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Purpose: Preoperative therapy is frequently employed in the management of esophageal adenocarcinoma. However, many patients are found to have advanced pathologic stage and have poor outcomes. A prognostic factor which identifies this patient population before surgery would be desirable, as alternative treatment strategies may be warranted., Methods: Between 2/08 and 1/12, 60 evaluable patients with locally advanced esophageal adenocarcinoma enrolled in single-arm phase II trial of induction chemotherapy, surgery, and post-operative adjuvant chemo-radiotherapy (CRT). A clinical stage of T3, N1, or M1a (AJCC 6th) was required for eligibility. Induction chemotherapy with epirubicin 50 mg/m 2 d1, oxaliplatin 130 mg/m 2 d1, and fluorouracil 200 mg/m 2 /day continuous infusion for 3 weeks, was given every 21 days for 3 cycles and was followed by surgical resection. Adjuvant CRT consisted of 50-55 Gy @ 1.8-2.0 Gy/day and 2 cycles of cisplatin (20 mg/m 2 /day) and fluorouracil (1000 mg/m 2 /day) given as 96-h infusions during weeks 1 and 4 of radiotherapy. Dysphagia was assessed at baseline and after induction chemotherapy., Results: Persistent dysphagia was associated with worse distant metastatic control [HR 3.48 (1.43-8.43), p = 0.006], recurrence free survival [HR 3.04 (1.34-6.92), p = 0.008], and overall survival [HR 3.31 (1.43-7.66), p = 0.005]. Persistent dysphagia was associated with more advanced pathologic T descriptor (pT) (p = 0.048) and N descriptor (pN) (p = 0.002), a greater median number of involved lymph nodes (3 v 1, p = 0.003), and greater residual tumor viability (p = 0.05). No patients with persistent dysphagia had pT0-T2 or pN0 disease., Conclusions: Persistent dysphagia after induction chemotherapy is associated with more advanced pathologic stage and inferior outcomes.

Objectives: To (1) assess the continuous distribution of the percentage of residual primary cancer in resection specimens after induction therapy for locally advanced esophageal adenocarcinoma, (2) determine the effects of residual primary cancer on survival after esophagectomy, (3) ascertain interplay between residual primary cancer and classical classifications of response to induction therapy (ypTNM), and (4) identify predictors of residual primary cancer., Methods: From January 2006 to November 2012, 188 patients (78%) underwent accelerated chemoradiotherapy, and 52 patients (22%) underwent chemotherapy alone followed by esophagectomy for adenocarcinoma. Mean age was 61 ± 9.2 years, and 89% were male. Residual primary cancer, assessed as the percentage of residual primary cancer cells in resection specimens, was quantified histologically by a gastrointestinal pathologist. Random Forest technology was used for data analysis., Results: Twenty-five specimens (10%) had no residual primary cancer (ypT0), 79 (33%) had 1% to 25% residual cancer, 91 (38%) had 26% to 75%, and 45 (19%) had >75%. Survival was worse with increasing residual primary cancer, plateauing at 75%. Greater residual primary cancer was associated with worse survival across the spectrum of higher ypTN. Higher ypT, larger number of positive nodes, and use of induction chemotherapy rather than induction chemoradiotherapy were associated with greater residual primary cancer., Conclusions: Less residual primary cancer in response to preoperative therapy is associated with a linear increase in survival after esophagectomy for locally advanced esophageal adenocarcinoma; however, survival is poorer than for resected early-stage cancers. Therefore, for patients with poor prognostic indicators, including higher percentage of residual primary cancer, the role of adjuvant therapy needs to be further examined in an attempt to improve survival., (Copyright © 2016. Published by Elsevier Inc.)

