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Background: The authors hypothesized that cytoreductive surgery (CRS, comprising gastrectomy combined with metastasectomy) in addition to systemic chemotherapy (SC) is associated with a better survival than chemotherapy alone for patients with metastatic gastric adenocarcinoma (MGA)., Methods: Patients with MGA who received SC between 2004 and 2016 were identified using the National Cancer Database (NCDB). Nearest-neighbor 1:1 propensity score-matching was used to create comparable groups. Overall survival (OS) was compared between subgroups using Kaplan-Meier analyses. Immortal bias analysis was performed among those who survived longer than 90 days., Results: The study identified 29,728 chemotherapy-treated patients, who were divided into the following four subgroups: no surgery (NS, n = 25,690), metastasectomy alone (n = 1170), gastrectomy alone (n = 2248), and CRS (n = 620) with median OS periods of 8.6, 10.9, 14.8, and 16.3 months, respectively (p < 0.001). Compared with the patients who underwent NS, the patients who had CRS were younger (58.9 ± 13.4 vs 62.0 ± 13.1 years), had a lower proportion of disease involving multiple sites (4.6% vs 19.1%), and were more likely to be clinically occult (cM0 stage: 59.2% vs 8.3%) (p < 0.001 for all). The median OS for the propensity-matched patients who underwent CRS (n = 615) was longer than for those with NS (16.4 vs 9.3 months; p < 0.001), including in those with clinical M1 stage (n = 210). In the Cox regression model using the matched data, the hazard ratio for CRS versus NS was 0.56 (95% confidence interval [CI], 0.49-0.63). In the immortal-matched cohort, the corresponding median OS was 17.0 versus 9.5 months (p < 0.001)., Conclusions: In addition to SC, CRS may be associated with an OS benefit for a selected group of MGA patients meriting further prospective investigation.

The one-year and median overall survival (mOS) rates of advanced gastroesophageal adenocarcinomas (GEA) are ∼50% and <12 months, respectively. Baseline spatial and temporal molecular heterogeneity of targetable alterations may be a cause of failure of targeted/immunooncologic therapies. This heterogeneity, coupled with infrequent incidence of some biomarkers, has resulted in stalled therapeutic progress. We hypothesized that a personalized treatment strategy, applied at first diagnosis then serially over up to three treatment lines using monoclonal antibodies combined with optimally sequenced chemotherapy, could contend with these hurdles. This was tested using a novel clinical expansion-platform type II design with a survival primary endpoint. Of 68 patients by intention-to-treat, the one-year survival rate was 66% and mOS was 15.7 months, meeting the primary efficacy endpoint (one-sided P = 0.0024). First-line response rate (74%), disease control rate (99%), and median progression-free survival (8.2 months) were superior to historical controls. The PANGEA strategy led to improved outcomes warranting a larger randomized study. SIGNIFICANCE: This study highlights excellent outcomes achieved by individually optimizing chemotherapy, biomarker profiling, and matching of targeted therapies at baseline and over time for GEA. Testing a predefined treatment strategy resulted in improved outcomes versus historical controls. Therapeutic resistance observed in correlative analyses suggests that dual targeted inhibition may be beneficial. This article is highlighted in the In This Issue feature, p. 211 ., (©2020 American Association for Cancer Research.)

Background: Metastasectomy of isolated colorectal liver metastases (CRLM) requires significant clinical expertise and may not be readily available or offered. The authors hypothesized that hospitals that treat a greater percentage of patients from higher income catchment areas are more likely to perform metastasectomies regardless of patient or tumor characteristics., Methods: Using the National Cancer Data Base, the authors classified facilities into facility income quartiles (FIQs) based on the percentage of patients from the wealthiest neighborhoods (by zip code). Quartile 1 included facilities with <2.1% of the patients residing within the highest income zip codes, quartile 2 included facilities with 2.2% to 15.6% of patients residing within the highest income zip codes, quartile 3 included facilities with 15.7% to 40.2% of patients residing within the highest income zip codes, and quartile 4 included facilities with 40.3% to 90.5% of patients residing within the highest income ZIP codes. Patient, tumor, and facility characteristics were analyzed using a multivariate logistic regression to identify associations between metastasectomy and FIQ., Results: Patients with CRLM were more likely to undergo metastasectomy at facilities in the highest FIQ compared with the lowest FIQ (18% vs 11% in FIQ4; P = .001). This trend was not observed in the resection of primary tumors for nonmetastatic CRLM (rates of 95% vs 93%; P = .94). After adjusting for individual insurance status, distance traveled, zip code-level individual income, tumor, and host, patients who were treated at the highest FIQ facilities were found to be more likely to undergo metastasectomy (odds ratio, 1.29; 95% CI, 1.02-1.72 [P = .03])., Conclusions: Metastasectomy for CRLM is more likely to occur at facilities that serve a greater percentage of patients from high-income catchment areas, regardless of individual patient characteristics. This disparity uniquely affects those patients with advanced cancers for which specialized expertise for therapy is necessary., (© 2019 American Cancer Society.)

