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Background: Cancer Associated Macrophage-Like cells (CAMLs) are polynucleated circulating stromal cells found in the bloodstream of numerous solid-tumor malignancies. Variations within CAML size have been associated with poorer progression free survival (PFS) and overall survival (OS) in a variety of cancers; however, no study has evaluated their clinical significance in esophageal cancer (EC)., Methods: To examine this significance, we ran a 2 year prospective pilot study consisting of newly diagnosed stage I-III EC patients (n = 32) receiving chemoradiotherapy (CRT). CAML sizes were sequentially monitored prior to CRT (BL), ~ 2 weeks into treatment (T1), and at the first available sample after the completion of CRT (T2)., Results: We found CAMLs in 88% (n = 28/32) of all patient samples throughout the trial, with a sensitivity of 76% (n = 22/29) in pre-treatment screening samples. Improved 2 year PFS and OS was found in patients with CAMLs < 50 μm by the completion of CRT over patients with CAMLs ≥ 50 μm; PFS (HR = 12.0, 95% CI = 2.7-54.1, p = 0.004) and OS (HR = 9.0, 95%CI = 1.9-43.5, p = 0.019)., Conclusions: Tracking CAML sizes throughout CRT as a minimally invasive biomarker may serve as a prognostic tool in mapping EC progression, and further studies are warranted to determine if presence of these cells prior to treatment suggest diagnostic value for at-risk populations.

Objective: To discern recurrence risk stratification and investigate its influence on postoperative surveillance in patients with esophageal adenocarcinoma (EAC) after neoadjuvant chemoradiotherapy (CRT)., Background: Reports documenting recurrence risk stratification in EAC after neoadjuvant CRT are scarce., Methods: Between 1998 and 2014, 601 patients with EAC who underwent neoadjuvant CRT followed by esophagectomy were included for analysis. The pattern, site, timing, and frequency of the first recurrence and potential prognostic factors for developing recurrences were analyzed. This cohort was used as the training set to propose a recurrence risk stratification system, and the stratification was further validated in another cohort of 172 patients., Results: A total of 150 patients (25.0%) achieved pathologic complete response (pCR) after neoadjuvant CRT and the rest were defined as the non-pCR group (n = 451) in the training cohort. After a median follow-up of 63.6 months, the pCR group demonstrated a significantly lower locoregional (4.7% vs 19.1%) and distant recurrence rate (22.0% vs.44.6%) than the non-pCR group (P < 0.001). Based on independent prognostic factors, patients were stratified into 4 recurrence risk categories: pCR with clinical stage I/II, pCR with clinical stage III, non-pCR with pN0, and non-pCR with pN+, with corresponding 5-year recurrence-free survival rates of 88.7%, 65.8%, 55.3%, and 33.0%, respectively (P < 0.001). The risk stratification was reproducible in the validation cohort., Conclusions: We proposed a recurrence risk stratification system for EAC patients based on pathologic response and pretreatment clinical stage. Risk-based postoperative surveillance strategies could be developed for different risk categories.

Background and Purpose: Circulating lymphocytes are exquisitely sensitive to radiation exposure, even to low scattered doses which can vary drastically between radiation modalities. We compared the relative risk of radiation-induced lymphopenia between intensity modulated radiation therapy (IMRT) or proton beam therapy (PBT) in esophageal cancer (EC) patients undergoing neoadjuvant chemoradiation therapy (nCRT)., Material and Methods: EC patients treated with IMRT and PBT were propensity matched based on key clinical variables. Treatment-associated lymphopenia was graded using CTCAE v.4.0. Using matched cohorts, univariate and multivariable multiple logistic regression was used to identify factors associated with increased risk of grade 4 lymphopenia as well as characterize their relative contributions., Results: Among the 480 patients treated with nCRT, 136 IMRT patients were propensity score matched with 136 PBT patients. In the matched groups, a greater proportion of the IMRT patients (55/136, 40.4%) developed grade 4 lymphopenia during nCRT compared with the PBT patients (24/136, 17.6%, P < 0.0001). On multivariable analysis, PBT was significantly associated with a reduction in grade 4 lymphopenia risk (odds ratio, 0.29; 95% confidence interval, 0.16-0.52; P < 0.0001)., Conclusion: PBT is associated with significant risk reduction in grade 4 lymphopenia during nCRT in esophageal cancer., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: A randomised phase 2 trial of trimodality with or without induction chemotherapy (IC) in oesophageal cancer (EC) patients showed no advantage in overall survival (OS) or pathologic complete response rate. To identify subsets that might benefit from IC, a secondary analysis was done., Methods: The trial had accrued 126 patients (NCT 00525915). Recursive partitioning and proportional hazards regression with interactions were performed., Results: The median follow-up of surviving patients was 6.7 years and the median OS duration was 3.8 years (95% confidence interval (CI), 2.6-5.8 years). OS was associated with tumour length (P=0.03), cT (P=0.02), cN (P=0.04), clinical stage (P=0.01), and tumour grade (P<0.001). The effect of IC differed according to tumour grade. Among patients with well or moderately differentiated (WMD) ECs (n=59), the 5-year survival rate was 74% with IC and 50% without IC, P=0.001. IC had no effect on OS of patients with poorly differentiated (PD) ECs (31% and 28%, respectively; interaction, P=0.04; IC, P=0.03). In the multivariate reduced model, WMD with IC was an independent prognosticator for better OS (HR=0.41, 95% CI, 0.25-0.67; P=<0.001). The following four EC phenotypes emerged for OS: (1) very high risk (PD, cN2/N3), (2) high risk (PD, cN0/N1, stage cIII), (3) moderate risk (PD, cN0/N1, stage cI/II or WMD without IC), and (4) low risk (WMD with IC). The 5-year survival rates were 11%, 27%, 48%, and 74%, respectively (P<0.001)., Conclusions: Our data show that IC significantly prolonged OS of WMD EC patients who undergo trimodality; prospective evaluation is needed.

Background: Early metabolic response after preoperative induction chemotherapy (IC) appears to predict histologic response and prognosis in esophageal cancer (EC), but the usefulness of this approach needs further development., Objective: We evaluated metabolic response after one cycle of IC using positron emission tomography (PET) to correlate PET response and outcomes., Patients and Methods: We retrospectively analyzed PET data from a randomized phase 2 trial (NCT00525915) of chemoradiation and surgery with or without IC for the treatment of EC. PET was performed at baseline, after one cycle of IC, and 5-7 weeks after chemoradiation. The relationship between PET response (≥35% reduction in standardized uptake value [SUV]) after IC and treatment response was analyzed., Results: In 63 patients who received IC, the mean initial SUV max prior to treatment was 11.9 ± 8.04 and mean SUV max after one cycle of IC was 6.47 ± 4.45. The mean SUV reduction after IC was 39.3%. Eleven of 37 PET responders achieved a pathologic complete response (pCR), but only two of 22 PET non-responders did (univariate logistic regression; odds ratio: 4.25, 95% confidence interval: 0.83-21.77; p = 0.08). PET responders to IC had significantly longer overall survival (OS) than PET nonresponders (log-rank p = 0.009). PET response after chemoradiation was not correlated with OS (log-rank p = 0.15)., Conclusion: Early PET response after IC is prognostic, but subsequent PET changes (for example, after chemoradiation) are not prognostic. Early PET response might have the potential of predicting pCR.

Objective: The goal of surveillance after therapy of localized esophageal cancer (LEC) is to identify actionable relapses amenable to salvage; however, the current surveillance algorithms are not optimized. We report on a large cohort of LEC patients with actionable locoregional relapses (LRRs)., Methods: Between 2000 and 2013, 127 (denominator = 752) patients with actionable LRR were identified. Histologic/cytologic confirmation was the gold standard. All surveillance tools (imaging, endoscopy, fine needle aspiration) were assessed., Results: Most patients were men (89%), had adenocarcinoma (79%), and had no new symptoms (72%) when diagnosed with LRR. In trimodality patients, endoscopic confirmation of positron emission tomography-computed tomography-suspected LRR occurred in only 44%, and 56% required additional tools (e.g., fine needle aspiration). Alternatively, in bimodality patients, endoscopy confirmed LRRs in 81%. Trimodality patients had a higher risk of subsequent LRR/distant metastases after the first LRR than the bimodality patients (p = 0.03). In all patients, 78% of the subsequent relapses were distant. For patients who were salvaged, survival was significantly prolonged (50.6 vs. 25.1 months, p < 0.01)., Conclusions: Patients live longer after successful salvage of the LRR than if salvage is not possible. After LRR, patients have a high risk of subsequent distant metastasis and whether the second relapse is local or distant, survival is uniformly poor., (© 2018 S. Karger AG, Basel.)