Introduction: Preoperative chemoradiotherapy improves local control in patients with locoregionally advanced adenocarcinoma of the esophagus and gastroesophageal junction (GEJ). Distant failure remains common, however, suggesting potential benefit from additional chemotherapy. This phase II study investigated the addition of induction chemotherapy to surgery and adjuvant chemoradiotherapy., Methods: Patients with cT3-4 or N1 or M1a (American Joint Committee on Cancer 6th edition) adenocarcinoma of the esophagus and GEJ were eligible. Induction chemotherapy, with epirubicin 50 mg/m/d, oxaliplatin 130 mg/m/d, and fluorouracil 200 mg/m/d continuous infusion for 3 weeks, was given every 21 days for three courses, followed by surgery. Adjuvant chemoradiotherapy consisted of 50 to 55 Gy at 1.8 to 2.0 Gy/d and two courses of cisplatin (20 mg/m/d) and fluorouracil (1000 mg/m/d) during weeks 1 and 4 of radiotherapy., Results: Between February 2008 and January 2012, 60 evaluable patients enrolled. Resection was accomplished in 54 patients (90%) and adjuvant chemoradiotherapy in 48 (80%) patients. Toxicity included unplanned hospitalization in 18% of patients during induction chemotherapy and 19% of patients during adjuvant chemoradiotherapy. There was one chemotherapy-related and two postoperative deaths. With a median follow-up of 43 months, the projected 3-year locoregional control is 88%, distant metastatic control 46%, relapse-free survival 41%, and overall survival 47%. Symptomatic response to chemotherapy and the percentage of remaining viable tumor at surgery proved the strongest predictors of survival and distant control., Conclusions: Chemotherapy, surgery, and adjuvant chemoradiotherapy are feasible and produce outcomes similar to other multimodality treatment schedules in locoregionally advanced adenocarcinoma of the esophagus and GEJ. Symptomatic response and less residual tumor at surgery were associated with improved outcomes.

Objectives: Intramucosal esophageal cancer treatment is evolving. Less-invasive therapies have emerged, necessitating review of safety, effectiveness, and determinants of long-term outcome after esophagectomy to clarify the role of this traditional, maximally invasive, and potentially harmful therapy., Methods: From January 1983 to January 2011, 164 patients underwent esophagectomy alone for intramucosal adenocarcinoma. Cancers were subdivided by depth of invasion: lamina propria 50 (30%) and muscularis mucosa 114 (70%; inner 42 [26%], middle 16 [10%], and outer 56 [34%]). We assessed complications and esophagectomy-related mortality (safety) and cancer recurrence (effectiveness), and identified determinants of long-term outcomes., Results: Barrett esophagus (P = .005), larger cancers (P < .001), worse histologic grade (P < .001), lymphovascular invasion (P < .001), and overstaging (P = .02) were associated with deeper cancers. One patient had regional lymph node metastases (0.6%). Seventy-five patients (46%) had complications. Seven of 9 deaths within 6 months were esophagectomy related, 6 from respiratory failure. Seven patients had recurrence, all within 4 years. Five-, 10-, and 15-year survivals were 82%, 69%, and 60%, respectively, which were similar to those of a matched general population. Determinants of late mortality were older age (P = .004), poorer lung function (P < .0001), longer cancer (P = .04), postoperative pneumonia (P = .06), cancer recurrence (P < .0001), and second cancers (P < .0001)., Conclusions: Survival after esophagectomy for intramucosal adenocarcinoma is excellent, determined more by patient than cancer characteristics. Patient selection and respiratory function are crucial to minimize harm. Considering the outcome of emerging therapies, esophagectomy should be reserved for patients with a long intramucosal adenocarcinoma or those in whom endoscopic therapies fail or are inappropriate., (Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Conventional chemotherapeutic agents are of limited benefit in patients with recurrent or metastatic cancer of the esophagus or gastroesophageal junction (GEJ). We report results from a phase II trial in this population using gefitinib, an oral epidermal growth factor receptor inhibitor., Patients and Methods: Eligibility required a diagnosis of esophageal or GEJ adenocarcinoma or squamous cell carcinoma, which was either metastatic or recurrent and incurable after initial therapy. No more than one prior chemotherapy regimen was permitted. Treatment consisted of gefitinib 250 mg daily for a minimum of 8 weeks., Results: Between April 2003 and January 2010, 58 patients, including 18 who were chemotherapy-naïve, were entered into this trial. Toxicity was modest, although most experienced grade 1-2 diarrhea and/or skin rash. There were 4 partial responders (7%) and 10 patients with stable disease (17%). The clinical benefit (partial response and stable disease) lasted for a median 6.1 months. Median survival for all patients was 5.5 months with survival projections at 1-year of 24.6% and at 2-years of 12.5%., Conclusion: Gefitinib was well tolerated but of limited efficacy in patients with recurrent or metastatic esophageal or GEJ cancer. Further study of this or similar agents will require better patient selection.

