Trimodality Therapy For Esophageal Cancer Research Articles

A Prospective Pilot Study of Pencil Beam Scanning Proton Radiation Therapy as a Component of Trimodality Therapy for Esophageal Cancer

PurposeTo evaluate the safety and efficacy of pencil beam scanning (PBS) proton radiotherapy (RT) in trimodality therapy for esophageal cancer. MethodsThis prospective pilot study was planned to accrue 30 patients with locally advanced esophageal or gastroesophageal junction (GEJ) carcinoma, medically suitable for chemoRT (CRT) followed by esophagectomy. PBS proton RT consisted of 25 fractions, 50 Gy to tumor + 1 cm and 45 Gy to a 3.5 cm mucosal expansion and regional lymph nodes. Chemotherapy was weekly carboplatin (AUC = 2) and paclitaxel (50 mg/m2). At 4-8 weeks after CRT, patients underwent restaging and potential esophagectomy. The primary endpoint was acute grade 3+ adverse events (AEs) attributed to CRT. Overall (OS) and progression-free survival (PFS) were assessed by Kaplan-Meier methodology; local-regional recurrence (LRR) and distant metastases (DM) rates were assessed by cumulative incidence methodology. The Functional Assessment of Cancer Therapy-Esophagus (FACT-E) assessed quality of life. ResultsThirty eligible patients enrolled June 2015-April 2017. Median age was 68 years. Histology was adenocarcinoma in 87% and location was distal esophagus/GEJ in 90%. Stage was T3-4 in 87% and N1-3 in 80%. All patients completed the planned RT dose. Acute grade 3+ AEs occurred in 30%, most commonly leukopenia and neutropenia. Acute grade 3+ non-hematologic AEs occurred in 3%. Esophagectomy was performed in 90% of patients (R0 in 93%). Pathologic complete response rate was 40%. Major post-operative complications (Clavien-Dindo score ≥ III) occurred in 34%. Postoperative mortality at 30 days was 3.7%. Median follow-up was 5.2 years. 5-year outcome estimates were OS 46%, PFS 39%, LRR 17%, and DM 40%. FACT-E scores (medians) were baseline (145), end of CRT (136, p=0.0002 vs. baseline), before esophagectomy (144), 12 months (146), and 24 months (157). ConclusionsPBS proton RT is feasible and safe as a component of trimodality therapy for esophageal cancer.

Risk stratification of postoperative cardiopulmonary toxicity after trimodality therapy for esophageal cancer.

Postoperative toxicity for esophageal cancer impacts patient quality of life and potentially overall survival (OS). We studied whether patient and toxicity parameters post-chemoradiation therapy predict for post-surgical cardiopulmonary total toxicity burden (CPTTB) and whether CPTTB was associated with short and long-term outcomes. Patients had biopsy-proven esophageal cancer treated with neoadjuvant chemoradiation and esophagectomy. CPTTB was derived from total perioperative toxicity burden (Lin etal. JCO 2020). To develop a CPTTB risk score predictive for major CPTTB, recursive partitioning analysis was used. From 3 institutions, 571 patients were included. Patients were treated with 3D (37%), IMRT (44%), and proton therapy (19%). 61 patients had major CPTTB (score ≥ 70). Increasing CPTTB was predictive of decreased OS (p<0.001), lengthier post-esophagectomy length of stay (LOS, p<0.001), and death or readmission within 60 days of surgery (DR60, p<0.001). Major CPTTB was also predictive of decreased OS (hazard ratio = 1.70, 95% confidence interval: 1.17-2.47, p=0.005). The RPA-based risk score included: age ≥ 65, grade ≥ 2 nausea or esophagitis attributed to chemoradiation, and grade ≥ 3 hematologic toxicity attributed to chemoradiation. Patients treated with 3D radiotherapy had inferior OS (p=0.010) and increased major CPTTB (18.5% vs. 6.1%, p<0.001). CPTTB predicts for OS, LOS, and DR60. Patients with 3D radiotherapy or age ≥ 65 years and chemoradiation toxicity are at highest risk for major CPTTB, predicting for higher short and long-term morbidity and mortality. Strategies to optimize medical management and reduce toxicity from chemoradiation should be strongly considered.