Purpose: To compare clinical outcomes between proton beam therapy (PBT) and intensity modulated radiation therapy (IMRT) in patients with esophageal cancer (EC) treated with definitive chemoradiotherapy (CRT)., Methods and Materials: From 2007 through 2014, 343 EC patients who received definitive CRT with either PBT (n=132) or IMRT (n=211) were retrospectively analyzed. Survival, recurrence, and treatment toxicity were compared between groups. A Cox proportional hazards regression model was performed to test the association between patient/treatment variables and survival., Results: Patient/treatment variables were overall well balanced, except for age and race. Compared with IMRT, PBT had significantly better overall survival (OS; P=.011), progression-free survival (PFS; P=.001), distant metastasis-free survival (DMFS; P=.031), as well as marginally better locoregional failure-free survival (LRFFS; P=.075). No significant differences in rates of treatment-related toxicities were observed between groups. On multivariate analysis, IMRT had worse OS (hazard ratio [HR] 1.454; P=.01), PFS (HR 1.562; P=.001), and LRFFS (HR 1.461; P=.041) than PBT. Subgroup analysis by clinical stage revealed considerably higher 5-year OS (34.6% vs 25.0%, P=.038) and PFS rates (33.5% vs 13.2%, P=.005) in the PBT group for patients with stage III disease. However, no significant intergroup differences in survival were identified for stage I/II patients., Conclusions: Compared with IMRT, PBT might be associated with improved OS, PFS, and LRFFS, especially in EC patients with locally advanced disease. These results need confirmation by prospective studies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This study aimed to determine whether 18 F-FDG PET response after induction chemotherapy before concurrent chemoradiotherapy can identify patients with esophageal adenocarcinoma who may benefit from subsequent esophagectomy. Methods: We identified and analyzed 220 patients with esophageal adenocarcinoma who had received induction chemotherapy before chemoradiotherapy, with or without surgery, with curative intent; all underwent 18 F-FDG PET scanning before and after induction chemotherapy. 18 F-FDG PET responders were defined as patients who achieved complete response (CR) after induction chemotherapy (maximum SUV ≤ 3.0). The predictive value of 18 F-FDG PET response for patient outcomes was evaluated. Results: Overall, 86 patients had bimodality therapy (BMT; induction chemotherapy + chemoradiotherapy) and 134 had trimodality therapy (TMT; induction chemotherapy + chemoradiotherapy with surgery). Forty-eight patients (21.8%) achieved an 18 F-FDG PET CR after induction chemotherapy. 18 F-FDG PET CR was found to correlate with overall survival (OS) and progression-free survival (PFS) in BMT patients. For TMT patients, 18 F-FDG PET CR predicted pathologic response ( P = 0.003) but not survival. Among 18 F-FDG PET nonresponders, TMT patients had significantly better survival than did BMT patients ( P < 0.001). However, among 18 F-FDG PET responders, BMT patients had OS ( P = 0.201) and PFS ( P = 0.269) similar to that of TMT patients. After propensity score-matched analysis, 18 F-FDG PET responders treated with BMT versus TMT still had comparable OS and PFS, but TMT was associated with better locoregional control. Conclusion: 18 F-FDG PET response to induction chemotherapy could be a useful imaging biomarker to identify patients with esophageal adenocarcinoma who could benefit from subsequent esophagectomy after chemoradiotherapy. Compared with BMT, TMT can significantly improve survival in 18 F-FDG PET nonresponders. However, outcomes for 18 F-FDG PET responders were similar after either treatment (BMT or TMT). Prospective validation of these findings is warranted., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Reports are limited regarding clinical and pretreatment features that might predict a pathological complete response (pathCR) after treatment in patients with esophageal cancer (EC). This might allow patient selection for different strategies. This study examines the association of a pathCR with pretreatment variables, overall survival (OS), recurrence-free survival (RFS), and patterns of recurrence in a large cohort from a single institution., Methods: The baseline clinical features of 911 consecutive patients with EC who were treated with trimodality therapy from January 2000 to November 2013 were analyzed. A pathCR was defined as a surgical specimen with no residual carcinoma (primary or nodes). Logistic regressions were used to identify independent baseline features associated with a pathCR. We applied log-rank testing and Cox models to determine the association between a pathCR and the time-to-event outcomes (OS and RFS)., Results: Of 911 patients, 218 (23.9%) achieved a pathCR. The pathCR rate was 23.1% for adenocarcinoma and 32.2% for squamous cell carcinoma. A lower pathCR rate was observed for 1) older patients (>60 years), 2) patients with poorly differentiated tumors, 3) patients with signet ring cells (SRCs), and 4) patients with a higher T stage. Patients with a pathCR had longer OS and RFS than those without a pathCR (P = .0021 and P = .0011, respectively). Recurrences occurred more in non-pathCR patients. Distant metastases were the most common type of recurrence. PathCR patients developed brain metastases at a marginally higher rate than non-pathCR patients (P = .051)., Conclusions: In this large cohort study, a pathCR is confirmed to be associated with better OS and RFS. The presence of a poorly differentiated tumor or SRCs reduces the likelihood of a pathCR. Future research should focus on molecular classifiers. Cancer 2017;123:4106-4113. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Purpose: To assess the contribution of induction chemotherapy (IC) before definitive chemoradiation therapy (dCRT) in patients with esophageal cancer (EC) based on recursive partitioning analysis (RPA)., Methods and Materials: A total of 496 eligible patients with EC staged by positron emission tomography (PET) who received dCRT from 1998 to 2015 were included, 162 (32.7%) of whom underwent IC before dCRT. RPA was used to risk-stratify patients on the basis of independent prognostic factors to predict progression-free survival (PFS). Outcomes were compared between treatment groups., Results: The median follow-up time was 49.1 months (range, 7.0-155.9 months) for survivors. Compared with the non-IC group, the IC group had a comparable 5-year PFS rate (21.0% vs 23.4%; P=.726) in the whole cohort. Multivariate analysis identified age, performance status, primary tumor length, baseline PET maximum standard uptake value (SUV max ), and maximum lymph node diameter as independent prognostic factors for PFS. RPA segregated patients into 3 prognostic groups: low-risk group (PET SUV max <9.7 and tumor length ≤5 cm), intermediate-risk group (PET SUV max ≥9.7 and age ≥67), and high-risk group (PET SUV max <9.7 and tumor length >5 cm, or PET SUV max ≥9.7 and age <67). Significant improvements in PFS (P=.006) and locoregional failure-free survival (P=.028) in the IC group in comparison with the non-IC group were observed in high-risk patients, whereas no differences in survival were found between the 2 treatment groups in low-risk or intermediate-risk patients. After propensity score matching, the high-risk group still demonstrated a significantly improved PFS with IC (P=.009)., Conclusions: The RPA prognostic grouping provides a useful method of selecting high-risk EC patients who may benefit from IC before receiving dCRT. Prospective validation is warranted., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To compare heart and cardiac substructure radiation exposure using intensity-modulated radiotherapy (IMRT) vs. proton beam therapy (PBT) for patients with mid- to distal esophageal cancer who received chemoradiation therapy., Methods and Materials: We identified 727 esophageal cancer patients who received IMRT (n=477) or PBT (n=250) from March 2004 to December 2015. All patients were treated to 50.4Gy with IMRT or to 50.4 cobalt Gray equivalents with PBT. IMRT and PBT dose-volume histograms (DVHs) of the whole heart, atria, ventricles, and four coronary arteries were compared. For PBT patients, passive scattering proton therapy (PSPT; n=237) and intensity-modulated proton therapy (IMPT; n=13) DVHs were compared., Results: Compared with IMRT, PBT resulted in significantly lower mean heart dose (MHD) and heart V5, V10, V20, V30, and V40as well as lower radiation exposure to the four chambers and four coronary arteries. Compared with PSPT, IMPT resulted in significantly lower heart V20, V30, and V40 but not MHD or heart V5 or V10. IMPT also resulted in significantly lower radiation doses to the left atrium, right atrium, left main coronary artery, and left circumflex artery, but not the left ventricle, right ventricle, left anterior descending artery, or right coronary artery. Factors associated with lower MHD included PBT (P<0.001), smaller planning target volume (PTV; P<0.001), and gastroesophageal junction (GEJ) tumor (P<0.001). Among PBT patients, factors associated with lower MHD included IMPT (P=0.038), beam arrangement other than AP/PA (P<0.001), smaller PTV (P<0.001), and GEJ tumor (P<0.001)., Conclusions: In patients with mid- to distal esophageal cancer, PBT results in significantly lower radiation exposure to the whole heart and cardiac substructures than IMRT. Long-term studies are necessary to determine how this cardiac sparing effect impacts the development of coronary artery disease and other cardiac complications., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: Host immunity may affect the outcome in patients with esophageal cancer. We sought to identify factors that influenced absolute lymphocyte count (ALC) nadir during chemoradiation therapy (CRT) for esophageal cancer (EC) and looked for clinically relevant associations with survival., Methods and Materials: 504 patients with stage I-III EC (2007-2013) treated with neoadjuvant or definitive CRT with weekly ALC determinations made during treatment were analyzed. Grade of lymphopenia from ALC nadir during CRT was based on Common Terminology Criteria for Adverse Events version 4.0. Associations of ALC nadir with survival were examined using multivariate Cox proportional hazards analysis (MVA) and competing risks regression analysis., Results: The median follow-up time was 36 months. The incidences of grade 1, 2, 3, and 4 ALC nadir during CRT were 2%, 12%, 59%, and 27%, respectively. The impact was lymphocyte-specific because this was not seen for monocyte or neutrophil count. On MVA, grade 4 ALC nadir (G4 nadir) was significantly associated with worse overall and disease-specific survival outcomes. Predictors of G4 nadir included distal tumor location, definitive CRT, taxane/5-fluorouracil chemotherapy, and photon-based radiation type (vs proton-based). Radiation type strongly influenced the mean body dose exposure, which was a strong predictor for G4 nadir (odds ratio 1.22 per Gray, P<.001)., Conclusions: G4 nadir during CRT for EC was associated with poor outcomes, suggesting a role of host immunity in disease control. This observation provides a rationale to prospectively test chemotherapeutic and radiation treatment strategies that may have a lower impact on host immunity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: To assess the impact of histology on recurrence patterns and survival outcomes in patients with esophageal cancer (EC) treated with definitive chemoradiotherapy (CRT)., Methods: We analyzed 590 consecutive EC patients who received definitive CRT from 1998 to 2014, including 182 patients (30.8%) with squamous cell carcinoma (SCC) and 408 (69.2%) with adenocarcinoma. Recurrence pattern and timing, survival, and potential prognostic factors were compared., Results: After a median follow-up time of 58.0months, the SCC group demonstrated a comparable locoregional recurrence rate (42.9% vs. 38.0%, P=0.264) but a significantly lower distant failure rate (27.5% vs. 48.0%, P<0.001) than adenocarcinoma group. No significant difference was found in overall survival or locoregional failure-free survival between groups, whereas the SCC group was associated with significantly more favorable recurrence-free survival (P=0.009) and distant metastasis-free survival (P<0.001). The adenocarcinoma group had higher hematogenous metastasis rates of bone, brain, and liver, whereas the SCC group had a marginally higher regional recurrence rate. Among patients who received salvage surgery after locoregional recurrence, no significant difference in survival was found between groups (P=0.12)., Conclusions: The patterns and sites of recurrence, survival outcomes, and prognostic factors were significantly different between esophageal SCC and adenocarcinoma., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: The therapeutic gains of neoadjuvant chemoradiation therapy (nCRT) followed by esophagectomy may be offset by increased incidences of morbidity and mortality in elderly patients. This study aimed to determine the impact of age on the risks and benefits of trimodality therapy for esophageal cancer., Methods and Materials: We evaluated 571 patients treated with trimodality therapy at 3 high-volume tertiary cancer centers in the United States from 2007 to 2013. Two hundred two of 571 (35%) patients were 65 years or older at diagnosis and were classified as elderly. Toxicity and treatment parameters for the elderly cohort were compared with the younger cohort (ages 22-64) by the use of univariate (UVA) and multivariable (MVA) logistic analyses. Age was analyzed as a continuous hazard for cardiac and pulmonary toxicities. Survival was assessed by the Kaplan-Meier method., Results: Elderly patients had a higher risk for postoperative cardiac toxicities (UVA: odds ratio [OR] 2.2, P<.001; MVA: OR 2.07, P=.004) and pulmonary toxicities (UVA: OR 2.0, P<.001; MVA: OR 2.03, P<.001) and a higher 90-day postoperative mortality (5.4% vs 2.2%, P=.049). Of the elderly patients, 6.9% experienced acute respiratory distress syndrome compared with 3.8% of younger patients (P=.11). Cardiac toxicity was linearly associated with age, and the relative risk increased by 61% for every additional decade of age. There was no difference in postoperative gastrointestinal or wound adverse events or in length of hospital stay. Grade 3+ acute toxicities from nCRT were infrequent and were clinically similar regardless of age. Freedom from esophageal cancer and disease-free survival were similar, but overall survival was significantly shorter in the elderly cohort., Conclusions: Elderly patients experienced more postoperative cardiopulmonary toxicities and mortality than did younger patients after nCRT. Compared with contemporary outcomes for trimodality therapy, both cohorts had acceptable rates for adverse events and disease control. For appropriately selected elderly patients, trimodality therapy for esophageal cancer is a reasonable treatment option., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: The optimal treatment approach for patients ≥80 years ("elderly") with esophageal cancer is not well established. We assessed the clinical outcomes in elderly patients treated with definitive chemoradiation therapy (CCRT) at our institution., Methods and Materials: 56 consecutive patients ≥80 years with esophageal cancer treated with conventional CCRT between 2001 and 2016 were propensity score matched 1:2 to generate 2 younger patient cohorts treated with CCRT without surgery: "intermediate" (65-79 years, n=112) and "younger" (<65 years, n=112). Treatment related toxicity was assessed using the Common Terminology Criteria for Adverse Events version 4.0. The rates of overall survival (OS) and recurrence-free survival (RFS) were calculated with the Kaplan-Meier method., Results: The median ages of the 3 cohorts were 81 years (elderly, 80-92 years), 71 years (intermediate, 65-79 years), and 58 years (younger, 20-64 years). The elderly cohort was more likely to have cardiac comorbidities. Although the clinical complete response (cCR) rate deviated significantly among the 3 cohorts, (78%, 72%, and 56%; P=.004), the data failed to identify statistically significant differences among RFS, 2-year, and 5-year OS, or in median survival, which was 15.5 months, 23.6 months, and 20.2 months (P=.468), respectively. The overall severe toxicity rates were 38%, 32%, and 30%, respectively (P=.644), including comparable rate of radiation pneumonitis (P>.05). The elderly cohort, however, did show statistically significant evidence of an increased rate of severe radiation pneumonitis (grade ≥3) which was observed to be 11% versus 4% and 0%, respectively (P=.003)., Conclusions: The studied elderly population showed evidence of similar long-term clinical efficacy after definitive CCRT when compared with cohorts of younger patients with similar prognostic status. An increased rate of pulmonary toxicity was identified, without evidence of differences for nonpulmonary severe adverse events. Understanding the prognostic risk factors of pulmonary toxicity after CCRT may effectuate improved long-term outcomes for elderly population., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Relative radiation dose exposure to vital organs in the thorax could influence clinical outcomes in esophageal cancer (EC). We assessed whether the type of radiation therapy (RT) modality used was associated with postoperative outcomes after neoadjuvant chemoradiation (nCRT)., Patients and Methods: Contemporary data from 580 EC patients treated with nCRT at 3 academic institutions from 2007 to 2013 were reviewed. 3D conformal RT (3D), intensity modulated RT (IMRT) and proton beam therapy (PBT) were used for 214 (37%), 255 (44%), and 111 (19%) patients, respectively. Postoperative outcomes included pulmonary, GI, cardiac, wound healing complications, length of in-hospital stay (LOS), and 90-day postoperative mortality. Cox model fits, and log-rank tests both with and without Inverse Probability of treatment Weighting (IPW) were used to correct for bias due to non-randomization., Results: RT modality was significantly associated with the incidence of pulmonary, cardiac and wound complications, which also bore out on multivariate analysis. Mean LOS was also significantly associated with treatment modality (13.2days for 3D (95%CI 11.7-14.7), 11.6days for IMRT (95%CI 10.9-12.7), and 9.3days for PBT (95%CI 8.2-10.3) (p<0.0001)). The 90day postoperative mortality rates were 4.2%, 4.3%, and 0.9%, respectively, for 3D, IMRT and PBT (p=0.264)., Conclusions: Advanced RT technologies (IMRT and PBT) were associated with significantly reduced rate of postoperative complications and LOS compared to 3D, with PBT displaying the greatest benefit in a number of clinical endpoints. Ongoing prospective randomized trial will be needed to validate these results., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to identify patients with esophageal cancer who may benefit from induction chemotherapy (IC) before neoadjuvant chemoradiotherapy (nCRT) on the basis of a prognostic scoring model., Methods: Between 1998 and 2015, 535 patients with esophageal cancer who underwent nCRT were included for analysis, including 218 patients who received IC before nCRT (IC group) and 317 patients who did not receive IC (non-IC group). A prognostic scoring model was developed to predict disease-free survival (DFS) on the basis of a Cox proportional hazards model., Results: The median follow-up time was 63.5 months (range 8.0-178.5) for survivors. The 5-year DFS rates were similar between the IC and non-IC groups (53.7% vs. 45.1%, p = 0.196). Multivariate analysis determined that histologic grade, tumor location, baseline positron emission tomography maximum standard uptake value, and lymph node size were independent prognostic factors for DFS. A prognostic scoring system was constructed by using these four factors, with the total score ranging from 0 to 6.2. When the median value was used as a cutoff, low-risk (≤3.5) and high-risk (>3.5) groups were identified. In the high-risk group, patients who received IC had a nonsignificantly higher pathologic complete response rate (p = 0.272) and a significantly better DFS (p = 0.03) than patients who did not receive IC. After propensity score matching, the high-risk group demonstrated a significantly improved DFS with IC, a benefit that was not observed in the low-risk group., Conclusions: On the basis of the prognostic scoring model, the addition of IC to nCRT may provide a DFS benefit in high-risk patients with a risk score higher than 3.5. Prospective validation is warranted., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: To evaluate radiation modality effects on pericardial effusion (PCE), pleural effusion (PE) and survival in esophageal cancer (EC) patients., Materials and Methods: We analyzed data from 470 EC patients treated with definitive concurrent chemoradiotherapy (CRT). Bayesian semi-competing risks (SCR) regression models were fit to assess effects of radiation modality and prognostic covariates on the risks of PCE and PE, and death either with or without these preceding events. Bayesian piecewise exponential regression models were fit for overall survival, the time to PCE or death, and the time to PE or death. All models included propensity score as a covariate to correct for potential selection bias., Results: Median times to onset of PCE and PE after RT were 7.1 and 6.1months for IMRT, and 6.5 and 5.4months for 3DCRT, respectively. Compared to 3DCRT, the IMRT group had significantly lower risks of PE, PCE, and death. The respective probabilities of a patient being alive without either PCE or PE at 3-years and 5-years were 0.29 and 0.21 for IMRT compared to 0.13 and 0.08 for 3DCRT. In the SCR regression analyses, IMRT was associated with significantly lower risks of PCE (HR=0.26) and PE (HR=0.49), and greater overall survival (probability of beneficial effect (pbe)>0.99), after controlling for known clinical prognostic factors., Conclusions: IMRT reduces the incidence and postpones the onset of PCE and PE, and increases survival probability, compared to 3DCRT., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: We reviewed survival outcomes and factors associated with improved outcomes for patients with stage IVB esophageal cancer who received multimodality therapy with initial chemotherapy followed by concurrent chemoradiation (CRT)±surgery., Methods: We retrospectively identified 96 patients with stage IVB esophageal carcinoma (with positive nonregional lymph nodes and/or distant organ metastasis) treated at a single institution with chemotherapy followed by concurrent CRT, with or without surgery. The Cox proportional hazard model was used to test associations between overall survival (OS), disease-free survival (DFS), locoregional relapse, distant metastasis-free survival, and potential predictive factors., Results: Median patient age at diagnosis was 59 years. The median OS time among all patients was 21.0 months, and 1-, 2-, and 5-year OS rates were 84.4%, 46.8%, and 17.9%, respectively; corresponding DFS time and rates were 8.1 months and 37%, 24.6%, and 24.6%, respectively. On multivariate analysis, factors that predicted improved OS with aggressive multimodal therapy included young age; lack of anorexia, fatigue at diagnosis; distant nodal metastasis without organ metastasis at diagnosis; and radiographic response to initial chemotherapy. A subset of 14 patients who had surgery after chemotherapy and concurrent CRT also had better median OS (not reached vs. 20 mo for 82 patients who did not receive surgery, P=0.001), DFS (14.6 vs. 5.9 mo, P=0.021), and distant metastasis-free survival (26.7 vs. 9.2 mo, P=0.042)., Conclusions: Aggressive local therapy with radiation and potentially surgery after initial palliative chemotherapy can improve prognosis for a select group of patients with stage IVB esophageal cancer.