Objectives: Submucosal esophageal cancers (pT1b) are considered superficial, implying good survival. However, some are advanced, metastasizing to regional lymph nodes. Interplay of cancer characteristics and lymphatic anatomy may create a watershed, demarcating low-risk from high-risk cancers. Therefore, we characterized submucosal cancers according to depth of invasion and identified those with high likelihood of lymph node metastases and poor survival., Methods: From 1983 to 2010, 120 patients underwent esophagectomy for submucosal cancers at Cleveland Clinic. Correlations were sought among cancer characteristics (location, dimensions, histopathologic cell type, histologic grade, and lymphovascular invasion [LVI]), and their associations with lymph node metastasis were identified by logistic regression. Associations with mortality were identified by Cox regression., Results: As submucosal invasion increased, cancer length (P < .001), width (P < .001), area (P < .001), LVI (P = .007), and grade (P = .05) increased. Invasion of the deep submucosa (P < .001) and LVI (P = .06) predicted lymph node metastases: 45% (23/51) of deep versus 10% (3/29) of middle-third and 7.5% (3/40) of inner-third cancers had lymph node metastases, as did 46% (12/26) with LVI versus 18% (17/94) without. Older age and lymph node metastases predicted worse 5-year survival: 94% for younger pN0 patients, 62% for older pN0 patients, and 36% for pN1-2 patients regardless of age., Conclusions: Submucosal cancer characteristics and lymphatic anatomy create a watershed for regional lymph node metastases in the deep submucosa. This previously unrecognized divide distinguishes superficial submucosal cancers with good survival from deep submucosal cancers with poor survival. Aggressive therapy of more superficial cancers is critical before submucosal invasion occurs., (Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: Esophageal high-grade dysplasia/tumor in situ (HGD/Tis) management is in evolution. However, treatment decisions must be made on clinical staging, which may not reflect pathologic staging. Long-term randomized trial information, large treatment series, and cancer registry data do not exist to guide treatment decisions. This evaluation of esophagectomy for clinically diagnosed HGD (cHGD) serves as a reference point for future therapies., Methods: From a 1296-patient prospective esophagectomy database, 134 patients were diagnosed with cHGD (HGD without detectable mass at biopsy) before esophagectomy (mean age 60 ± 10 years, 120 [90%] male, and 132 [99%] Caucasian). Median follow-up was 7.1 years., Results: Histopathologic cell type was adenocarcinoma in 124 (93%) patients. Pathologic T (tumor) classification (pT) was 77 (57%) pHGD, 46 (34%) pT1a, eight (6%) pT1b, and one each (1%) indefinite for dysplasia, low-grade dysplasia, and pT2. Three (2%) had regional lymph node metastases (pT1N1M0). There was one hospital death (0.7%) and four deaths from recurrent cancer. Survival at 1 month, 6 months, and 5, 10, and 15 years was 99%, 97%, 96%, 94%, 82%, and 75%, respectively. Survival was at least that of a matched population. Older age and poor lung function predicted worse survival. Sixteen patients developed nonesophageal cancers, 6.1 times greater than expected., Conclusions: Despite clinical staging errors, survival following esophagectomy for cHGD is excellent. The diagnosis of cHGD does not alter survival referenced to the matched general population; however, cHGD patients appear to be at increased risk of second nonesophageal primary cancers. Therapy for cHGD should be patient specific, because patient and not cancer characteristics determine survival., (Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Background: Concurrent chemoradiotherapy (CCRT) for locoregionally advanced esophageal or gastroesophageal junction cancer produces high locoregional control rates but suboptimal distant metastatic control (DMC) and overall survival. This phase II study added gefitinib (G) to our previously tested CCRT regimen in an effort to improve these outcomes., Methods: Eligibility required T3, N1, or M1a esophageal or gastroesophageal junction squamous cell or adenocarcinoma staged by esophageal ultrasound and positron emission tomography/computed tomography. Four-day continuous intravenous infusions of cisplatin (20 mg/m/d) and fluorouracil (1000 mg/m/d) began on day 1 of preoperative radiation (30 Gy and 1.5 Gy bid). Surgery followed in 4 to 6 weeks, and an identical course of CCRT 6 to 10 weeks postoperatively. G 250 mg/d was given with preoperative CCRT for 4 weeks and restarted with postoperative therapy for 2 years. Results were retrospectively compared with our historical series of 93 patients given CCRT without G., Results: Between April 2003 and July 2006, 80 patients were enrolled. Patient and tumor characteristics were similar to our historical series. G did not increase toxicity except for development of rash in 42 (53%) and diarrhea in 44 (55%) 3-year Kaplan-Meier estimates (G versus non-G treated patients) included: overall survival (42% versus 28%, p = 0.06), DMC (40% versus 32%, p = 0.33), and locoregional control (76% versus 77%, p = 0.74). Intolerance for G maintenance occurred in 48% of patients. Patients who experienced G related diarrhea appeared to have improved outcomes., Conclusions: Although G did not worsen CCRT toxicity, maintenance therapy proved difficult. This contemporary cohort of patients enjoyed superior survival, which does not solely reflect a decrease in DMC and merits further investigation.