Risk Stratification of Postoperative Cardiopulmonary Toxicity after Trimodality Therapy for Esophageal Cancer

<h3>Purpose/Objective(s)</h3> Postoperative toxicity after trimodality therapy for esophageal cancer profoundly impacts patient quality of life and may impact overall survival (OS). We interrogated a large, multi-institutional database of patients to refine a surrogate to report cardiopulmonary total toxicity burden (CPTTB) and study whether toxicity attributed to chemoradiation (CRT) predicted for this endpoint. <h3>Materials/Methods</h3> Our group assessed a multi-institutional database of patients diagnosed with biopsy-proven esophageal cancer and treated with neoadjuvant CRT, followed by surgical resection. CPTTB was defined using the pre-existing analysis of total toxicity burden (Lin et al. JCO 2020). A subset of these variables (myocardial infarction, non-ischemic cardiac toxicity, pleural effusion, pneumonia, and acute respiratory distress syndrome) was utilized. (Table). CPTTB was validated for its impact on OS, length of postoperative hospital stay (LOS), and death or readmission within 60 days of surgery (DR60). To predict for CPTTB, recursive partitioning analysis was used. Variables utilized in the highest fidelity RPA models were incorporated into the final score. <h3>Results</h3> From 3 institutions, 571 patients were included. Most patients had stage 2A (28%) or 3 (61%) adenocarcinoma (93%). Patients were treated with 3D (37%), IMRT (44%), and proton therapy (19%). Median CPTTB was 0 (interquartile range [IQR]: 0-30), with 61 patients having major CPTTB (defined as CPTTB ≥ 70). Increasing CPTTB as a continuous variable and major CPTTB were predictive of decreased OS (p<0.001 and p=0.005), LOS (p<0.001) and DR60 (p<0.001). Next, an RPA-based model was developed predictive of major CPTTB. This risk score involved one point for: age ≥ 65, grade ≥ 2 nausea or esophagitis attributed to CRT, and grade ≥ 3 hematologic toxicity attributed to CRT. This model was predictive of CPTTB (area under the curve [AUC]: 0.66) and DR60 (p=0.017). A score of 1 showed an odds ratio (OR) of 5.15 (95% CI: 1.54-17.26, p=0.008), and a score of 2-3 showed OR of 9.78 (95% CI: 2.91-32.82, p<0.001) for major CPTTB. The CPTTB risk score was also predictive of continuous CPTTB (p<0.001). Patients treated with 3D radiotherapy had increased major CPTTB (18.5% vs. 6.1%, p<0.001), but the model demonstrated higher predictive power for major CPTTB (AUC=0.70) among patients treated with IMRT or proton therapy. <h3>Conclusion</h3> CPTTB predicts for OS, LOS, and DR60. Patients with age ≥ 65 years and CRT toxicity are at highest risk for major CPTTB and may benefit from further pre-operative management or even omission of surgery. 3D radiotherapy is associated with increased toxicity.

Conditional Survival after Trimodality Therapy for Esophageal Cancer: A Re-evaluation of Prognostic Factors Over Time

Feldman, Hope MD; Niu, Jiangong PhD; Zhou, Nicolas DO; Hofstetter, Wayne L. MD, FACS; Mehran, Reza J. MD, FACS; Rice, David C. MBBCh; Vaporciyan, Ara A. MD, FACS; Walsh, Garrett L. MD, FACS; Giordano, Sharon MD; Rajaram, Ravi MD Author Information

Trimodality therapy for esophageal cancer: The role of surgical and radiation treatment parameters in the development of anastomotic complications.