Background: There is considerable interest in a neoadjuvant approach for resectable pancreatic ductal adenocarcinoma (PDAC). This study evaluated perioperative gemcitabine + erlotinib (G+E) for resectable PDAC., Methods: A multicenter, cooperative group, single-arm, phase II trial was conducted between April 2009 and November 2013 (ACOSOG Z5041). Patients with biopsy-confirmed PDAC in the pancreatic head without evidence of involvement of major mesenteric vessels (resectable) were eligible. Patients (n = 123) received an 8-week cycle of G+E before and after surgery. The primary endpoint was 2-year overall survival (OS), and secondary endpoints included toxicity, response, resection rate, and time to progression. Resectability was assessed retrospectively by central review. The study closed early due to slow accrual, and no formal hypothesis testing was performed., Results: Overall, 114 patients were eligible, consented, and initiated protocol treatment. By central radiologic review, 97 (85%) of the 114 patients met the protocol-defined resectability criteria. Grade 3+ toxicity was reported in 60% and 79% of patients during the neoadjuvant phase and overall, respectively. Twenty-two of 114 (19%) patients did not proceed to surgery; 83 patients (73%) were successfully resected. R0 and R1 margins were obtained in 67 (81%) and 16 (19%) resected patients, respectively, and 54 patients completed postoperative G+E (65%). The 2-year OS rate for the entire cohort (n = 114) was 40% (95% confidence interval [CI] 31-50), with a median OS of 21.3 months (95% CI 17.2-25.9). The 2-year OS rate for resected patients (n = 83) was 52% (95% CI 41-63), with a median OS of 25.4 months (95% CI 21.8-29.6)., Conclusions: For resectable PDAC, perioperative G+E is feasible. Further evaluation of neoadjuvant strategies in resectable PDAC is warranted with more active systemic regimens.

Survival for esophageal cancer has improved over the past four decades, probably as a result of a combination of more accurate staging, improved surgical outcomes, advances in adjuvant and neoadjuvant therapies, and the increasing implementation of multimodality treatment. Surgical resection still remains the mainstay in the treatment of localized esophageal adenocarcinoma. Multiple techniques have been described for esophagectomy, which are based on either a transthoracic or transhiatal approach. Despite proponents of each technique touting potential advantages such as superior oncologic resection with more extensive transthoracic lymphadenectomy compared to the relatively limited morbidity and mortality with a transhiatal resection, the superiority of one technique over another is not clear and may be relegated to a topic of historical significance in the era of minimally invasive surgery. With the increased acceptance of neoadjuvant multimodality therapy, both approaches have been shown to have acceptable outcomes. And in the hands of experienced surgeons, both techniques can provide excellent short-term results. Moreover, surgeon and hospital volume have shown to be strongly associated with improved operative morbidity and oncologic outcomes, which may supersede the type of approach selected for an individual patient.

Background: The benefit of adjuvant therapy following resection of early stage, node-negative gastric adenocarcinoma following a margin negative (R0) resection is unclear., Methods: The National Cancer Data Base was used to identify patients with a T2N0 gastric adenocarcinoma (tumor invasion into the muscularis propria) who underwent R0 resection. Patients treated with neoadjuvant therapy and those for whom lymph node count was unavailable were excluded from the analysis. Kaplan-Meier and Cox regression were used to evaluate differences in and predictors of overall survival., Results: A total of 1687 patients underwent R0 resection for T2N0 gastric adenocarcinoma between 2003-2011. Adjuvant chemotherapy treatment was administered to 7.1 and 14.1 % received adjuvant chemoradiation; 65.4 % had <15 lymph nodes examined. Multivariate Cox regression identified higher Charlson score, <15 lymph nodes examined, higher tumor grade, and tumor location in the cardia as factors associated with significantly decreased overall survival. With a median follow-up of 36 months, the 5-year overall survival was 71 % for patients with ≥15 lymph nodes examined and 53 % for those with <15 lymph nodes (p < 0.001). In patients who had <15 lymph nodes examined, there was an overall survival benefit for adjuvant chemoradiation (hazard ratio 0.71, p = 0.043). In patients with ≥15 lymph nodes examined, no survival benefit for adjuvant therapy was identified (p > 0.74)., Conclusions: Adequate lymph node dissection and pathologic staging is critical in directing optimal treatment of patients with early gastric cancer. Understaging as a result of suboptimal lymphadenectomy may explain the perceived benefit of adjuvant chemoradiation after an R0 resection for T2N0 gastric cancer.

Objectives: Our objectives were to (1) compare 30- and 90-day mortality rates after esophagectomy, (2) compare drivers of 30- and 90-day mortality, and (3) examine whether 90-day mortality affects hospital rankings., Background: Operative mortality has traditionally been assessed at 30 days. Ninety-day mortality has been suggested as a more appropriate indicator of quality, particularly after complex cancer surgery., Methods: Esophagectomies for nonmetastatic esophageal cancer patients diagnosed between 2007 and 2011 were identified in the National Cancer Data Base. Mortality rates were examined by patient demographics, tumor characteristics, and hospital procedural volume. Risk-adjusted hierarchical logistic regression models examined hospital performance for mortality., Results: A total of 15,796 esophagectomy patients at 977 hospitals were available for analysis. Ninety-day overall mortality was more than double the 30-day mortality (8.9% vs 4.2%; P < 0.0001). In multivariate analysis, while both 30- and 90-day mortality were associated with patient factors such as age, comorbidity, and hospital volume, only 90-day mortality was influenced by tumor- and management-related variables such as stage, tumor location, and receipt of neoadjuvant therapy. Hospital performance was examined as top 10%, middle 10% to 90%, and lowest 10% as ranked using risk-adjusted odds of mortality. There was moderate correlation between ranking based on 30- and 90-day mortality [weighted κ = 0.45 (95% confidence interval, 0.39-0.52)]. Compared with 30-day mortality rankings, nearly 20% of hospitals changed their ranking category when 90-day mortality rankings were used., Conclusions: Examination of 90-day mortality after esophagectomy reflects cancer patient management decisions and may provide actionable targets for quality improvement.