Introduction: Mature results are presented from a phase II trial of postoperative concurrent chemoradiotherapy in patients with poor-prognosis cancer of the esophagus and gastroesophageal junction after primary surgical resection., Methods: Resected patients with a pathologic stage of T3, N1, or M1a were eligible for this trial. Concurrent chemoradiotherapy was begun between 6 and 10 weeks after surgery and consisted of radiotherapy (1.8 Gy/d to a planned dose of 50.4-59.4 Gy), concurrent with two cycles of 5-fluorouracil (1000 mg/m/d) and cisplatin (20 mg/m/d), both given as 4-day continuous intravenous infusions during the first and fourth weeks of the radiation., Results: Between 1995 and 2006, 50 patients were enrolled. The median age was 59 (range, 33-76) years, and most patients were male (86%), Caucasian (96%), and had undergone a transthoracic esophagogastrectomy (74%) for what proved to be a node positive (86%) adenocarcinoma (86%). Postoperative concurrent chemoradiotherapy was accompanied by neutropenia requiring hospitalization for fever in only four patients (8%) and no toxic deaths. With a median follow-up of 47 (range, 36-124) months, the Kaplan-Meier 4-year projected overall survival is 51%, freedom from recurrence 50%, distant metastatic control 56%, and locoregional control 86%. An earlier pathologic stage was the only predictor for a better outcome., Conclusions: This schedule of postoperative concurrent chemoradiotherapy has acceptable toxicity for patients with poor-prognosis esophageal and gastroesophageal junction cancer after surgery. Outcomes are better than historical results after surgery alone and justify further investigation of this approach.

Hypothesis: Limited information is available on late complications of multimodality therapy for locally advanced esophageal cancer. This study focuses on postesophagectomy benign pleural and pericardial complications to determine their prevalence, temporal pattern, and treatment, and their association with induction chemoradiotherapy and influence on survival., Methods: Between March 1987 and November 2001, 291 patients with clinical stage > or = IIA esophageal cancer underwent esophagectomy; 106 received induction chemoradiotherapy. A propensity score incorporating clinical stage and histopathology was used to identify 100 matched pairs of induction chemoradiotherapy and surgery-only patients. Among these, occurrence of pleural effusion, pericardial effusion, and pericarditis was ascertained by follow-up. Time-related occurrence, risk factors, and association with survival were assessed by repeated-events analyses., Results: During follow-up, 61 induction chemoradiotherapy patients experienced at least one pleural or pericardial complication, as did 46 propensity-matched surgery-only patients. Most occurred within 1 year, with 1-year freedom from occurrence only 34% after induction chemoradiotherapy and 59% after surgery only (p = 0.02). Risk of pleural effusion was nearly twice as great (hazard ratio 1.7, p = 0.0004) and pericardial complications 5 times greater (hazard ratio 5.3, p = 0.0005) after induction chemoradiotherapy than after surgery alone. Complications after induction chemoradiotherapy required intervention somewhat more frequently (58% versus 47%, p = 0.18), although they did not diminish subsequent survival (p > 0.8)., Conclusions: Benign pleural and pericardial complications occur surprisingly frequently after esophagectomy, particularly when induction chemoradiotherapy is employed. This must be factored into discussions of morbidity for multimodality treatment strategies for locally advanced esophageal cancer and should be considered distinct from acute toxicity of induction chemoradiotherapy reported.

