constipation. Tell young adults, coaches, religious leaders, and employers that CRC is no longer an “old person’s disease.” With commitment and effort, let’s prevent our own superheroes from developing colon cancer.

Screening Should Begin at Age 45 in Average Risk Adults

In December 1995, the United States Preventive Services Task Force (USPSTF) first recommended that primary care physicians screen adults 50-75 years of age for CRC.23 The Balanced Budget Act of 1997 provided Medicare coverage for CRC screening beginning January 1, 1998.24 In 2005, the American College of Gastroenterology (ACG) Committee on Minority Affairs and Cultural Diversity published a paper reporting increased CRC incidence in Blacks as compared to NHW. Blacks develop CRC at a younger age, have more proximal adenomas and cancers, and are less likely to have been screened for CRC. They are often diagnosed at advanced cancer stages resulting in the highest rates of death and the shortest survival. The ACG was the first society to recommend that Blacks begin CRC screening at age 45.25 One year later, the American Society for Gastrointestinal Endoscopy (ASGE) also endorsed the starting age at 45 years.26 From 2006-2015, CRC incidence in Blacks dropped by more than 2.5% and death rates also fell from 2007-2016, with sharper declines as compared to NHW.27

In 2018, the ACS Task Force led by Dr. Andrew Wolf reviewed microsimulation modeling and a systematic analysis of evidence including the recent rise in EOCRC to publish the ACS guideline recommending that all average risk adults begin CRC screening at age 45, regardless of race.28 Further support for this recommendation emerged from the more than 40,000 patient New Hampshire colonoscopy registry confirming that the incidence of advanced polyps and CRC was similar in adults aged 45-49 years old as compared to 50-54-yearold adults.29 Comparing screening strategies in a validated Markov model in 2019, Ladabaum et al. suggested that CRC screening at age 45 years is likely to be cost effective.30 Given the mounting evidence in favor of earlier age screening, in October 2020 the USPSTF published an updated draft guideline for CRC screening (see Table 2).12

Save the Next Generation: Screening for Those with a Family History of CRC or Advanced Adenoma

Individuals who have a first-degree relative (parent, sibling or child) with colorectal cancer or advanced adenomas are at higher risk to develop CRC and should undergo more aggressive screening beginning at a younger age. Advanced adenomas are defined as a polyp ³ 10 mm in size or having high grade dysplasia or villous histology. Family history in a first-degree relative (FDR) increases CRC risk regardless of age at diagnosis of the affected relative, however risk is highest if the affected relative is under age 60. The United States Multisociety Task Force (USMSTF) currently recommends that these individuals should be screened at an earlier age (see Table 3).31

Screening saves lives, but when we treat a colon cancer or remove an advanced polyp, it is imperative that patients inform their FDR, especially their children to begin screening at an earlier age to ensure that we save the next generation.

Dietary/Lifestyle Modifications Can Decrease CRC Risk

When patients discover they have polyps on routine colonoscopy screening, they often ask “what can I do to prevent polyps and to decrease my chances of being diagnosed with colon cancer?” Defining CRC risk factors can help educate patients about approaches to prevent the disease. Aging, family history, and genetics are non-modifiable and beyond the patient’s control. In contrast, dietary and lifestyle modifications can be made and provide a tangible means by which patients can take charge of their health.

A recent review of eighty meta-analyses of studies evaluating CRC prevention found that red/ processed meat consumption and frequent alcohol intake were associated with an increased risk of CRC. Red meats such as beef, pork, and lamb have long been implicated as potential contributors to CRC development.32 Red and processed meats contain high levels of sulfur which are metabolized by the gut microbiome resulting in the formation of hydrogen sulfide which can cause epithelial DNA damage, promote inflammation, and disrupt the colonic mucus layer.33 There is a 12-21% increased risk of CRC with meat consumption that is dose dependent with 10-30% higher risk for each increment of 100g/day of total or red meat ingested. No significant effect was reported with animal fat or protein intake. Interestingly, there was a 20% reduction in rectal cancer risk for high versus low consumption of poultry. Alcohol intake was also associated with a significant dosedependent increased risk of CRC. Even the lowest consumption (25 g/day, 1-2 drinks) increased CRC risk 8-10%, but heavy drinkers (>50 g/day, >4 drinks) had over 50% higher risk. The relative risk was greater for rectal cancer versus colon cancer. For similar intake, men had an overall greater risk of CRC. The review also demonstrated that aspirin and non-steroidal anti-inflammatory drugs, magnesium, and folate are associated with a decreased incidence of CRC. High consumption of fruit and vegetables, fiber, and dairy products are also protective.32

Lifestyle modifications can also impact CRC risk. Similar to alcohol intake, tobacco also has a dose dependent increased risk of CRC, with highest risks among long-standing smokers or those with high amounts of tobacco consumption. CRC subtypes in smokers demonstrate increased microsatellite instability and cancers developing via serrated pathways.34 Other factors associated with a higher risk of CRC include obesity, a sedentary lifestyle, and Type 2 diabetes.3 Encouraging patients to limit alcohol intake, quit smoking, increase physical activity, and avoid excess weight gain are all positive steps patients can take towards decreasing their chances of CRC development.

Practical Resources to Assist Patients with Screening Options

Discussions about CRC screening options take time. Navigating patients to the right test based on personal/family history or risks can be complicated. Two useful tools to assist you or your colleagues are the Colorectal Cancer Alliance Online Patient Navigation Tool and the ACS Conversation Cards (see Table 4).

Summary

Colorectal cancer remains one of the leading cancer diagnoses and causes of death in the United States.3 The 80% in Every Community campaign encourages all of us to promote CRC screening in the “communities” we belong to.13 Communities are more than our clinic or endoscopy patients. Communities are more than geographic locations such as cities, counties, or states. Especially during March, National Colorectal Cancer Awareness Month, we are challenged to broaden our definition of community to consider family, workplaces, fellowship groups, social clubs, school organizations, and sports leagues within our community umbrella. By sharing information about the benefits of CRC screening, together we can prevent colon cancer, and together we can save lives.

References

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  4. Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 2007;50:113–30.
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  6. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2017, National Cancer Institute. Accessed January 19, 2021. https://seer.cancer.gov/csr/1975_2017/
  7. Richardson LC, Tai E, Rim SH, et al. Centers for Disease Control and Prevention (CDC). Vital Signs: Colorectal Cancer Screening, Incidence, and Mortality – United States, 2002-2010. MMWR 2011;60(26):884-89.
  8. Djenaba AJ, King JB, Dowling NF, et al. CDC. Vital Signs: Colorectal Cancer Screening Test Use — United States, 2018. MMWR 2020;69(10);253–59.
  9. CDC. National Comprehensive Cancer Control Program – Colorectal cancer screening rates 2020. Accessed January 19, 2021. https://www.cdc.gov/ cancer/ncccp/screening-rates/index.htm
  10. Bhandari A, Woodhouse M, Gupta S. Colorectal cancer is a leading cause of cancer incidence and mortality among adults younger than 50 years in the USA: a SEER-based analysis with comparison to other young-onset cancers. J Invest Med 2017;65(2):311-15.
  11. United States Preventive Services Task Force Draft Recommendation Colorectal Cancer Screening – 2020. Accessed January 19, 2021. https:// uspreventiveservicestaskforce.org/uspstf/draft-recommendation/colorectal-cancer-screening3#:~:text=The%20USPSTF%20recommends%20 that%20clinicians,this%20age%20group%20is%20small.
  12. Wender R, Brooks D, Sharpe K, et al: The national colorectal cancer roundtable. Gastroenterol Clin N 2020; 30(3):499-509.
  13. Epic Health Research Network. Delayed cancer screenings—A second look, 2020. Accessed January 19, 2021.https://www.ehrn.org/articles/ delayed-cancer-screenings-a-second-look
  14. Komodo Health. New colorectal cancer diagnoses fall by one-third and colonoscopies grind to a halt during height of COVID-19, 2020. Accessed January 19, 2021. https://www.komodohealth.com/insights/2020/05/newcolorectal-cancer-diagnoses-fall-by-one-third-and-colonoscopies-grind-toa-halt-during-height-of-covid-19
  15. Sharpless, NE. COVID-19 and cancer. Science 2020;368(6497):1290.
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  18. Willauer AN, Liu Y, Pereira AA, et al: Clinical and molecular characterization of early-onset colorectal cancer. Cancer 2019;125(12):2002-10.
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  21. Hofseth LJ, Hebert JR, Chanda A, et al: Early-onset colorectal cancer: initial clues and current views. Nat Rev Gastro Hepat 2020;17:352-64.
  22. Levin B, Bond JH. Colorectal cancer screening: Recommendations of the U.S. Preventive Services Task Force. Gastroenterology 1996; 111(5):1381- 84.
  23. Centers for Medicare & Medicaid Services. National coverage determination (NCD) for colorectal cancer screening tests, 2014. Accessed January 19, 2021. https://www.cms.gov/medicare-coverage-database/details/ncddetails.aspx?NCDId=281&ncdver=4&CoverageSelection=National&bc= gAAAACAAAQAA&
  24. Agrawal S, Bhupinderjit A, Bhutani M, et al: Colorectal cancer in African Americans. Am J Gastroenterol 2005;100(3):515-23.
  25. Davila RE, Rajan E, Baron TH, et al: ASGE guideline: colorectal cancer screening and surveillance. Gastrointest Endosc 2006;63(4):546-57.
  26. DeSantis CE, Miller KD, Sauer AG, et al: Cancer statistics for African Americans, 2019. CA Cancer J Clin 2019;69(3):211-23.
  27. Wolf AM, Fontham ET, Church TR, et al: Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin 2018;68(4):250-81.
  28. Butterly LF, Siegel RL, Fedewa S, et al: Colonoscopy outcomes in average-risk screening equivalent young adults: Data from the New Hampshire colonoscopy registry. Am J Gastroenterol 2021;116(1):171-79.
  29. Ladabaum U, Mannalithara A, Meester RG, et al: Cost-effectiveness and national effects of initiating colorectal cancer screening for averagerisk persons at age 45 years instead of 50 years. Gastroenterology 2019;157(1):137-48.
  30. Rex DK, Boland CR, Dominitz JA, et al: Colorectal cancer screening: Recommendations for physicians and patients from the U.S. Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol 2017;112(7):1016-30. 32. Chapelle N, Martel M, Toes-Zoutendijk E, et al. Recent advances in clinical practice: colorectal cancer chemoprevention in the average-risk population. Gut 2020;69:2244-55.
  31. Nguyen LH, Ma W, Wang DD, et al. Association between sulfur-metabolizing bacterial communities in stool and risk of distal colorectal cancer in men. Gastroenterology 2020;158:1313-25.
  32. Slattery ML, Curtin K, Anderson K, et al: Associations between cigarette smoking, lifestyle factors, and microsatellite instability in colon tumors. JNCI 2000;92(22):1831-36.
  33. Colorectal Cancer Alliance. Colon cancer can be prevented: Get your screening options here, 2019. Accessed January 19, 2021. https://quiz. getscreened.org/
  34. American Cancer Society. Understanding colorectal cancer screening, 2018. Accessed January 19, 2021. https://www.cancer.org/content/dam/ cancer-org/cancer-control/en/booklets-flyers/conversation-cards-colorectal-cancer-screening.pd

