Colorectal Endoscopic Submucosal Dissection: Past, Present, and Factors Impacting Future Dissemination.

First performed in the stomach for removal of localized gastric tumors, endoscopic submucosal dissection (ESD) has evolved into a technique that is increasingly being employed to resect colorectal lesions. As opposed to endoscopic mucosal resection (EMR), ESD allows the endoscopist to remove large specimens en bloc to provide accurate pathologic evaluation and lower local recurrence rates. ESD is an ideal technique for resection of lesions without lymph node metastases and is becoming the standard of care in Japan as outcomes data has proven it to be equally efficacious, less invasive, and inexpensive as compared with surgery; however, potential risk for complications is high and the procedure is currently not widely available in the Western world. As more interest, endoscopist training, and data supporting the technique's use mount, ESD will also likely become the standard of care in the Western world for resection of localized colorectal lesions.

A multicenter, U.S. experience of single-balloon, double-balloon, and rotational overtube-assisted enteroscopy ERCP in patients with surgically altered pancreaticobiliary anatomy (with video).

BACKGROUND: Data on overtube-assisted enteroscopy to facilitate ERCP in patients with surgically altered pancreaticobiliary anatomy, or long-limb surgical bypass, is limited. OBJECTIVE: To evaluate and compare ERCP success by using single-balloon (SBE), double-balloon (DBE), or rotational overtube enteroscopy. DESIGN: Consecutive patients identified retrospectively. SETTING: Eight U.S. referral centers. PATIENTS: Long-limb surgical bypass patients with suspected pancreaticobiliary diseases. INTERVENTION: Overtube-assisted enteroscopy ERCP. MAIN OUTCOME MEASUREMENTS: Enteroscopy success: visualizing the pancreaticobiliary-enteric anastomosis or papilla. ERCP success: completing the intended pancreaticobiliary intervention. Clinical success: greater than 50% reduction in abdominal pain or level of hepatic enzyme elevations or resolution of jaundice. RESULTS: From January 2008 through October 2009, 129 patients had 180 enteroscopy-ERCPs. Anatomy was Roux-en-Y: gastric bypass (n = 63), hepaticojejunostomy (n = 45), postgastrectomy (n = 6), Whipple procedure (n = 10), and other (n = 5). ERCP success was 81 of 129 (63%). Enteroscopy success: 92 of 129 (71%), of whom 81 of 92 (88%) achieved ERCP success. Reasons for ERCP failure (n = 48): afferent limb entered but pancreaticobiliary anastomosis and/or papilla not reached (n = 23), cannulation failure (n = 11), afferent limb angulation (n = 8), and jejunojejunostomy not identified (n = 6). Select interventions: anastomotic stricturoplasty (cautery ± dilation, n = 16), stone removal (n = 21), stent (n = 25), and direct cholangioscopy (n = 11). ERCP success rates were similar between Roux-en-Y gastric bypass and other long-limb surgical bypass and among SBE, DBE, and rotational overtube enteroscopy. Complications were 16 of 129, 12.4%. LIMITATIONS: Retrospective study. CONCLUSION: (1) ERCP is successful in nearly two-thirds of long-limb surgical bypass patients and in 88% when the papilla or pancreaticobiliary-enteric anastomosis is reached. (2) Enteroscopy success in long-limb surgical bypass is similar among SBE, DBE, and rotational overtube enteroscopy methods. (3) Referral of long-limb surgical bypass patients who require ERCP to high-volume institutions may be considered before more invasive percutaneous or surgical alternatives.

Effect of a retrograde-viewing device on adenoma detection rate during colonoscopy: the TERRACE study.

