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CANCERS OF THE ESOPHAGUS AND PANCREAS
Audio-Digest General Surgery
Volume 60, Issue 13
July 7, 2013

Gastroesophageal Reflux Disease (GERD) with Barrett Esophagus – Thomas W. Rice, MD
Esophagectomy for Dysplasia – Dr. Rice
Staging of Esophageal Cancer – Dr. Rice
Pancreatic Cancer – Jennifer Tseng, MD

   
Highlights From The 12th Annual Surgery Of The Foregut Symposium, Presented By Cleveland Clinic Florida
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The following is an abstracted summary, not a verbatim transcript, of the lectures/discussions on this audio program.

General Surgery Program Info  Accreditation InfoCultural & Linguistic Competency Resources

Cancers of the Esophagus and Pancreas

Highlights from the 12th Annual Surgery of the Foregut Symposium, presented by Cleveland Clinic Florida

Educational Objectives

The goal of this program is to improve the surgical management of esophageal and pancreatic cancer. After hearing and assimilating this program, the clinician will be better able to:

1. Recognize the role of antireflux surgery in the treatment of Barrett esophagus.

2. Assess patients with esophageal cancer (EC) for esophagectomy.

3. Stage patients with EC using the mostly recently updated criteria.

4. Consider neoadjuvant therapy in appropriate patients with resectable pancreatic cancer (PC).

5. Predict surgical and population-based outcomes of patients with PC.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose.

Gastroesophageal Reflux Disease (GERD) with
Barrett Esophagus

Thomas W. Rice, MD, Professor of Surgery, the Daniel and Karen Lee Chair in Thoracic Surgery, Cleveland Clinic, OH

Barrett esophagus (BE): intestinalization of distal to mid esophagus due to reflux of gastric contents; diagnostic criteria — presence of goblet cells; cells basally oriented

Antireflux surgery: theory — causes regression of Barrett epithelium and halts progression to cancer; leads to outcomes similar to those of patients without BE; Zaninotto study — resting pressure of lower esophageal sphincter (LES) changed from <10 mm Hg to >10 mm Hg after surgery; fundoplication improves total and abdominal length of LES and decreases acid reflux; fundoplication eliminated BE in 8 of >30 patients with short-segment disease; however, procedure much less successful in patients with long-segment BE (distribution of BE unchanged after medical therapy); regression of BE — not reported in long-segment disease; some regression seen in BE of <3 cm; study — range of variability between endoscopies 1.6 to 1.4 cm; therefore, changes attributed to regression of BE of <3 cm may fall within variability of endoscopic examinations (true regression must be greater than range of variability); progression to cancer — antireflux surgery may decrease, but does not eliminate, risk for esophageal cancer (EC); indications for surgery (same as for non-BE disease) include volume regurgitation despite control of GERD symptoms with proton-pump inhibitors (PPI), mechanical obstruction due to paraesophageal hernias, and ulcer and stricture due to BE; all patients need long-term surveillance; surgery unlikely to affect regression or progression to cancer

Treatment of acid and bile to improve BE: Csendes study — treatment with highly selective vagotomy (HSV) did not reduce recurrence of GERD; HSV not recommended for nondysplastic BE due to additional time and risk associated with operation; Parise study — no increase in morbidity or mortality seen with fundoplication, HSV, and duodenal switch procedures; some improvement in control of symptoms seen in patients with short-segment BE, but recurrences occur; HSV and duodenal switch — fail to completely halt exposure of esophagus to acid; HSV, duodenal switch, partial gastrectomy, and Roux-en-Y — do not reduce exposure to acid; good results seen only in patients with short-segment BE; reserve for complex patients after failed surgery if alternative to esophagectomy needed

Antireflux surgery plus ablation or endoscopic mucosal resection (EMR): fundoplication and argon plasma coagulation (APC) — 40% of patients had complete regression of BE after fundoplication and APC; 15% had visible ablation, but BE persisted; 30% had <95% eradication; fundoplication and radiofrequency ablation (RFA) — can decrease length and remove circumferential BE; removes low-grade dysplasia and reduces amount of BE; >3 RFA treatments associated with complete resolution of metaplasia and dysplasia; no genetic mutations seen in neosquamous mucosa after therapy, but tissue not normal (oxidative stress high)

Regenerative surgery: Pittsburgh study — complete submucosal resection of BE segment preformed; esophagus lined with porcine dermis extracellular matrix (Surgisis); stent placed, then later removed; long-term replacement of BE with squamous epithelium reported in 3 cases

