Total Lesion Glycolysis Assessment Identifies a Patient Fraction With a High Cure Rate Among Esophageal Adenocarcinoma Patients Treated With Definitive Chemoradiation.

OBJECTIVE: We aimed to determine whether tumor metabolism could be prognostic of cure in L-EAC patients who receive definitive chemoradiation. SUMMARY BACKGROUND DATA: Patients with inoperable localized esophageal adenocarcinoma (L-EAC) often receive definitive chemoradiation; however, biomarkers and/or imaging variables to prognosticate cure are missing. METHODS: Two hundred sixty-six patients with L-EAC who had chemoradiation but not surgery were analyzed from the prospectively maintained EAC databases in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center (Texas, USA) between March 2002 and April 2015. Maximum standardized uptake value (SUVmax) and total lesion glycolysis (TLG) from the positron emission tomography data were evaluated. RESULTS: Of 266 patients, 253 (95%) were men; the median age was 67 years (range 20-91 yrs) and 153 had poorly differentiated L-EAC. The median SUVmax was 10.3 (range 0-87) and the median TLG was 85.7 (range 0-3227). Both SUVmax and TLG were higher among those with: tumors >5 cm in length, high clinical stage, and high tumor and node categories by TNM staging (all P < 0.0001). Of 234 patients evaluable for cure, 60 (25.6%) achieved cure. In the multivariable logistic regression model, low TLG (but not low SUVmax) was associated with cure (continuous TLG value: odds ratio 0.70, 95% confidence interval (CI) 0.54-0.92). TLG was quantified into 4 quartile categorical variables; first quartile (Q1; <32), second quartile (Q2; 32.0-85.6), third quartile (Q3; 85.6-228.4), and fourth quartile (Q4; >228.4); the cure rate was only 10.3% in Q4 and 5.1% in Q3 but increased to 28.8% in Q2, and 58.6% in Q1. The cross-validation resulted in an average accuracy of prediction score of 0.81 (95% CI, 0.75-0.86). CONCLUSIONS: In this cross-validated model, 59% of patients in the 1st quartile were cured following definitive chemoradiation. Baseline TLG could be pursued as one of the tools for esophageal preservation.

Surgeon Assessment of Gastric Cancer Lymph Node Specimens with a Video of Technique.

INTRODUCTION: In the majority of US institutions, gastrectomy specimens are sent for pathologic examination without surgeon assessment or standardized technique of lymph node (LN) assessment for gastric cancer. We conducted a quality improvement project at a US cancer center utilizing surgeon assessment of gastric LNs, and created a video to illustrate a technique of standardized lymph node assessment. METHODS: Convenience sampling was employed among patients with gastric adenocarcinomas who underwent curative-intent D2 gastrectomy between July 2016 and June 2017. For each patient, a surgeon assessed gastric LNs by harvesting individual LNs, followed by conventional evaluation by a pathologist. RESULTS: We enrolled 17 patients for this quality improvement project. Eight patients underwent total gastrectomy, and nine patients underwent subtotal gastrectomy. Twelve patients underwent preoperative chemoradiation therapy, three underwent preoperative chemotherapy alone, and two underwent upfront surgery. The median number of examined LNs was 43. All patients had ≥ 16 LNs examined, and 88% of patients had ≥ 30 LNs examined. CONCLUSION: Surgeon assessment of gastric LN specimens was feasible and effective to provide high-quality pathologic LN assessment after gastrectomy in gastric adenocarcinoma patients. Standardization of the technical methods for gastric LN evaluation is needed to improve the accuracy and quality of gastric cancer staging in the US. The provided video can help inform standardization of gastric LN assessment.

Racial disparities in preoperative chemotherapy use in gastric cancer patients in the United States: Analysis of the National Cancer Data Base, 2006-2014.