Background: It is currently unclear whether the superior normal organ-sparing effect of intensity-modulated radiotherapy (IMRT) compared with 3-dimensional radiotherapy (3D) has a clinical impact on survival and cardiopulmonary mortality in patients with esophageal cancer (EC)., Methods: The authors identified 2553 patients aged > 65 years from the Surveillance, Epidemiology, and End Results (SEER)-Medicare and Texas Cancer Registry-Medicare databases who had nonmetastatic EC diagnosed between 2002 and 2009 and were treated with either 3D (2240 patients) or IMRT (313 patients) within 6 months of diagnosis. The outcomes of the 2 cohorts were compared using inverse probability of treatment weighting adjustment., Results: Except for marital status, year of diagnosis, and SEER region, both radiation cohorts were well balanced with regard to various patient, tumor, and treatment characteristics, including the use of IMRT versus 3D in urban/metropolitan or rural areas. IMRT use increased from 2.6% in 2002 to 30% in 2009, whereas the use of 3D decreased from 97.4% in 2002 to 70% in 2009. On propensity score inverse probability of treatment weighting-adjusted multivariate analysis, IMRT was not found to be associated with EC-specific mortality (hazard ratio [HR], 0.93; 95% confidence interval [95% CI], 0.80-1.10) or pulmonary mortality (HR, 1.11; 95% CI, 0.37-3.36), but was significantly associated with lower all-cause mortality (HR, 0.83; 95% CI, 0.72-0.95), cardiac mortality (HR, 0.18; 95% CI, 0.06-0.54), and other-cause mortality (HR, 0.54; 95% CI, 0.35-0.84). Similar associations were noted after adjusting for the type of chemotherapy, physician experience, and sensitivity analysis removing hybrid radiation claims., Conclusions: In this population-based analysis, the use of IMRT was found to be significantly associated with lower all-cause mortality, cardiac mortality, and other-cause mortality in patients with EC., (© 2015 American Cancer Society.)