Esophagectomy for Dysplasia

Dr. Rice

Anatomy and histology: high-grade dysplasia found on surface of BE; nuclei hyperchromatic, dark, and variable; tend to rise from basement membrane toward surface; esophageal wall — consists of mucosa (epithelium, lamina propria, and muscularis mucosa), submucosa, and muscularis propria; lymphatics — multiple small lymphatic channels seen in lamina propria; sparse in submucosa (increased only in deep portion); submucosa lymphatics may connect directly to thoracic duct (patients with submucosal EC may have concurrent metastases to regional and distal lymph nodes)

Submucosal EC: consider submucosal layer as esophageal divide when considering need for esophagectomy; patients with intramucosal EC have better outcomes than patients with submucosal EC; study — patients with submucosal EC had longer, wider, and larger lesions; EC >2 cm at endoscopy likely submucosal; histologic grade more undifferentiated with increased invasion of tumor; lymphovascular invasion increased with depth of tumor (likely precursor to lymphatic metastases); metastases uncommon with invasion of inner and middle submucosa; 50% of patients with invasion of deep submucosa have multiple nodal metastases; risk factors for lymphatic metastases included invasion into SM3 (deep submucosa) and lymphovascular invasion; mortality — survival 70% at 5 yr in patients with stage PN0; survival 36% in patients with regional lymph node metastases; older patients with PN0 disease had higher mortality than those <56 yr of age; effect of age lost after development of lymph node metastases

Intramucosal EC: study — survival after esophagectomy equal to that of persons of matched age, sex, and ethnicity; hazard of death occurs early, then plateaus to that of general population; mortality increases markedly with depth of tumor invasion (tumors >0.5 mm deep warrant aggressive therapy); recurrence — usually occurs within 2 to 3 yr; poor lung function and older age decrease survival; freedom from new cancer similar to that in general population (hazard increases with time)

High-grade dysplasia (HGD): glands with malignant appearance that have not reached lamina propria (lymph node metastasis should not occur); study — patients resected due to persistent BE after endoscopic therapy; not all patients had histologic HGD; sensitivity and positive predictive value of HGD on endoscopic biopsy only 79% and 57%, respectively

Esophagectomy for HGD: study — after surgery, regional lymph node metastases rare and survival good; predictors of survival — younger age; good lung function (poor function cancels effect of age); survival similar to that in matched population; outcomes more closely associated with characteristics of patients than those of EC; techniques — patients require dissection of 10 regional lymph nodes (with fewer nodes, N1 disease may be missed); most of apparent therapeutic effect of lymphadenectomy likely due to stage migration; excellent long-term survival requires excellent reconstruction; resection less important than reconstruction; minimally invasive approaches risk low intrathoracic anastomosis (leads to hiatal hernia with no LES pressure); treatment decisions — endoscopic therapy appropriate for older patients and those with poor lung function; proceed to esophagectomy if esophagus damaged due to strictures or ulceration; educate younger patients with good lung function about benefits and risks; endoscopic therapy with subsequent esophagectomy, if needed, likely best option

Staging of Esophageal Cancer

Dr. Rice

Seventh edition staging (American Joint Committee in Cancer, 2010): Worldwide Esophageal Cancer Collaboration (WECC) formed; 13 institutions submitted data set of 8000 resections (4700 used for staging); patients treated with resection alone (no chemotherapy or radiation therapy); used pTNM staging; included only mucosal EC

Survival: 45% at 5 yr in patients undergoing esophagectomy for EC; cell type — significant survival difference seen between adenocarcinoma and squamous cell carcinoma; grade — survival declines with degree of differentiation; location — survival progressively improves with descent from upper to lower esophagus; metastases — survival reasonable if no lymph node metastases present, and markedly decreases with first positive lymph node; incremental decrease occurs with each additional node; survival approaches 0% when >9 lymph nodes affected

Analysis of staging: Random Forest Analysis — divides patient survival into risk-adjusted groups; ensures that survival monotonically decreasing, distinctive between groups, and homogeneous within group; G (histologic grade), cell type, and location important in early stages; increasing depth of tumor invasion and number of positive nodes become more important as tumors advance; analysis performed within groups to ensure homogeneity of survival

