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Contains fulltext : 251435.pdf (Publisher’s version ) (Open Access) INTRODUCTION: The recent POLDER trial investigated the effects of external beam radiotherapy (EBRT) on dysphagia caused by incurable oesophageal cancer. An estimated life expectancy of minimally three months was required for inclusion. However, nearly one-third of the included patients died within three months. The aim of this study was to investigate if the use of prediction models could have improved the physician's estimation of the patient's survival. METHODS: Data from the POLDER trial (N = 110) were linked to the Netherlands Cancer Registry to retrieve patient, tumour, and treatment characteristics. Two published prediction models (the SOURCE model and Steyerberg model) were used to predict three-month survival for all patients included in the POLDER trial. Predicted survival probabilities were dichotomised and the accuracy, sensitivity, specificity, and the area under the curve (AUC) were used to evaluate the predictive performance. RESULTS: The SOURCE and Steyerberg model had an accuracy of 79% and 64%, and an AUC of 0.76 and 0.60 (p = .017), respectively. The SOURCE model had higher specificity across survival cut-off probabilities, the Steyerberg model had a higher sensitivity beyond the survival probability cut-off of 0.7. Using optimal cut-off probabilities, SOURCE would have wrongfully included 16/110 patients into the POLDER and Steyerberg 34/110. CONCLUSION: The SOURCE model was found to be a more useful decision aid than the Steyerberg model. Results showed that the SOURCE model could be used for three-month survival predictions for patients that are considered for palliative treatment of dysphagia caused by oesophageal cancer in addition to clinicians' judgement.

PURPOSE To analyze the effect of radiation dose escalation to the primary tumor on local tumor control in definitive chemoradiation (dCRT) for patients with esophageal cancer. PATIENTS AND METHODS Patients with medically inoperable and/or irresectable esophageal carcinoma, referred for dCRT, were randomly assigned between a standard dose (SD) of 50.4 Gy/1.8 Gy for 5.5 weeks to the tumor and regional lymph nodes and a high dose (HD) up to a total dose of 61.6 Gy to the primary tumor. Chemotherapy consisted of courses of concurrent carboplatin (area under the curve 2) and paclitaxel (50 mg/m2) in both arms once a week for 6 weeks. The primary end point was local progression-free survival. RESULTS Between September 2012 and June 2018, 260 patients were included. Squamous cell carcinoma (SCC) was present in 61% of patients, and 39% had adenocarcinoma (AC). Radiation treatment was completed by 94%, and 85% had at least five courses of chemotherapy. The median follow-up time for all patients was 50 months. The 3-year local progression-free survival (LPFS) was 70% in the SD arm versus 73% in the HD arm (not significant). The LPFS for SCC and AC was 75% versus 79% and 61% versus 61% for SD and HD, respectively (not significant). The 3-year locoregional progression-free survival was 52% and 59% for the SD and HD arms, respectively ( P = .08). Overall, grade 4 and 5 common toxicity criteria were 12% and 5% in the SD arm versus 14% and 10% in the HD arm, respectively ( P = .15). CONCLUSION In dCRT for esophageal cancer, radiation dose escalation up to 61.6 Gy to the primary tumor did not result in a significant increase in local control over 50.4 Gy. The absence of a dose effect was observed in both AC and SCC.