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MEDICAL BULLETIN BOARD

Treating Gastrointestinal Dysfunctions Takes Centerstage at the Aspen 2021 Nutrition Science & Practice Conference

February 2021 • Volume XLV, Issue 2

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Silver Spring, MD – Live educational sessions and oral abstract presentations on cutting-edge research and evidence-based practices are only part of the virtual ASPEN 2021 Nutrition Science & Practice Conference on March 20-23. ASPEN21 also offers opportunities to exchange ideas and experiences with experts and colleagues from around the globe.

Presentations of particular interest to GI clinicians are available each day of the conference. Highlights include:

  • March 20: Post Graduate Pre-Conference Course: Select GI Disease States and Nutritional Implications
  • March 21: Nutritional Management of Treatment Induced Gastrointestinal Complications
  • March 22: Advances in Preventing Parenteral Nutrition Associated Side Effects
  • March 23: Nutritional Metabolomics: Back to the Future of Nutrition and Metabolic Support

ASPEN21 provides opportunities to join an array of focused breakout sessions, specialty forums, exhibits, poster presentations, and corporate symposia.

For program details, continuing education information, and to register for the full conference, individual days, and pre-conference courses, visit: nutritioncare.org/conference21

About American Society for Parenteral and Enteral Nutrition

ASPEN, the American Society for Parenteral and Enteral Nutrition, is dedicated to improving patient care by advancing the science and practice of nutrition support therapy and metabolism. Founded in 1976, ASPEN is an interdisciplinary organization whose members are involved in the provision of clinical nutrition therapies, including parenteral and enteral nutrition.

For more information about ASPEN, please visit: nutritioncare.org

Waltham, Massachusetts – January 26, 2021 – Echosens, a high-technology company offering the FibroScan family of products, announces its partnership with Gastrologix to provide independent GI practices in its group purchasing organization (GPO) with the enhanced services of FibroScan, a non-invasive device that helps to assess liver health.

FibroScan is used by GI physicians to identify and address nonalcoholic fatty liver disease (NAFLD) and its more severe form nonalcoholic steatohepatitis (NASH), which have been recognized as leading causes of liver disease and key contributors to increased cardiovascular disease (CVD) mortality among people living with Type 2 diabetes.

“Given the alarming rise in liver disease, FibroScan will help independent GI practices to improve patient outcomes and reduce the costs associated with managing chronic liver conditions,” says Stephen Somers, principal of Gastrologix. “This innovative technology should be an integral part of a chronic care management program in any independent GI practice. In addition to providing a valuable service to patients, FibroScan can help sustain the practice financially as well.”

NAFLD has become the most common chronic liver disease in the world and affects between 25% to 30% of adults in the United States. About 20% of patients with NAFLD will progress to NASH, with about 25% of these individuals likely to develop liver fibrosis. Because NAFLD and NASH are tightly intertwined with obesity, diabetes and lifestyle, patients benefit from coordinated engagement to support changes in lifestyle that affect liver disease progression and result in better outcomes.

Jon Gingrich, CEO, Echosens North America, says “We’re excited to be able to bring FibroScan to the Gastrologix customer base. GI practices are at the forefront of the fight against the liver disease epidemic and can use our technology as part of their efforts to improve outcomes, save lives and, in these challenging times, initiate income repair for their practices.”

About Echosens

Echosens, the developer of FibroScan®, is an innovative high-technology company offering a full range of products and services supporting physicians in their assessment and management of patients with chronic liver diseases. FibroScan is supported by over 2,500 peer-reviewed publications and examinations are covered by Medicare, Medicaid and many insurance plans.

For more information, please visit: echosens.us

About Gastrologix

Gastrologix is the only Group Purchasing Organization (GPO) in the U.S. working strictly on behalf of independent gastroenterologists. Gastrologix works with independent GI practices in a business development capacity to lower costs, operate more efficiently and expand services, so that GI physicians can remain independent and continue to provide a valuable alternative to the more expensive care provided in hospitals.

Sebela Pharmaceuticals Announces U.S. Launch of Sutab® Tablets, an Alternative to Liquid Colonoscopy Preparation
SUTAB® Tablets with Active Sulfate Ingredients is the First Tablet Colonoscopy Preparation to Receive FDA Approval in Over 10 Years

ROSWELL, GA, Jan., 2021—Sebela Pharmaceuticals® today announced that SUTAB® (sodium sulfate, magnesium sulfate, and potassium chloride) tablets, the first tablet colonoscopy preparation to receive approval from the U.S. Food and Drug Administration (FDA) in over 10 years, is now available in the United States.

SUTAB is a sulfate-based tablet colonoscopy preparation that is taken orally in a split-dose administration starting the evening before a colonoscopy. The tablets offer a safe and effective alternative to liquid colonoscopy preparations, which traditionally require consuming large volumes of poor-tasting solution and can often be a barrier to patients’ willingness to undergo colonoscopy screening for colorectal cancer.1

The American Cancer Society and the U.S. Preventive Services Task Force recommend adults undergo screening for colorectal cancer beginning at age 45.2 Colonoscopy is the gold standard detection method for colorectal cancer, a leading cause of cancer-related deaths that can be more effectively treated if caught early through screening.3 Within the last decade, the rate of colonoscopy procedures has increased significantly with approximately 18 million people now screened annually for colorectal cancer.

“Alternative colonoscopy preparations, like SUTAB, can play an important role in encouraging more patients to get screened for colorectal cancer,” said Alan Cooke, President and CEO of Sebela Pharmaceuticals. “With the introduction of SUTAB tablets, we hope to take yet another important step toward removing some of the burden often associated with the preparation process – allowing more patients to feel confident in their choice to undergo a colonoscopy.”

The FDA approved SUTAB on November 10, 2020. The approval was based on positive Phase 3 clinical trials, which evaluated the safety and efficacy of SUTAB compared to FDAapproved preparations in 941 patients, including a traditional polyethylene glycol and ascorbate preparation (PEG-EA) for bowel cleansing prior to a colonoscopy.4

A high rate of cleaning success was seen with SUTAB (92.4%), which demonstrated non-inferiority to PEG-EA (89.3%).4 Likewise, the percentage of patients rating their overall experience with SUTAB as “excellent” or “good” was higher than those rating PEG-EA (71.6% vs. 59.8%, respectively).4 For a future colonoscopy, 78% of patients said they would request SUTAB again.4

SUTAB is now available by prescription in the U.S. and is competitively priced with other branded colonoscopy preparations. Patients can pay as little as $40 with a Braintree copay card.