BACKGROUND: Although colonoscopy is currently the optimal method for detecting colorectal polyps, some are missed. The Third Eye Retroscope provides an additional retrograde view that may detect polyps behind folds. OBJECTIVE: To determine whether the addition of the Third Eye Retroscope to colonoscopy improves the adenoma detection rate. DESIGN: Prospective, multicenter, randomized, controlled trial. SETTING: Nine European and U.S. centers. PATIENTS: Of 448 enrolled subjects, 395 had data for 2 procedures. INTERVENTIONS: Subjects underwent same-day tandem examinations with standard colonoscopy (SC) and Third Eye colonoscopy (TEC). Subjects were randomized to SC followed by TEC or TEC followed by SC. MAIN OUTCOME MEASUREMENTS: Detection rates for all polyps and adenomas with each method. RESULTS: In the per-protocol population, 173 subjects underwent SC and then TEC, and TEC yielded 78 additional polyps (48.8%), including 49 adenomas (45.8%). In 176 subjects undergoing TEC and then SC, SC yielded 31 additional polyps (19.0%), including 26 adenomas (22.6%). Net additional detection rates with TEC were 29.8% for polyps and 23.2% for adenomas. The relative risk of missing with SC compared with TEC was 2.56 for polyps (P < .001) and 1.92 for adenomas (P = .029). Mean withdrawal times for SC and TEC were 7.58 and 9.52 minutes, respectively (P < .001). The median difference in withdrawal times was 1 minute (P < .001). The mean total procedure times for SC and TEC were 16.97 and 20.87 minutes, respectively (P < .001). LIMITATIONS: Despite randomization and a large cohort, there was disparity in polyp prevalence between the 2 groups of subjects. CONCLUSION: The Third Eye Retroscope increases adenoma detection rate by visualizing areas behind folds. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01044732.).

Spiral enteroscopy: a novel method of enteroscopy by using the Endo-Ease Discovery SB overtube and a pediatric colonoscope.

BACKGROUND: Pathologic diagnosis and therapeutic interventions on the small bowel have been difficult and challenging for gastroenterologists. In the last few years, significant advances have been made in this direction. New diagnostic and therapeutic modalities for visualizing the small bowel have been introduced. Furthermore, increased indications for small-bowel imaging and therapeutics have been recognized. However, the currently available methods have limitations, and development of newer, rapid, minimally invasive, safe, and readily available techniques is needed. OBJECTIVE: Our purpose was to evaluate the safety and efficacy of a novel method of spiral enteroscopy using a specialized overtube (Endo-Ease Discovery SB) with a pediatric colonoscope (PCF-140L). DESIGN: Case series. SETTING: Two international tertiary referral centers. PATIENTS: Twenty-seven adult patients with obscure GI bleeding were enrolled in this study. INTERVENTION: Spiral enteroscopy with the Endo-Ease Discovery SB overtube and a pediatric colonoscope. MAIN OUTCOME MEASUREMENTS: Depth of insertion, time of procedure, and complications. RESULTS: Average depth of insertion was 176 cm (range 80-340 cm) from ligament of Treitz, and average time of procedure was 36.5 minutes (range 90-65 minutes). Eleven patients had minor complications, which included minimal mucosal trauma and sore throat. LIMITATIONS: Small number of patients with a case series study design. CONCLUSIONS: Preliminary data suggest that use of Endo-Ease Discovery SB overtube for enteroscopy is a safe and effective technique for visualization of the small bowel.

Successful Endoscopic Reduction of an Ileocolonic Intussusception in an Adult With Peutz-Jeghers Syndrome.

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder characterized by hamartomatous polyps throughout the gastrointestinal tract, mostly causing gastrointestinal bleeding and recurrent intestinal obstructions. Few intussusception related to PJS occurs reportedly in adults. Unlike pediatric cases almost all reported cases end up with surgical resection. Here we present a case of PSJ-related intussusception in an adult patient treated successfully with endoscopic approach, with no surgical intervention required.

Cetuximab with concurrent chemoradiation for esophagogastric cancer: assessment of toxicity.