Background: Surgical margin involvement is an important outcome after pancreatic cancer surgery; however, variation in pathologic review practices may limit its use as a quality indicator. Our objectives were to assess variation in hospital performance and the reliability of margin involvement after pancreatic cancer surgery., Methods: From the National Cancer Data Base, patients who underwent pancreatic resection for stage I to III adenocarcinoma were identified. Risk-adjusted surgical margin involvement was evaluated using hierarchical regression methods, and variation in hospital performance and reliability was determined., Results: From 1,002 hospitals, 14,889 patients underwent pancreatic resection for adenocarcinoma, and 3,573 (24.0 %) had an involved surgical margin (R1 22.8 %; R2 1.2 %). The strongest predictors associated with margin involvement were T stage [T3: odds ratio (OR) 2.08, 95 % confidence interval (CI) 1.68-2.59; T4: OR 7.26, 95 % CI 5.50-9.60; vs. T1] and tumor size (2-3.9 cm: OR 1.66, 95 % CI 1.39-1.98, ≥ 4 cm: OR 2.28, 95 % CI 1.90-2.74; vs. <2 cm). Factors associated with a decreased likelihood of margin involvement were the use of neoadjuvant therapy and hospital type (academic and National Cancer Institute-designated comprehensive cancer centers vs. community). At the hospital level, the mean risk-adjusted surgical margin involvement rate was 25.9 % and ranged 10.1 to 50.5 %. Twenty-one (2.1 %) hospitals had lower-than-expected and 17 (1.7 %) had higher-than-expected margin involvement. A minimum acceptable reliability of 0.4 was met after 13 cases and was achieved by 249 hospitals that performed 79 % of pancreatic resections assessed., Conclusions: Despite differences in pathologic evaluation practices, hospitals can be feasibly and reliably provided comparative data on surgical margin status after resection for pancreatic cancer.

Importance: There is growing interest in reducing the variations and deficiencies in the multidisciplinary management of gastric cancer., Objective: To define optimal treatment strategies for gastric adenocarcinoma (GC)., Design, Setting, and Participants: RAND/UCLA Appropriateness Method involving a multidisciplinary expert panel of 16 physicians from 6 countries., Interventions: Gastrectomy, perioperative chemotherapy, adjuvant chemoradiation, surveillance endoscopy, and best supportive care., Main Outcomes and Measures: Panelists scored 416 scenarios regarding treatment scenarios for appropriateness from 1 (highly inappropriate) to 9 (highly appropriate). Median appropriateness scores from 1 to 3 were considered inappropriate; 4 to 6, uncertain; and 7 to 9, appropriate. Agreement was reached when 12 of 16 panelists scored the scenario similarly. Appropriate scenarios agreed on were subsequently scored for necessity., Results: For patients with T1N0 disease, surgery alone was considered appropriate, while there was no agreement over surgery alone for patients T2N0 disease. Perioperative chemotherapy was appropriate for patients who had T1-2N2-3 or T3-4 GC without major symptoms. Adjuvant chemoradiotherapy was classified as appropriate for T1-2N1-3 or T3-4 proximal GC and necessary for T1-2N2-3 or T3-4 distal GC. There was no agreement regarding surveillance imaging and endoscopy following gastrectomy. Surveillance endoscopy was deemed to be appropriate after endoscopic resection. For patients with metastatic GC, surgical resection was considered inappropriate for those with no major symptoms, unless the disease was limited to positive cytology alone, in which case there was disagreement., Conclusions and Relevance: Patients with GC being treated with curative intent should be considered for multimodal treatment. For patients with incurable disease, surgical interventions should be considered only for the management of major bleeding or obstruction.

Concurrent chemotherapy and radiotherapy (chemoradiotherapy) for the management of pancreatic adenocarcinoma in either adjuvant or locally regional advanced settings produces predictable acute toxicities that are proportional in severity to the intensity and type of systemic therapy and to the parameters of radiotherapy. In addition, relevant to the adjuvant setting, surgery for pancreatic cancer often produces physiologic alterations that may impact a patient's ability to tolerate chemoradiotherapy. Failures to anticipate, monitor, and proactively manage the effects of surgery and toxicities of chemoradiotherapy can result in the need for unplanned treatment interruptions and/or inability to complete all planned therapy. In this review, complications of pancreatic cancer itself and of pancreatic resection as well as toxicities of chemoradiotherapy are delineated, and approaches to their management before, during, and after chemoradiotherapy are presented. Planning for the treatment of side effects before the anticancer therapy begins facilitates therapy administration and improves patient tolerance.