BACKGROUND: No studies have investigated whether race/ethnicity is associated with the recommended use of preoperative chemotherapy or subsequent outcomes in gastric cancer. To determine whether there is such an association, analyses of patients with gastric cancer in the National Cancer Data Base (NCDB) were performed. METHODS: Patients with clinical T2-4bN0-1M0 gastric adenocarcinoma, as defined by the eighth edition of the American Joint Committee on Cancer staging manual, who underwent gastrectomy from 2006 to 2014 were identified from the NCDB. Multiple logistic regression was conducted to examine factors associated with preoperative chemotherapy use. RESULTS: This study identified 16,945 patients who met the criteria, and 8286 of these patients (49%) underwent preoperative chemotherapy. The use of preoperative chemotherapy remarkably increased over the study period, from 34% in 2006 to 65% in 2014. Preoperative chemotherapy was more commonly used for cardia tumors than noncardia tumors (83% vs 44% in 2014). In a multivariable analysis, races and ethnicities other than non-Hispanic (NH) white race were associated with less frequent use of preoperative chemotherapy in comparison with NH whites after adjustments for social, tumor, and hospital factors. The insurance status and the education level mediated an enhanced effect of racial/ethnic disparities in preoperative chemotherapy use. The use of preoperative chemotherapy and radiation therapy was associated with reduced racial/ethnic disparities in overall survival. CONCLUSIONS: Racial/ethnic disparities in the use of preoperative chemotherapy and in outcomes exist among patients with gastric cancer in the United States. Efforts to improve the access to high-quality cancer care in minority groups may reduce racial disparities in gastric cancer in the United States. Cancer 2018;124:998-1007. © 2018 American Cancer Society.

Medical management of gastric cancer: a 2017 update.

Gastric cancer remains a considerable health burden throughout the world. The Cancer Genome Atlas (TCGA) analysis has recently unveiled 4 genotypes of gastric cancer with data not ready to change treatment strategy yet. A multimodality approach to therapy is the cornerstone of screening, diagnosing, staging, treating and supporting patients with gastric cancer. The evidence-based approach to localized gastric cancer (>cT1b) is to use an either preoperative or postoperative strategy to maximize the benefit of surgery. The focus of future research is to optimize chemotherapy regimens, determine the role of radiation therapy and investigate the effect of treatment timing. In metastatic gastric cancer, biologic therapies have been introduced targeting markers shown to be prognostic. The results of ongoing randomized controlled phase 3 trials using targeted and immunotherapy agents, either in combination or alone, have the potential to alter the current treatment landscape of advanced gastric cancer.

Patterns of relapse in patients with localized gastric adenocarcinoma who had surgery with or without adjunctive therapy: costs and effectiveness of surveillance.

PURPOSE: After therapy of localized gastric adenocarcinoma (GAC) patients, the costs of surveillance, relapse patterns, and possibility of salvage are unknown. MATERIALS AND METHODS: We identified 246 patients, who after having a negative peritoneal staging, received therapy (any therapy which included surgery) and were surveyed (every 3-6 months in the first 3 years, then yearly; ∼10 CTs and ∼7 endoscopies per patient). We used the 2016 Medicare dollars reimbursed as the "costs" for surveillance. RESULTS: Common features were: Caucasians (57%), men (60%), poorly differentiated histology (76%), preoperative chemotherapy (74%), preoperative chemoradiation (59%), and had surgery (100%). At a median follow-up of 3.7 years (range, 0.1 to 18.3), the median overall survival (OS) was 9.2 years (95% CI, 6.0 to 11.2). Tumor grade (p = 0.02), p/yp stage (p < 0.001), % residual GAC (p = 0.05), the R status (p = 0.01), total gastrectomy (p = 0.001), and relapse type (p = 0.02) were associated with OS. Relapse occurred in 79 (32%) patients (only 8% were local-regional) and 90% occurred within 36 months of surgery. P/yp stage (p < 0.001) and total gastrectomy (p = 0.01) were independent prognosticators for OS in the multivariate analysis. Only 1 relapsed patient had successful salvage therapy. The estimated reimbursement for imaging studies and endoscopies was $1,761,221.91 (marked underestimation of actual costs). CONCLUSIONS: The median OS of localized GAC patients was excellent with infrequent local-regional relapses. Rigorous surveillance had a low yield and high "costs". Our data suggest that less frequent surveillance intervals and limiting expensive investigations to symptomatic patients may be warranted.

Is endoscopic ultrasound examination necessary in the management of esophageal cancer?

