Ashman, Jonathan B.

159 Background: Intensity-modulated proton therapy (IMPT) with small spot size has the potential to reduce dose to normal tissues but also introduces new confounding factors such as setup uncertainty, range uncertainty, and interplay effects due to breathing motion. We investigated plan quality and robustness of IMPT with small spot size for distal esophageal adenocarcinoma (DEA). Methods: 19 patients with DEA treated by IMPT were retrospectively evaluated. Spot sizes ranged from 2 to 6mm, with spot spacing of 5mm. All plans were generated using a commercial treatment planning system. In-house-developed dose-evaluation software modeled time-dependent spot delivery to incorporate interplay effects. Dose-volume-histogram (DVH) indices were used to evaluate plan quality and robustness was evaluated using the DVH band method. Results: For plan quality, median values of clinical target volume D95% and D5%-D95% (normalized to the prescribed doses), total lung mean dose, heart mean dose, and cord Dmax were 1.014, 0.035, 3.82Gy[RBE], 7.73Gy[RBE], 39.16Gy[RBE], respectively. For plan robustness, median band widths of the aforementioned DVH indices were 0.018, 0.048, 0.60Gy[RBE], 4.17Gy[RBE], and 2.36Gy[RBE], respectively. For interplay effects, median values of the aforementioned DVH indices were 0.99, 0.061, 4.07Gy[RBE], 7.87Gy[RBE], and 39.66Gy[RBE], respectively. Seven patients underwent esophagectomy after neoadjuvant chemoradiation, and five, three, and one of them achieved downstaging, near complete response, and pathologic complete response, respectively; R0 resection was achieved in all cases. For all patients, acute side effects were mostly limited to grades 1-2 only. The only grade 3 adverse events were related to feeding tube placement (8 patients); there were no RT-induced pneumonitis or other lung-related toxicities. Conclusions: IMPT plans with small spot size for DEA have good target dose coverage, homogeneity and normal tissue protection. Treatment plans are also robust to uncertainties and interplay effects. Early clinical results demonstrate low acute toxicity and encouraging clinical and pathologic response.

Background. We sought to study the association between RPS case volume and outcomes. Although a relationship has been demonstrated between case volume and patient outcomes in some cancers, such a relationship has not been established for retroperitoneal sarcomas (RPSs). Study Design. The National Cancer Database (NCDB) was queried for patients undergoing treatment for primary RPS diagnosed between 2004 and 2013. Mean annual patient volume for RPS resection was calculated for all hospitals and divided into low volume (<5 cases/year), medium volume (5–10 cases/year), and high volume (>10 cases/year). Risk-adjusted regression analyses were performed to identify predictors of 30-day surgical mortality, R0 margin status, and overall survival (OS). Results. Our study population consisted of 5,407 patients with a median age of 61 years, of whom 47% were male and 3,803 (70%) underwent surgical resection. Absolute 30-day surgical mortality and R0 margin rate following surgery for low-, medium-, and high-volume institutions were 2.4%, 1.3%, and 0.5% (p=0.027) and 68%, 65%, and 82%, (p<0.001), respectively. Five-year overall survival rates for low, medium, and high-volume institutions were 56%, 57%, and 66%, respectively (p<0.001). Patients treated at low-volume institutions had a significantly higher risk of 30-day mortality (adjusted OR = 4.66, 95% CI 2.26–9.63) and long-term mortality (adjusted HR = 1.56, 95% CI 1.16–2.11) compared to high-volume institutions. Conclusion. We demonstrate the existence of a hospital sarcoma service line volume-oncologic outcome relationship for RPS at the national level and provide benchmark data for cancer care delivery systems and policy makers.