BackgroundHere, we investigated the relationship between clinical parameters, including the site of surgical anastomosis and radiation dose to the anastomotic region, and anastomotic complications in esophageal cancer patients treated with trimodality therapy.MethodsBetween 2007 and 2016, esophageal cancer patients treated with trimodality therapy at a tertiary academic cancer center were identified. Patient, treatment, and outcome parameters were collected. Radiation dose to the gastric regions were extracted. Anastomotic complication was defined as leak and/or stricture. We used Fisher's exact and Wilcoxon rank‐sum tests to compare the association between clinical parameters and anastomotic complications.ResultsOf 89 patients identified, the median age was 63 years, 82% (n = 73) were male, and 82% had distal (n = 47) or gastroesophageal junction (n = 26) tumors. Median follow‐up was 25.8 months. Esophagectomies were performed with cervical (65%, n = 58) or thoracic anastomoses (35%, n = 31). Anastomotic complications developed in 60% (n = 53). Cervical anastomosis was associated with anastomotic complications (83%, n = 44/53, p < 0.01). Radiation to any gastric substructure was not associated with anastomotic complications (p > 0.05). In the subset of patients with distal/gastroesophageal junction tumors undergoing esophagectomy with cervical anastomosis where radiation was delivered to the future neoesophagus, 80% (n = 35/44) developed anastomotic complications. In this high‐risk subgroup, radiation was not associated with anastomotic complications (p > 0.05).ConclusionsOur analysis did not demonstrate an association between radiation dose to gastric substructures and anastomotic complications. However, it showed an association between esophagectomy with cervical anastomosis and anastomotic complications. Patients with distal/gastroesophageal junction tumors who undergo esophagectomy with cervical anastomosis have higher rates of anastomotic complications unrelated to radiation to gastric substructures.

777 IS ADJUVANT CHEMOTHERAPY FOR ESOPHAGEAL CANCER WITH RESIDUAL DISEASE AFTER TRIMODALITY THERAPY FUTILE? A NATIONWIDE MULTICENTRIC SURVEY

Abstract For patients with resectable locally advanced esophageal cancer (EC), trimodality therapy associating neoadjuvant chemoradiation and surgery is the standard of care. However, the risk of recurrence for patients with residual disease (RD) remains high and there is no established adjuvant treatment modality in this setting. Adjuvant immunotherapy recently exhibited promising results but ACT could also play a beneficial role. This study evaluated the potential benefit of ACT in RD after trimodality therapy for EC. Methods A multicenter database for the surgical treatment of EC collected data from 30 university hospitals (2000–2010). Patients with RD in completely resected EC after trimodality therapy where included and separated in an ACT group and a non-ACT group. Demographics, tumor and treatment characteristics, morbidity, overall and recurrence-free survival (OS and RFS) where compared. Uni and multivariate analysis were performed to identify factors associated with OS. Survival analysis of patients treated with and without ACT was performed in a propensity score matched study. Results From 2944 patients included, 484 had RD after trimodality therapy, and 9.3% (n = 45) were treated with ACT. There were no major differences in demographics, preoperative tumor and treatment characteristics between groups. Major complications where higher in the non-ACT group (31 vs 20%, p = 0.018). ACT group had more nodal involvement (78 vs 45%, p &amp;lt; 0.001). OS and RFS were significantly worse in the ACT group (median: 36.0 vs 46.7mo, p &amp;lt; 0.001 and 25.5 vs 47.9mo, p = 0.029 respectively). After multivariate analysis, ACT was independently associated with worse OS (HR = 3.69, p &amp;lt; 0.001). In the propensity matched study, OS and RFS remained worse in ACT group. Conclusion This study supports current recommendations concerning ACT abstention in EC with RD after trimodality therapy. In light of the promising results of the BMS Checkmate 577 study, adjuvant immunotherapy in this setting should therefore be considered as the first choice of treatment.

A Multi-Institutional Analysis of Radiation Dosimetric Predictors of Toxicity After Trimodality Therapy for Esophageal Cancer