Purpose: To develop methods for evaluation and mitigation of dosimetric impact due to respiratory and diaphragmatic motion during free breathing in treatment of distal esophageal cancers using intensity-modulated proton therapy (IMPT)., Methods: This was a retrospective study on 11 patients with distal esophageal cancer. For each patient, four-dimensional computed tomography (4D CT) data were acquired, and a nominal dose was calculated on the average phase of the 4D CT. The changes of water equivalent thickness (ΔWET) to cover the treatment volume from the peak of inspiration to the valley of expiration were calculated for a full range of beam angle rotation. Two IMPT plans were calculated: one at beam angles corresponding to small ΔWET and one at beam angles corresponding to large ΔWET. Four patients were selected for the calculation of 4D-robustness-optimized IMPT plans due to large motion-induced dose errors generated in conventional IMPT. To quantitatively evaluate motion-induced dose deviation, the authors calculated the lowest dose received by 95% (D95) of the internal clinical target volume for the nominal dose, the D95 calculated on the maximum inhale and exhale phases of 4D CT DCT0 andDCT50 , the 4D composite dose, and the 4D dynamic dose for a single fraction., Results: The dose deviation increased with the average ΔWET of the implemented beams, ΔWETave. When ΔWETave was less than 5 mm, the dose error was less than 1 cobalt gray equivalent based on DCT0 and DCT50 . The dose deviation determined on the basis of DCT0 and DCT50 was proportionally larger than that determined on the basis of the 4D composite dose. The 4D-robustness-optimized IMPT plans notably reduced the overall dose deviation of multiple fractions and the dose deviation caused by the interplay effect in a single fraction., Conclusions: In IMPT for distal esophageal cancer, ΔWET analysis can be used to select the beam angles that are least affected by respiratory and diaphragmatic motion. To further reduce dose deviation, the 4D-robustness optimization can be implemented for IMPT planning. Calculation of DCT0 and DCT50 is a conservative method to estimate the motion-induced dose errors.

Background: Among patients with localized esophageal cancer (LEC), 35% or more develop distant metastases (DM) as first relapse, most in the first 24 months after local therapy. Implementation of novel strategies may be possible if DM can be predicted reliably. We hypothesized that clinical variables could help generate a DM nomogram., Patients and Methods: Patients with LEC who completed multimodality therapy were analyzed. Various statistical methods were used, including multivariate analysis to generate a nomogram. A concordance index (c-index) was established and validated using the bootstrap method., Results: Among 629 patients analyzed (356 trimodality/273 bimodality), 36% patients developed DM as first relapse. The median overall survival from DM was only 8.6 months (95% CI, 7.0-10.2). In a multivariate analysis, the variables associated with a higher risk for developing DM were poorly differentiated histology (hazard ratio [HR], 1.76; P<.0001), baseline T3/T4 primary (HR, 3.07; P=.0006), and baseline N+ LEC (HR, 2.01; P<.0001). Although variables associated with a lower risk for DM were age of 60 years or older (HR, 0.75; P=.04), squamous cell carcinoma (HR, 0.54; P=.013), and trimodality therapy (HR, 0.58; P=.0001), the bias-corrected c-index was 0.67 after 250 bootstrap resamples., Conclusions: Our nomogram identified patients with LEC who developed DM with a high probability. The model needs to be refined (tumor and blood biomarkers) and validated. This type of model will allow implementation of novel strategies in patients with LEC., (Copyright © 2016 by the National Comprehensive Cancer Network.)

Introduction: To delineate an optimal clinical target volume (CTV) for gastroesophageal junction (GEJ) cancers by comparing locoregional versus extended locoregional radiation (RT) volumes., Materials: This retrospective analysis examined 222 patients (111 matched pairs treated with locoregional versus extended locoregional RT) with nonmetastatic GEJ carcinomas treated with concurrent chemoradiation ± surgery. The CTV for locoregional volumes was defined as gross tumor volume + elective coverage of first-echelon nodes and sometimes the celiac axis. The CTV for extended locoregional volumes was defined as gross tumor volume + elective coverage of celiac and splenic (± porta) nodes. Variables used for matching included sex, stage, performance status, histology, receipt of induction chemotherapy, type of concurrent chemotherapy, RT modality, receipt of surgery, type of surgery, and Siewert classification. Regression models stratified by matched pairs were fit to estimate effect of RT volume on clinical endpoints., Results: Adjusting p values for multiple testing, patients treated with extended locoregional versus locoregional RT had increased odds of grade 2+ acute chemoradiation-associated gastrointestinal toxicity (odds ratio: 2.92, adj. p = 0.0447). However, differing RT volumes were not significantly associated with postoperative complication rates, pathologic T-stage, frequency of positive perigastric/regional nodes on surgical specimen, distant-metastases progression-free survival, locoregional progression-free survival, or overall survival (adj. p > 0.05). Of the patients who did (n = 124) and did not (n = 72) receive elective celiac RT, two (1.6%) and two patients (2.8%), respectively, relapsed in the celiac nodes. No patients failed in the splenic or porta nodes., Conclusions: Most GEJ cancers can be safely treated without elective inclusion of splenic/porta nodes.

Background/aim: Malignant nodes in patients with localized esophageal adenocarcinoma (L-EAC) portend a poor prognosis. We assessed the correlation of the distribution of nodes with the outcome of patients undergoing chemoradiation/surgery (trimodality therapy)., Methods: We studied 209 L-EAC patients who had confirmed or suspicious nodes at baseline staging. All patients received trimodality therapy and were grouped according to the nodal geography: above the diaphragm (AD), below the diaphragm (BD), or above and below the diaphragm (ABD). Survival estimates were calculated using the Kaplan-Meier method, and the outcomes of the groups were assessed by the log-rank test., Results: Patients were primarily Caucasian (91%) and male (93%), with a baseline stage III L-EAC (89%). The median follow-up was 2.8 years (range, 0.4-11.7). Of the 209 patients, 35% (n = 73) had AD nodes, 20% (n = 41) had BD nodes, and 45% (n = 95) had ABD nodes. ABD patients had a 5-year overall survival rate of 33%, whereas this rate was 55% in AD patients and 60% in BD patients (p = 0.02). Patients with a higher histology grade were also at a higher risk of relapse and had a poor survival (p < 0.01 for both)., Conclusions: L-EAC patients in the ABD group had the worst outcome after trimodality treatment compared to those in the AD or BD group. Novel strategies are needed for ABD patients., (© 2015 S. Karger AG, Basel.)

Background: We have limited knowledge of the geographic distribution of resistant esophageal adenocarcinoma (EAC) in resected specimens, but its clinical importance can be enormous., Method: We selected patients with baseline stage III EAC who had had chemoradiation followed by surgery and had residual EAC (resistant cases only). Outcomes were correlated with various endpoints (percentage of resistant EAC and anatomic distribution)., Results: A total of 100 clinical stage III patients were studied; 90% had an R0 resection, and 99% had either moderate or poorly differentiated EAC. Twelve percent had >50% residual cancer, 31% had 11-50% residual cancer, 53% had 1-10% residual cancer, and 3% had positive nodes only. Each compartment was frequently involved: mucosa/submucosa (66%), muscularis propria (76%), and serosa (62%); all compartments were involved in 35% of the cases. Lack of EAC (meaning response) was observed in the mucosa/submucosa (34%), muscularis propria (24%), serosa (38%), and nodes (42%). Although the endoscopic biopsies prior to surgery showed no EAC in 79% of the patients, in the surgical specimens, resistant EAC was frequently occurring in the mucosa/submucosa (66%)., Conclusion: Contrary to our hypothesis that resistant EAC would be frequent in the nodes, our data show that its distribution is heterogeneous and unpredictable. Most importantly, the postchemoradiation biopsies are misleading, and a decision to delay/avoid surgery based on negative biopsies can be detrimental for the patients., (© 2015 S. Karger AG, Basel.)