Introduction. Optimization of outcomes of extra-abdominal STS is not clearly understood. We sought to determine whether hospital surgical volume and adherence to NCCN guidelines, or both, are associated with outcomes in the treatment of extra-abdominal soft tissue sarcoma (STS).Methods. The National Cancer Database (NCDB) was queried for patients undergoing surgery for extra-abdominal STS diagnosed from 2003 to 2007. Mean annual hospital volume for STS surgery was divided into volume terciles (1T ≤3, 2T 4–10, and 3T ≥11 cases/year). Adherence to NCCN guidelines was determined. Primary outcome was overall survival.Results. Our study population consisted of 13,684 patients with a median age of 56 years. 3T hospitals were more likely to adhere to NCCN guidelines for stage III patients (63% versus 47%;p≤0.001) than 1T hospitals. On multivariable analysis, adherence to NCCN guidelines was associated with improved survival (HR = 0.79, CI 0.73–0.87;p<0.001), but hospital volume was not (3T versus 1T: HR = 0.92, CI 0.82–1.02;p=0.12). Five-year overall survival was comparable for compliant groups at 1T, 2T, and 3T hospitals (72%, 72.4%, and 72.6%, resp.). 3T hospitals were not associated with a lower risk of 30-day mortality (OR 0.70, 95% CI 0.44–1.11) compared to 1T hospitals but did have a higher R0 resection rate (OR 1.43, 95% CI 1.32–1.54).Conclusions. Adherence to NCCN guidelines, irrespective of hospital volume, is associated with improved overall survival for patients with extra-abdominal STS. High-volume hospitals more often adhere to guidelines, but low-volume hospitals that follow national guidelines may achieve comparable outcomes.

Background and aim Thoracic radiation therapy (XRT) for cancer is associated with the development of significant coronary artery disease that may require coronary artery bypass grafting surgery (CABG). Contemporary acute surgical outcomes and long-term postoperative survival of patients with prior XRT have not been well characterised. Methods This was a retrospective, single-centre study of patients with a history of thoracic XRT who required CABG and who were propensity matched against 141 controls who underwent CABG over the same time period. The objectives were to assess early CABG outcomes and long-term survival in patients with prior XRT. Results Thirty-eight patients with a history of previous thoracic XRT underwent CABG from 1994 to 2013. The median time from XRT exposure to surgery was 7.9 years (IQR: 2.5–18.4 years). Perioperative adverse events were similar in the XRT group and controls; however, there was a trends lower utilisation of internal mammary artery (IMA) grafts in the XRT group (89%vs98%, P=0.13). After a median postoperative follow-up of 5.4 years (IQR 0.9–9.4 years), no difference in long-term all-cause mortality was observed. Conclusion Patients with prior thoracic XRT who undergo CABG have similar long-term all-cause mortality compared with controls. Isolated CABG after thoracic XRT is not associated with higher perioperative complications, but IMA graft use may be limited by prior XRT.

165 Background: Distant metastases are common in primary esophageal cancer, but data conflict regarding the rates of brain metastases (BM) ranging from 0% to 13%. We sought to investigate whether the incidence of BM from esophageal malignancies is increasing in the modern era. Methods: After IRB approval, a single institution retrospective review identified 583 patients (pts) treated between 1/1997 and 1/2016 for stage I-IV cancer of the esophagus/esophagogastric junction with at least 3 months follow-up. Data collected included demographic information, primary diagnosis date and staging, histologic subtype, treatment regimens for primary and BM, date of BM diagnosis, status of neurologic symptoms and extracranial disease at BM diagnosis, and date of death. Data were analyzed by Fischer’s exact test and Kaplan-Meier analysis. Results: The overall cohort was comprised of 495 pts (85%) with adenocarcinoma and 82 pts (14%) with squamous cell carcinoma. 492 pts (84%) were male; the median age was 68 years (range 26-90). BM were identified in 22 pts (3.8%) with a median latency of 11 months from the primary diagnosis. Of the pts with BM, the primary histology was adenocarcinoma in 21 pts and squamous cell carcinoma in 1 pt ( P = 0.3). BM developed in 12 pts who were initially treated for locally advanced disease and in 10 pts who presented with distant metastases. Diagnosis of BM was at the time of initial presentation in 4 of these 10 stage IV pts. A solitary BM was identified in 9 pts. Initial treatments of BM were surgical resection followed by stereotactic radiosurgery (SRS; n = 5); surgical resection followed by whole brain radiotherapy (WBRT; n = 1); WBRT alone (n = 13); SRS alone (n = 3). Overall survival (OS) following diagnosis of BM was 18% at 1 year with a median of 4 months. OS was superior for pts who had surgical resection as initial treatment of BM compared to pts treated with WBRT or SRS alone (1-year OS 67 vs. 0%; median OS 13.5 vs. 3 months; P = 0.003). Conclusions: The incidence of BM is low in esophageal cancer with no statistically significant increased rate of BM developing in patients with adenocarcinoma compared with squamous cell carcinoma. Outcomes were poor overall for pts who developed BM, but pts who were appropriate for neurosurgical resection had improved survival.