Background: A relationship between higher volume providers and improved outcomes has been suggested by some studies and has been used to construct guidelines for many diseases. For gastric cancer (GC), however, optimal volume cutoffs are not clear., Methods: A multidisciplinary expert panel of 16 physicians from 6 countries scored 120 scenarios regarding provider characteristics for gastric resections for GC. Appropriateness of scenarios was scored from 1 (highly inappropriate) to 9 (highly appropriate). Median appropriateness scores from 1 to 3 were considered inappropriate, 4 to 6 uncertain, and 7 to 9 appropriate. Agreement was reached when 12 of 16 panelists scored the statement similarly. Appropriate scenarios agreed on were scored subsequently for necessity., Results: Surgeon and hospital practice volume scenarios were evaluated. The panel felt it was inappropriate for surgeons doing ≤2 GC cases per year to perform a multivisceral resection (MVR), D2 lymphadenectomy (D2-LND), or laparoscopic total gastrectomy, and ≤6 GC cases per year for an MVR involving a pancreatoduodenectomy (MVR-PD), or endoscopic mucosal resections (EMR). It was considered appropriate for surgeons doing ≥11 GC cases per year to perform open gastrectomy or D2-LND, and ≥20 GC cases per year for any MVR, laparoscopic gastrectomy, or EMR. For hospitals, it was considered inappropriate for hospitals managing ≤4 GC cases per year to perform D2-LND or laparoscopic total gastrectomy, and ≤10 GC cases per year, for MVR-PD or EMR. Hospital volumes ≥21 cases per year was considered appropriate for any GC procedure. It was inappropriate for an MVR to be performed in a hospital without interventional radiology services and for a MVR-PD in a hospital with no level I intensive care unit., Conclusion: Appropriate and inappropriate provider volumes for a variety of gastric procedures have been defined by an international expert panel., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Background: Methodological limitations of prior studies have prevented progress in the treatment of patients with borderline resectable pancreatic adenocarcinoma. Shortcomings have included an absence of staging and treatment standards and pre-existing biases with regard to the use of neoadjuvant therapy and the role of vascular resection at pancreatectomy., Methods: In this manuscript, we review limitations of studies of borderline resectable PDAC reported to date, highlight important controversies related to this disease stage, emphasize the research infrastructure necessary for its future study, and present a recently-approved Intergroup pilot study (Alliance A021101) that will provide a foundation upon which subsequent well-designed clinical trials can be performed., Results: We identified twenty-three studies published since 2001 which report outcomes of patients with tumors labeled as borderline resectable and who were treated with neoadjuvant therapy prior to planned pancreatectomy. These studies were heterogeneous in terms of the populations studied, the metrics used to characterize therapeutic response, and the indications used to select patients for surgery. Mechanisms used to standardize these and other issues that are incorporated into Alliance A021101 are reviewed., Conclusions: Rigorous standards of clinical trial design incorporated into trials of other disease stages must be adopted in all future studies of borderline resectable pancreatic cancer. The Intergroup trial should serve as a paradigm for such investigations.

Background and Objectives: Positive peritoneal cytology equates M1 disease in patients with gastric cancer. Diagnostic peritoneal lavage (DPL) is a proven test to detect occult visceral injury in trauma patients. The objective of this study is to determine whether DPL can be used to assess peritoneal cytology in patients with gastric cancer., Methods: Patients with gastric adenocarcinoma were prospectively enrolled to undergo DPL prior to diagnostic laparoscopy (DL). Saline was instilled through a percutaneous catheter and fluid was collected for cytology (DPL-cyt). Washings obtained during DL were used as controls (DL-cyt)., Results: DPL was successful in 22/27 patients (81.5%). Among the 22 successful DPLs, 12 had positive cytology (54.5%). Positive DPL-cyt specimens matched DL-cyt specimens in 12/12 cases (specificity = 100%). One of 10 cases with negative DPL-cyt was positive on the final DL-cyt (sensitivity = 92%). There were six patients with negative DPL-cyt who had visible M1 disease diagnosed with DL (DPL evaluation of M1 disease, sensitivity 54.5%, specificity = 100%)., Conclusions: DPL is a safe method of detecting positive cytology in patients with gastric cancer, however gross M1 disease may be missed without visual inspection. The specific role of DPL in the staging workup of patients with gastric cancer remains to be determined., (Copyright © 2013 Wiley Periodicals, Inc.)

Purpose: We designed American College of Surgeons Oncology Group (ACOSOG) Z6041, a prospective, multicenter, single-arm, phase II trial to assess the efficacy and safety of neoadjuvant chemoradiation (CRT) and local excision (LE) for T2N0 rectal cancer. Here, we report tumor response, CRT-related toxicity, and perioperative complications (PCs)., Methods: Clinically staged T2N0 rectal cancer patients were treated with capecitabine and oxaliplatin during radiation followed by LE. Because of toxicity, capecitabine and radiation doses were reduced. LE was performed 6 weeks after CRT. Patients were evaluated for clinical and pathologic response. CRT-related complications and PCs were recorded., Results: Ninety patients were accrued; 6 received nonprotocol treatment. The remaining 84 were 65% male; median age 63 years; 83% Eastern Cooperative Oncology Group performance score 0; 92% white; mean tumor size 2.9 cm; and average distance from anal verge 5.1 cm. Five patients were considered ineligible. Therapy was completed per protocol in 79 patients, but two patients did not undergo LE. Among 77 eligible patients who underwent LE, 34 patients achieved a pathologic complete response (44%) and 49 (64%) tumors were downstaged (ypT0-1), but 4 patients (5%) had ypT3 tumors. Five LE specimens contained lymph nodes; one T3 tumor had a positive node. All but one patient had negative margins. Thirty-three (39%) of 84 patients developed CRT-related grade ≥3 complications. Rectal pain was the most common PC., Conclusions: CRT before LE for T2N0 tumors results in a high pathologic complete response rate and negative resection margins. However, complications during CRT and after LE are high. The true efficacy of this approach will ultimately be assessed by the long-term oncologic outcomes.