Objective: Grading Barrett's dysplasia at the lower end of the metaplasia-dysplasia spectrum (negative, indefinite, and low-grade dysplasia) suffers from poor interobserver agreement, even among gastrointestinal pathologists. Data evaluating interobserver agreement in Barrett's mucosal biopsies with changes at the upper end of the dysplasia spectrum (high-grade dysplasia, intramucosal, and submucosal adenocarcinoma) have not been published. The accurate categorization of pretreatment biopsies drives therapeutic decision making, but if the diagnostic distinction between cancer and high-grade dysplasia in Barrett's biopsies is inconsistent, then the use of these diagnoses to make management decisions is suspect. To this end, our aim was to assess interobserver reproducibility among a group of gastrointestinal pathologists in the interpretation of preresection biopsies., Methods: All study pathologists agreed upon the histologic criteria distinguishing four diagnostic categories, including high-grade dysplasia; high-grade dysplasia with marked distortion of glandular architecture, cannot exclude intramucosal adenocarcinoma; intramucosal adenocarcinoma; and submucosally invasive adenocarcinoma. The histologic criteria were used to independently review preresection biopsies from 163 consecutive Barrett's esophagus patients with at least high-grade dysplasia who ultimately underwent esophagectomy. Reviewers recorded the specific histologic criteria used to categorize each case and Kappa statistics were calculated to assess interobserver agreement., Results: Using kappa statistics, the overall agreement was only fair (kappa= 0.30). Agreement for high-grade dysplasia was moderate (kappa= 0.47), while agreement for high-grade dysplasia with marked architectural distortion, cannot exclude intramucosal adenocarcinoma and intramucosal adenocarcinoma were only fair (kappa= 0.21 and 0.30, respectively) and agreement for submucosal adenocarcinoma was poor (kappa= 0.14)., Conclusions: The overall poor interobserver reproducibility among gastrointestinal pathologists who see a high volume of Barrett's cases calls into question treatment regimens based on the assumption that high-grade dysplasia, intramucosal adenocarcinoma, and submucosal adenocarcinoma can reliably be distinguished in biopsy specimens.

Objective: To ascertain whether fluorodeoxyglucose positron emission tomography is indicated for clinical staging of superficial cancer, we sought to determine if it accurately classifies tumor (T), regional nodal (N), and distant metastases (M), including distinguishing high-grade dysplasia (Tis) from invasive cancer (T1)., Methods: Fifty-eight superficial esophageal cancer patients had preoperative positron emission tomography, 53 (91%) fused with computed tomography. Tumor characteristics, esophagoscopy findings, and pTNM were compared with positron emission tomography cTNM. pT1 was subdivided into intramucosal cancers with lamina propria or muscularis mucosa invasion and submucosal cancers with inner or outer invasion., Results: Fluorodeoxyglucose uptake increased with pT, from 5/11 (45%) for pTis to 11/16 (69%) for pT1 (outer submucosa), P=0.07, as it did for standardized uptake value, median 0 for pTis to 2.7 for pT1 (outer submucosa), P=0.06. Positron emission tomography could not differentiate Tis (5/11, 45%) from T1 (26/47, 55%; P=0.03). Regional nodal fluorodeoxyglucose uptake in three patients (standardized uptake value 2.8, 4.9, 11) was false positive; in six pN1 patients, it was false negative. Positron emission tomography had 0% sensitivity and positive predictive value for N1. There were no distant metastases; one patient developed a pulmonary metastasis 15 months postoperatively. Positron emission tomography detected three (5%) distant hypermetabolic sites, all synchronous tumors (papillary thyroid cancer, adrenal pheochromocytoma, rectal adenoma). Only increasing tumor length was related to greater fluorodeoxyglucose uptake (P=0.004) and higher standardized uptake value (P=0.001)., Conclusions: Because positron emission tomography can neither differentiate pTis from T1 nor classify T, N, and M, it is not indicated in staging superficial esophageal cancer. Finding a synchronous primary tumor in approximately every 20th patient is its only benefit. Better, less expensive screening tools are available for common synchronous malignancies.

Objectives: This is a report of mature results from a phase II trial of an accelerated multimodality treatment program for locoregionally advanced cancer of the esophagus and gastroesophageal junction with a focus on the impact of clinical heterogeneity on outcomes. A split course of pre- and postoperative hyperfractionated radiation therapy and concurrent chemotherapy was used in an effort to limit perioperative mortality., Methods: Eligibility required a diagnosis of esophageal or gastroesophageal junction cancer and an esophageal ultrasound stage of at least T3, N1, or M1A. Patients received a 12-day induction course of radiation (1.5 Gy twice a dose to a dose of 30 Gy) concurrent with 4-day continuous intravenous infusions of cisplatin (20 mg/m2 per day) and 5-fluorouracil (1000 mg/m2 per day) beginning on day 1. Surgery followed in 4 to 6 weeks followed 6 to 10 weeks later by a second, identical course of chemoradiotherapy., Results: From October 1999 through March 2003, 93 patients were enrolled; 96% were white, 86% male, and 83% had adenocarcinoma. Resection was possible in 83 patients (89%) with 4 (5%) perioperative deaths. With a median follow up of 50 months (range, 34-72 months), the 3-year projected overall survival rate is 27.9%, freedom from recurrence 30.5%, and distant metastatic control 32.4%. Locoregional control in resected patients is 86%. Freedom from recurrence and distant control were significantly better in patients with 1) earlier pretreatment clinical stage, 2) earlier postinduction pathologic stage, 3) squamous cell cancer, and 4) a pathologic response., Conclusions: This accelerated multimodality treatment program is feasible and perioperative mortality proved acceptable. Despite excellent locoregional control, freedom from recurrence, and overall survival proved disappointing reflecting the frequency of distant metastases. Heterogeneity in patient populations makes comparisons with similar nonrandomized experiences problematic.