To learn more, visit: SUTAB.com

SUTAB was developed by Braintree, the makers of SUPREP® Bowel Prep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) Oral Solution for adults—the market leader in branded colonoscopy preparations.5 Braintree, a leader in gastroenterology, is part of Sebela Pharmaceuticals.

Important Safety Information

SUTAB® (sodium sulfate, magnesium sulfate, potassium chloride) tablets for oral use is an osmotic laxative indicated for cleansing of the colon in preparation for colonoscopy in adults.

DOSAGE AND ADMINISTRATION: A low residue breakfast may be consumed. After breakfast, only clear liquids may be consumed until after the colonoscopy. Administration of two doses of SUTAB (24 tablets) are required for a complete preparation for colonoscopy. Twelve (12) tablets are equivalent to one dose. Water must be consumed with each dose of SUTAB and additional water must be consumed after each dose. Complete all SUTAB tablets and required water at least 2 hours before colonoscopy.

CONTRAINDICATIONS: Use is contraindicated in the following conditions: gastrointestinal obstruction or ileus, bowel perforation, toxic colitis or toxic megacolon, gastric retention.

WARNINGSAND PRECAUTIONS: Risk of fluid and electrolyte abnormalities: Encourage adequate hydration, assess concurrent medications and consider laboratory assessments prior to and after each use; Cardiac arrhythmias: Consider pre-dose and post-colonoscopy ECGs in patients at increased risk; Seizures: Use caution in patients with a history of seizures and patients at increased risk of seizures, including medications that lower the seizure threshold; Patients with renal impairment or taking concomitant medications that affect renal function: Use caution, ensure adequate hydration and consider laboratory testing; Suspected GI obstruction or perforation: Rule out the diagnosis before administration.

ADVERSE REACTIONS: Most common gastrointestinal adverse reactions are: nausea, abdominal distension, vomiting and upper abdominal pain.

DRUG INTERACTIONS: Drugs that increase risk of fluid and electrolyte imbalance.6

About SUTAB®

SUTAB® (sodium sulfate, magnesium sulfate, potassium chloride) tablets for oral use is an osmotic laxative indicated for cleansing of the colon in preparation for colonoscopy in adults. Cleaning the colon helps a healthcare provider see the inside of a colon more clearly during a colonoscopy. Safety and effectiveness of SUTAB® in pediatric patients have not been established.6

About Sebela Pharmaceuticals®

Sebela Pharmaceuticals is a US-focused, growth oriented specialty pharmaceutical company developing and commercializing gastroenterology, women’s health, and dermatology prescription products. Braintree, a part of SebelaPharmaceuticals, is a pioneer in gastroenterology therapy for bowel cleansing prior to colonoscopy screening for colorectal cancer having developed multiple innovative prescription colonoscopy preparation and constipation products including SUTAB®, SUPREP® Bowel Prep Kit, GoLYTELY® and NuLYTELY®. Our gastroenterology product line also includes Motofen®, Analpram HC® and recently approved Pizensy™ (indicated for chronic idiopathic constipation in adults). Sebela Pharmaceuticals has multiple further advances in colonoscopy preparation therapy in clinical development. Sebela Pharmaceuticals also has two next generation intra-uterine devices (IUDs) for contraception in development that hold the promise of a better patient experience in addition to excellent efficacy. Sebela Pharmaceuticals has offices in Roswell, GA; Braintree, MA; and Dublin, Ireland, has annual net sales of $200-250 million and has grown to over 300 employees through strategic acquisitions and organic growth.

Please visit sebelapharma.com for more information or call 800-874-6756

Forward Looking Statements

This press release and any statements made for and during any presentation or meeting contain forward-looking statements related to Sebela Pharmaceuticals under the safe harbor provisions of Section 21E of the Private Securities Litigation Reform Act of 1995 and are subject to risks and uncertainties that could cause actual results to differ materially from those projected. These statements may be identified by the use of forward-looking words such as “anticipate,” “planned,” “believe,” “forecast,” “estimated,” “expected,” and “intend,” among others. There are a number of factors that could cause actual events to differ materially from those indicated by such forward-looking statements. These factors include, but are not limited to, the development, launch, introduction and commercial potential of SUTAB®; growth and opportunity, including peak sales and the potential demand for SUTAB®, as well as its potential impact on applicable markets; market size; substantial competition; our ability to continue as a growing concern; our need for additional financing; uncertainties of patent protection and litigation;

uncertainties of government or third-party payer reimbursement; dependence upon third parties; our financial performance and results, including the risk that we are unable to manage our operating expenses or cash use for operations, or are unable to commercialize our products, within the guided ranges or otherwise as expected; and risks related to failure to obtain FDA clearances or approvals and noncompliance with FDA regulations. As with any pharmaceutical under development, there are significant risks in the development, regulatory approval and commercialization of new products. There are no guarantees that future clinical trials discussed in this press release will be completed or successful or that any product will receive regulatory approval for any indication or prove to be commercially successful. While the list of factors presented here is considered representative, no such list should be considered to be a complete statement of all potential risks and uncertainties. Unlisted factors may present significant additional obstacles to the realization of forward-looking statements. Forward-looking statements included herein are made as of the date hereof, and Sebela Pharmaceuticals does not undertake any obligation to update publicly such statements to reflect subsequent events or circumstances except as required by law.

References

  1. Parra-Blanco A, Ruiz A, Alvarez-Lobos M, et al. Achieving the best bowel preparation for colonoscopy. World J Gastroenterol.Published online December 21, 2014. doi: 10.3748/wjg.v20.i47.17709
  2. U.S. Preventative Services Task Force. Colorectal Cancer: Screening. https://www.uspreventiveservicestaskforce.org/uspstf/draft-recommendation/colorectal-cancer-screening3. October 27, 2020. Accessed December 21, 2020.
  3. Doubeni CA, Corley DA, Quinn VP, et al. Effectiveness of screening colonoscopy in reducing the risk of death from right and left colon cancer: a large communitybased study. Gut. 2018;67(2):291-298.
  4. Di Palma JA, Bhandari R, Cleveland M, et al. A safety and efficacy comparison of a new sulfate-based tablet bowel preparation versus a PEG and ascorbate comparator in adult subjects undergoing colonoscopy. Am J Gastroenterol. Published online November 6, 2020. doi: 10.14309/ajg.0000000000001020
  5. IQVIA. National Prescription Audit Report. December 2020.
  6. SUTAB® [package insert]. Braintree Laboratories, Inc., Braintree, MA: 2020.

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INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #110

Ulcerative Colitis in the Elderly: Indications and Outcomes of Ileal Pouch-Anal Anastomosis (IPAA)

February 2021 • Volume XLV, Issue 2
Patricio B. Lynn,David M. Schwartzberg

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Introduction

Inflammatory Bowel Disease (IBD) prevalence is increasing worldwide; as the population is also aging, IBD in the elderly, and especially elderlyonset IBD (E-IBD) is a rising concern.1-3 There are 2 populations of E-IBD patients: elderly onset IBD patients and individuals with progression of the disease diagnosed earlier in life.4 A populationbased study from the Netherlands showed that the incidence of E-IBD increased from 11.71 to 23.66 per 100,000 from 1991 to 2010.5 The age definition of what is “elderly onset IBD” varies in the literature as a standard age is not agreed upon, largely secondary to local clinical practices.6 Most cut-off values are approximately 60 years of age, but reports as young as 50 years old as well as studies analyzing outcomes of septuagenarians are available.4

The prevalence of elderly-onset IBD has been reported between 8-9%.6-8 The incidence of elderly UC (E-UC) in the United States is 6-8/100,000 per year and is more common than the diagnosis of elderly Crohn’s disease (12.5% vs. 5%).4 Charpentier et al. reported the largest populationbased study of elderly-onset IBD and demonstrated that 1 out of 8 incident cases of ulcerative colitis (UC) and 1 out of 20 incident cases of Crohn’s Disease (CD) )were in individuals older than 60 years of age.7

It has been suggested that E-IBD may have a more benign clinical presentation and a better prognosis than the younger-onset disease.8,9 Elderly patients with CD present with an increased incidence of colitis rather than ileocolitis and therefore suffer from less stricturing, fistulizing, and perineal disease compared to a younger cohort.10.11 Similarly, elderly UC patients compared to younger patients, tend to have less frequent pancolitis, a higher rate of leftsided disease, lower progression rates, and lower risk of hospitalization.8,9,12 Conversely, elderly IBD patients may be at higher risk of malignant and infectious complications related to medical therapy, however, the influence of these occurrences on overall mortality is not clear.13

The diagnosis of E-IBD is challenging as many other colonic pathologies can simulate IBD in the older age group.14 There are often diagnostic delays as clinical presentations suggest nonsteroidal anti-inflammatory drug (NSAID)-induced intestinal injury, diverticular-associated disease, intestinal ischemia and infectious colitis including Clostridium difficile colitis. Delay in diagnosis or misdiagnosis can result in significant morbidity what can be especially troublesome in a population with reduced functional reserve as is the elderly.

In this review, we will summarize the indications and outcomes of surgical treatment for elder UC patients.