PurposeThis multi-institutional review explored associations between radiation dose-volume histogram (DVH) parameters and cardiopulmonary toxicities with trimodality therapy for esophageal cancer. Methods and MaterialsWe reviewed 465 consecutive patients with esophageal cancer treated with chemoradiation therapy followed by surgery at 2 tertiary-care institutions between 2007 and 2013. Using logistic regression, we assessed associations between lung and heart DVH parameters and cardiopulmonary toxicities and survival. Statistically significant variables were subsequently included in multivariable models, which incorporated age, smoking history, previous history of heart disease, and type of chemotherapy. ResultsThe median age of the patients was 61 years (interquartile range, 54-68 years), and 86% were men. At baseline, 60% of the patients had known cardiac risk factors, 64% were current or former smokers, and 10% had other pulmonary comorbidities. Most patients had stage II to III (96%) adenocarcinoma (94%) of the distal esophagus. The radiation therapy (RT) modalities used were 3-dimensional conformal RT (38%), intensity modulated RT (41%), and proton therapy (20%). An increased heart dose was associated with increased risk of cardiac toxicity on univariable analysis (V20 Gy: odds ratio [OR], 1.20; 95% CI, 1.08-1.33; P = .001) (V30 Gy: OR, 1.24; 95% CI, 1.11-1.38; P < .0001) (V40 Gy: OR, 1.18; 95% CI, 1.03-1.35; P = .018). No lung DVH metrics were associated with lung toxicity. Heart V30 Gy was associated with adverse events on multivariable analysis (OR, 1.15; 95% CI, 1.04-1.26; P = .0047). ConclusionsWe observed an association between heart dose and cardiac toxicity for esophageal cancer. The risk of cardiac toxicity was 5%, 10%, and 15% when the heart V30 Gy dose was 14%, 20%, and 30%, respectively. For every 10% increase in V30 Gy, there was a corresponding 24% increase in the relative risk of cardiac toxicity.

Comparing Healthcare Utilization, Hospitalization, and Costs with Neoadjuvant Intensity-Modulated Radiation Therapy (IMRT) versus Proton Beam Therapy (PBT) for Esophageal Cancer

In the setting of tri-modality therapy for esophageal cancer (EC), prior studies demonstrate that neoadjuvant proton therapy (PBT) compared with intensity-modulated radiation therapy (IMRT) yields lower toxicity burden and fewer postoperative complications. However, it is not known whether there are also benefits of neoadjuvant PBT for healthcare utilization outcomes in EC patients undergoing surgery. We hypothesized that patients treated neoadjuvantly with PBT vs. IMRT plus esophagectomy would demonstrate healthcare utilization outcomes benefits, specifically, lower postoperative costs and shorter hospitalization length of stay (LOS). We tested differences in healthcare utilization outcomes in 287 patients treated with neoadjuvant PBT vs. IMRT, first in a retrospective test cohort (N = 237), and then in a prospective validation cohort of patients enrolled in a randomized trial of PBT vs. IMRT [NCT 01512589] (N = 50). These healthcare utilization outcomes were a pre-specified secondary outcome in this trial. In patients receiving neoadjuvant PBT (N = 81 test, 21 validation) vs. IMRT (N = 156 test, 29 validation) chemoradiation followed by esophagectomy, we compared costs (healthcare charges), length of stay (LOS) for esophagectomy, and postoperative complications (POC). Absolute (Δ = $PBT-$IMRT) and relative costs as in cost ratios (CR = $PBT/$IMRT) were calculated, compared using generalized linear models with gamma distribution. LOS was compared using negative binomial regression. There were no significant differences in patient characteristics by treatment group in both test and validation cohorts, including age, gender, race, histology, stage, location in the esophagus, radiation dose, and comorbidities. Neoadjuvant chemoradiation costs were higher for PBT vs. IMRT in both the test and validation cohorts: Test CR = 1.80 (95% CI 1.72-1.90, P<0.001); Δ = +$57,319; Validation CR = 1.50 (95% CI 1.40-1.61, P<0.001); Δ = +$55,958. As expected, surgery costs for esophagectomy did not significantly differ in PBT vs. IMRT in either cohort. Mean LOS during hospitalization for esophagectomy were lower for PBT vs. IMRT in both cohorts (Test LOS 8.4 vs. 10.4 days; P<0.001; Validation LOS 9.1 vs. 13 days; P = 0.02). Shorter LOS (P<0.001) and fewer POCs (P<0.001) were associated with lower postoperative costs in test cohort. Hospitalization costs for esophagectomy were lower for PBT vs. IMRT in both the test and validation cohorts: Test CR = 0.77 (95% CI 0.65-0.92, P = 0.004); Δ = - $15,251; Validation CR = 0.47 (95% CI 0.30-0.74; P = 0.002); Δ = - $46,923. After adjusting for covariates, costs remained higher for PBT in the chemoradiation period but lower in the postoperative period. Despite up-front chemoradiation costs, substantial healthcare costs were recovered after PBT during the period at highest risk for POCs, during hospitalization after esophagectomy.