Despite substantial efforts at early diagnosis, accurate staging and advanced treatments, esophageal cancer (EC) continues to be an ominous disease worldwide. Risk factors for esophageal carcinomas include obesity, gastroesophageal reflux disease, hard-alcohol use and tobacco smoking. Five-year survival rates have improved from 5% to 20% since the 1970s, the result of advances in diagnostic staging and treatment. As the most sensitive test for locoregional staging of EC, endoscopic ultrasound (EUS) influences the development of an optimal oncologic treatment plan for a significant minority of patients with early cancers, which appropriately balances the risks and benefits of surgery, chemotherapy and radiation. EUS is costly, and may not be available at all centers. Thus, the yield of EUS needs to be thoughtfully considered for each patient. Localized intramucosal cancers occasionally require endoscopic resection (ER) for histologic staging or treatment; EUS evaluation may detect suspicious lymph nodes prior to exposing the patient to the risks of ER. Although positron emission tomography (PET) has been increasingly utilized in staging EC, it may be unnecessary for clinical staging of early, localized EC and carries the risk of false-positive metastasis (over staging). In EC patients with evidence of advanced disease, EUS or PET may be used to define the radiotherapy field. Multimodality staging with EUS, cross-sectional imaging and histopathologic analysis of ER, remains the standard-of-care in the evaluation of early esophageal cancers. Herein, published data regarding use of EUS for intramucosal, local, regional and metastatic esophageal cancers are reviewed. An algorithm to illustrate the current use of EUS at The University of Texas MD Anderson Cancer Center is presented.

Clinical Benefit and Health-Related Quality of Life Assessment in Patients Treated with Cisplatin/S-1 Versus Cisplatin/5-FU: Secondary End Point Results From the First-Line Advanced Gastric Cancer Study (FLAGS).

PURPOSE: Patient-reported outcomes (PRO) of health-related quality of life (HRQoL) and time to worsening of clinical benefit parameters were evaluated as secondary end points in the phase 3 first-line advanced gastric cancer study (FLAGS) trial of cisplatin/S-1 versus cisplatin/5-fluorouracil (5-FU) in patients with previously untreated advanced gastric cancer. METHODS: The primary PRO end point was the Trial Outcome Index of the Functional Assessment of Cancer Therapy-Gastric (FACT-Ga). FACT-Ga was completed at the beginning of the first 4 cycles, cycle 6, and then every 3 cycles thereafter. The Chemotherapy Convenience and Satisfaction Questionnaire (CCSQ) was administered before the first 4 cycles; clinical benefit parameters (performance status, weight loss, and anorexia) were assessed at baseline, prior to study drug administration on day 1 of each cycle after cycle 1, and at the end of study treatment. RESULTS: Compliance to questionnaire fulfillment was more than 80 % through cycle 9. Significantly, fewer patients treated with cisplatin/S-1 reported worsened physical well-being (PWB) scores (45.1 versus 51.7 %, p = 0.044) and experienced significantly longer time to worsening in PWB scores, with a median of 4.5 months (95 % confidence interval (CI), 3.1-5.1) compared to 3.0 months (2.8-4.6) with cisplatin/5-FU (CF) (p = 0.01). Patients receiving cisplatin/S-1 also reported significantly higher best and worst score of PWB as well as CCSQ scores and a longer median time to worsening in clinical benefit parameters. CONCLUSIONS: Differences in secondary end points of PWB, CCSQ scores, and clinical benefit parameters favoring the cisplatin/S-1 arm provide further evidence for considering this combination a standard therapeutic option for first-line treatment of advanced gastric cancer.

Anti-angiogenic agent ramucirumab: meaningful or marginal?

Ramucirumab (IMC-1121B) targets VEGFR-2. Ramucirumab is being investigated in many malignancies including gastric cancer. The Phase III trial in patients with advanced breast cancer failed to improve the primary end point The REGARD trial, a Phase III study, in patients with advanced gastric cancer in the second line setting, had a marginal improvement in overall survival but did not achieve the expected hazard ratio target (of 0.69) and the median duration of therapy with ramucirumab was meager 8 weeks (only 2 weeks longer than the placebo's). Other notable agents in the second line setting are docetaxel and irinotecan. Preliminary results of the RAINBOW trial suggest that ramucirumab may be providing more than marginal advantage. In this review, we briefly summarize the process of angiogenesis and address the emerging cost-benefit issues that surround all newly developed agents including ramucirumab.

Risk assessment of esophageal adenocarcinoma using γ-H2AX assay.