Indications for Surgery & Surgical Risk

Irrespective of age, surgery is indicated for medically refractory or fulminant disease, complicated disease behavior, intestinal hemorrhage, and malignancy. 15-17 The concern for malignancy and opportunistic infection in the E-IBD patients is significant compared to younger cohorts, especially when on therapeutic IBD treatment. 11 Intolerance to medications, similar to younger populations, may prompt surgical intervention, particularly with regards to chronic use of corticosteroids, which is associated with increased mortality. 4 The debate on ‘top-down’ versus ‘bottom-up’ therapy remains, however recent evidence has shown that a ‘topdown’ approach is more efficacious in the E-IBD population. 18 Anti-TNF agents are of debatable efficacy in the elder population as some studies suggest that anti-TNFs have limited response rates, poor adherence, higher association with severe infections compared with younger populations, and have a higher rate of malignancy and mortality. 4 Immunomodulators are associated with a risk of lymphoproliferative disorders and non-melanotic skin cancers, as well as a 12% relapse rate at 1 year after discontinuation in UC. 4 These risks must be discussed in the shared-decision process and balanced with the risks of surgical treatment; e.g. restorative proctocolectomy. Aminosalicylates are generally safe in the elderly population, still with a risk of nephrotoxicity. Mild-to-moderate UC patients on aminosalicylates monotherapy may avoid surgery, however the necessity of chronic rectal and oral therapy may result in low compliance. 4

Additionally, approximately, 25% of all intestinal surgeries for IBD are performed in patients ≥55 years old.19 Most of the surgeries for older patients with IBD are elective,20 with disease progression through medical management being the most common indication.21,22 Improving the quality of daily living over long-term sequelae of the disease is paramount and consultation with a surgeon before progression of the disease may allow the patient to make a better-informed decision about continuing medical therapy versus surgery.14 Unlike the young population, procedural risk must be balanced with cancer surveillance with age over 75 years as an additional risk factor for hospitalization after endoscopy.11,23 E-IBD patients are more than twice as likely to suffer from surgical complications, with an increased hospital length of stay compared to younger patients.24 Dysplasia and cancer are major concerns in the elderly population and are frequent reasons for surgery in some UC series.25

Unique to the E-IBD population are other risk factors such as poor nutritional status, medication interactions, functional impairment, and limited mobility. A variety of factors (poor dentition, early satiety, decreased access to healthy food, limited mobility) can result in nutrient deficiencies. Polypharmacy with drug interactions and overall deconditioning may adversely affect post-operative recovery. 5 Despite medical comorbidities, there are no specific operations that should be avoided in older patients and restorative proctocolectomy remains an option in selective patients with E-UC. 11

Outcomes of Surgical Treatment for the Elderly UC Patient

Surgical treatment in elderly patients with IBD is frequently avoided because of a perceived increase in surgical risk. In a report of 30 patients from 2014, Ikeuchi et al. reviewed the surgical experience of elderly patients with UC. Selective cases had a 30- day mortality of 0.8%, however this number was increased to 27% in the emergency setting. Sepsis by methicillin-resistant Staphylococcus aureus or fungus and respiratory tract infection were the most common causes of death after emergency surgery.26

Mortality for emergency surgery in UC patients has been reported at 5.3%.27

Elderly patients with IBD have an increased rate of postoperative complications, an increased length of hospital stay and increased operative time.20,24 Although this increase in surgical complication rates could be attributed to the comorbidities of the elderly, the increased rate of postoperative complications and length of hospital stay remained unchanged after adjustment for comorbidities in one study.24 Other authors did not find differences in surgical morbidity and mortality among older patients with UC (undergoing restorative proctocolectomy)28 or with CD.29 A multicentric retrospective study, including 6 reference centers from Europe, found that elderly patients presented similar number of overall postoperative complications compared to a match cohort of younger patient.30 Nevertheless, the complication profile was different; elderly patients presented more Clavien-Dindo grade IV-V (requiring surgical treatment or leading to death), whereas younger patients had more grade III (requiring intervention other than surgery).

In a 113 patient series from a tertiary center, UC patients ≥65 years of age were found to have a significantly decreased frequency of surgeryassociated adverse outcomes from 50% during 1960–1984 to 27%. The same trend was observed for mortality, 13% for the first period, and 2.7% in the latter period, indicating better outcomes in experienced tertiary centers.31

It is fundamental that surgeons, physicians, patients, and family discuss thoroughly the benefits and risks of surgery so that a fully informed decision could be made. Earlier surgical intervention for elderly UC patients should be considered since complications such as toxic megacolon, perforation, massive hemorrhage, and mortality are more common in the elderly when surgery is delayed.21 In UC, the severity of the episode and promptness of the surgical intervention are the most important determinants of surgical outcome after colectomy. Morbidity of severe UC increases from prolonged ineffective medical treatment. Delaying surgery based on a patient’s age may increase mortality, whereas prompt surgical intervention has been associated with dramatic reductions in mortality in elderly patients with severe colitis.21

Restorative Proctocolectomy in Elderly Ulcerative Colitis Patients

Restorative proctocolectomy with IPAA continues to be the surgical technique of choice.32,33 The dogma of “no pouch-anal anastomosis over 50” established in the early 1990s is now obsolete.33 Age is not considered a contraindication for performing ileal pouch-anal anastomosis (IPAA).34 The American Society of Colon and Rectal Surgeons recommends in its practice parameters that “chronologic age should not by itself be used as an exclusion criterion”. 17 However, careful consideration should be given to underlying comorbidities, patient’s mental status, and anal sphincter function to distinguish the “fit from the frail”. Pouch procedures are feasible in suitably motivated elderly individuals who understand the risks and potential functional difficulties that often accompany this procedure.17

Elderly patients should be evaluated regarding anal function before considering IPAA. The success of this operation in the elderly requires good anal sphincter function as pre-operative incontinence contraindicates pouch surgery.33,35,36 Careful patient selection with good sphincteric function and adequate cognitive abilities are necessary for adaptation to IPAA. Patients with a pre-existing diagnosis of anorectal dysfunction/ fecal incontinence may have better function and quality of life with permanent ileostomy.20,37

A J-pouch configuration with stapled anastomosis including a <2cm rectal cuff would be preferable in elderly patients whenever possible to an S-pouch configuration with mucosectomy and handsewn anastomosis. The first approach is associated with better functional results in terms of major and minor, nocturnal, and diurnal incontinence, due to the preservation of the anal transitional zone and a better emptying.30

A diverting loop ileostomy in the elderly patient, i.e., defunctioning the distal anastomosis may well reduce the incidence of a leak.38 An anastomotic leak will compromise the clinical and functional outcome, especially in the elderly in the setting of pelvic sepsis. Surgeons willing to perform an IPAA in the elderly should be patient, humble, and wise enough to know when to divert a patient.

When performing complex surgical procedures demanding sophisticated perioperative care, it has been shown that institutions performing larger numbers of operations have better outcomes than those who only operate on such cases occasionally; this also applies to institutions undertaking pouch surgery.39 High volume institutions manage adverse events better, and that leads to better pouch salvage rates in the face of complications.40 If available, it is appropriate for IPAAs to be referred to highvolume specialized institutions.

Minimally Invasive approaches have been gaining acceptance for UC and IPAA surgery, even in the elderly. In the aforementioned European multicentric study, more than 50% of the IPAA performed in the elderly were done laparoscopically.30 Two meta-analyses have found that laparoscopic IPAA when compared to open surgery is associated with a shorter hospital stay, earlier return of bowel function, better cosmesis,41 and lower rates of surgical site infection.42 Although the experience with robotic surgery is limited for IPAA, in small case series, it has shown similar results to those of laparoscopic surgery but these studies were done in the general population without differentiating according to age.43

Morbidity/Mortality

Table 1. resumes the surgical outcomes of the most representative series of IPAA in the elderly population.