134 Background: Brain metastasis (BM) is an uncommon site of failure in patients (pts) with esophageal cancer (EC) with reported rates between 1-6%. EC pts are living longer with the wider adoption of trimodality therapy and, as with other malignancies, this may change the patterns of failure. We evaluated the incidence and outcomes of BM in EC at Mayo Clinic in Arizona. Methods: A retrospective review identified pts who developed BM from cancer of the esophagus or gastroesophageal junction. A total of 321 patients treated for stage I-IV EC (adenocarcinoma, n = 273; squamous, n = 46; small cell, n = 2) were identified between 1997 and 2012. Fisher’s exact test was used for comparisons. Actuarial survival was calculated using Kaplan-Meier analysis. Results: BM developed in 13 pts (4%), all of whom had adenocarcinoma. Nine pts initially presented with T3 and/or node-positive disease. Four pts presented with metastatic disease to other sites, but only 1 of this group was diagnosed with BM at initial presentation. The median time from initial diagnosis to BM detection was 12 months (range 0-40). All pts were symptomatic at diagnosis. BM was solitary in 6 pts, multiple in 6 pts, and unknown in 1 pt. The posterior fossa was involved in 9 pts. The brain represented the first site of failure in 9 pts. Treatment included surgical resection (n = 5), stereotactic radiosurgery (n = 4), and whole brain radiotherapy (n = 9). Median overall survival was 24 months from initial diagnosis and 5 months from BM detection. Among pts with adenocarcinoma, 3/119 (2.5%) were diagnosed between 1997-2006 compared to 10/154 (6.5%) between 2007-2012 (P = 0.1). Conclusions: The brain remains an uncommon site of failure among pts with EC. A recent series reported an incidence of BM in 13% of pts, raising the possibility of a changing failure pattern. In our series, BM was detected in only 4% of pts. Our study is suggestive of a trend towards increased incidence of BM in more recent years, although it did not reach statistical significance and could be a consequence of the retrospective nature of the study. Both series found BM limited only to pts with adenocarcinoma, and a possible association has been reported between HER-2 overexpression and BM in EC. Therefore, BM in EC may be an interesting area for future study.

20 Background: Esophageal adenocarcinoma (EAC) incidence is rising and prognosis is uniformly poor, even with early stage disease. Barrett esophagus (BE) serves as a premalignant marker for EAC, with an estimated progression of 0.5% per year. Low-grade (LGD) and high-grade dysplasia (HGD) confer a higher risk of progression, providing an opportunity for intervention and surveillance. Aims: To evaluate a large cohort of patients undergoing endoscopic evaluation of BE and thereby better understand the natural history of BE and dysplasia. Methods: A retrospective review of endoscopic databases was conducted for all patients with the diagnosis of BE undergoing upper endoscopy at a tertiary academic medical center from 1991-2010. All endoscopy and accompanying pathology reports were reviewed. Only those patients with 2 biopsies documenting specialized intestinal metaplasia were analyzed. Results: 848 patients underwent upper endoscopy for evaluation of BE. Of these, 674 patients met inclusion criteria, at a mean follow up of 66.6 months. Table 1 depicts the distribution of patients according to their histology at presentation. 22 (3.2%) patients presented with established EAC, while EAC developed in 51 (7.6%). Of patients with HGD, LGD, or no dysplasia (ND) at presentation, EAC ultimately developed in 30.6%, 6.6%, and 2.7%, respectively. EAC developed in 4 patients despite RFA treatment for ND (2) or LGD (2). HGD developed in 6 such patients after treatment for ND (3) and LGD (3). Only 1 patient in each RFA-treated cohort required esophagectomy, while the others cleared dysplasia or EAC with continuous treatment. Conclusions: In this large cohort of patients with Barrett’s esophagus, higher grade of dysplasia at first endoscopy was associated with development of EAC. Continuous surveillance during and after endoscopic treatment is necessary and often results in clearance of dysplasia and EAC. [Table: see text]