Rationale: Strategies to stage and treat cancer rely on a presumption of either localized or widespread metastatic disease. An intermediate state of metastasis termed oligometastasis(es) characterized by limited progression has been proposed. Oligometastases are amenable to treatment by surgical resection or radiotherapy., Methods: We analyzed microRNA expression patterns from lung metastasis samples of patients with ≤ 5 initial metastases resected with curative intent., Results: Patients were stratified into subgroups based on their rate of metastatic progression. We prioritized microRNAs between patients with the highest and lowest rates of recurrence. We designated these as high rate of progression (HRP) and low rate of progression (LRP); the latter group included patients with no recurrences. The prioritized microRNAs distinguished HRP from LRP and were associated with rate of metastatic progression and survival in an independent validation dataset., Conclusion: Oligo- and poly- metastasis are distinct entities at the clinical and molecular level.

We performed a phase II trial to evaluate a docetaxel-based regimen in locoregionally advanced esophageal cancer. Untreated stage II-IVa esophageal cancer patients with performance status 0-2 were included. Tumor resectability was determined prior to initiation of study. Induction docetaxel (75 mg/m(2)) and cisplatin (75 mg/m(2)) day 1 with prophylactic filgrastim was delivered every 21 days for 3 cycles. Subsequent concomitant chemoradiotherapy (CRT) utilized weekly docetaxel (20 mg/m(2)) and concurrent radiotherapy (2 Gy/day) in resectable/resected patients (50 Gy) and in unresectable patients (66 Gy). A total of 78 patients (15 squamous cell carcinoma, 60 adenocarcinoma, 3 mixed/undifferentiated; 68 men, 10 women; median age 61 years) were accrued. The regimen was administered to 59 (76%) potentially resectable patients and 13 (17%) unresectable patients; 6 patients (8%) received the regimen post-operatively. Response rate in 66 evaluable patients following induction chemotherapy was 30%. Sixty-nine patients underwent CRT. Ten patients had disease progression during CRT. Forty-five out of 59 potentially resectable patients underwent esophagectomy after CRT, and 42 patients had complete tumor resection with negative margins. Eighteen out of 59 patients who were potentially resectable patients had pathologic complete response (pCR-31%). Grade 3/4 toxicity during induction chemotherapy included leucopenia, neutropenia, vomiting, and neuropathy. Esophagitis was the predominant toxicity during CRT. Median overall survival was 11.4 months for unresectable patients, 14.3 months for resectable patients and 10.4 months for patients who received the regimen post-operatively (log-rank P = 0.2492). Docetaxel-based CRT regimen is active and tolerable in esophageal cancer. The observed pCR in the potentially resectable group indicates good local control.

Background: Standardization of surgical and pathologic techniques is crucial to the interpretation of studies evaluating adjuvant therapies for pancreatic cancer (PC)., Methods: To assess the degree to which treatment administered prior to enrollment of patients in trials of adjuvant therapy is quality controlled, the operative and pathology reports of patients in American College of Surgeons Oncology Group (ACOSOG) Z5031-a national trial of chemoradiation following pancreaticoduodenectomy (PD)-were rigorously evaluated. We analyzed variables with the potential to influence staging or outcome., Results: 80 patients reported to have undergone R0 (75%) or R1 (25%) pylorus-preserving (38%) or standard (62%) PD were evaluated. A search for metastases was documented in 96% of cases. The proximity of the tumor to the superior mesenteric vein was reported in 69%; vein resection was required in 9% and lateral venorrhaphy in 14%. The method of dissection along the superior mesenteric artery (SMA) was described in 68%, being ultrasonic dissection (17%), stapler (24%), and clamp and cut (59%). SMA skeletonization was described in 25%, and absence of disease following resection was documented in 24%. The surgeon reported marking the critical SMA margin in 25%; inking was documented in 65% of cases and evaluation of the SMA margin was reported in 47%. A range of 1-49 lymph nodes was evaluated. Only 34% of pathology reports met College of American Pathologists criteria., Conclusions: Trials of adjuvant therapy following PD suffer from a lack of standardization and quality control prior to patient enrollment. These data suggest areas for improvement in the design of multidisciplinary treatment protocols.

Esophageal cancer continues to represent a formidable challenge for both patients and clinicians. Relative 5-year survival rates for patients have improved over the past three decades, probably linked to a combination of improved surgical outcomes, progress in systemic chemotherapy and radiotherapy, and the increasing acceptance of multimodality treatment. Surgical treatment remains a fundamental component of the treatment of localized esophageal adenocarcinoma. Multiple approaches have been described for esophagectomy, which can be thematically grouped under two major categories: either transthoracic or transhiatal. The main controversy rests on whether a more extended resection through thoracotomy provides superior oncological outcomes as opposed to resection with relatively limited morbidity and mortality through a transhiatal approach. After numerous trials have addressed these issues, neither approach has consistently proven to be superior to the other one, and both can provide excellent short-term results in the hands of experienced surgeons. Moreover, the available literature suggests that experience of the surgeon and hospital in the surgical management of esophageal cancer is an important factor for operative morbidity and mortality rates, which could supersede the type of approach selected. Oncological outcomes appear to be similar after both procedures.