Changes in staging: location — all cancers within 5 cm of gastroesophageal (GE) junction that invade esophagus staged as EC, and all those below staged as gastric cancer (determined at endoscopy); measured from incisors in 5-cm intervals; measurements extend to lower thoracic esophagus (includes first 5 cm of stomach); nonanatomic tumor factors — include pathologic cell type and histologic grade; T — Tis (carcinoma-in-situ) now called high-grade dysplasia; T4 subclassified into 4a (resectable invasion into adjacent structures) and 4b (nonresectable invasion); N — regional lymph node redefined as any found in bed of esophagus, from cricopharyngeus to celiac; subclassification — N0 (no metastasis); N1 (1 to 2 nodes); N2 (3 to 6 nodes); N3 (7 nodes); M — redefined as any distant metastases

Final stage groupings: stages IA, IB, and IIA depend on depth of tumor invasion, absence of metastases to regional lymph nodes, and degree of differentiation; adenocarcinoma — well- and moderately differentiated grouped together; poorly differentiated cancers have worst survival; stage IIB and beyond driven by T, N, and M

Squamous cell carcinoma — depends on histologic grade; T1 — well differentiated (better outcomes than moderately or poorly differentiated); T2 and T3 — well-differentiated, lower tumors (IB) have best outcomes; upper, poorly differentiated cancers (IIB) have worst outcomes; intermediate cancers (IIA) either lower and poorly differentiated or upper to middle and well differentiated (have similar survival)

Aims for eighth edition: refine and expand staging — ignore current definitions of stages 0 and stage IV; obtain closer to 100% homogeneity in survival for stages 0 and IIIC; obtain more data for uncommon stages; study model’s effect on clinical staging and staging after induction chemoradiation and surgery; assess other nonanatomic factors that affect survival; add survival data for nonesophagectomy therapies used in stages 0 and IV, and for cancer of cervical esophagus; clinical decision models — construct validated models for recurrence and death with various modalities of treatment; prognostic model — for predicting potential for survival given stage and patient characteristics; to be web-based

Pancreatic Cancer

Jennifer Tseng, MD, Associate Professor and Chief of Surgical Oncology (Beth Israel Deaconess Medical Center), Harvard Medical School, Boston, MA

Pancreatectomy: Tseng study — surmounting learning curve requires 60 cases per surgeon for open and 70 cases per surgeon for minimally invasive procedures; marked difference seen in rate of positive margins in first vs second 60 cases performed; technical advances — allow resection in previously unresectable patients

Adjuvant therapy: resection considered for cancer of pancreatic head, stage I or II, with no involvement of superior mesenteric vein or artery; typically, patients undergo surgery, followed by chemotherapy or chemoradiation therapy; 80% of patients have positive lymph nodes and many have micrometastatic disease after pancreatectomy; adjuvant therapy considered only after recovery from surgery and any complications; improves overall survival, but may not be received or completed due to surgical complications, delayed recovery, older age, poor performance status, comorbidities, patient refusal, or disease progression

Neoadjuvant approach: patient undergoes staging computed tomography (CT); treated with chemoradiation therapy, systemic chemotherapy, or other modalities; staging CT repeated; patient treated with surgery if resectable; potential barriers — clinician acceptance; no randomized studies available (likely not possible to sufficiently power any future study); decision analysis — used in absence of sufficiently powered randomized clinical trials; involves creation of mathematical models with all relevant data added to determine best outcomes; study — Marcov model created of patient cohort with resectable PC; patients randomized to neoadjuvant vs adjuvant strategies; when life expectancy alone considered, neoadjuvant strategy dominated after 6.9 cycles (average survival 20.85 mo); surgery-first strategy inferior after 6.3 cycles (survival 18.9 mo); greater dominance of neoadjuvant strategy seen when quality of adjusted life expectancy (QUALE) considered (20.85 QUALEs vs 18.45 QUALEs with surgery first); neoadjuvant strategy may subject fewer patients to morbidity and mortality of pancreatectomy, thus reserving operation for patients most likely to benefit; studies — show pancreatic cancer is systemic disease; neoadjuvant, cytotoxic, and antimetastatic therapies recommended before surgical therapy; long-term survival after pancreatectomy unchanged over 3 decades; factors that favor upfront surgery — younger age in better health; patient preference; lack of tissue diagnosis; cancer other than adenocarcinoma; patient cannot be stented; factors that favor neoadjuvant therapy — poor performance status; biopsy-proven adenocarcinoma; vascular involvement; availability of multidisciplinary team