A recent European multi-centric study of the International Pouch Database included 77 patients aged ≥ 65 years and 154 younger control patients that were matched according to comorbidities. Postoperative complications (32.4 vs. 27.2%) and pouch failure (5.1 vs. 5.1%) were similar between the groups, but elderly patients presented more Clavien-Dindo IV-V complications (20 vs. 4%, p = 0.04), as well as longer length of stay (13.3 vs. 11.5 days, p = 0.007). Mortality was recorded in 1 patient in the elderly group. Laparoscopy was associated with a shorter operative time [p = 0.0001], length of stay [p = 0.0001], with a similar complication rate to open surgery.30

In contrast to previous findings, Delaney et al. showed a pouch failure rate of 5.9% in those over 55 years of age at the time of surgery, which is significantly higher compared to patients ≤55 (p < 0.000001).33

Pouch anastomotic leakage is the most dreaded complication of IPAA surgery, leading to pelvic sepsis and eventually to pouch failure. The incidence is quite variable, ranging from 0% to 25%, depending on the definition and time of onset.30

A systematic review of 12 studies (4327 young vs. 513 elderly patients), found that complication rates were comparable except for an increased rate of small-bowel obstruction in the younger patients. Dehydration and electrolyte loss was a significant problem in patients over 65.44

Functional Outcomes

In a review of functional outcomes in elderly patients undergoing IPAA surgery (50 years of age), compared with younger patients, at 1 year, 24-hour stool frequency was significantly higher in the elderly patient group 6.79±3.39 vs. 5.55±1.48 (p<0.0001). Perfect/near perfect continence was reported in 55.09 % of older patients vs. 74.75 % of the younger patients (p < 0.0001). 44

Dayton et al. reported daytime incontinence rates significantly higher in the elderly patients (13.95 vs. 5.56 %, p < 0.0001), as well as worse night-time incontinence rates (29.65 vs. 12.53 %, p < 0.0001)(45). Nocturnal seepage at 1 year after surgery was 49% in older patients versus 34 % of younger ones (p = 0.0002). Those studies that reported the quality of incontinence (solids vs. mucus/flatus), revealed no difference between older and younger patients; 11.04 % versus 7.37% (p=0.165 ) for mucus/flatus and 5.06 % versus 4.19% (p=0.633) for solids. 33

A few studies found no significant difference in pad or anti-diarrheal medication usage between older and younger patients. Tan et al. reported medication usage in 41.7 versus 33% (p = 0.323) older versus younger, a daytime pad usage of 16.7 versus 2.75% (p = 0.024), and night-time pad usage of 8.25 versus 16.7 % (p = 0.389) in older and younger groups respectively. 45

The ability to discriminate between flatus and feces is affected by age, in the systematic review by Ramage et al., 15.75 % younger versus 23.81 % older patients were unable to discriminate, but this difference did not reach statistical significance (p = 0.3409). 44 Lewis et al. found that 14/18 older versus 17/18 younger patients were able to defer defecation for more than 15 minutes. 46

Overall, anorectal function seems to deteriorate with time across all ages; however, after 10 years, there is no significant difference in incontinence rates between age groups.44

Quality of Life

Despite differences in postoperative function, a limited number of studies have reported quality of life outcomes that are comparable between older and younger UC patients after IPAA.33

A single institution retrospective study reporting outcomes after IPAA of 1895 patients (72% with UC) with 62 patients being ≥65 or older, reported a 28% and 33% rate of social or sexual restriction, respectively, with sexual restriction being statistically significant compared with younger patients (p=0.035).33 Nevertheless, most elderly UC patients (89%) stated that they would opt to undergo IPAA again, and 96% would recommend the procedure to others.33

Chapman et al. examined differences in restrictions between age groups. There were no significant differences in sexual, work, social, or family activities noted between those <45 and those >45 at follow-up, except for sexual function beyond 5 years which was significantly worsened in the >55 age category. Seventy percent of patients >55 reported improved or unaffected social activities following surgery; 84% and 82 % reported that undergoing IPAA had improved or not affected work and family life.47

CONCLUSION

Surgical management of IBD in elderly patients remains a challenge. Indications for surgical treatment are similar compared with younger patients but special attention for dysplasia/ neoplasia in the elderly should be considered. Surgery for IBD in elderly patients has been associated with longer operative time, greater postoperative complications, and longer length of stay, but this should not preclude surgical treatment. Communication among treating physicians is imperative to determine optimal surgical timing. IPAA remains as the preferred treatment for “fit” elderly UC patients with acceptable functional results. Preoperative anorectal function should be considered when offering this approach. Better outcomes are obtained in high-volume centers with experience in the management of these patients.