Objectives: Complete Barrett's eradication endoscopic mucosal resection (CBE-EMR) is the endoscopic removal of all Barrett's epithelium with the curative intent of eliminating high-grade dysplasia (HGD)/intramucosal carcinoma (IMC) and reducing the risk of metachronous lesion development. We report our single tertiary referral center's long-term clinical experience using this modality in HGD/IMC management., Methods: In this study, we retrospectively reviewed all patients who had CBE-EMR for Barrett's esophagus (BE) with HGD/IMC who had been entered into our center's prospectively collected database. High-definition white-light and narrow-band imaging examinations were used according to the protocol. Staging endoscopic ultrasound was done before CBE-EMR to exclude invasive disease or suspicious lymphadenopathy. High-dose proton pump inhibition was instituted after initial treatment, and Seattle-type surveillance biopsies were performed on follow-up every 6 months once the CBE-EMR procedure was completed., Results: A total of 49 patients (mean age 67 years, median 65, s.d. 11; 75% men) with histologically confirmed BE and HGD (33), IMC (16), underwent CBE-EMR from August 2003 to August 2008. The mean BE segment length was 3.2 cm (median 2, s.d. 2.2); 26 patients had short-segment BE, and 30 had visible lesions. A total of 106 EMR procedures were performed. On initial EMR, two patients had superficial submucosal carcinoma invasion (sm1) and two had IMC with lymphatic channel invasion. All four patients were referred for esophagectomy, but one opted for continued endoscopic management, without evidence of residual or recurrent carcinoma. A total of 14 patients await completion of EMR (9) or first follow-up endoscopy (5). CBE-EMR therapy was completed in 32 patients by an average of 2.1 sessions (median 2, s.d. 0.9). Surveillance biopsies showed normal squamous epithelium in 31 of 32 (96.9%) patients (mean remission time 22.9 months, median 17, s.d. 16.7, interquartile range 11-38). In all, 10 of 46 patients who continued in the endoscopic protocol had subsquamous Barrett's epithelium on EMR specimens and/or treatment endoscopy biopsies. Overall, 1 of these 10 patients had Barrett's underneath squamous mucosa on most recent surveillance biopsies. CBE-EMR upstaged pre-EMR pathology results in 7 of 49 (14%) of patients and downstaged pathology in 15 of 49 (31%) patients. In all, 18 of 49 (37%) patients developed symptomatic esophageal stenosis after a mean of 24.4 days (median 13.5, s.d. 27.8); all were successfully managed by endoscopic treatment. No perforations or uncontrollable bleeding occurred., Conclusions: To our knowledge, this is the largest American single-center experience demonstrating that CBE-EMR with close endoscopic surveillance is an effective treatment modality for BE with HGD/IMC. Although the rate of stenosis development is significant, it is easily treated by endoscopic dilation. Patients considering endoscopic ablation should be counseled appropriately. The role of CBE-EMR in patients with lymphatic invasion or superficial submucosal invasion remains to be defined.

Background & Aims: Recent studies have claimed long neoplasia-free survival rates with endoscopic mucosal resection of high-grade dysplasia (HGD) in Barrett's esophagus (BE). However, reports have contended that approximately 40% of patients who have esophagectomy for HGD have occult invasive cancer. The aim of this study was to use explicit criteria to determine the true prevalence of invasive adenocarcinoma in reports of patients who had esophagectomy for HGD in BE., Methods: Studies reporting rates of esophageal cancer in patients who underwent esophagectomy for HGD in BE were gathered using MEDLINE and PUBMED. We defined invasive esophageal adenocarcinoma (IEAC) as tumor with submucosal invasion or beyond. Intramucosal carcinoma (IMC) was not considered IEAC., Results: Twenty-three articles were selected for analysis. Most investigators reported rates of invasive cancer in the esophagectomy specimen, and the pooled average was 39.9% among the 441 patients who underwent an esophagectomy for HGD. Reported rates varied from 0% to 73%. A total of 267 patients had American Joint Committee on Cancer stage 0 postoperatively, 132 patients had stage I, 23 patients had stage IIa, 10 patients had stage IIb, and 9 patients had stage III. Fourteen studies provided differentiation between intramucosal and submucosal invasion. Among 213 patients, only 12.7% had IEAC, whereas 87.3% had HGD or IMC. The IEAC rate of 11% among patients with visible lesions is greater than the rate of 3% among patients with no visible lesion., Conclusions: By using strict pathologic definitions of invasive disease, the present study indicates the true prevalence of IEAC in BE and HGD may have been overestimated significantly. Separating IMC from IEAC is clinically relevant because endoscopic techniques potentially may treat IMC.

Background: Preoperative combined-modality therapy (CMT) is considered the treatment approach of choice for rectal cancer. To examine the effect of CMT on distal intramural spread (DIS), we determined the extent of DIS in rectal cancer specimens after CMT., Methods: Specimens from 20 patients after preoperative CMT and total mesorectal excision for rectal cancer were analyzed for extent of DIS. Specimens were washed, fixed in formalin, and sectioned in 5-mm cuts from the distal border of the residual tumor to the distal resection margin., Results: Eleven patients (55%) had DIS. Two patients had a complete pathologic response (10%). The mean extent of DIS was 0.50 cm (standard deviation, 0.64 cm; range, 0.0 to 2.5 cm). Only 1 patient in the study had DIS beyond 1 cm from the residual tumor. Six of the patients have died at a median of 30.4 months after operation (range, 19.0 to 51.1 months). No correlation was found between the extent of residual DIS and survival., Conclusions: Our study shows that the vast majority of patients with rectal cancer after neoadjuvant CMT have no tumor cells beyond 1 cm from the residual tumor. Our data suggest that a 2-cm margin of resection when feasible from the macroscopic tumor margin after neoadjuvant CMT is adequate.