An Institutional Experience of Post-Operative Anastomotic Complications Following Trimodality Therapy for Esophageal Cancer

An Institutional Experience of Post-Operative Anastomotic Complications Following Trimodality Therapy for Esophageal Cancer

A multicenter study of trimodality therapy for patients 75 years and older with esophageal cancer.

131 Background: Trimodality therapy is the standard of care for patients with resectable cancer of the esophagus. However, patients ≥75 years have been underrepresented or excluded from landmark clinical trials to date. We investigated the feasibility and safety of treatment of esophageal cancer with trimodality therapy in patients’ ≥ 75 years. Methods: We performed a retrospective review of all patients ≥75 years who received trimodality therapy for esophageal cancer in 3 high volume tertiary cancer institutions from June 2007 to June 2013. All patients received neoadjuvant radiation with concomitant chemotherapy followed by esophagectomy. Toxicities and clinical outcomes were abstracted from the electronic medical record and partially from a prospectively maintained database. Overall and disease-free survival were estimated using the Kaplan-Meier method. Results: Five hundred seventy patients were treated with trimodality therapy for esophageal cancer from 2007-2013. Of these, 38 patients (7%) were 75 or older at the time of diagnosis. At diagnosis, comorbidities included coronary artery disease (32%), atrial fibrillation (11%) and COPD (13%). The majority of patients (87%) received 50.4Gy/28 fractions. 5-fluorouracil (5-FU)/cisplatin was the most common chemotherapy regimen (37%), followed by 5-FU/docetaxel (24%). A total of 13 patients (34%) developed acute grade ≥3 toxicity associated with neoadjuvant therapy. The most common acute grade 3 toxicities were haematological (10%), nausea (8%), esophagitis (5%) and fatigue (5%). Significant postoperative complications included respiratory (empyema, ARDS, pleural effusion) (39%), arrhythmia (32%), anastomotic leak (5%), and ileus (5%). There were 2 deaths (5%) within 90 days of surgery: one was secondary to empyema, the other developed DIC and sepsis. Median overall survival and disease free survival were 4.4 and 2.3 years respectively. Conclusions: Trimodality treatment is a reasonable approach for management of carefully selected elderly patients with esophageal cancer, with similar rates of cancer outcomes, and treatment related morbidity and mortality as compared to younger patients.

Radiation dose mapping and anastomotic complications after trimodality therapy for esophageal cancers

Background and purposeThere is conflicting evidence with respect to the correlation between neoadjuvant chemoradiation and anastomotic complications following trimodality therapy in patients with esophageal cancer. We aimed to analyze the relationship between their dosimetry and any resulting anastomotic complications. Materials and methodsThe medical records of 51 consecutive patients who underwent trimodality therapy between 2007 and 2014 were retrospectively reviewed. We analyzed the differences in the mean dose received by regions of the esophagus relative to the landmark of the azygous vein and the stomach to correlate the development of an anastomotic complication using nonparametric rank-sum tests. ResultsAnastomotic leakage and stricture rates were 12% and 22%, respectively. Patients with anastomotic complications received a statistically significant higher mean dose to the esophagus at the level of the azygous vein (0.0 cm) and lower (up to −2.7 cm) (28.4–42.2 Gy vs. 10.3–27.6 Gy, p < 0.04). There were no differences noted in mean gastric doses. Median follow up time was 30.9 months. Median overall survival and disease free survival of our patient cohort was 34.4 months and 22.5 months, respectively. The development of an anastomotic complication did not affect survival outcomes. ConclusionPatients who experienced anastomotic complication after trimodality therapy for esophageal cancer were more likely to have received a higher mean esophageal dose around the proximity of the azygous vein, where intrathoracic anastomoses most commonly occur. Communication between surgical and radiation oncologists regarding the anastomotic location may be an important consideration in planning for trimodality therapy in reducing potential anastomotic complications.