Objective: The study objective was to develop a treatment algorithm for cT2N0M0 esophageal cancer by determining (1) errors in clinical staging and (2) consequences of overtreatment and undertreatment of incorrectly clinically staged patients., Methods: Of 742 clinically staged patients, 61 (8.2%) had cT2N0M0 cancer; 45 underwent surgery alone; 8 underwent surgery and postoperative adjuvant therapy; and 8 underwent induction therapy, then surgery. As reference, 31 of 666 patients (4.7%) who underwent surgery first had pT2N0M0 cancer and a 5-year survival of 61% +/- 9.3%. Referent values were calculated from 445 clinically staged patients who underwent surgery first. Unmatched and matched survival comparisons were made using the log-rank test., Results: Only 7 of 53 cT2N0M0 cancers treated with surgery first were pT2N0M0 (13% positive predictive value). Of incorrectly staged cT2N0M0 cancers (46/53), 29 (63%) were overstaged and 17 (37%) were understaged. Most overstaged cancers were pT1 (11 [38%] T1a and 15 [52%] T1b), and most understaged cancers were pN1 (13 [76%]). Matched overstaged patients treated by surgery alone (25/28) had a 5-year survival similar to that of patients with pTNM (69% +/- 9.8% vs 63% +/- 13%, P =.8). Understaged patients did better at 5 years than patients with pTNM if they had postoperative adjuvant therapy, not surgery alone (43% +/- 22% vs 10% +/- 9.5%, P = .17). Induction therapy decreased 5-year survival compared with all other treatment strategies (13% +/- 12% vs 52% +/- 7.4%, P =.05)., Conclusions: Patients with cT2N0M0 cancers should undergo surgery first with lymphadenectomy. Clinically understaged patients should receive postoperative adjuvant therapy. In the unlikely event that patients with cT2N0M0 cancers are found to have an uncommon pT2N0M0 cancer, they will have acceptable survival with surgery alone.

Background: Brain metastases from esophageal cancers are uncommon, yet our impression was that they occurred more frequently than expected after esophagectomy plus adjuvant therapy. Therefore, we determined (1) incidence and prevalence of, risk factors for, and survival after development of brain metastases following esophagectomy for esophageal cancer, and (2) their association with adjuvant therapy., Methods: From 1985 to 2002, 403 patients (52%) underwent esophagectomy alone and 369 esophagectomy plus adjuvant therapy (118 [15%] preoperative only, 124 [16%] postoperative only, and 127 [16%] both). Hazard-function methodology was used to characterize time-related occurrence of brain metastases and risk factors. Inferences were confirmed by propensity analysis., Results: Twenty-nine patients developed brain metastases, 20 within 1 year; 6 had undergone surgery alone, and 23 had adjuvant therapy. Prevalence was 2.5% 5 years after surgery alone, but 8.4%, 7.0%, and 18.4% after preoperative adjuvant therapy only, postoperative adjuvant therapy only, and both, respectively (p < 0.0001). Greater number of locoregional lymph node metastases was associated with brain metastases after surgery alone (p = 0.04). Distant metastases (p = 0.03) and both preoperative and postoperative adjuvant therapy (p = 0.004) were risk factors. Median survival after diagnosis of brain metastases was 3.5 months. Postesophagectomy propensity-matched survival was shorter after adjuvant therapy than after surgery alone; thus, time available for developing brain metastases after surgery alone was slightly lower., Conclusions: A dose-related increased incidence of brain metastases after adjuvant therapy for esophageal cancer cannot be explained by increased longevity. Adjuvant therapy itself, not just advanced disease, appears to create conditions conducive to developing these rapidly fatal metastases.