We did expressional profiling on 24 paired samples of normal esophageal epithelium, Barrett's metaplasia, and esophageal adenocarcinomas. Matching tissue samples representing the three different histologic types were obtained from each patient undergoing esophagectomy for adenocarcinoma. Our analysis compared the molecular changes accompanying the transformation of normal squamous epithelium with Barrett's esophagus and adenocarcinoma in individual patients rather than in a random cohort. We tested the hypothesis that expressional profiling may reveal gene sets that can be used as molecular markers of progression from normal esophageal epithelium to Barrett's esophagus and adenocarcinoma. Expressional profiling was done using U133A GeneChip (Affymetrix), which represent approximately two thirds of the human genome. The final selection of 214 genes permitted the discrimination of differential gene expression of normal esophageal squamous epithelium, Barrett's esophagus, and adenocarcinoma using two-dimensional hierarchical clustering of selected genes. These data indicate that transformation of Barrett's esophagus to adenocarcinoma is associated with suppression of the genes involved in epidermal differentiation, including genes in 1q21 loci and corresponding to the epidermal differentiation complex. Correlation analysis of genes concordantly expressed in Barrett's esophagus and adenocarcinoma revealed 21 genes that represent potential genetic markers of disease progression and pharmacologic targets for treatment intervention. PCR analysis of genes selected based on DNA array experiments revealed that estimation of the ratios of GATA6 to SPRR3 allows discrimination among normal esophageal epithelium, Barrett's dysplasia, and adenocarcinoma.

The efficacy of replication-deficient adenoviral vectors in gene therapy is confined to the number of tumor cells the vector infects. To focus and enhance the therapeutic efficacy, we employed a conditionally replication-competent adenoviral vector with a tissue-specific promoter, DF3/MUC1, in a human esophageal adenocarcinoma model. Our results demonstrate that Ad.DF3.E1A.CMV.TNF (Ad.DF3.TNF) specifically replicates in Bic-1 (DF3-producing cells) and mediates an enhanced biologic effect due to increased TNF-alpha in the same DF3-producing cells. We also show that the increased TNF-alpha interacts with ionizing radiation to produce greater tumor regression and a greater delay in tumor regrowth in Bic-1 (DF3-producing cells) compared to Seg-1 (DF3 non-producers). Tumor cell targeting using conditionally replication-competent adenoviral vectors with tumor-specific promoters to drive viral replication and deliver TNF-alpha provides a novel approach to enhancing tumor radiosensitivity.

Gene therapy is a modality for the treatment of solid tumors that involves the introduction of a suicide gene into the tumor cells. Genetic radiotherapy involves the placement of a radiation-sensitive promoter upstream from a suicide gene. Because of their irregular vasculature some solid tumors are chronically hypoxic and hence are resistant to conventional treatment with chemotherapy and ionizing radiation (IR). The purpose of this study was to demonstrate that regional tumor hypoxia could be exploited to improve local tumor control. The cDNA coding the erythropoietin hypoxia-responsive element (EPO) was placed upstream from the Egr-TNF-alpha construct. WIDR human colon adenocarcinoma cells were injected into the right hind limb of nude mice and treated with Epo-Egr-TNF-alpha plasmid with or without IR. Tumor volumes were measured by calipers and tumor necrosis factor (TNF)-alpha content of the tumor was determined by enzyme-linked immunosorbent assay. Treatment with the combined regimen of Epo-Egr-TNF-alpha plasmid + IR resulted in significant tumor growth delay. Tumor TNF-alpha content was increased by 30 per cent in the combined treatment group compared with each treatment alone. Regional tumor hypoxia can be exploited successfully to induce tumor growth delay, enhance local control, and enhance the therapeutic ratio.

Background: The ability to infect tumor cells limits the antitumor effects of gene therapy. The addition of radiotherapy to treatment with Ad.Egr.TNF.11D, a replication-deficient adenovirus containing a radiation-inducible promoter, early growth response-1, and the tumor necrosis factor-alpha (TNFalpha) complementary DNA may enhance the therapeutic ratio., Methods: Seg-1 human esophageal adenocarcinoma cells were treated with Ad.Egr.TNF.11D with or without radiation. TNFalpha levels were quantified with enzyme-linked immunosorbent assay. Athymic nude mice bearing Seg-1 tumors were randomized to buffer, ionizing radiation, Ad.Egr.TNF.11D, and combination therapy. Tumor growth delay was used to compare treatment regimens. TNFalpha levels were measured in tumor homogenates and plasma., Results: Seg-1 cells treated with Ad.Egr.TNF.11D and ionizing radiation demonstrated increased TNFalpha levels at 72 hours compared with cells exposed to vector alone (124 +/- 0 pg/mL vs. 31.11 +/- 22 pg/mL; P =.008). In vivo, Ad.Egr.TNF.11D-treated tumors expressed low TNFalpha levels (151.5 +/- 107.11 pg/mg protein) compared with tumors receiving combined treatment (793.92 +/- 489.13 pg/mg protein; P =.067). Increased TNFalpha levels were associated with increased tumor growth delay after combined treatment (P <.05)., Conclusions: Radiotherapy enables focal stimulation of TNFalpha expression in Ad.Egr.TNF.11D-infected cells and thus improves local tumor control.