A Multi-institutional Analysis of Dosimetric Predictors of Toxicity Following Trimodality Therapy for Esophageal Cancer

Abstract Purpose This multi-institutional review explored associations between radiation dose-volume histogram (DVH) parameters and cardiopulmonary toxicities with trimodality therapy for esophageal cancer. Methods and Materials We reviewed 465 consecutive patients with esophageal cancer treated with chemoradiation therapy followed by surgery at 2 tertiary-care institutions between 2007 and 2013. Using logistic regression, we assessed associations between lung and heart DVH parameters and cardiopulmonary toxicities and survival. Statistically significant variables were subsequently included in multivariable models, which incorporated age, smoking history, previous history of heart disease, and type of chemotherapy. Results The median age of the patients was 61 years (interquartile range, 54-68 years), and 86% were men. At baseline, 60% of the patients had known cardiac risk factors, 64% were current or former smokers, and 10% had other pulmonary comorbidities. Most patients had stage II to III (96%) adenocarcinoma (94%) of the distal esophagus. The radiation therapy (RT) modalities used were 3-dimensional conformal RT (38%), intensity modulated RT (41%), and proton therapy (20%). An increased heart dose was associated with increased risk of cardiac toxicity on univariable analysis (V20 Gy: odds ratio [OR], 1.20; 95% CI, 1.08-1.33; P = .001) (V30 Gy: OR, 1.24; 95% CI, 1.11-1.38; P Conclusions We observed an association between heart dose and cardiac toxicity for esophageal cancer. The risk of cardiac toxicity was 5%, 10%, and 15% when the heart V30 Gy dose was 14%, 20%, and 30%, respectively. For every 10% increase in V30 Gy, there was a corresponding 24% increase in the relative risk of cardiac toxicity.

A Prospective Study Assessing Early Cardiotoxicity after Trimodality Therapy for Esophageal Cancer

A Prospective Study Assessing Early Cardiotoxicity after Trimodality Therapy for Esophageal Cancer

A Prospective Pilot Study of Pencil Beam Scanning (PBS) Proton Radiation Therapy (RT) as a Component of Trimodality Therapy for Esophageal Cancer

A Prospective Pilot Study of Pencil Beam Scanning (PBS) Proton Radiation Therapy (RT) as a Component of Trimodality Therapy for Esophageal Cancer

Validation of a Nomogram Predicting Survival After Trimodality Therapy for Esophageal Cancer

Recently, a nomogram was developed for the prediction of overall survival (OS) after treatment with neoadjuvant chemoradiotherapy (nCRT) combined with surgery for esophageal or junctional cancer. The nomogram included clinical nodal category, pathologic tumor category, and number of positive lymph nodes in the resection specimen. The aim of this study was to externally validate the nomogram in an international multiinstitutional cohort of patients, and to explore the prognostic use of the nomogram for the prediction of progression-free survival (PFS) after nCRT plus surgery. Patients with potentially resectable esophageal or junctional carcinoma that underwent nCRT plus surgery between 1998 and 2015 at 3 academic centers were included. The discriminative ability of thenomogram for the prediction of OS and PFS wasquantified by Harrell's C-statistic. Calibration of the nomogram was visually assessed by plotting actualOS and PFS probabilities against predicted probabilities. Some 975 patients were included. The discriminative ability of the nomogram for OS was moderate (C-statistic, 0.61) and comparable to that of the initial cohort (C-statistic, 0.63). The nomogram was also useful for the prediction of PFS (C-statistic, 0.64). Calibration of the nomogram was accurate for both OS and PFS, with predicted estimates corresponding closely with the actual observed estimates. The nomogram accurately predicted OS and PFS after nCRT plus surgery in an independent international cohort of esophageal cancer patients. The current validated model may enable risk-stratified adjuvant treatment allocation and identify patients in need of routine surveillance after treatment.

Heart Dose and Outcomes in Radiation Treatment for Esophageal Cancer.