Study Objective: To evaluate the effects of induction concurrent chemoradiotherapy (cCRT) on pulmonary function and postoperative acute respiratory complications (PARCs)., Design: A retrospective review of our patients treated with induction cCRT to determine the impact on pulmonary function and identify predictors of PARCs. Correlations were sought between patient demographics, clinical characteristics, pre-cCRT and post-cCRT pulmonary function, radiotherapy dose, chemotherapy agents, and the development of PARCs., Participants: One hundred fifty-five patients treated in three separate clinical trials were identified; 47 patients received 30 Gy (150 cGy bid) of radiation concurrently with a single course of cisplatin/5-fluorouracil (5FU), and 108 patients received 45 Gy (150 cGy bid in a split course) concurrent with two courses of either cisplatin/5FU (n = 69) or cisplatin/paclitaxel (n = 39). Esophagectomy was performed in 141 of these 155 patients following cCRT., Results: cCRT was only associated with significant worsening of the diffusion capacity of the lung for carbon monoxide (Dlco), which decreased a median of 21.7% in the 45-Gy group (p = 0.007), and 8.6% in the 30-Gy group (p = 0.07). This Dlco decrease was statistically greater in the 45-Gy group than in the 30-Gy group (p = 0.02). PARCs developed in 18 patients. Percentage of predicted FEV(1) and FVC, both before and after cCRT, were both significantly higher in patients without PARCs than in patients with PARCs (p = 0.031 and p = 0.010, respectively). Post-cCRT Dlco was also significantly worse in patients with PARCs (p = 0.002). PARCs occurred significantly more often among those treated with 45 Gy (17 of 102 patients) compared to those treated with 30 Gy (1 of 39 patients) [p = 0.025]. In the 18 patients with PARCs, the median survival was only 2.1 months. This was significantly less than the 16.4-month median survival in the 123 patients who did not have PARCs (p = 0.001)., Conclusions: In patients treated with induction cCRT, higher radiation doses result in increasing impairment of gas exchange. PARCs were more likely in those patients with lower lung volumes, lower post-cCRT Dlco, and in those receiving higher radiation doses. These acute respiratory complications were also associated with a significant reduction in patient survival.

Objective: We sought to compare the outcome of patients with esophageal cancer who had either modified Collard or standard hand-sewn cervical esophagogastric anastomoses in reconstruction during esophagectomy., Methods: From March of 1996 to October of 2002, 274 patients with esophageal cancer underwent esophagectomy with gastric replacement and cervical esophagogastric anastomosis. Beginning in March of 2001, a modified Collard technique (stapled) was used in most patients (n = 86) for cervical esophagogastric anastomosis; a standard hand-sewn technique (sewn) was used in all others (n = 188). Using a propensity score based on 8 variables (age, gender, race, surgeon, surgical approach, pathologic stage, histologic cell type, and induction chemoradiotherapy), 85 patient pairs were matched and followed for time-related events. Outcome comparisons included cervical wound infection, cervical anastomotic leak, other hospital complications, length of stay, anastomotic dilatation, reflux symptoms, and survival., Results: At 30 days, freedom from cervical wound infection was 92% for stapled versus 71% for sewn anastomoses ( P = .001), and freedom from cervical anastomotic leak was 96% versus 89% ( P = .09), respectively. Other hospital complications occurred in 58% and 49%, respectively ( P = .17). Median length of stay was 10 days for both ( P = .3). At 2 years, freedom from anastomotic dilatation was 34% for stapled versus 10% for sewn anastomoses ( P < .0001), and the mean number of dilatations per patient was 2.4 versus 4.1 ( P = .0001), respectively. Reflux was rare for both. Thirty-day, 6-month, and 24-month survivals were 98%, 91%, and 77% for stapled anastomoses and 98%, 88%, and 69% for sewn anastomoses ( P = .3)., Conclusions: The modified Collard anastomotic technique dramatically reduces morbidity after esophagectomy. It should replace hand-sewn esophagogastric anastomoses.