Surgical Outcomes Analysis and Research (SOAR) score challenge: mortality for pancreatectomy decreasing (5% in mid 2005), but complication rate unchanged; approach — nationwide inpatient sample used; >16,000 discharges of patients undergoing pancreatectomy reviewed; a priori choice made of explanatory variables (age, sex, comorbidities, diagnosis, procedure performed, and hospital volume); logistic regression model used; in-hospital death used as outcome (median beta coefficients transformed to integers); point assignments made (eg, higher points given for older age or being sicker); national score — divided into 3 groups; perioperative mortality 1.3%, 4.9%, and 14.3% for lowest, middle, and highest risk groups, respectively; score useful to factor and sum characteristics of individual patients; corresponds to mortality risk group; easily calculable; goodness of fit excellent; however, does not reflect mortality of large hospital centers; score modification — web-based tool created to calculate simple risk score for death after pancreatectomy; patient’s Charlson morbidity score combined with predictors for age, sex, diagnosis, procedure, and hospital volume; customizable by factoring in specific in-hospital mortality

Population-based outcomes: Smith studies — patient outcomes after pancreatic resection improve in patients >65 yr of age (eligible for Medicare); insurance associated with better outcomes, but causality unproven; counties with higher rates of insurance had lower death rates from PC and other cancers; highest survival seen in counties with highest numbers of insured patients; Massachusetts model — poorer or black or nonwhite patients less likely to travel to obtain treatment for PC; outcomes poorer; complication rates higher; low income, Medicaid, or being uninsured predicts treatment at low-volume centers; regionalization of PC care applied unequally

Acknowledgements

Drs. Rice and Tseng were recorded at the 12th Annual Surgery of the Foregut Symposium, held February 17-20, 2013, in Coral Gables, FL, and sponsored by Cleveland Clinic Florida. Information on continuing education programs presented by the Cleveland Clinic, Florida, can be found at clevelandclinicfloridacme.org. The Audio-Digest Foundation thanks the speakers and Cleveland Clinic Florida for their cooperation in the production of this program.

Suggested Reading

Bright T et al: Randomized trial of argon plasma coagulation versus endoscopic surveillance for Barrett esophagus after antireflux surgery: late results. Ann Surg 246:1016, 2007; Csendes A et al: Dysplasia and adenocarcinoma after antireflux surgery in patients with Barrett’s esophagus: the need for long-term subjective and objective follow-up. Ann Surg 235:178, 2002; dos Santos RS et al: Radiofrequency ablation for Barrett’s esophagus and low-grade dysplasia in combination with an antireflux procedure: a new paradigm. J Thorac Cardiovasc Surg 139:713, 2010; Haeno H et al: Computational modeling of pancreatic cancer reveals kinetics of metastasis suggesting optimum treatment strategies. Cell 148:362, 2012; Hill JS et al: A simple risk score to predict in-hospital mortality after pancreatic resection for cancer. Ann Surg Oncol 17:1802, 2010; McDade TP et al: Inequal benefits from regionalization of cancer care: The pancreatic cancer surgery paradigm. J Clin Oncol 30: (15 Suppl)4059, 2012; Parise P et al: Barrett’s esophagus: surgical treatments. Ann NY Acad Sci 1232:175, 2011; Ragulin-Coyne E et al: Perioperative mortality after pancreatectomy: a risk score to aid decision –making. Surgery 152(3 Suppl 1): S120, 2012; Piperdi M et al: A neoadjuvant strategy for pancreatic adenocarcinoma increases the likelihood of receiving all components of care: lessons from a single-institution database. HPB (Oxford) 12: 204, 2010; Raja S et al: Esophageal submucosa: the watershed for esophageal cancer. J Thorac Cardiovasc Surg 142:1403, 2011; Rice TW et al: Esophagectomy for clinical high-grade dysplasia. Eur J Cardiothorac Surg 40:113, 2011; Rice TW et al: 7th edition of the AJCC Cancer Staging Manual: esophagus and esophagogastric junction. Ann Surg Oncol 17:1721, 2010; Rice TW et al: Worldwide esophageal cancer collaboration. Dis Esophagus 22:1, 2009; Simons JP et al: National complication rate after pancreatectomy: beyond mere mortality. J Gastrointest Surg 13:1798, 2009; Tuveson DA, Neoptolemos JP: Understanding metastasis in pancreatic cancer: a call for new clinical approaches. Cell 148:21, 2012; Winter JM et al: Survival after resection of pancreatic adenocarcinoma: results from a single institution over three decades. Ann Surg Oncol 19:169, 2012; Yajin S et al: The normal configuration and interindividual differences in intramural lymphatic vessels of the esophagus. J Thorac Cardiovasc Surg 137:1406, 2009; Zaninotto G et al: Long-term follow-up of Barrett’s epithelium: medical versus antireflux surgical therapy. J Gastrointest Surg 16:7, 2012.


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