PURPOSE: To determine the feasibility and toxicity of the addition of cetuximab with paclitaxel, carboplatin, and radiation for patients with esophagogastric cancer on a Phase II study. METHODS AND MATERIALS: Patients with locoregional esophageal and proximal gastric cancer without distant organ metastases were eligible. All patients received cetuximab, paclitaxel, and carboplatin weekly for 6 weeks with 50.4 Gy radiation. RESULTS: Sixty patients were enrolled, 57 with esophageal cancer and 3 with gastric cancer. Forty-eight had adenocarcinoma and 12 had squamous cell cancer. Fourteen of 60 patients (23%) had Grade 3 dermatologic toxicity consisting of a painful, pruritic acneiform rash on the face outside of the radiation field. The rates of Grades 3 and 4 esophagitis were 12% and 3%, respectively. Three patients had Grade 3/4 cetuximab hypersensitivity reactions and were not assessable for response. Forty of 57 patients (70%) had a complete clinical response after chemoradiation. CONCLUSION: Cetuximab can be safely administered with chemoradiation for esophageal cancer. Dermatologic toxicity and hypersensitivity reactions were associated with the addition of cetuximab. There was no increase in esophagitis or other radiation-enhanced toxicity.

Phase I/II study of trastuzumab, paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing, esophageal adenocarcinoma.

PURPOSE: To determine the overall survival for patients with locally advanced, HER2 overexpressing, esophageal adenocarcinoma receiving trastuzumab, paclitaxel, cisplatin, and radiation on a Phase I-II study. METHODS AND MATERIALS: Patients with adenocarcinoma of the esophagus without distant organ metastases and 2+/3+ HER2 overexpression by immunohistochemistry (IHC) were eligible. All patients received cisplatin 25 mg/m2 and paclitaxel 50 mg/m2 weekly for 6 weeks with radiation therapy (RT) 50.4 Gy. Patients received trastuzumab at dose levels of 1, 1.5, or 2 mg/kg weekly for 5 weeks after an initial bolus of 2, 3, or 4 mg/kg. RESULTS: Nineteen patients were entered: 7 (37%) had celiac adenopathy, and 7 (37%) had retroperitoneal, portal adenopathy, or scalene adenopathy. Fourteen of 19 patients (74%) had either 3+ HER2 expression by immunohistochemistry, or an increase in HER2 gene copy number by HER2 gene amplification or high polysomy by fluorescence in situ hybridization. The median survival of all patients was 24 months and the 2-year survival was 50%. CONCLUSIONS: Assessment of the effect of trastuzumab in the treatment of patients with esophageal adenocarcinoma overexpressing HER2 is limited by the small number of patients in this study. Overall survival, however, was similar to prior studies without an increase in toxicity. Evaluation of HER2 status should be performed in future trials for patients with adenocarcinoma of the esophagus that investigate therapies targeting the HER family.

Gemcitabine, paclitaxel, and radiation for locally advanced pancreatic cancer: a Phase I trial.

PURPOSE: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities of gemcitabine, paclitaxel, and concurrent radiation for pancreatic cancer. METHODS AND MATERIALS: Twenty patients with locally unresectable pancreatic cancer were studied. The initial dose level was gemcitabine 75 mg/m(2) and paclitaxel 40 mg/m(2) weekly for 6 weeks. Concurrent radiation to 50.4 Gy was delivered in 1.8 Gy fractions. The radiation fields included the primary tumor, plus the regional peripancreatic, celiac, and porta hepatis lymph nodes. RESULTS: Dose-limiting toxicities of diarrhea, dehydration, nausea, and anorexia occurred in 3 of 3 patients at the second dose level of gemcitabine, 150 mg/m(2)/week. An intermediate dose level of gemcitabine, 110 mg/m(2)/week, was added, but gastrointestinal toxicity and pulmonary pneumonitis were encountered. The MTD therefore was gemcitabine 75 mg/m(2)/week with paclitaxel 40 mg/m(2)/week and concurrent radiation. Two of 11 patients treated at the MTD had Grade 3/4 toxicity. Four of 10 assessable patients treated at the MTD responded (40%), including one pathologic complete response. CONCLUSION: The maximum tolerated dosage of gemcitabine is 75 mg/m(2)/week with paclitaxel 40 mg/m(2)/week and conventional 50.4 Gy radiation fields. A Phase II Radiation Therapy Oncology Group study is under way.