References

  1. Molinie F. Opposite evolution in incidence of Crohn’s disease and ulcerative colitis in Northern France (1988-1999). Gut. 2004 Jun 1;53(6):843–8.
  2. Cosnes J, Rousseau CG, Seksik P, Cortot A. Epidemiology and Natural History of Inflammatory Bowel Diseases. Gastroenterology. Elsevier Inc; 2011 May 1;140(6):1785–1794. e4.
  3. Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing Incidence and Prevalence of the Inflammatory Bowel Diseases With Time, Based on Systematic Review. Gastroenterology. Elsevier Inc; 2012 Jan 1;142(1):46– 54.e42.
  4. Tran V, Limketkai BN, Sauk JS. IBD in the Elderly: Management Challenges and Therapeutic Considerations. Curr Gastroenterol Rep. 2019 Nov 27;21(11):60.
  5. Jeuring SFG, van den Heuvel TRA, Zeegers MP, Hameeteman WH, Romberg-Camps MJL, Oostenbrug LE, et al. Epidemiology and Long-term Outcome of Inflammatory Bowel Disease Diagnosed at Elderly Age—An Increasing Distinct Entity? Inflammatory Bowel Diseases. 2016 Jun;22(6):1425–34.
  6. Duricova D, Burisch J, Jess T, Gower-Rousseau C, Lakatos PL. Age-related differences in presentation and course of inflammatory bowel disease: an update on the population-based literature. Journal of Crohn’s and Colitis. 2014 Nov;8(11):1351–61.
  7. Charpentier C, Salleron J, Savoye G, Fumery M, Merle V, Laberenne J-E, et al. Natural history of elderly-onset inflammatory bowel disease: a population-based cohort study. Gut. 2014 Mar;63(3):423–32.
  8. Ruel J, Ruane D, Mehandru S, Gower-Rousseau C, Colombel J-F. IBD across the age spectrum: is it the same disease? Nature reviews Gastroenterology & hepatology. 2014 Feb;11(2):88– 98.
  9. Ha CY, Katz S. Clinical implications of ageing for the management of IBD. Nature reviews Gastroenterology & hepatology. 2014 Feb;11(2):128–38.
  10. Ananthakrishnan AN, Shi HY, Tang W, Law CCY, Sung JJY, Chan FKL, et al. Systematic Review and Meta-analysis: Phenotype and Clinical Outcomes of Older-onset Inflammatory Bowel Disease. Journal of Crohn’s and Colitis. 2016 Sep 28;10(10):1224–36.
  11. Dorreen A, Heisler C, Jones J. Treatment of Inflammatory Bowel Disease in the Older Patient. Inflammatory Bowel Diseases. 2018 May 18;24(6):1155–66.
  12. Gower-Rousseau C, Vasseur F, Fumery M, Savoye G, Salleron J, Dauchet L, et al. Epidemiology of inflammatory bowel diseases: new insights from a French population-based registry (EPIMAD). Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2013 Feb;45(2):89–94.
  13. Cottone M, Kohn A, Daperno M, Armuzzi A, Guidi L, D’Inca R, et al. Advanced age is an independent risk factor for severe infections and mortality in patients given anti-tumor necrosis factor therapy for inflammatory bowel disease. Clin Gastroenterol Hepatol. 2011 Jan;9(1):30–5.
  14. Butter M, Weiler S, Biedermann L, Scharl M, Rogler G, Bischoff-Ferrari HA, et al. Clinical manifestations, pathophysiology, treatment and outcome of inflammatory bowel diseases in older people. Maturitas. 2018 Apr;110:71–8.
  15. Strong SA, Koltun WA, Hyman NH, Buie DW. Practice Parameters for the Surgical Management of Crohnʼs Disease. Diseases of the colon and rectum. 2007 Nov;50(11):1735–46.
  16. Kornbluth A, Sachar DB, Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Vol. 105, The American journal of gastroenterology. 2010. pp. 501–23–quiz524.
  17. Ross H, Steele SR, Varma M, Dykes S, Cima R, Buie WD, et al. Practice Parameters for the Surgical Treatment of Ulcerative Colitis. Diseases of the colon and rectum. 2014 Jan;57(1):5–22.
  18. Kariyawasam VC, Kim S, Mourad FH, Selinger CP, Katelaris PH, Brian Jones D, et al. Comorbidities Rather Than Age Are Associated With the Use of Immunomodulators in Elderly-onset Inflammatory Bowel Disease. Inflammatory Bowel Diseases. 2019 Jul 17;25(8):1390–8.
  19. Kaplan GG, Hubbard J, Panaccione R, Shaheen AAM, Quan H, Nguyen GC, et al. Risk of comorbidities on postoperative outcomes in patients with inflammatory bowel disease. Arch Surg. 2011 Aug;146(8):959–64.
  20. Ananthakrishnan AN, McGinley EL, Binion DG. Inflammatory bowel disease in the elderly is associated with worse outcomes: a national study of hospitalizations. Inflammatory Bowel Diseases. 2009 Feb;15(2):182–9.
  21. Gisbert JP, Chaparro M. Systematic review with meta-analysis: inflammatory bowel disease in the elderly. Aliment Pharmacol Ther. 2014 Jan 9;39(5):459–77.
  22. Nimmons D. Elderly patients and inflammatory bowel disease. WJGPT. 2016;7(1):51.
  23. Tran AH, Man Ngor EW, Wu BU. Surveillance colonoscopy in elderly patients: a retrospective cohort study. JAMA Intern Med. 2014 Oct;174(10):1675–82.
  24. Page MJ, Poritz LS, Kunselman SJ, Koltun WA. Factors affecting surgical risk in elderly patients with inflammatory bowel disease. Journal of Gastrointestinal Surgery. 2002 Jul;6(4):606– 13.
  25. Pinto RA, Canedo J, Murad-Regadas S, Regadas SF, Weiss EG, Wexner SD. Ileal pouch-anal anastomosis in elderly patients: is there a difference in morbidity compared with younger patients? Colorectal Disease. 2011 Jan 21;13(2):177–83.
  26. Ikeuchi H, Uchino M, Matsuoka H, Bando T, Hirata A, Takesue Y, et al. Prognosis following emergency surgery for ulcerative colitis in elderly patients. Surg Today. 2014 Jan;44(1):39–43.
  27. Singh S, Al-Darmaki A, Frolkis AD, Seow CH, Leung Y, Novak KL, et al. Postoperative Mortality Among Patients With Inflammatory Bowel Diseases: A Systematic Review and Meta-analysis of Population-Based Studies. Gastroenterology. Elsevier, Inc; 2015 Oct 1;149(4):928–37.
  28. Bauer JJ, Gorfine SR, Gelernt IM, Harris MT, Kreel I. Restorative proctocolectomy in patients older than fifty years. Diseases of the colon and rectum. 1997 May;40(5):562–5.
  29. Carlomagno N, Grifasi C, Dumani X, Conte Lo D, Renda A. Clinical management of Crohn’s disease in the elderly. Ann Ital Chir. 2013 May;84(3):263–7.
  30. Colombo F, Sahami S, de Buck Van Overstraeten A, Tulchinsky H, Mege D, Dotan I, et al. Restorative Proctocolectomy in Elderly IBD Patients: A Multicentre Comparative Study on Safety and Efficacy. Journal of Crohn’s and Colitis. 2016 Dec 7;:jjw209.
  31. Almogy G, Sachar DB, Bodian CA, Greenstein AJ. Surgery for ulcerative colitis in elderly persons: changes in indications for surgery and outcome over time. Arch Surg. 2001 Dec;136(12):1396–400.
  32. Dignass A, Lindsay JO, Sturm A, Windsor A, Colombel J-F, Allez M, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management. 2012. pp. 991–1030.
  33. Delaney CP, Fazio VW, Remzi FH, Hammel J, Church JM, Hull TL, et al. Prospective, Age-Related Analysis of Surgical Results, Functional Outcome, and Quality of Life After Ileal Pouch-Anal Anastomosis. Ann Surg. 2003 Aug;238(2):221–8.
  34. Val JHD. Old-age inflammatory bowel disease onset: A different problem? World J Gastroenterol. 2011;17(22):2734.
  35. Kiran RP, El-Gazzaz G, Remzi FH, Church JM, Lavery IC, Hammel J, et al. Influence of age at ileoanal pouch creation on long-term changes in functional outcomes. Colorectal Dis. 2011 Feb;13(2):184–90.
  36. Farouk R, Pemberton JH, Wolff BG, Dozois RR, Browning S, Larson D. Functional outcomes after ileal pouch-anal anastomosis for chronic ulcerative colitis. Ann Surg. 2000 Jun;231(6):919–26.
  37. Stallmach A, Hagel S, Gharbi A, Settmacher U, Hartmann M, Schmidt C, et al. Medical and surgical therapy of inflammatory bowel disease in the elderly — Prospects and complications. Journal of Crohn’s and Colitis. European Crohn’s and Colitis Organisation; 2011 Jun 1;5(3):177–88.
  38. Weston-Petrides GK, Lovegrove RE, Tilney HS, Heriot AG, Nicholls RJ, Mortensen NJM, et al. Comparison of outcomes after restorative proctocolectomy with or without defunctioning ileostomy. Arch Surg. 2008 Apr 1;143(4):406–12.
  39. Burns EM, Bottle A, Aylin P, Clark SK, Tekkis PP, Darzi A, et al. Volume analysis of outcome following restorative proctocolectomy. Br J Surg. 2011 Mar;98(3):408–17.
  40. Raval MJ, Schnitzler M, O’Connor BI, Cohen Z, McLeod RS. Improved outcome due to increased experience and individualized management of leaks after ileal pouch-anal anastomosis. Ann Surg. 2007 Nov;246(5):763–70.
  41. Ahmed Ali U, Keus F, Heikens JT, Bemelman WA, Berdah SV, Gooszen HG, et al. Open versus laparoscopic (assisted) ileo pouch anal anastomosis for ulcerative colitis and familial adenomatous polyposis. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD006267.
  42. Bartels SAL, Gardenbroek TJ, Ubbink DT, Buskens CJ, Tanis PJ, Bemelman WA. Systematic review and meta-analysis of laparoscopic versus open colectomy with end ileostomy for non-toxic colitis. Br J Surg. 2013 May;100(6):726–33.
  43. Rencuzogullari A, Gorgun E, Costedio M, Aytac E, Kessler H, Abbas MA, et al. Case-matched Comparison of Robotic Versus Laparoscopic Proctectomy for Inflammatory Bowel Disease. Surg Laparosc Endosc Percutan Tech. 2016 Jun;26(3):e37–40.
  44. Ramage L, Qiu S, Georgiou P, Tekkis P, Tan E. Functional out comes following ileal pouch-anal anastomosis (IPAA) in older patients: a systematic review. Int J Colorectal Dis. 2016 Jan 12;31(3):481–92.
  45. Dayton MT, Larsen KR. Should older patients undergo ileal pouch-anal anastomosis? Am J Surg. 1996 Nov;172(5):444–7– discussion447–8.
  46. Lewis WG, Sagar PM, Holdsworth PJ, Axon AT, Johnston D. Restorative proctocolectomy with end to end pouch-anal anastomosis in patients over the age of fifty. Gut. 1993 Jul;34(7):948–52.
  47. Chapman JR, Larson DW, Wolff BG, Dozois EJ, Cima RR, Pemberton JH, et al. Ileal pouch-anal anastomosis: does age at the time of surgery affect outcome? Arch Surg. 2005 Jun;140(6):534–9–discussion539–40.
  48. Tan HT, Connolly AB, Morton D, Keighley MR. Results of restorative proctocolectomy in the elderly. Int J Colorectal Dis. 1997;12(6):319–22.
  49. Delaney CP, Dadvand B, Remzi FH, Church JM, Fazio VW. Functional outcome, quality of life, and complications after ileal pouch-anal anastomosis in selected septuagenarians. Diseases of the colon and rectum. 2002 Jul;45(7):890–4–discussion894.
  50. Ho KS, Chang CC, Baig MK, Börjesson L, Nogueras JJ, Efron J, et al. Ileal pouch anal anastomosis for ulcerative colitis is feasible for septuagenarians. Colorectal Dis. 2006 Mar;8(3):235–8.
  51. Pellino G, Sciaudone G, Candilio G, Camerlingo A, Marcellinaro R, Rocco F, et al. Complications and functional outcomes ofrestorative proctocolectomy for ulcerative colitisin the elderly. BMC Surgery. BioMed Central Ltd; 2013 Oct 8;13(Suppl 2):S9.
  52. Pellino G, Sciaudone G, Candilio G, De Fatico GS, Landino I, Canonico S, et al. International Journal of Surgery. International Journal of Surgery. Elsevier; 2014 Oct 1;12(Supplement 2):S56–9.
  53. Cohan JN, Bacchetti P, Varma MG, Finlayson E. Outcomes after ileoanal pouch surgery in frail and older adults. J Surg Res. 2015 Oct;198(2):327–33.

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FROM THE LITERATURE

Risk of Metachronous Large Serrated Polyps in Patients with 5- to 9-mm Proximal Hyperplastic Polyps

February 2021 • Volume XLV, Issue 2

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Data on metachronous risk for patients with index proximal 5- to 9-mm hyperplastic polyps (HPs) is limited. The clinical significance of these polyps is unclear. Data suggested sessile serrated polyps (SSPs), traditional serrated adenomas (TSAs), and large (greater than 1 cm) HPs are high-risk lesions require close surveillance. Data was used from the New Hampshire Colonoscopy Registry (NHCR) was examined for the risk of metachronous large HPs and advanced neoplasms (ANs) in patients with 5- to 9-mm proximal HPs.

Adults with at least 1 polyp resected at index colonoscopy and a surveillance examination 12 months or more after the index were evaluated for the risk for metachronous large (1 cm or greater) SPs and ANs, villous elements, highgrade dysplasia or colorectal cancer (CRC). The risks with proximal 5- to 9-mm HP at index examination were compared with individuals with index findings of large (greater than 1 cm) HPs or any SSPs or TSAs, nonsignificant HPs (less than 1 cm in rectosigmoid, or less than 5 mm anywhere in the colon), high-risk adenomas (As) or greater than 3 adenomas (no SPs), and low-risk adenomas and SPs.

Absolute and adjusted risks of metachronous polyps from a regression model that included age, sex, BMI, smoking, previous polyp history, family history of CRC, year of diagnosis, endoscopist, SP detection rates, and months to surveillance examination were presented.