Background: Previous assessments of endoscopic ultrasound (EUS) classification of esophageal cancer are dominated by symptomatic patients with advanced stage disease. Fewer data exist on EUS errors in a cohort balanced between early and advanced disease., Purpose: Assess EUS errors in classification of esophageal cancer in a more balanced cohort, and identify clinical and tumor characteristics associated with EUS errors., Methods: A total of 266 patients underwent EUS and esophagectomy without preoperative chemoradiotherapy. Pathologic classification of disease extent: 108 (41%) tumors were confined to the esophageal wall (pTis-pT2, pN0, pM0); 158 (59%) were advanced beyond (pT3-pT4, pN1, or pM1). Logistic regression analysis was performed to identify correlates of error in T classification and disease extent using 10 clinical and tumor characteristics (gender, age, dysphagia, weight loss, tumor length, location, traversability, morphology, histopathologic type, and histologic grade)., Results: EUS erroneously predicted pathologic T (pT) in 119 patients (45%). When T classification was dichotomized into tumors whose depth of invasion was not beyond the muscularis propria (pTis-pT2) and those beyond (pT3-pT4), errors occurred in 42 patients (16%). EUS erroneously predicted N classification in 67 patients (25%), and was insensitive to the presence of distant metastases. EUS misclassified disease extent in 40 patients (15%). Logistic regression analysis indicated that weight loss and tumor length were the only clinical and tumor characteristics correlated with EUS errors; more weight loss was associated with decreased odds of misclassification, while the odds of misclassification were four to six times greater for intermediate length tumors than for shorter tumors., Conclusions: EUS errors, particularly in predicting pT, are more frequent than previously reported. Weight loss and tumor length are the only clinical and tumor characteristics correlated with EUS errors.

Objective: We sought to evaluate the effectiveness of clinical staging of depth of tumor invasion (cT), the relationship of cT to survival, the benefits of downstaging cT, and the role of cT in treatment decisions., Methods: The accuracy of determining T by means of endoscopic ultrasonography and the relationship of cT to survival were assessed in 209 patients undergoing esophagectomy alone for esophageal carcinoma. The benefit of downstaging cT was assessed in 128 patients undergoing induction therapy and esophagectomy. The role of cT in treatment decisions was determined by integrating these results with the results of previous work., Results: Compared with pathologic T (pT), cT was 87% accurate, 82% sensitive, 91% specific, 89% positively predictive, and 86% negatively predictive of tumors confined to (< or =T2) or invading beyond (>T2) the esophageal wall. In cN0, increasing cT was predictive of progressively poorer survival. For each category of pT N0, cT accurately predicted survival, except for pT3, which was underestimated (P <.0001). In cN0, downstaging by induction therapy was beneficial only if tumors invaded beyond the wall (> or =cT3, P =.0003). In cN1, it was beneficial only when downstaging was synchronous in cT3/T4 (P <.001)., Conclusions: cT should be the principal determinant of treatment in cN0. In cN0, if endoscopic ultrasonography identifies tumors of greater than cT2, multimodality therapy should be considered. However, only when cT3/T4 tumors are downstaged to pT2 or less will patients benefit, but their survival will not equal that of patients with tumors of cT2 or less having esophagectomy alone. If endoscopic ultrasonography identifies tumors of cT2 or less, esophagectomy alone should be used because induction therapy might adversely affect survival.

Objective: Cancer staging is dynamic, reflecting accrual of knowledge and experience in treatment. The objectives of this study were to assess current esophageal cancer staging and to determine whether refinements of classification and stage grouping are necessary., Methods: From 1983 through November 2000, 480 patients underwent esophagectomy without induction therapy. Depth of tumor invasion (T), regional lymph node status (N), distant status (M), number of metastatic regional lymph nodes, and histopathologic type and grade were subjected to survival-tree analysis, multivariable Cox and hazard function analysis, and residual misclassification risk analysis., Results: Inhomogenity of survival was found within and lack of distinction was found between current American Joint Committee on Cancer staging groups, supporting the need for refinement. T1 and N1 were redefined on the basis of survival differences. T1a is intramucosal cancer, T1b is submucosal cancer (P =.008), N1 is 1 or 2 metastatic regional lymph nodes, and N2 is 3 or more metastatic regional lymph nodes (P =.01). Current subclassification of M1 is not warranted (P =.9). Histopathologic type (P =.17) and grade (P =.3) minimally refined staging. Reassignment of staging groups constrained by American Joint Committee on Cancer definitions of stages 0 and IV produced less monotonic, distinctive, and homogeneous survival than free assignment of staging groups., Conclusions: Current American Joint Committee on Cancer staging of esophageal cancer is inadequate. Refinement requires redefinition of T1, N1, and M1 classifications. Stage grouping within the constraints of American Joint Committee on Cancer definitions produces less accurate prognosis than free assignment based on survival data.