Spiral enteroscopy: prime time or for the happy few?

Spiral enteroscopy is the newest of the deep enteroscopy techniques. The current technique employs an overtube with a raised spiral at the distal end to pleat the small intestine and achieve deep small bowel intubation. Although spiral enteroscopy is a novel technique, the learning curve is comparable to the balloon enteroscopy techniques. There is some evidence of improved speed of spiral enteroscopy procedures with superior control compared to the balloon endoscopy technologies. Altered surgical anatomy deep enteroscopy has been shown to have similar safety and efficacy to competitive technologies, particularly in cases of Roux-en-Y ERCP cases. Spiral enterosopy is safe and effective for deep small bowel enteroscopy and diagnostic yield and therapeutic yields are similar to alternate technologies. There are bright future applications of the technology with enteroscopes and an integrated spiral. Spiral enteroscopy is an advanced technique that can be performed by any skilled endoscopist.

Retrograde-viewing device improves adenoma detection rate in colonoscopies for surveillance and diagnostic workup.

AIM: To determine which patients might benefit most from retrograde viewing during colonoscopy through subset analysis of randomized, controlled trial data. METHODS: The Third Eye® Retroscope® Randomized Clinical Evaluation (TERRACE) was a randomized, controlled, multicenter trial designed to evaluate the efficacy of a retrograde-viewing auxiliary imaging device that is used during colonoscopy to provide a second video image which allows viewing of areas on the proximal aspect of haustral folds and flexures that are difficult to see with the colonoscope's forward view. We performed a post-hoc analysis of the TERRACE data to determine whether certain subsets of the patient population would gain more benefit than others from use of the device. Subjects were patients scheduled for colonoscopy for screening, surveillance or diagnostic workup, and each underwent same-day tandem examinations with standard colonoscopy (SC) and Third Eye colonoscopy (TEC), randomized to SC followed by TEC or vice versa. RESULTS: Indication for colonoscopy was screening in 176/345 subjects (51.0%), surveillance after previous polypectomy in 87 (25.2%) and diagnostic workup in 82 (23.8%). In 4 subjects no indication was specified. Previously reported overall results had shown a net additional adenoma detection rate (ADR) with TEC of 23.2% compared to SC. Relative risk (RR) of missing adenomas with SC vs TEC as the initial procedure was 1.92 (P = 0.029). Post-hoc subset analysis shows additional ADRs for TEC compared to SC were 4.4% for screening, 35.7% for surveillance, 55.4% for diagnostic and 40.7% for surveillance and diagnostic combined. The RR of missing adenomas with SC vs TEC was 1.11 (P = 0.815) for screening, 3.15 (P = 0.014) for surveillance, 8.64 (P = 0.039) for diagnostic and 3.34 (P = 0.003) for surveillance and diagnostic combined. Although a multivariate Poisson regression suggested gender as a possibly significant factor, subset analysis showed that the difference between genders was not statistically significant. Age, bowel prep quality and withdrawal time did not significantly affect the RR of missing adenomas with SC vs TEC. Mean sizes of adenomas detected with TEC and SC were similar at 0.59 cm and 0.56 cm, respectively (P = NS). CONCLUSION: TEC allows detection of significantly more adenomas compared to SC in patients undergoing surveillance or diagnostic workup, but not in screening patients (ClinicalTrials.gov Identifier: NCT01044732).

Spiral enteroscopy and push enteroscopy.

Spiral enteroscopy is a new technique for endoscopic evaluation of the small bowel. Currently, more than 3000 cases have been performed worldwide. The Discovery SB device has been approved by the Food and Drug Administration and has been granted a CE mark. The technique is safe and effective for management and detection of small bowel pathology. Recent studies of spiral enteroscopy have demonstrated diagnostic yield, total time of procedure, and depth of insertion that compare favorably with double and single balloon enteroscopy. The strengths of spiral enteroscopy are rapid advancement in the small bowel and controlled, stable withdrawal that facilitates therapy. Future studies will be needed to compare competing technologies. Push enteroscopy is a readily available, safe and effective technique for detecting and treating proximal gut pathology. If performed without an overtube, complications are rare. Use of a dedicated push enteroscope with an overtube is generally reserved for specific indications in which a moderate increase in depth of insertion into the small bowel is required. When capsule endoscopy and deep small bowel enteroscopy are not available, push enteroscopy is a reasonable option with low risk and moderate yield. Push enteroscopy will remain an important part of the armamentarium of the modern endoscopist.