PurposeStudies have shown that radiation dose to the heart may be associated with worse outcomes in patients receiving chemoradiation for lung cancer. As esophageal cancer radiation treatment can result in relatively high cardiac doses, we evaluated a single-institution database of patients treated for esophageal cancer for heart dose and outcomes.MethodsWe retrospectively reviewed 59 patients with stage IIA-IIIB esophageal cancer treated with neoadjuvant chemoradiation to 50.4 Gy followed by esophagectomy from 2007-2015. Patient demographics and outcome data, including pathological response, local recurrence, distant metastases, and overall survival, were obtained. Mean heart dose (MHD), heart V5, V40, and V50, were calculated. Differences in patient characteristics between the three radiation therapy modalities: three-dimensional (3D) conformal radiotherapy (3D-CRT), intensity modulated radiotherapy (IMRT), and proton beam radiation therapy (PBT) were tested using non-parametric Kruskal-Wallis (K-W) analysis of variance (ANOVA). Patient characteristics and heart dosimetric parameters were screened by univariate Cox regression for an association to overall survival, and univariate predictors (p < 0.05) were then selected as inputs into a multivariate Cox regression model using stepwise backward elimination. Kaplan-Meier risk-stratified survival curves were plotted for the best univariate or multivariate Cox model variables. An exploratory subgroup univariate Cox regression was conducted in each of the treatment modalities (proton, IMRT, 3D-CRT).ResultsThe median follow-up was 20 months. The median overall survival was 73 months. Eleven patients (20%) experienced a complete pathologic response (pCR). Only two patients (4%) experienced a local recurrence. On univariate analysis, predictors of survival were age, prior radiation, pathologic response in involved lymph nodes, and tumor length post-treatment. On a multivariate analysis, only pathologic nodal response (yN) remained significant (p = 0.007). There was no relationship between any heart dosimetric variables analyzed and any clinical outcomes.ConclusionsIn this retrospective review, radiation dose to the heart was not associated with inferior treatment outcomes in patients receiving trimodality therapy for esophageal cancer.

Next-generation sequencing to identify predictors of survival after trimodality therapy for esophageal cancer.

153 Background: Tumor mutation profiling has changed the prognostication and treatment of a wide variety of malignances. However, little is known about whether mutation profiles affect outcome in localized esophageal cancer treated with multimodality therapy. SMAD4 is a gene involved in the regulation of the TGF-β signal transduction pathway by negatively controlling the growth of epithelial cells and has been implicated as a prognostic factor in pancreatic cancer. We undertook an exploratory analysis of tumor mutation profiles, including SMAD4 status, in localized esophageal cancer patients treated with trimodality therapy at our institution. Methods: We identified 66 Stage II-III esophageal cancer patients treated with chemoradiation followed by surgery who had some form of tumor mutation profiling available. Only patients with mutation profiling from pre-treatment biopsy or post-chemoradiation surgical specimen (i.e. not from a subsequent metastatic lesion) were included. Twenty-two patients underwent next-generation sequencing assessing 341 candidate genes via targeted sequencing. Log-rank test was used to assess correlation of mutations to overall survival, and to pathologic response. Results: The median follow-up was 17.1 months. SMAD4 loss was identified in 3 of 22 patients (13.6%) who underwent next-generation sequencing, and was significantly associated with inferior overall survival (p=0.023). No other candidate genes were significantly associated with survival, and no genes were significantly associated with pathologic response. Conclusions: To our knowledge, this is the first analysis of next-generation mutation profiling and outcome in non-metastatic esophageal cancer patients treated with trimodality therapy. Due to the limited numbers, this was an exploratory analysis only. We identified SMAD4 loss as a potential adverse prognostic factor for survival. More next-generation sequencing data from non-metastatic esophageal cancer patients treated with multimodality therapy is needed to further elucidate the potential relationship of SMAD4 loss or other mutations with outcome.

Trimodality Therapy for Esophageal Cancer: Radiation to the Gastric Conduit Is Not Associated With Post-operative Anastomotic Complication