A total of 8560 NHCR participants were included (44.8% women, average age 59 years, standard deviation 9.1). Similar to those with large HPs or any SSPs/TSAs at index examination (OR 7.63), individuals with proximal 5- to 9-mm HPs had an elevated risk for metachronous large SPs (OR 4.77), as compared with adults with low-risk conventional adenomas.

It was concluded that NHCR data suggested similar to adults with large HPs or any SSPs or TSAs at index examination, individuals with index 5-9 mm HPs proximal to sigmoid are at increased risk for metachronous large SPs. Surveillance intervals should be considered appropriately.

Anderson, J., Robinson, C., Butterly, L. “Increased Risk of Metachronous, Large, Serrated Polyps in Individuals with 5-9 mm Proximal Hyperplastic Polyps: Data From The New Hampshire Colonoscopy Registry.” Gastrointestinal Endoscopy; Vol. 92, No. 2, 2020, pp. 387-393.

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FROM THE LITERATURE

Comparison of Oral Anticoagulants and Warfarin on Post-endoscopic Gi Bleeding and Thromboembolic Events in Elective Endoscopy

February 2021 • Volume XLV, Issue 2

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Direct oral anticoagulants (DOACs), were considered to produce higher risk of gastrointestinal bleeding (GIB), compared with Warfarin. To compare the risk further, including thromboembolic (TE) events, a retrospective cohort study of patients 18 years or older in a large, integrated healthcare system in Southern California who had undergone an outpatient GI endoscopic procedure and were taking a DOAC or Warfarin between January 1, 2013 and October 1, 2019, comparing bleeding and thrombosis risk in the 30 days after the endoscopic procedure. Multivariate logistic regression analysis was carried out and adjusted for covariates.

Between January 1, 2013 and October 1, 2019, a total of 6765 outpatient GI endoscopic procedures were identified in which patients received pre-procedure prescriptions for either a DOAC (1587), or Warfarin (5178). Overall, there was no significant difference in post-procedure GI bleeding (OR 1.165), or TE (OR 0.929) between the DOAC and Warfarin groups. Subgroup analysis revealed a higher risk of GIB associated with DOAC, specifically with EGD procedures (OR 1.8).

It was concluded that there was no significant difference in the overall post-endoscopic risk of GIB and TE events among patients with preprocedure use of DOACs, compared with patients on Warfarin. There may, however, be a higher risk of GIB in patients taking DOACs and undergoing EGD.

Tin, A., Kwok, K., Dong, E., et al. “Impact of Direct-Acting Oral Anticoagulants and Warfarin on Post-Endoscopic GI Bleeding and Thromboembolic Events in Patients Undergoing Elective Endoscopy.” Gastrointestinal Endoscopy, 2020; Vol. 92, pp. 284-292.

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Guidelines for Authors

February 2021 • Volume XLV, Issue 2

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Practical Gastroenterology publishes articles for the primary care physician, and your article
should therefore have a nuts-and-bolts slant. We urge you to keep the nonspecialist in mind
as you write your article. We cannot stress strongly enough the importance of focusing your
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hospital stay, procedures, techniques, etc.) whenever and wherever possible.

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1) Jacobson IM, McHutchison JG, Dusheiko GM, et al. Telaprevir for previously untreated chronic
hepatitis C virus infection. N Engl J Med. 2011;364:2405–2416.

2) Bernatsky S, Clarke AE, Suissa S. Hematologic malignant neoplasms after drug exposure in
rheumatoid arthritis. Arch Intern Med. 2008;168:378-81

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FRONTIERS IN ENDOSCOPY, SERIES #70

Proximal Esophageal Stenting: Indications, Risks and Benefits

February 2021 • Volume XLV, Issue 2
Eric Tatro,Douglas G. Adler

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Introduction

F or decades, esophageal stents have been a mainstay of treatment for patients with malignant dysphagia.1,2,3 More recently, self-expanding metal stents (SEMS) have been shown to be a highly successful treatment option in benign esophageal strictures which have failed multiple dilation attempts.4,5 Inherent potential complications associated with esophageal stenting include migration, pain or globus sensation, hemorrhage, perforation, and airway compromise among others; some of these are common (pain), others rare (airway compromise).

Placement of a SEMS in the proximal esophagus has been associated with higher incidence of complications in some studies.6,7,8 Furthermore, advanced radiotherapy techniques have been shown to effectively reduce malignant dysphagia, causing some to consider this treatment as first-line therapy over SEMS placement in the upper esophagus in this specific group of patients.9,10,11 This manuscript will review the role, uses, indications, and adverse events of SEMS in the proximal esophagus.

Challenges of Proximal Esophageal Stenting

Anatomically, the proximal esophagus is defined as the area of the esophagus between the upper C6 pharyngoesophageal junction and lower T1 vertebrae, approximately 20-22cm proximal from the incisors.12,13 Practically speaking, the proximal esophagus is visualized rather than measured, and endoscopists will delineate the proximal, mid, and distal esophagus based on endoscopic visualization. Historically, pathology of the proximal esophagus, including tumors, strictures, fistulas, and leaks, has posed a technical challenge to surgeons due to the decreased mobility of this area and the unique anatomic limitations of the thoracic inlet.14 These structural limitations underpin some of the previously described practical challenges of proper esophageal stent placement in this location.15,16

Stenting in the proximal esophagus has inherent risks due to the proximity to the cricopharyngeal sphincter. Respiratory complications including tracheal compression, tracheoesophageal fistula formation (or worsening of an existing fistula), stent migration, and aspiration pneumonia have been implicated.1,4,5,17,18

Rates of tracheal compression in patients undergoing proximal esophageal stenting vary. In a series of 442 patients, 40 of which underwent upper esophageal stenting, 0.9% experienced tracheal compression with half of these patients needing additional airway stenting for symptomatic disease.19 An association with proximal esophageal stenting and aspiration pneumonia has been shown in some studies, with a proposed mechanism of the proximal flare of the stent impairing swallow function, but incidence rates vary across the literature.2,7

Esophagorespiratory fistula formation (ERF) is another potentially serious complication of proximal esophageal stenting. In a study of 442 patients, 5.9% developed ERF after receiving combined-stenting of the esophagus and airway, with 1.8% developing ERF with esophageal stenting only.8 Proposed efforts to mitigate these risks include pre- and post-procedural bronchoscopy, elevating the head of the bed during the procedure, reducing water flushes, and using techniques to prevent migration including endoscopic clips and suturing.5,6,20

Benign Indications For Proximal Esophageal Stenting

Esophageal Leaks

Esophageal leaks or perforations are commonly iatrogenic, resulting as a consequence of esophagectomy for various indications, both benign and malignant. Stephens et al. documented 89 patients with 5 different types of esophageal leaks treated with esophageal stenting. In the majority of the patients, the esophageal leak was a complication post-esophagectomy. Of those patients’s with a proximal esophageal leak, stenting was employed successfully in treating this iatrogenic complication.4

Esophageal leaks can also, less commonly, form as a complication of previous esophageal stenting. Although some authors have reported success with conservative management and close surveillance of contained esophageal leaks, esophageal stenting is a successful modality in treatment of esophageal leaks.21,22,23,24

Benign Strictures

The majority of the published literature describing esophageal stenting for stenosis focuses on palliation in esophageal malignancy. In addition to this welldocumented indication, esophageal stenting can be a successful treatment option in benign esophageal strictures. Common causes of benign esophageal strictures include gastroesophageal reflux, injury from esophageal surgery, radiotherapy, and caustic ingestion. In refractory strictures, or in those which fail multiple dilations, stenting is often the treatment of choice.25,26 In 2010, a meta-analysis including 199 patients from 8 studies demonstrated that placement of self-expanding removable stents significantly improved dysphagia in those who had failed multiple dilations for benign esophageal strictures.27

Malignant Indications for Proximal Esophageal Stenting

Malignant Strictures

The majority of esophageal malignancies are unresectable at diagnosis.28 Palliation of symptoms, most commonly dysphagia secondary to malignant esophageal stenosis or obstruction, is a primary treatment goal in these patients (who have an overall 5-year survival rate of 5 to 15%).29 Placement of SEMS for malignant stenosis of the proximal esophagus is an effective method to relieve dysphagia and improve quality of life. (Figure 1a-c)