A phase I study of docetaxel, oxaliplatin, and capecitabine in patients with metastatic gastroesophageal cancer.

OBJECTIVES: Docetaxel, capecitabine, and oxaliplatin are important new agents in esophagogastric cancer. The Brown University Oncology Group initiated a phase I study to determine the maximum tolerated dose of weekly docetaxel, oxaliplatin, and capecitabine. METHODS: Patients with metastatic esophageal and gastric cancers received docetaxel and oxaliplatin on days 1 and 8 and capecitabine in divided doses, twice daily, on days 1 to 10, with each cycle repeated every 21 days. Patients were enrolled in cohorts of 3 at escalating dose levels. The docetaxel dose ranged from 30 to 35 mg/m2, the oxaliplatin dose from 40 to 50 mg/m2, and the capecitabine dose from 750 to 850 mg/m2 BID. RESULTS: Sixteen patients were enrolled over 4 dose levels. The median age was 59 years. Eight patients had esophageal cancer and 9 had gastric cancer. Grade 3/4 dose-limiting toxicities of diarrhea, nausea, fatigue, and febrile neutropenia occurred in 3 of 4 patients at dose level 3. An intermediate dose level was added (2A), reducing the capecitabine dose to 750 mg/m2. One of 6 patients had a dose-limiting toxicity at level 2A. CONCLUSIONS: Oxaliplatin 50 mg/m2 and docetaxel 30 mg/m2 day 1 and 8 with capecitabine 750 mg/m2 BID for 10 days in 21-day cycles may represent a promising, easily administered regimen for metastatic esophageal and gastric cancer. A phase II study will be initiated.

Docetaxel, capecitabine and carboplatin in metastatic esophagogastric cancer: a phase II study.

PURPOSE: A Phase I investigation of docetaxel, carboplatin, and capecitabine at our institution demonstrated the safety and tolerability of this regimen in patients with metastatic esophagogastric cancer. The objectives of this Phase II study were to determine the response rate, toxicity, and survival for patients with metastatic esophagogastric cancer treated with this regimen. MATERIALS AND METHODS: Chemotherapy naïve patients with metastatic esophageal or gastric cancer received a regimen comprised of docetaxel 40 mg/m(2), days 1 and 8, carboplatin AUC = 2, Days 1 and 8, and capecitabine 2000 mg/m(2), Days 1-10 in 21-Day cycles. Patients were treated until disease progression or unacceptable toxicity. RESULTS: Twenty-five patients were treated with a median of 4 cycles of chemotherapy. Twelve of 25 patients (48 percent) had a Grade 3/4 toxicity. There were no Grade 4 nonhematologic toxicities, and 1 patient (4 percent) had neutropenic fever. There were 3 complete responses, and 9 partial responses, for an overall response rate of 48 percent. The median survival was 8 months (95% confidence interval, 5.5-13 months), and the 1-year survival was 36 percent. CONCLUSIONS: Weekly docetaxel and carboplatin with capecitabine was an easily administered outpatient regimen. The response rate and 1-year survival were similar to more complex regimens. Future trials may investigate the substitution of carboplatin with more active agents.

Paclitaxel poliglumex (PPX-Xyotax) and concurrent radiation for esophageal and gastric cancer: a phase I study.