Background/objectives: Uracil and tegafur in a 4:1 molar concentration ratio (UFT; Bristol-Myers Squibb, Wallingford, CT) has broad anti-tumor activity for cancers arising from the gastrointestinal tract. However, there are no published data regarding the efficacy of leucovorin-modulated UFT in patients with pancreatic cancer. The objective of this trial was to determine the activity and evaluate the toxicity of UFT plus oral calcium leucovorin in patients with advanced pancreatic adenocarcinoma., Patients and Methods: Fourteen patients with advanced measurable adenocarcinoma of the pancreas were enrolled onto the trial. Patients received 300 mg/m2/d UFT plus 90 mg/d leucovorin administered orally in divided doses every eight hours for 28 days repeated every 35 days. Objective tumor response was evaluated after two courses of therapy., Results: Fourteen patients were evaluable for response and toxicity. No objective responses were seen. The median (range) time to progression and survival were 14 (1.6-37), and 15 (1.9-62) weeks, respectively. Toxicity was mild with severe (grade 3 or 4) hyperbilirubinemia, pain, diarrhea, transaminitis, venous thrombus, weakness, renal failure, confusion, and edema/ascites seen in three (21%), one (7%), two (14%), one (7%), one (7%), one (7%), one (7%), one (7%), and two (14%) patients, respectively., Conclusion: In the 14 patients evaluable, UFT 300 mg/m2/d plus oral leucovorin 90 mg/d administered for 28 days did not demonstrate anti-tumor activity against advanced pancreatic adenocarcinoma; however, this oral regimen was well tolerated and devoid of neutropenia, significant oral mucositis or diarrhea.

Purpose: To determine whether combination 5-fluorouracil, cisplatin, and interferon alfa, an active regimen in advanced esophageal cancer, is efficacious as induction therapy before esophagectomy., Materials and Methods: Forty-four patients with potentially resectable esophageal/gastroesophageal junction adenocarcinoma or squamous cell carcinoma were entered into a phase I/II study of this chemotherapeutic regimen and concurrent external-beam radiotherapy before resection. The initial 16 patients were treated with prolonged-infusion 5-fluorouracil (300 mg/m2 on days 1 to 28), cisplatin (20 mg/m2 on days 1 to 5 and 24 to 28), interferon alfa (3 x 10(6) U/m2 intravenously on days 1 to 5 and 24 to 28; subcutaneous injection every other day on days 6 to 23), and radiation (4000 cGy). The subsequent 28 patients were treated over 21 days with two modifications: dose escalation of 5-fluorouracil (250 to 350 mg/m2) and double-fractionated radiotherapy to a total dose of 4500 cGy., Results: Forty-one patients completed chemoradiotherapy and were evaluable for toxicity. Adverse events were substantial but tolerable, and most toxic episodes were hematologic and gastrointestinal. Three patients died, and one patient had progressive disease before resection. Of the 37 patients eligible for curative resection, 36 had all gross tumor removed. Thirty-three (80%) patients had a major pathologic response: 10 (24%) with no residual tumor and 23 with only microscopic residual tumor. Median survival for all patients was 27 months and for responders was 36 months., Conclusions: This combination regimen is active but yields results similar to those of other chemoradiotherapy phase II trials; therefore, the contribution of interferon alfa to treatment efficacy remains uncertain. The true worth of preoperative chemoradiotherapy is unknown pending results of phase III trials.

Background: Preoperative chemoradiation therapy (CRT) potentially benefits a subgroup of patients with esophageal cancer. The ability to administer aggressive CRT may depend on the initial nutritional status and the ability to sustain nutrition during therapy. Parenteral nutrition support during CRT may lead to complications that limit its usefulness and negate any potential benefit., Methods: Data were analyzed to evaluate the role of parenteral nutrition support (PNS) in patients receiving CRT. Forty-five consecutive patients with locoregional esophageal cancer, enrolled in a phase I/II trial of induction CRT, were analyzed. On the basis of the nutrition support received, two groups were defined as follows: group I (with PNS, n = 30) and group II (without PNS, n = 15). Results were compared in terms of chemotherapy (CT) dose tolerated, morbidity of CRT, response rates, and surgical outcome in groups with and without PNS., Results: The two groups were comparable for demographic data, stage and site of disease, and performance status. There was no significant difference between the groups in the nutritional parameters (weight and serum albumin) before and after CRT. Group I patients received significantly more (% of total calculated dose) CT compared with group II (5-fluorouracil [5-FU], 86.4% vs 68.8%, p = .02; cisplatin [CDDP], 90.8% vs 78.2%, p = .05; and interferon alpha-2b [IFN-alpha], 95.4% vs 79.8%, p = .05, in groups I and II, respectively). Major (grade III/IV) adverse effects of CT were hematologic (group I, 93.3% vs group II, 86.6%, p = .59) and gastrointestinal (group I, 56.67% vs group II, 33.3%, p = .2). Postsurgical staging revealed complete response in 10 (22%) and a major response in 23 (51%) patients, although the response rates were similar in the two groups (group I, 76.6% vs group II, 66.6%, p = .8). Surgical morbidity (51.8% vs 61.5%, p = .73), mortality (7.4% vs 7.6%, p = 1.00), and hospital stay (22.5 vs 19.6 days, p = .63) were also similar in the two groups., Conclusions: PNS can be provided to these patients without an increased risk of CRT or resection-related morbidity. Although early and prolonged PNS facilitates administration of complete CRT doses, no benefit is derived from the administration of more CRT in the present regimen. The utility of PNS in this setting is unclear and, until further clarified, should not be applied routinely to this cohort of patients.