BACKGROUND: Mutagen-induced DNA damage as measured in peripheral blood lymphocytes (PBL) has been associated with increased risks of cancers. The formation of γ-H2AX is an early cellular response to DNA double-strand breaks (DSB). We hypothesize that higher level of radiation-induced γ-H2AX in PBLs may be associated with an increased risk of esophageal adenocarcinoma. METHODS: Laser scanning cytometer-based immunocytochemical method was used to measure baseline and irradiation-induced γ-H2AX levels in PBLs from 211 patients with esophageal adenocarcinoma and 211 healthy controls. The ratio of induced γ-H2AX level to baseline level was used to evaluate individual susceptibility to DSBs. Relative risks for esophageal adenocarcinoma associated with γ-H2AX were assessed by multivariable logistic regression analysis. RESULTS: Radiation-induced γ-H2AX level and the γ-H2AX ratio were significantly higher in cases than in controls. Dichotomized at the median in controls, a significantly increased risk for esophageal adenocarcinoma was observed in association with high γ-H2AX ratio [OR = 2.94; 95% confidence interval (CI), 1.83-4.72]. Quartile analyses showed significant dose-response associations between higher γ-H2AX ratio and increased risk of esophageal adenocarcinoma (Ptrend, 1.64E-06). In addition, joint effect between γ-H2AX ratio and smoking was observed: smokers who had high γ-H2AX ratio exhibited the highest risk of esophageal adenocarcinoma (OR = 5.53; 95% CI, 2.71-11.25) compared with never smokers with low γ-H2AX ratio. CONCLUSION: Radiation-induced DNA damage assessed by γ-H2AX ratio is associated with an increased risk of esophageal adenocarcinoma. IMPACT: γ-H2AX assay is a new and robust method to measure DSB damage in PBLs, which can be used to assess mutagen sensitivity and esophageal adenocarcinoma risk.

American Society of Clinical Oncology clinical practice guideline update on the use of chemotherapy sensitivity and resistance assays.

PURPOSE: To update the American Society of Clinical Oncology (ASCO) Technology Assessment guidelines on chemotherapy sensitivity and resistance assays (CSRAs) published in 2004. METHODS: An Update Working Group reviewed data published between December 1, 2003, and May 31, 2010. MEDLINE and the Cochrane Library were searched. The literature search yielded 11,313 new articles. The limits for "human and English" were used, and then standard ASCO search strings for randomized controlled trials, meta-analyses, guidelines, and reviews were added, yielding 1,298 articles for abstract review. Of these, only 21 articles met predefined inclusion criteria and underwent full text review, and five reports of randomized controlled trials were included for data extraction. RESULTS: Review of the literature does not identify any CSRAs for which the evidence base is sufficient to support use in oncology practice. RECOMMENDATIONS: The use of CSRAs to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting. Oncologists should make chemotherapy treatment recommendations based on published reports of clinical trials and a patient's health status and treatment preferences. Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority.

Assessment of K-ras mutation: a step toward personalized medicine for patients with colorectal cancer.

Some of the most significant therapeutic advances in the treatment of cancer have occurred in the management of colorectal metastases. The introduction of new cytotoxic chemotherapeutic and biologic agents has changed the approach to these patients from both an oncologic and a surgical perspective. In addition, an understanding of the molecular mechanisms by which these agents affect tumors is developing. This molecular information will be critical in the future in designing therapeutic regimens based on an individual tumor's genetic profile rather than treatment for a specific tumor type. The rapidly evolving treatment of colon cancer has provided several interesting genetic biomarkers/pathways/genes-/kinases that have been targeted or seem to play an important role. Of particular interest is the blockade of epidermal growth factor receptor (EGFR) with monoclonal antibodies. This treatment is efficacious when used alone or combined with chemotherapy. However, recent data revealed that patients with tumors positive for the K-ras mutation do not benefit from EGFR blockade. Compelling evidence has indicated that mutated K-ras is an important oncogene involved at the early stage of the development of colorectal cancer. Furthermore, mutations in the K-ras gene have been associated with aggressive tumor biology. K-ras mutational analysis is an important step in the overarching goal of developing personalized medicine. New treatment strategies are needed to more effectively treat patients with the K-ras mutation.

Patterns of care and locoregional treatment outcomes in older esophageal cancer patients: The SEER-Medicare Cohort.