Background: Chronic comorbidities and some of the commonly-used medications are thought to affect cancer patients' outcomes, but their relative impact on esophageal carcinoma (EC) has not been well studied. The purpose of the study was to identify the chronic comorbidities and/or commonly-used medications that impact EC patient survival., Methods: A total of 1174 EC patients treated with chemoradiotherapy (CRT) with or without surgery in one institution from 1998 to 2012 were retrospectively included. Seven kinds of frequently occurring chronic comorbidities and 18 types of regularly-taken medications were obtained from medical records. Since it is expected prognostic factors have different effects between surgery patients and non-surgery patients, the impact value of all variables and the corresponding interactions with surgery on survival were evaluated in Cox proportional hazards regression model. Overall mortality, EC-specific mortality and non EC-specific mortality were endpoints., Results: We found that atrial fibrillation was the only comorbidity that showed a significant impact on non-EC specific survival for all patients (HR 1.72, P = 0.03), whereas hypothyroidism was the only comorbidity that was evaluated as an independent predictive factor for overall survival (OS) (HR 0.59, P = 0.02) and EC-specific survival (HR 0.62, P = 0.05), but this association was seen only in the non-surgical patients. No other medications were found to have a significant impact for OS, EC-specific survival or non-EC specific survival in multivariable analysis., Conclusions: Our data indicate that certain comorbidities rather than medication use affect EC-specific survival or non EC-specific survival in EC patients treated with CRT with or without surgery. Comorbidity information may better guide individual treatment in EC.

Background: In the current study we present a validated miRNA signature to predict pathologic complete response (pCR) to neoadjuvant chemoradiation in esophageal adenocarcinoma., Methods: Three patient cohorts (discovery, n = 10; model, n = 43; and validation, n = 65) with locally advanced esophageal adenocarcinoma were analyzed. In the discovery cohort 754 miRNAs were examined in pretreatment tumor biopsy specimens using a TaqMan array. Of these, the 44 most significantly altered between tumors with pCR and non-pCR were examined in an additional 43 tumors using a Fluidigm 48.48 array. The 4 miRNAs (mir-505*, mir-99b, mir-451, and mir-145*) significantly predicting pCR in both cohorts were examined in an additional validation cohort (n = 65) using an Illumina array. These 4 miRNAs were used to generate an miRNA expression profile (MEP) score., Results: The 4 miRNAs profiled are highly significantly associated with pCR in the model cohort (Ptrend  = .008), the validation cohort (Ptrend  = .025), and the combined cohort (Ptrend  = 4.6 × 10(-4) ). The receiver-operator characteristic areas under the curves (AUCs) for the MEP score were 0.78 for the model cohort, 0.71 for the validation cohort, and 0.72 for the combined cohort. When combined with clinical variables, the MEP score AUCs increased to 0.89, 0.77, and 0.81, respectively Estimates from logistic regression based on the MEP were determined and used to generate a probability of pCR plot, which identifies a group of patients with very high (≥80%) and very low (≤10%) probability of pCR., Conclusions: The MEP score provides a validated means of predicting pCR to neoadjuvant chemoradiotherapy in esophageal adenocarcinoma that is robust across several analysis platforms., (© 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Purpose: Patients with esophageal carcinoma (EC) who are treated with definitive chemoradiotherapy (bimodality therapy [BMT]) experience frequent relapses. In a large cohort, we assessed the timing, frequency, and types of relapses during an aggressive surveillance program and the value of the salvage strategies., Patients and Methods: Patients with EC (N = 276) who received BMT were analyzed. Patients who had surgery within 6 months of chemoradiotherapy were excluded to reduce bias. We focused on local relapse (LR) and distant metastases (DM) and the salvage treatment of patients with LR only. Standard statistical methods were applied., Results: The median follow-up time was 54.3 months (95% CI, 48.4 to 62.4). First relapses included LR only in 23.2% (n = 64), DM with or without LR in 43.5% (n = 120), and no relapses in 33.3% (n = 92) of patients. Final relapses included no relapses in 33.3%, LR only in 14.5%, DM only in 15.9%, and DM plus LR in 36.2% of patients. Ninety-one percent of LRs occurred within 2 years and 98% occurred within 3 years of BMT. Twenty-three (36%) of 64 patients with LR only underwent salvage surgery, and their median overall survival was 58.6 months (95% CI, 28.8 to not reached) compared with those patients with LR only who were unable to undergo surgery (9.5 months; 95% CI, 7.8 to 13.3)., Conclusion: Unlike in patients undergoing trimodality therapy, for whom surveillance/salvage treatment plays a lesser role,(1) in the BMT population, approximately 8% of all patients (or 36% of patients with LR only) with LRs occurring more than 6 months after chemoradiotherapy can undergo salvage treatment, and their survival is excellent. Our data support vigilant surveillance, at least in the first 24 months after chemotherapy, in these patients., (© 2014 by American Society of Clinical Oncology.)

Background: The optimal radiation dose for treating esophageal squamous cell carcinoma (ESCC) has long been debated. We evaluated if doses greater than 50.4 Gy delivered with modern techniques are beneficial in terms of tumor control, survival, and toxicity., Methods: We included 193 consecutive patients with ESCC treated with definitive concurrent chemoradiotherapy from 1998 to 2012. Patients were treated to a dose of ≤50.4 Gy (low-dose, n = 137) or greater than 50.4 Gy (high-dose, n = 56). Tumor response, local-regional control, survival, and treatment toxicity were compared between groups., Results: High-dose group had a significantly lower local failure rate (17.9% versus 34.3%, p = 0.024) and a marginal better 5-year local-regional failure-free survival (68.7% versus 55.9%, p = 0.052) than the low-dose group. No significant differences were found between high- and low-dose groups in tumor complete response rate (p = 0.975), regional failure rate (p = 0.336), distant metastasis rate (p = 0.390), or 5-year overall survival (p = 0.617). No difference in the incidence of toxic effects was observed between the two groups except for grade 3 skin reaction (12.5% [high] versus 2.2% [low], p < 0.001) and grade greater than or equal to 3 esophageal stricture (32.1% [high] versus 18.2% [low], p = 0.037)., Conclusions: Local tumor control might be improved by higher dose of greater than 50.4 Gy, when delivered with modern techniques and concurrent chemotherapy, at the consequence of increased toxicity without impact on overall survival.

Background: Esophageal carcinoma is a significant worldwide health problem and the incidence is increasing faster than that of any other malignancy. 18F-2-deoxy-D-glucose (FDG)-positron emission tomography/computed tomography (PET/CT) is important in the management of patients with potentially resectable esophageal cancer and is useful in initial staging of locally advanced cancer and after neoadjuvant therapy. The purpose of this study is to determine the utility of FDG-PET/CT in the clinical staging of early-stage esophageal cancer., Methods: Subjects in this retrospective study were 79 consecutive patients with cTisN0 (high-grade dysplasia) and cT1N0 primary esophageal adenocarcinoma diagnosed by endoscopy and endoscopic ultrasound biopsy that were evaluated with preoperative FDG-PET/CT and had not received neoadjuvant therapy. Seventh edition American Joint Committee on Cancer cTNM and FDG-PET/CT were compared with postoperative pTNM staging. pT1 was subdivided into intramucosal cancers with lamina propria or muscularis mucosa invasion (pT1a) and submucosal cancers (pT1b)., Results: In pT staging, the frequency of FDG uptake increased with increasing pT, from pT1a 21 of 39 (53.8%) to pT1b 19 of 22 (55.8%). pTis was three of five (60.0%). Similarly, the maximum standardized uptake value of FDG-avid lesions increased with increasing pT, with median values of 3.7 for pTis, 3.8 for pT1a and 4.2 for T1b. In cN staging, FDG-PET/CT was negative in 76 patients and positive in three patients. All three patients with FDG-avid nodes on FDG-PET/CT were negative for metastatic disease on biopsy. In 12 patients with pN1 and in one patient with N2, FDG-PET/CT was falsely negative. Sensitivity and positive predictive value for pN disease were 0% and accuracy was 82%. There were no distant metastases. In cM staging, FDG-PET/CT was falsely positive in five patients (FDG avid nodules n = 3, distant nodal metastasis n = 2) and resulted in unwarranted biopsy in four patients., Conclusion: FDG-PET/CT is not useful in the TNM staging of primary adenocarcinoma of the esophagus when endoscopy and biopsy indicate cTis and cT1. In fact, FDGPET/CT can be detrimental to patient management. Because regional nodal metastases are uncommon and distant metastases rare, and as FDG-PET/CT can result in inappropriate clinical care, FDG-PET/CT should not be performed in the evaluation of early-stage esophageal cancer.

Introduction: Postoperative morbidities, such as anastomotic leaks, are common after trimodality therapy (chemoradiation followed by surgery) for esophageal cancer. We investigated for factors associated with an increased incidence of anastomotic leaks., Methods: Data from 285 esophageal cancer patients treated from 2000 to 2011 with trimodality therapy were analyzed. Anastomotic location relative to preoperative radiation field was assessed using postoperative computed tomographic imaging. Logistic regression was used to evaluate for factors associated with any or clinically relevant (CR) (≥ grade 2) leaks., Results: Overall anastomotic leak rate was 11% (31 of 285), and CR leak rate was 6% (17 of 285). Multivariable analysis identified body mass index (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.00-1.17; OR, 1.11, 95% CI, 1.01-1.22), three-field surgery (OR, 10.01; 95% CI, 3.83-26.21; OR, 4.83; 95% CI, 1.39-16.71), and within radiation field ("in-field") anastomosis (OR, 5.37; 95% CI, 2.21-13.04; OR, 8.63; 95% CI, 2.90-25.65) as independent predictors of both all grade and CR leaks, respectively. While patients with distal esophageal tumors and Ivor-Lewis surgery had the lowest incidence of all grade (6.5%) and CR leaks (4.2%), most of the leaks were associated with the anastomosis constructed within the field of radiation (in-field: 39% and 30% versus out-of-field: 2.6% and 1.0%, respectively, for total and CR leaks, p less than 0.0001, Fisher's exact test)., Conclusions: Esophagogastric anastomosis placed within the preoperative radiation field was a very strong predictor for anastomotic leaks in esophageal cancer patients treated with trimodality therapy, among other factors. Surgical planning should include a critical evaluation of the preoperative radiation fields to ensure proper anastomotic placement after chemoradiation therapy.