Since publication of the CROSS study, the majority of patients with locally advanced esophageal cancer are treated with neoadjuvant chemoradiotherapy prior to esophagectomy (trimodality therapy, TMT). The stomach, specifically the fundus and greater curvature, is used to re-create neo-esophagus and is often located in the pre-operative radiation (RT) field. This study aims to determine if RT to the stomach and its substructures correlate with anastomotic complication (AC). From 2007 to 2016, patients with esophageal cancer treated with TMT at a tertiary academic institution with restored digital RT plans were included in this IRB approved study. Clinical and pathologic data were obtained retrospectively. The stomach and its substructures were contoured on the preoperative RT planning scans and dosimetric parameters were extracted. AC was defined as a leak and/or a stricture. Fisher-exact and Wilcoxon rank-sum tests were used. 96 patients were included in the analysis. The median age was 63 (55-70); 82% of patients were male. Majority of the tumors were located in the distal esophagus (52%) and gastroesophageal junction (GEJ, 30%) versus 15% and 3% in the middle and proximal esophagus, respectively. Adenocarcinoma was the predominant histology (80%). Carboplatin and paclitaxel was used in majority of the patients (36%). Median RT dose was 45 Gy (range, 41.4-54 Gy). Transhiatal esophagectomy was the common surgery performed (50%), followed by Ivor-Lewis (33%), 3-incision (14%) and other (3%). AC developed in 57% of the patients (47 strictures,49%; 16 leaks, 17%; 8 both, 8%). Diabetes (DM) was more common in patients with AC (n=16, 29% vs. n=7, 17%, p=0.172). Esophagectomy type was associated with AC (p<0.000). The predominant type of surgery in patients with AC was transhiatal (62%) followed by 3-incision (18%), Ivor-Lewis (16%) and others (4%). The mean dose to the stomach, fundus, and greater curvature was 27 Gy (18-35 Gy), 33 Gy (23-45 Gy), and 23 Gy (13-33 Gy), respectively. RT dose to the stomach and its substructures were not associated with AC (p>0.05). Of the 47 patients with distal/GEJ tumor location and esophagectomies with cervical anastomoses, 72% of them developed AC (31 strictures, 66%; 11 leaks, 23%; 8= both, 17%). DM was more common in patients with AC (n=9, 27% vs. 0%, p=0.047). RT was not associated with AC (p>0.05). Our analysis does not demonstrate an association between RT to gastric substructures that form the neo-esophagus and AC. However, it does show an increased risk of AC in patients who undergo esophagectomies with cervical anastomosis. In this population, the majority with a leak had anastomosis in the neck and distal esophageal or GEJ tumor undergoing cervical anastomosis. Patients with distal tumors may be better served with anastomosis in the thorax rather than neck. Further analysis in a larger study population is needed to clarify associations.

A Multi-institutional Analysis of Trimodality Therapy for Esophageal Cancer in Elderly Patients

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. 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 65years 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. 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. 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.

Use of circulating tumor DNA levels to gauge necessity of surgery for patients undergoing trimodality therapy for esophageal cancer.

TPS214 Background: Up to 40% of patients receiving neoadjuvant esophageal chemoradiotherapy (CRT) are found to have no evidence of malignancy post-operatively. Given this, a sensitive and specific biomarker is needed, as reliable identification of complete responders may spare patients the morbidity and mortality of esophagectomies. Recent work with circulating tumor DNA (ctDNA) collected from the plasma of cancer patients indicates tumors routinely shed large amounts of DNA into the blood. This ctDNA can be systematically analyzed, quantification of which has been correlated with local and systemic disease burden. To further increase the specificity of analysis, the somatic mutations that arose in the tumor can be detected in ctDNA via targeted and whole genome sequencing. However, information on the feasibility of using ctDNA quantification as a biomarker for neoadjuvant response assessment is lacking. We hypothesize that quantification of ctDNA throughout trimodality therapy can be of practical use in the non-invasive monitoring of treatment response. The overall goal of this pilot project is to assess the feasibility and predictive utility of incorporating a sensitive, patient and tumor specific, plasma ctDNA quantification assay to more reliably identify complete responders following CRT. The long-term goal of this proposal is to apply these methods into prospective clinical trials for personalization of therapy by identifying neoadjuvant complete responders who may benefit from non-operative therapy. Methods: Pilot/feasibility study to evaluate the correlation between plasma ctDNA levels and pathologic treatment response. Plasma samples at different treatment time points (pre-CRT, during CRT, immediately pre-op and post-op) will be collected from 28 patients receiving pre-operative CRT followed by surgery for esophageal cancer. Patient-specific mutations will be identified through whole exome sequencing of paraffin-embedded pre-treatment biopsies. SafeSeqS PCR primers will be designed per patient for targeting of tumor mutations. Plasma-derived ctDNA will be assayed using the patient-specific SafeSeqS approach for each time point in triplicate.