88 Background: There is not yet a consensus on the efficacy and safety of IMRT for the treatment of patients with esophageal carcinomas. We report on our experience with outcomes and toxicity with IMRT for these patients. Methods: Fifty-five patients with esophageal carcinoma were treated with IMRT at our institution from 12/2008 and 12/2014. Medical records were retrospectively reviewed. All patients received concurrent chemotherapy (majority 5-FU with oxaliplatin). Thirty-one (56%) patients underwent surgery. Fifty (91%) received 50.4 Gy in 28 fractions. Seventy-three percent of cases were adenocarcinoma. Regions include mid-thoracic (15%), lower thoracic (64%), and GE junction (22%). Clinical uT-stages were as follows: T1 (2%), T2 (20%), T3 (69%), and T4a (5%). Clinical N-stages were as follows: N0 (33%), N1 (53%), N2 (13%), and N3 (2%). Results: Median follow-up for all patients was 15 months (1.5 - 64.5) and 25.5 months (1.5 - 64.5) for patients who were alive at follow-up (n = 31). Fifty-one (93%) patients completed RT. Of the 31 patients who underwent surgery, 9 (29%) were found to have a complete pathologic response. Site of first recurrence was local (n = 2, 4%), regional (n = 3, 6%), and distant (n = 14, 26%). At 12 and 24 months, overall survival was 72% and 58%, freedom from recurrence was 78% and 65%, and freedom from distant recurrence was 78% and 68%. On univariate analysis, improved OS was noted with patients who underwent surgery (RR 0.29) or were cN0 (RR 0.27). Twenty eight patients (51%) experienced > / = CTCAE v.4grade 3 acute toxicity; notable were hematologic (n = 14, 25%), esophagitis (n = 6, 11%), acute coronary event (n = 1, 2%), and post-chemoRT pneumonia (n = 1, 2%). Fifteen patients (31%) experienced > grade 3 late toxicity; notable were esophageal stricture (n = 7, 14%), post-op pneumonia (n = 3, 6%), post-CRT pneumonia (n = 2, 4%), and COPD exacerbation (n = 1, 2%). Conclusions: Patient receiving IMRT with concurrent chemotherapy for esophageal carcinomas have good LC rates, with or without surgery. Majority of patients are able to finish treatment with acceptable rates of late toxicity. Patient who underwent surgery or were cN0 had better OS.

110 Background: Anastomotic leaks can occur after esophagectomy and optimal management after minimally invasive esophagectomy (MIE) is not well defined. We reviewed endoscopic management of leaks after MIE in patients undergoing trimodality therapy at Mayo Clinic Arizona. Methods: Records of patients undergoing MIE from November, 2006 to February, 2015 were reviewed after appropriate IRB approval. Results: 148 patients underwent MIE including 136 (91.8%) thoracic and 12 (8.1%) cervical anastomoses. Clinically significant anastomotic leaks were observed in 13 (8.8%) patients with 2 (16%) cervical and 11 (8%) thoracic anastomosis at a median of 6.1 days (0-14). 11 (11%) patients treated with neoadjuvant chemoradiotherapy experienced esophageal leak and 2 who did not receive chemoradiotherapy (4%). For treatment of anastomotic leaks, 10 patients underwent VATS with pleural space irrigation and chest tube replacement, and 11 patients underwent stent deployment at the anastomosis for repair. Stents were placed such that the fistula/leak was in the fully covered portion with the greater portion of the stent residing in the esophageal remnant. Stents were removed at a mean of 54 days (28-114). In 2 patients, overgrowth into the stent body required stent-in-stent placement (fully covered) with removal of both stents. Stents were successful at sealing all leaks. Conclusions: Leaks after MIE represent a small, but significant, morbidity in MIE. The majority can be managed by endoscopic stent placement. Stenting is an effective management tool for postoperative leaks in locally advanced esophageal malignancies.