Body mass index (BMI) is a risk factor for comorbid illnesses and cancer development. It was hypothesized that obesity status affects disease outcomes and treatment-related toxicities in esophageal cancer patients treated with chemoradiotherapy (CRT). From March 2002 to April 2010, 405 patients with non-metastatic esophageal carcinoma at MD Anderson Cancer Center treated with either definitive or neoadjuvant CRT were retrospectively analyzed. Patients were categorized as either obese (BMI ≥ 25 kg/m(2) ) or nonobese (BMI < 25 kg/m(2) ). Progression-free survival and overall survival times were examined using the Kaplan-Meier method and Cox proportional hazards regression analysis. One hundred fifteen (28.4%) patients were classified as nonobese and 290 (71.6%) as obese. Obese patients were more likely than others to have several comorbid diseases (P < 0.001), adenocarcinoma located distally (P < 0.001), and have undergone surgery (P = 0.004). Obesity was not associated with either worse operative morbidity/mortality (P > 0.05) or worse positron emission tomography tumor response (P = 0.46) on univariate analysis, nor with worse pathologic complete response (P = 0.98) on multivariate analysis. There was also no difference in overall survival, locoregional control, or metastasis-free survival between obese and nonobese patients (P = 0.86). However, higher BMI was associated with reduced risk of chemoradiation-induced high-grade esophagitis (P = 0.021), esophageal stricture (P < 0.001), and high-grade hematologic toxicity (P < 0.001). In esophageal cancer patients treated with CRT, obesity is not predictive of poorer disease outcomes or operative morbidities; instead, data suggest it may be associated with decreased risk of acute chemotherapy- and radiotherapy-related treatment toxicities., (© 2013 Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.)

Purpose: Operable thoracic esophageal/gastroesophageal junction carcinoma (EC) is often treated with chemoradiation and surgery but tumor responses are unpredictable and heterogeneous. We hypothesized that aldehyde dehydrogenase-1 (ALDH-1) could be associated with response., Methods: The labeling indices (LIs) of ALDH-1 by immunohistochemistry in untreated tumor specimens were established in EC patients who had chemoradiation and surgery. Univariate logistic regression and 3-fold cross validation were carried out for the training (67% of patients) and validation (33%) sets. Non-clinical experiments in EC cells were performed to generate complimentary data., Results: Of 167 EC patients analyzed, 40 (24%) had a pathologic complete response (pathCR) and 27 (16%) had an extremely resistant (exCRTR) cancer. The median ALDH-1 LI was 0.2 (range, 0.01-0.85). There was a significant association between pathCR and low ALDH-1 LI (p ≤ 0.001; odds-ratio [OR] = 0.432). The 3-fold cross validation led to a concordance index (C-index) of 0.798 for the fitted model. There was a significant association between exCRTR and high ALDH-1 LI (p ≤ 0.001; OR = 3.782). The 3-fold cross validation led to the C-index of 0.960 for the fitted model. In several cell lines, higher ALDH-1 LIs correlated with resistant/aggressive phenotype. Cells with induced chemotherapy resistance upregulated ALDH-1 and resistance conferring genes (SOX9 and YAP1). Sorted ALDH-1+ cells were more resistant and had an aggressive phenotype in tumor spheres than ALDH-1- cells., Conclusions: Our clinical and non-clinical data demonstrate that ALDH-1 LIs are predictive of response to therapy and further research could lead to individualized therapeutic strategies and novel therapeutic targets for EC patients., (Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Background: Locally advanced esophageal cancer is often treated with a trimodality approach. While a substantial proportion of such patients initially achieve a clinical complete response (cCR) after chemoradiation, only a small proportion achieve durable control. We analyzed patients who reached cCR after definitive chemoradiation for esophageal cancer to identify clinical predictors of local disease recurrence., Methods: We identified 141 patients who obtained initial cCR after definitive chemoradiation without surgery for esophageal cancer from 2002 through 2009. The initial response to treatment was assessed by endoscopic evaluation and biopsy results, with cCR defined as having no evidence of disease present. Patterns of failure were categorized as in-field (within the planned treatment volume [PTV]), outside the radiation treatment field, or both., Results: At a median follow-up of 22 months (range, 6-87 months), 77 patients (55 %) had experienced disease recurrence (local or both). Of first failures, 32 (23 %) were outside the radiation field, followed by 30 (21 %) within the field, and 15 (11 %) were both. By multivariate analysis, in-field failure after cCR was associated with a pretreatment standardized uptake value on positron emission tomography of >10 (subhazard ratio [SHR] 3.31, p = 0.023) and poorly differentiated tumors (SHR 3.69, p = 0.031). All failures, in-field and out-of-field, correlated with non-Caucasian ethnicity (SHR 2.55, p = 0.001), N1 disease (SHR 2.05, p = 0.034), T3/T4 disease (SHR 3.56, p = 0.011), and older age (SHR 0.96, p = 0.008)., Conclusions: Our data suggest that selected clinical characteristics can be used to predict failure patterns after definitive chemoradiation. Such risk-assessment strategies can help individualize therapy.

Purpose: The primary purpose of surveillance of patients with esophageal adenocarcinoma (EAC) and/or esophagogastric junction adenocarcinoma after local therapy (eg, chemoradiotherapy followed by surgery or trimodality therapy [TMT]) is to implement a potentially beneficial salvage therapy to overcome possible morbidity/mortality caused by locoregional failure (LRF). However, the benefits of surveillance are not well understood. We report on LRFs and salvage strategies in a large cohort., Patients and Methods: Between 2000 and 2010, 518 patients with EAC who completed TMT were analyzed for the frequency of LRF over time and salvage therapy outcomes. Standard statistical techniques were used., Results: For 518 patients, the median follow-up time was 29.3 months (range, 1 to 149 months). Distant metastases (with or without LRF) occurred in 188 patients (36%), and LRF only occurred in 27 patients (5%). Eleven of 27 patients had lumen-only LRF. Most LRFs (89%) occurred within 36 months of surgery. Twelve patients had salvage chemoradiotherapy, but only five survived more than 2 years. Four patients needed salvage surgery, and three who survived more than 2 years developed distant metastases. The median overall survival of 27 patients with LRF was 17 months, and 10 patients (37%) survived more than 2 years. Thus, only 2% of all 518 patients benefited from surveillance/salvage strategies., Conclusion: Our surveillance strategy, which is representative of many others currently being used, raises doubts about its effectiveness and benefits (along with concerns regarding types and times of studies and costs implications) to patients with EAC who have LRF only after TMT. Fortunately, LRFs are rare after TMT, but the salvage strategies are not highly beneficial. Our data can help develop an evidence-based surveillance strategy.

Background: The contribution of induction chemotherapy (IC) before preoperative chemoradiation for esophageal cancer (EC) is not known. We hypothesized that IC would increase the rate of pathologic complete response (pathCR)., Methods: Trimodality-eligibile patients were randomized to receive no IC (Arm A) or IC (oxaliplatin/FU; Arm B) before oxaliplatin/FU/radiation. Surgery was attempted ∼5-6 weeks after chemoradiation. The pathCR rate, post-surgery 30-day mortality, overall survival (OS), and toxic effects were assessed. Bayesian methods and Fisher's exact test were used., Results: One hundred twenty-six patients were randomized dynamically to balance the two arms for histology, baseline stage, gender, race, and age. Fifty-five patients in Arm A and 54 in Arm B underwent surgery. The median actuarial OS for all patients (54 deaths) was 45.62 months [95% confidence interval (CI), 27.63-NA], with median OS 45.62 months (95% CI 25.56-NA) in Arm A and 43.68 months (95% CI 27.63-NA) in Arm B (P = 0.69). The pathCR rate in Arm A was 13% (7 of 55) and 26% (14 of 54) in Arm B (two-sided Fisher's exact test, P = 0.094). Safety was similar in both arms., Conclusions: These data suggest that IC produces non-significant increase in the pathCR rate and does not prolong OS. Further development of IC before chemoradiation may not be beneficial. Clinical trial no.: NCT 00525915 (www.clinicaltrials.gov).