PURPOSE: Optimal management of elderly patients with nonmetastatic esophageal cancer is unclear. Outcomes data after locoregional treatment are lacking for this group. METHODS: We assessed outcomes associated with standard locoregional treatments in 2,626 patients (age > 65 years) from the Surveillance Epidemiology and End Results (SEER)-Medicare cohort diagnosed with nonmetastatic esophageal cancer from 1992 to 2002. In patients treated with radiotherapy alone (RT), surgery alone (S), chemoradiotherapy (CRT), or preoperative chemotherapy followed by surgery (CRT + S), overall and disease-free survival were compared using proportional hazards regression. Postoperative complications were compared using logistic regression. RESULTS: Mean age was 76 +/- 6 years. Seven percent underwent CRT + S, 39% CRT, 30% S, and 24% RT. One-year survival was 68% (CRT + S), 52% (CRT), 53% (S), and 16% (RT), respectively (p < 0.001). Patients who underwent CRT + S demonstrated improved overall survival compared with S alone (hazard ratio [HR] = 0.81; 95% confidence interval [CI], 0.66-0.98; p = 0.03) and RT (HR = 0.44; 95% CI, 0.35-0.55; p < 0.0001); and comparable survival to CRT (HR = 0.82; 95% CI, 0.67-1.01; p = 0.06). Patients who underwent CRT + S also had comparable postoperative mortality (HR = 0.96; 95% CI, 0.87-1.07; p = 0.45) and complications (OR = 0.89; 95% CI, 0.70-1.14; p = 0.36) compared with S alone. CONCLUSIONS: Preoperative chemoradiotherapy may be an acceptable treatment option in appropriately selected older esophageal cancer patients. This treatment modality did not appear to increase surgical complications and offered potential therapeutic benefit, particularly compared with surgery alone.

Preoperative chemo-radiation-induced ulceration in patients with esophageal cancer: a confounding factor in tumor response assessment in integrated computed tomographic-positron emission tomographic imaging.

HYPOTHESIS: Positron emission tomography can be useful in predicting response of esophageal cancer after preoperative chemo-radiation therapy (CRT). We evaluated the use of integrated computed tomography (CT)-PET among patients with esophageal cancer being considered for resection after CRT. METHODS: Three reviewers blinded to clinical and pathologic staging retrospectively reviewed the CT-PET scans of patients with esophageal cancer after preoperative CRT who underwent esophagectomy. [F]-fluoro-2-deoxy-D-glucose uptake for residual malignancy was determined by visual analysis and semi-quantitatively when standardized uptake value (SUV) was > or =4. RESULTS: Forty-two patients underwent esophageal resection. Using visual analysis, CT-PET had a sensitivity of 47% and specificity of 58% in detecting residual malignancy. Using semi-quantitative analysis, 19 patients had a SUV > or =4 in the region of the primary esophageal tumor and were interpreted as having residual malignancy (sensitivity 43%, specificity 50%). Of these 19, six had complete pathologic response to CRT. These false-positive results, due to therapy-induced ulceration detected at endoscopy, limit the use of CT-PET alone in detecting residual malignancy. Similarly, sensitivity (25%) and specificity (73%) of endoscopy/biopsy in detecting residual malignancy were poor. However, the accuracy of CT-PET in detecting residual malignancy was improved when combined with endoscopic findings. In the absence of ulceration at endoscopy, 8 of 8 patients with SUV > or =4 after chemo-radiation had residual malignancy at surgery. CONCLUSIONS: CRT-induced ulceration results in false-positive results on CT-PET and precludes accurate detection of residual esophageal tumor. However, CT-PET in combination with endoscopy is useful in identifying patients with a high risk of residual tumor post-CRT.

Predictors of esophageal cancer risk: assessment of susceptibility to DNA damage using comet assay.

Individuals' susceptibility to DNA damage could be identified by mutagen-challenged assays. We tested the hypothesis that susceptibility to DNA damage, measured by comet assay, may be associated with increased esophageal cancer (EC) risk. We recruited 102 subjects with previously untreated EC and 112 healthy controls. Baseline (untreated), benzo[a]pyrene diol epoxide (BPDE)-induced, and gamma-radiation-induced DNA damage were quantified by the Olive tail moment parameter. The mean tail moment was significantly higher in cases than in controls at baseline (case vs. control: 2.6 vs. 1.9, P < 0.01), after BPDE induction (case vs. control: 3.8 vs. 2.7, P < 0.01), and after gamma-radiation-induction (case vs. control: 5.0 vs. 3.8, P < 0.01). When data were dichotomized with the median values in the controls, a significantly increased risk for EC was observed for high baseline tail moment [odds ratio (OR) = 5.7, 95% confidence interval (CI) = 2.9-11.4], high BPDE-induced tail moment (OR = 5.8, 95% CI = 2.9-11.8), and high gamma-radiation-induced tail moment (OR = 4.6, 95% CI = 2.4-8.8). Further, the association between DNA damage and EC was stronger in never smokers than in ever smokers. Compared with subjects not sensitive to both mutagens, individuals sensitive to only one mutagen showed a 3.4-fold risk for EC and those sensitive to both mutagens showed an 8.7-fold risk for EC. Thus, we conclude that susceptibility to DNA damage as assessed by comet assay might help identify individuals with high EC risk.