OBJECTIVES: To determine the maximal tolerated dose (MTD) and dose limiting toxicities of poly(l-glutamic acid)-paclitaxel (PPX) and concurrent radiation (PPX/RT) for patients with esophageal and gastric cancer. METHODS: Patients with esophageal or gastric cancer receiving chemoradiation for loco-regional, adjuvant, or palliative intent were eligible. The initial dose of PPX was 40 mg/m2/wk, for 6 weeks with 50.4 Gy radiation. Dose levels were increased in increments of 10 mg/m2/wk of PPX. RESULTS: Twenty-one patients were enrolled over 5 dose levels. Sixteen patients had esophageal cancer and 5 had gastric cancer. Twelve patients received PPX/RT as definitive loco-regional therapy, 4 patients had undergone resection and received adjuvant PPX/RT, and 5 patients had metastatic disease and received PPX/RT for palliation of dysphagia. Dose limiting toxicities of gastritis, esophagitis, neutropenia, and dehydration developed in 3 of 4 patients treated at the 80 mg/m2 dose level. Four of 12 patients (33%) with loco-regional disease had a complete clinical response. CONCLUSIONS: The maximally tolerated dose of PPX with concurrent radiotherapy is 70 mg/m2/wk for patients with esophageal and gastric cancer.

Erlotinib and chemoradiation followed by maintenance erlotinib for locally advanced pancreatic cancer: a phase I study.

OBJECTIVES: A phase I trial was conducted to determine the maximally tolerated dose of erlotinib with concurrent gemcitabine, paclitaxel, and radiation for patients with locally advanced pancreatic cancer and to gather preliminary data on maintenance erlotinib after chemoradiation. METHODS: Patients received gemcitabine, 75 mg/m2, and paclitaxel, 40 mg/m, weekly for 6 weeks with 50.4 radiation to the primary tumor and draining lymph nodes with a 2- to 3-cm margin. Erlotinib was administered over 3-dose levels (50-100 mg/d) with chemoradiation then all patients received 150 mg/d maintenance until disease progression. RESULTS: Seventeen patients were assessable for toxicity; 13 with locally advanced disease and 4 who had undergone resection but had positive margins. At erlotinib dosages > or =75 mg/d with chemoradiation the dose-limiting toxicities were diarrhea, dehydration, rash, myelosuppression, and small bowel stricture. Maintenance erlotinib, 150 mg/d, was well tolerated. The median survival of the 13 patients with locally advanced disease was 14.0 months and 6 of 13 (46%) had a partial response. CONCLUSIONS: The maximum tolerated dose of erlotinib with gemcitabine, paclitaxel and concurrent radiation is 50 mg/d for patients with locally advanced pancreatic cancer. Full dose maintenance erlotinib is well tolerated. Promising preliminary activity and overall survival were demonstrated.

Phase I study of docetaxel, capecitabine, and carboplatin in metastatic esophagogastric cancer.

OBJECTIVES: A phase I trial was conducted to determine the maximally tolerated dose (MTD) and dose-limiting toxicities (DLTs) of docetaxel, capecitabine, and carboplatin for first-line treatment of patients with metastatic esophageal and gastric cancers. METHODS: Twenty-eight patients were treated over 5 dose levels in a 21-day cycle. Patients received carboplatin (AUC = 2) on days 1 and 8, docetaxel (35-40 mg/m2) on days 1 and 8, and capecitabine (500-2000 mg/m2) on days 1 to 10. RESULTS: There were no DLTs in the first cycle of treatment. Dose reductions were required in 10 of 15 patients at the final dose level due to neutropenia, nausea, vomiting, diarrhea, dehydration, and hand/foot syndrome following a median of 3 cycles of treatment. Therefore, escalation beyond dose level 5 was not attempted. The MTD was docetaxel, 40 mg/m2 days 1 and 8; carboplatin, AUC = 2 days 1 and 8; and capecitabine, 1500 to 2000 mg/m2 days 1 to 10 in a 21-day cycle. Ten of 25 patients who could be evaluated (40%) responded and 8 of 14 patients treated at the final dose level responded (57%). CONCLUSIONS: Cumulative gastrointestinal toxicities and neutropenia were the DLTs of docetaxel, capecitabine, and carboplatin. This combination represents an easily administered, active regimen for patients with metastatic gastric and esophageal cancers. Further evaluation of this regimen is indicated.