Background: Patients with localized esophageal adenocarcinoma (EAC) who achieve a clinical complete response (clinCR) after preoperative chemoradiation (trimodality therapy; TMT) or definitive chemoradiation (bimodality therapy; BMT) live longer than those who achieve a

Trimodality therapy with neoadjuvant chemoradiation followed by surgery significantly improves the survival of locally advanced (clinical stage IIA-III) esophageal cancer patients compared to treatment with surgery alone. This has resulted in an increased use of neoadjuvant therapy in recent years, yet little is known regarding how this increase has impacted the utilization of surgery in the treatment of locally advanced disease. Although previous reports of experimental protocols suggest that 90-95% of patients complete trimodality therapy including a surgical resection, trimodality therapy completion among adenocarcinoma patients eligible for curative resection has not been evaluated in a nonprotocol setting. We sought to (i) assess the completion of trimodality therapy among locally advanced esophageal adenocarcinoma patients; (ii) characterize the reasons for avoiding surgery; and (iii) identify factors associated with failure to complete trimodality therapy. We identified 296 patients with locally advanced esophageal adenocarcinoma eligible for trimodality therapy at our institution. All patients were evaluated in a multidisciplinary setting and considered eligible for curative resection after initial staging and physiologic assessment. Multivariable logistic regression was used to identify factors associated with failure to complete trimodality therapy. Of 296 trimodality-eligible patients, 33% (97/296) did not complete trimodality therapy. Reasons for not undergoing surgery included patient choice (27.8%, 27/97), distant progression of disease during chemoradiation (23.7%, 23/97), and physician preference for surveillance (23.7%, 23/97). In addition, 17.5% (17/97) of patients had physical deterioration in performance status, and treatment-related deaths occurred in 7.2% (7/97) prior to surgery. In the total study population (n = 296), multivariable logistic regression identified older age (≥70 years: odds ratio [OR] = 6.611, 95% confidence interval [CI]: 2.900-15.071), pretreatment standard uptake value (6.8-10.1: OR = 2.393, 95% CI: 1.050-5.455; ≥15.8: OR = 3.623, 95% CI: 1.604-8.186), and a radiation dose of 50.4 Gy (OR = 5.312, 95% CI: 2.365-11.929) as being significantly associated with failure to complete trimodality therapy. Among the subgroup of patients that successfully completed chemoradiation (n = 266), older patients (≥70 years: OR = 9.606, 95% CI: 3.637-25.372), those with a comorbidity score of 2 or higher (OR = 4.059, 95% CI: 1.257-13.103), and those that received a radiation dose of 50.4 Gy (OR = 4.878, 95% CI: 1.974-12.054) were at a significantly higher risk of not completing trimodality therapy. Trimodality therapy completion among patients with locally advanced esophageal adenocarcinoma in a nonprotocol setting is considerably lower than what has previously been reported in clinical trials. Our findings suggest that a selective approach to surgery is commonly utilized in clinical practice. Trimodality-eligible patients that are older and have a higher comorbidity score are at risk for not completing trimodality therapy., (© 2013 Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.)

Purpose: While trimodality therapy for esophageal cancer has improved patient outcomes, surgical complication rates remain high. The goal of this study was to identify modifiable factors associated with postoperative complications after neoadjuvant chemoradiation., Methods and Materials: From 1998 to 2011, 444 patients were treated at our institution with surgical resection after chemoradiation. Postoperative (pulmonary, gastrointestinal [GI], cardiac, wound healing) complications were recorded up to 30 days postoperatively. Kruskal-Wallis tests and χ(2) or Fisher exact tests were used to assess associations between continuous and categorical variables. Multivariate logistic regression tested the association between perioperative complications and patient or treatment factors that were significant on univariate analysis., Results: The most frequent postoperative complications after trimodality therapy were pulmonary (25%) and GI (23%). Lung capacity and the type of radiation modality used were independent predictors of pulmonary and GI complications. After adjusting for confounding factors, pulmonary and GI complications were increased in patients treated with 3-dimensional conformal radiation therapy (3D-CRT) versus intensity modulated radiation therapy (IMRT; odds ratio [OR], 2.018; 95% confidence interval [CI], 1.104-3.688; OR, 1.704; 95% CI, 1.03-2.82, respectively) and for patients treated with 3D-CRT versus proton beam therapy (PBT; OR, 3.154; 95% CI, 1.365-7.289; OR, 1.55; 95% CI, 0.78-3.08, respectively). Mean lung radiation dose (MLD) was strongly associated with pulmonary complications, and the differences in toxicities seen for the radiation modalities could be fully accounted for by the MLD delivered by each of the modalities., Conclusions: The radiation modality used can be a strong mitigating factor of postoperative complications after neoadjuvant chemoradiation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: We investigated the radiographic and pathologic response rate of esophageal adenocarcinoma treated with neoadjuvant chemoradiation in patients taking metformin., Material and Methods: Two hundred eighty-five patients with esophageal adenocarcinoma treated with concurrent chemoradiation (CRT) followed by esophagectomy from 1997 to 2012 were included in the study, including 29 diabetics taking metformin, 21 diabetics not taking metformin and 235 non-diabetics. Pre- and post-treatment positron emission tomography (PET) scans were available for 204 patients. Pathologic response was graded at the time of surgery. Response rates were compared using both the χ(2) statistic as well as ANOVA with post-hoc LSD analysis. Multivariate logistic regression analysis was performed to control for predictors of pathologic complete response (CR) after CRT., Results: The overall rate of pathologic CR for the study population was 20%. The pathologic CR rate was higher in patients taking metformin (34.5%), compared to diabetic patients not taking metformin (4.8%, p = 0.01) and non-diabetic patients (19.6%, p = 0.05). Pathologic CR was related to metformin dose, with ≥ 1500 mg/d associated with a higher CR rate. No significant difference seen in pre-CRT maximum tumor SUV (p = 0.93), however post-CRT maximum SUV was significantly decreased in patients taking metformin (p = 0.05). On multivariate logistic regression, metformin use was independently associated with pathologic CR (p = 0.04). Metformin use was also associated with decreased in field loco-regional failure following radiation (p = 0.05)., Conclusion: Metformin use is associated with a dose-dependent increased response to CRT in esophageal cancer and may be a sensitizer to this therapy.

Background: Trimodality therapy (TMT; chemoradiation plus surgery) has level-1 evidence for survival advantage for TMT-eligible esophagogastric cancer patients. Some patients, however, decline surgery after preoperative chemoradiation. The question of which patient should have esophagectomy and which one should not is unlikely to be answered by a prospective comparison; therefore, we matched the clinical covariates of several patients who had surgery with those who declined surgery (DS)., Methods: Between 2002 and 2011, we identified 623 patients in our databases. Of 623 patients, 244 patients had TMT and 61 TMT-eligible patients were in the DS group. Using the propensity-score method, we matched 16 covariates between 36 DS patients and 36 TMT patients., Results: Baseline characteristics between the two groups were balanced (p = NS). The median overall survival times were: 57.9 months (95% CI: 27.7 to not applicable, NA) for the DS group and 50.8 months (95% CI: 30.7 to NA) for the TMT group (p = 0.28). The median relapse-free survival times were: 18.5 (95% CI: 11.5-30.4) for the DS group and 26.5 months (95% CI: 15.5-NA) for the TMT group (p = 0.45). Eleven (31%) of 36 patients in the DS group had salvage surgery., Conclusions: Our results are intriguing but skewed by the patients who had salvage surgery in the DS group. Until highly reliable predictive models are developed for esophageal preservation, TMT must be encouraged for all TMT-eligible gastroesophageal cancer patients., (Copyright © 2013 S. Karger AG, Basel.)

Background: It is unclear whether patients undergoing trimodality therapy (TMT) should be screened or surveyed for brain metastases., Methods: We retrospectively analyzed esophageal cancer (EC) patients who underwent TMT between the years 2000 and 2010. All were systematically staged and surveyed but none had screening or surveillance brain imaging., Results: The median follow-up time for 518 patients was 29.3 months (range 1-149.2); all patients had adenocarcinoma of the esophagus. Of 188 (36.3%) patients who developed distant metastases, 20 (10.6% of 188 patients or 3.9% of 518 patients) had brain metastases. A higher baseline clinical stage (stage III or IVa) was associated with brain metastases. Most (90%) patients with brain metastases were diagnosed within 24 months of surgery. Sixteen patients had central nervous system symptoms at diagnosis. Twelve (60%) patients had solitary metastasis and 8 (40%) patients had multiple metastases. Although 17 patients received therapy for brain metastases, the median overall survival time of 20 patients was only 10.5 months (95% CI 6.6-14.0)., Conclusion: After TMT, 3.9% of EC patients developed brain metastases and their prognosis was poor. Our data suggest that screening and/or surveillance for brain metastases in the EC population undergoing TMT is not warranted., (Copyright © 2013 S. Karger AG, Basel.)

Purpose: Although 3-dimensional conformal radiotherapy (3D-CRT) is the worldwide standard for the treatment of esophageal cancer, intensity modulated radiotherapy (IMRT) improves dose conformality and reduces the radiation exposure to normal tissues. We hypothesized that the dosimetric advantages of IMRT should translate to substantive benefits in clinical outcomes compared with 3D-CRT., Methods and Materials: An analysis was performed of 676 nonrandomized patients (3D-CRT, n=413; IMRT, n=263) with stage Ib-IVa (American Joint Committee on Cancer 2002) esophageal cancers treated with chemoradiotherapy at a single institution from 1998-2008. An inverse probability of treatment weighting and inclusion of propensity score (treatment probability) as a covariate were used to compare overall survival time, interval to local failure, and interval to distant metastasis, while accounting for the effects of other clinically relevant covariates. The propensity scores were estimated using logistic regression analysis., Results: A fitted multivariate inverse probability weighted-adjusted Cox model showed that the overall survival time was significantly associated with several well-known prognostic factors, along with the treatment modality (IMRT vs 3D-CRT, hazard ratio 0.72, P<.001). Compared with IMRT, 3D-CRT patients had a significantly greater risk of dying (72.6% vs 52.9%, inverse probability of treatment weighting, log-rank test, P<.0001) and of locoregional recurrence (P=.0038). No difference was seen in cancer-specific mortality (Gray's test, P=.86) or distant metastasis (P=.99) between the 2 groups. An increased cumulative incidence of cardiac death was seen in the 3D-CRT group (P=.049), but most deaths were undocumented (5-year estimate, 11.7% in 3D-CRT vs 5.4% in IMRT group, Gray's test, P=.0029)., Conclusions: Overall survival, locoregional control, and noncancer-related death were significantly better after IMRT than after 3D-CRT. Although these results need confirmation, IMRT should be considered for the treatment of esophageal cancer., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Approximately 25% of patients with esophageal cancer (EC) who undergo preoperative chemoradiation, achieve a pathologic complete response (pathCR). We hypothesized that a model based on clinical parameters could predict pathCR with a high (≥60%) probability., Patients and Methods: We analyzed 322 patients with EC who underwent preoperative chemoradiation. All the patients had baseline and postchemoradiation positron emission tomography (PET) and pre- and postchemoradiation endoscopic biopsy. Logistic regression models were used for analysis, and cross-validation via the bootstrap method was carried out to test the model., Results: The 70 (21.7%) patients who achieved a pathCR lived longer (median overall survival [OS], 79.76 months) than the 252 patients who did not achieve a pathCR (median OS, 39.73 months; OS, P = 0.004; disease-free survival, P = 0.003). In a logistic regression analysis, the following parameters contributed to the prediction model: postchemoradiation PET, postchemoradiation biopsy, sex, histologic tumor grade, and baseline (EUS)T stage. The area under the receiver-operating characteristic curve was 0.72 (95% confidence interval [CI] 0.662-0.787); after the bootstrap validation with 200 repetitions, the bias-corrected AU-ROC was 0.70 (95% CI 0.643-0.728)., Conclusion: Our data suggest that the logistic regression model can predict pathCR with a high probability. This clinical model could complement others (biomarkers) to predict pathCR.