Profili et al. described a case series of 10 patients with inoperable proximal esophageal stenosis. Nine of these had malignant stenosis of the upper esophagus. Of the 9 patients with malignant stenosis, 8 were caused by squamous cell carcinoma, with 1 being caused by thyroid cancer. Three of the patients had a very proximal stenosis, involving the hypopharynx and proximal esophagus, with the rest involving proximal esophagus alone. Seven patients had balloon dilation first to facilitate introduction of the delivery system and to have more rapid expansion of the stent. The SEMS was then placed a few days afterward. The rational for delay was to “[shorten] operative time and thus [obtain] a greater patient compliance.” Dysphagia score improved immediately with overall clinical success described in 80% and technical success in 90%. The adverse events described in three of their patients respectively included the stent twisting immediately after placement in requiring balloon dilation, distal misplacement of the stent requiring another overlapping stent, and one stent positioned proximal to the epiglottis which interfered with swallowing. All of the patients in the cohort reported a foreign body sensation and mild pain, which resolved within one week without intervention.30 Verschuur et al. described a larger retrospective series of 104 patients with inoperable, malignant stenosis of the proximal esophagus. In this series, the mean distance from the UES (upper esophageal sphincter) to the upper tumor margin was 4.9 +/- 2.6 cm and 3.1 +/- 2.3cm to the upper stent margin. Of this cohort, 66 patients had primary esophageal carcinoma, and 38 patients had recurrent cancer after esophagectomy. Technical success was achieved in 96% of patients, with a pre-stenting mean dysphagia score of 3 (liquids only) improving to a mean score of 1 (some difficulty with solids). The degree of dysphagia improvement, which was self-reported, did not differ between those with primary esophageal cancer versus those with recurrent cancer after esophagectomy. Also, the proximity of the stented lesion to the UES was not found to be a significant factor in predicting degree of dysphagia relief. Patients who had a malignant stricture within 4 cm of the UES versus those with one within 5 to 8 cm of the UES did not significantly report a difference in dysphagia relief. However, the etiology of the stricture was found to be a predictor of stricture length, as those with primary esophageal cancer were found to have a significantly longer stricture compared with those who had recurrent cancer post-esophagectomy.31

Parker et al. performed a case-control study at a single Kenyan hospital in which those with proximal esophageal cancer were matched to random controls with distal esophageal cancer, forming a total of 93 case-control pairs with prospective follow-up for at least one month or until death. The proximal esophageal cancer group was composed of two sub-groups, those with a very proximal tumor, defined as one within 2cm of the UES, and another group including those with lesions within 2.1 to 6cm of the UES. The distal esophageal cancer group was defined as those with a tumor greater than 6cm from the UES. The average tumor length was 7.1 cm, with the proximal cancer group having a significantly longer tumor length compared to the distal cancer group. Seven patients with proximal cancer needed placement of 2 nested stents in order to bridge their entire tumor. Those with a very proximal cancer had a pre-stent mean dysphagia score of 3.2 and a post-stent score of 1.7. Those in the other proximal cancer group had a pre-stent dysphagia score of 3.5 and a post-stent score of 1.4. Those with distal esophageal lesions had a pre-stent dysphagia score of 3.3 and a post-stent dysphagia score of 1.5. The reported early complication rate was 6.5% for those in the proximal esophageal cancer group and 9.7% for those with distal esophageal malignancy. The reported late complication rate was 29.2% for those with proximal lesions versus 24.1% for those with distal lesions. Overall, there was no statistically significant difference found between the cases and the controls in overall efficacy of the interventions, complication rates, or survival.32

Malignant Esophagorespiratory Fistula

The presence of an esophagorespiratory fistula (ERF) secondary to proximal esophageal malignancy is another indication for stenting. Fistulas can form due to primary tumor involvement or as a consequence of treatments such as chemotherapy, radiation therapy, or a combination thereof. Malignant ERF has been demonstrated to have a higher incidence in the proximal esophagus than the distal esophagus in some studies.21 Success rates for sealing of malignant ERF with placement of covered stents vary from 70% to 100% in different series, with much of the reported data coming from mixed studies or those involving the middle or distal esophagus.20 (Figure 2a-c)

In Verschuur et al.’s retrospective analysis of 104 patients with malignant upper esophageal lesions treated by SEMS placement, 24 patients had ERF. Thirteen of these 24 patients had primary esophageal carcinoma, and the remaining 11 had recurrent cancer post-esophagectomy. Four patients received both a tracheal and esophageal stent as the lesion had either invaded the airway or compressed it. Successful sealing of the fistula with stent placement was reported in 19 of these 24 patients. Of the five patients whose fistula failed to seal, the leakage occurred at 7, 7, 12, 21, and 35 days respectively. Four of these were successfully re-stented, but the fifth patient, who was initially managed conservatively, died from aspiration pneumonia. Overall, their success rate was 79% in sealing malignant fistulas of the proximal esophagus.20

RISKS OF PROXIMAL ESOPHAGEAL STENTING

Pain or Globus

Foreign body sensation (globus), which is often perceived in the upper chest or throat, is a commonly reported complication seen after proximal esophageal stenting. In a study examining SEMS stents placed in 442 patients, 40 patients received a stent in the upper esophagus; of these 40 patients, 29 reported experiencing globus. Symptoms in this group resolved completely or partially in 3-7 days. This sensation was only found in those with proximal stenting. Pain also occurred more frequently with those stented in the proximal and middle esophagus.8 Severe pain can sometimes require stent removal if the patient cannot be made comfortable with pain medications. Bechtler et al. described the use of biliary SEMS in a series of 10 patients with proximal esophageal stenosis with mixed malignant and benign etiology. A total of 3 patients reported post-procedural pain. Two of the patients had mild pain treated with analgesics, but one had severe pain and globus necessitating stent removal the day after implantation. Of note, this patient’s stricture was within 10cm of the incisors, the most proximal in the group.33

Pain is a complication, which is not limited to upper esophageal stenting. Severe pain is a major complication, which can necessitate stent removal. Siddiqui et al. reported a retrospective study of 55 patients undergoing placement of SEMS for locally advanced esophageal cancer in the middle and distal esophagus. While the vast majority of the complications were minor, two patients had pain severe enough to necessitate removal.34

Migration

Migration is a relatively frequent complication in esophageal stenting when fully covered stents are used, regardless of anatomic location. One meta-analysis analyzed migration rates of benign esophageal stenting in 18 studies revealing an overall migration rate of 28.6% with high heterogeneity.35 Bakken et al.’s study of 56 patients and 104 stents placed found an overall migration rate of 35.6% with proximal stents having a significantly higher rate of migration.36 Yet not all studies have found anatomic location to be associated with stent migration.

One of the largest studies to investigate migration rates in FCSEMS looked at rates in stents placed in both benign and malignant strictures. In a multicenter, retrospective analysis, Thomas et al. analyzed data from 369 patients in whom 161 had benign strictures and 208 had malignant strictures. In those with benign disease, the total migration rate was 30%, and the clinically relevant migration rate (defined as stent migration requiring replacement) was 17%. In the 28 patients in whom a proximal stent for benign disease was placed the migration rates were 29% and 18%, respectively. In those with malignant strictures, the total migration rate was 23% and the clinically relevant migration rate was 14%. In the 11 patients in whom a proximal stent was placed for malignant disease, the migration rates were 9% and 9%, respectively. In this large analysis, anatomic location of stent placement was not found to be associated with an increased risk of migration. Stent type in the malignant group was found to be significantly associated with migration rate, with the Evolution stent having a higher rate of clinically relevant migration, compared to the Wallflex and Endomaxx stents.37

Major Complications

In a randomized trial comparing fully covered versus partially covered SEMS in malignant esophageal strictures, the authors found that proximal stricture location was independently associated with the occurrence of at least one major adverse event, including hemorrhage, pneumonia, stridor, and/or cervical spondylodiscitis.7 In a study of a total of 104 stents placed for benign esophageal disease, 4 procedures led to acute or subacute airway compromise, with 3 of these occurring in stents placed in the upper esophagus. Of note, 2 of these 3 patients with upper respiratory compromise had received prior radiation therapy.23

Verschuur’s study of 104 patients with stents placed for malignant stenosis of the upper esophagus had 22 patients with major complications, including 9 with aspiration pneumonia, 8 with hemorrhage, 7 with fistula formation, and 2 with perforation.20 Conversely, Gallo et al. described a series of 45 patients, of whom 35 had upper esophageal stenosis, in which very few major complications were seen after stenting. Twenty-two of these patients were treated with SEMS placement. There were two patients who developed severe pain, which required stent removal at 12 and 21 days poststenting, respectively. No major complications, such as serious hemorrhage, airway compromise, or pneumonia were seen.38 Parker et al. reported a case-control study comparing stent insertion in patients with proximal esophageal cancer versus matched controls with distal esophageal cancer. Ninety-three patients were included in each group. In the proximal malignancy group the number of patients with a perforation, bleeding, severe chest pain, procedure-related mortality, and 30- day mortality were 1, 1, 3, and 5 respectively. In the distal malignancy group the number of patients with the same complications were 6, 0, 1, 5, and 2 respectively. This study suggested that location of stent placement was not significantly associated with an increased incidence of major complications.21

CONCLUSION

Stenting of the proximal esophagus, although technically challenging, can be performed safely and effectively in both benign and malignant disease states. There is not sufficient evidence to preclude the use of proximal esophageal stents from a safety, morbidity, or mortality standpoint. Further investigation with randomized controlled trials and meta-analyses are necessary to investigate the existence of causal relationships between placement of proximal esophageal stents and the adverse events that this procedure has been associated with in the past.

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