Purpose: Proton beam therapy (PBT) is a promising modality for the management of thoracic malignancies. We report our preliminary experience of treating esophageal cancer patients with concurrent chemotherapy (CChT) and PBT (CChT/PBT) at MD Anderson Cancer Center., Methods and Materials: This is an analysis of 62 esophageal cancer patients enrolled on a prospective study evaluating normal tissue toxicity from CChT/PBT from 2006 to 2010. Patients were treated with passive scattering PBT with two- or three-field beam arrangement using 180 to 250 MV protons. We used the Kaplan-Meier method to assess time-to-event outcomes and compared the distributions between groups using the log-rank test., Results: The median follow-up time was 20.1 months for survivors. The median age was 68 years (range, 38-86). Most patients were males (82%) who had adenocarcinomas (76%) and Stage II-III disease (84%). The median radiation dose was 50.4 Gy (RBE [relative biologic equivalence]) (range, 36-57.6). The most common grade 2 to 3 acute toxicities from CChT/PBT were esophagitis (46.8%), fatigue (43.6%), nausea (33.9%), anorexia (30.1%), and radiation dermatitis (16.1%). There were two cases of grade 2 and 3 radiation pneumonitis and two cases of grade 5 toxicities. A total of 29 patients (46.8%) received preoperative CChT/PBT, with one postoperative death. The pathologic complete response (pCR) rate for the surgical cohort was 28%, and the pCR and near CR rates (0%-1% residual cells) were 50%. While there were significantly fewer local-regional recurrences in the preoperative group (3/29) than in the definitive CChT/PBT group (16/33) (log-rank test, p = 0.005), there were no differences in distant metastatic (DM)-free interval or overall survival (OS) between the two groups., Conclusions: This is the first report of patients treated with PBT/CChT for esophageal cancer. Our data suggest that this modality is associated with a few severe toxicities, but the pathologic response and clinical outcomes are encouraging. Prospective comparison with more traditional approach is warranted., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Accounting for interfractional changes in tumor location improves the accuracy of radiation treatment delivery. The purpose of this study was to quantify the interfractional displacement of the gastroesophageal junction (GEJ) based on standard treatment setup in patients with esophageal cancer undergoing radiation therapy., Methods and Materials: Free-breathing four-dimensional computed tomography (4D-CT) datasets were acquired weekly from 22 patients during treatment for esophageal adenocarcinoma. Scans were registered to baseline (simulation) 4D-CT scans by using bony landmarks. The distance between the center of the GEJ contour on the simulation scan and the mean location of GEJ centers on subsequent scans was used to assess changes in GEJ location between fractions; displacement was also correlated with clinical and respiratory variables., Results: The mean absolute random error was 1.69 mm (range, 0.11-4.11 mm) in the lateral direction, 1.87 mm (range, 0.51-4.09 mm) in the anterior-posterior (AP) direction, and 3.09 mm (range, 0.99-6.16 mm) in the superior-inferior (SI) direction. The mean absolute systemic GEJ displacement between fractions was 2.88 mm lateral (≥ 5 mm in 14%), mostly leftward; 2.90 mm (≥ 5 mm in 14%) AP, mostly anterior; and 6.77 mm (≥ 1 cm in 18%) SI, mostly inferior. Variations in tidal volume and diaphragmatic excursion during treatment correlated strongly with systematic SI GEJ displacement (r = 0.964, p < 0.0001; and r = 0.944, p < 0.0001, respectively) and moderately with systematic AP GEJ displacement (r = 0.678, p = 0.0005; r = 0.758, p < 0.0001, respectively). Systematic displacement in the inferior direction resulted in higher-than-intended doses (≥ 60 Gy) to the GEJ, with increased hot-spot to the adjacent stomach and lung base., Conclusion: We found large (>1-cm) interfractional displacements in the GEJ in the SI (especially inferior) direction that was not accounted for when skeletal alignment alone was used for patient positioning. Because systematic displacement in the SI direction had dosimetric impact and correlated with tidal volume, better accounting for depth of breathing is needed to reduce interfractional variability., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: The celiac lymph node axis acts as a gateway for metastatic systemic spread. The need for prophylactic celiac nodal coverage in chemoradiation therapy for esophageal cancer is controversial. Given the improved ability to evaluate lymph node status before treatment via positron emission tomography (PET) and endoscopic ultrasound, we hypothesized that prophylactic celiac node irradiation may not be needed for patients with localized esophageal carcinoma., Methods and Materials: We reviewed the radiation treatment volumes for 131 patients who underwent definitive chemoradiation for esophageal cancer. Patients with celiac lymph node involvement at baseline were excluded. Median radiation dose was 50.4 Gy. The location of all celiac node failures was compared with the radiation treatment plan to determine whether the failures occurred within or outside the radiation treatment field., Results: At a median follow-up time of 52.6 months (95% CI 46.1-56.7 months), 6 of 60 patients (10%) without celiac node coverage had celiac nodal failure; in 5 of these patients, the failures represented the first site of recurrence. Of the 71 patients who had celiac coverage, only 5 patients (7%) had celiac region relapse. In multivariate analyses, having a pretreatment-to-post-treatment change in standardized uptake value on PET >52% (odds ratio [OR] 0.198, p = 0.0327) and having failure in the clinical target volume (OR 10.72, p = 0.001) were associated with risk of celiac region relapse. Of those without celiac coverage, the 6 patients that later developed celiac failure had a worse median overall survival time compared with the other 54 patients who did not fail (median overall survival time: 16.5 months vs. 31.5 months, p = 0.041). Acute and late toxicities were similar in both groups., Conclusions: Although celiac lymph node failures occur in approximately 1 of 10 patients, the lack of effective salvage treatments and subsequent low morbidity may justify prophylactic treatment in distal esophageal cancer patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Local failure after definitive chemoradiation therapy for unresectable esophageal cancer remains problematic. Little is known about the failure pattern based on modern-day radiation treatment volumes. We hypothesized that most local failures would be within the gross tumor volume (GTV), where the bulk of the tumor burden resides., Methods: We reviewed treatment volumes for 239 patients who underwent definitive chemoradiation therapy and compared this information with failure patterns on follow-up positron emission tomography (PET). Failures were categorized as within the GTV, the larger clinical target volume (CTV, which encompasses microscopic disease), or the still larger planning target volume (PTV, which encompasses setup variability) or outside the radiation field., Results: At a median follow-up time of 52.6 months (95% confidence interval, 46.1-56.7 months), 119 patients (50%) had experienced local failure, 114 (48%) had distant failure, and 74 (31%) had no evidence of failure. Of all local failures, 107 (90%) were within the GTV, 27 (23%) were within the CTV, and 14 (12%) were within in the PTV. On multivariate analysis, GTV failure was associated with tumor status (T3/T4 vs T1/T2; odds ratio, 6.35; P = .002), change in standardized uptake value on PET before and after treatment (decrease >52%: odds ratio, 0.368; P = .003), and tumor size (>8 cm, 4.08; P = .009)., Conclusions: Most local failures after definitive chemoradiation for unresectable esophageal cancer occur in the GTV. Future therapeutic strategies should focus on enhancing local control., (Copyright © 2011 American Cancer Society.)

Purpose: We previously showed that 75% of radiation therapy (RT) failures in patients with unresectable esophageal cancer are in the gross tumor volume (GTV). We performed a planning study to evaluate if a simultaneous integrated boost (SIB) technique could selectively deliver a boost dose of radiation to the GTV in patients with esophageal cancer., Methods and Materials: Treatment plans were generated using four different approaches (two-dimensional conformal radiotherapy [2D-CRT] to 50.4 Gy, 2D-CRT to 64.8 Gy, intensity-modulated RT [IMRT] to 50.4 Gy, and SIB-IMRT to 64.8 Gy) and optimized for 10 patients with distal esophageal cancer. All plans were constructed to deliver the target dose in 28 fractions using heterogeneity corrections. Isodose distributions were evaluated for target coverage and normal tissue exposure., Results: The 50.4 Gy IMRT plan was associated with significant reductions in mean cardiac, pulmonary, and hepatic doses relative to the 50.4 Gy 2D-CRT plan. The 64.8 Gy SIB-IMRT plan produced a 28% increase in GTV dose and comparable normal tissue doses as the 50.4 Gy IMRT plan; compared with the 50.4 Gy 2D-CRT plan, the 64.8 Gy SIB-IMRT produced significant dose reductions to all critical structures (heart, lung, liver, and spinal cord)., Conclusions: The use of SIB-IMRT allowed us to selectively increase the dose to the GTV, the area at highest risk of failure, while simultaneously reducing the dose to the normal heart, lung, and liver. Clinical implications warrant systematic evaluation., (Copyright © 2012 Elsevier Inc. All rights reserved.)