Introduction: Despite evidence-based guidelines, variation in esophageal cancer care exists in daily practice. Many oncology networks deployed regional agreements to standardize the patient care pathway and reduce unwarranted clinical variation. The aim of this study was to explore the trends in variation of esophageal cancer care between participating hospitals of the Managed Clinical Network (MCN) in the Netherlands.Materials and methods: Patients with esophageal cancer diagnosed from 2012 to 2016 were selected from the Netherlands Cancer Registry. Variation on treatment strategies, lead time to start of treatment, and 2-year survival, were calculated and compared between five clusters of hospitals within the network.Results: A total of 1763 patients, diagnosed in 17 hospitals, were included. 71% of all patients received treatment with a curative intent, which ranged from 69% to 77% between the clusters of hospitals in 2015–2016. Although variation in treatment modalities between the clusters was observed in 2012–2014, no significant variation existed in 2015–2016, except for patients receiving no treatment at all. The 2-year overall survival of patients receiving treatment with a curative intent did not vary significantly between the clusters of hospitals (range: 56%–63%). Nevertheless, the median lead time before patients started treatment with a curative intent varied between clusters of hospitals in 2015–2016 (range: 34–47 days; p < 0.001).Conclusion: Limited variation in esophageal cancer treatment between clusters of hospitals in the MCN existed. This study shows that oncology networks can promote standardization of cancer care and reduce variation between hospitals through insight into variation.

Contains fulltext : 229287.pdf (Publisher’s version ) (Open Access) BACKGROUND AND PURPOSE: A matched comparison of external beam radiotherapy (EBRT) versus brachytherapy recently demonstrated that EBRT appears at least as effective for palliating dysphagia in patients with incurable esophageal cancer. The aim of this analysis was to compare patient-reported outcomes (PROs) after EBRT versus brachytherapy. MATERIALS AND METHODS: In a multicenter prospective cohort study, patients with incurable esophageal cancer requiring palliation of dysphagia were included to undergo EBRT (20 Gy in 5 fractions). This EBRT cohort was compared to the single-dose 12 Gy brachytherapy cohort of the previously reported SIREC-trial. Propensity score matching was applied to adjust for baseline imbalances. The primary endpoint of dysphagia improvement was reported previously. PROs were secondary outcomes and assessed at baseline and 3 months after treatment using EORTC QLQ-C30 and QLQ-OES18 questionnaires. RESULTS: A total of 115 enrolled EBRT patients and 93 brachytherapy patients were eligible. After matching, 69 well-balanced pairs remained. At follow-up, significant deteriorations in functioning (i.e. physical, role, social), pain, appetite loss, and trouble with taste were observed after brachytherapy. In the EBRT group, such deterioration was observed only for role functioning, while significant improvements in trouble with eating and pain were found. Between-group comparison showed mostly comparable PRO changes, but significantly favored EBRT with regard to nausea, vomiting, pain, and appetite loss. CONCLUSION: Short course EBRT results in similar or better PROs at 3 months after treatment compared to single-dose brachytherapy for the palliation of malignant dysphagia. These findings further support its use and inclusion in clinical practice guidelines.

358 Background: The recently published POLDER trial investigated the effects of external beam radiotherapy (EBRT) on dysphagia caused by incurable esophageal cancer. As the effects of EBRT were presumed not to be immediate, an estimated life expectancy of minimally three months was required for inclusion. However, nearly a third of the included patients died within three months. The aim of this study was to investigate if the use of prediction models could have improved the physician’s estimation of the patient’s survival, and thus the eligibility for EBRT treatment. Methods: Data from the POLDER trial (N = 110) were linked to the Netherlands Cancer Registry to retrieve additional patient, tumor and treatment characteristics. Two published prediction models (the SOURCE model and Steyerberg model) were used to predict overall survival for all patients included in the POLDER trial. Predicted survival probabilities were dichotomized (predicted deceased/alive at three months) and the positive predictive value, negative predictive value, sensitivity, specificity and the area under the curve (AUC) were used to evaluate the predictive performance. DeLong’s test was used to test the difference between the AUCs of the SOURCE and Steyerberg models for statistical significance. Results: In the POLDER trial, 35 patients were unjustly presumed to survive three months. Predicting survival at three months, the SOURCE and Steyerberg model had an AUC of 0.76 and 0.60 respectively. The difference between the AUCs of the models was significant (p =.017). Under optimal survival cut-off scores, SOURCE would have incorrectly predicted 16 patients to survive three months. For the Steyerberg model this was 22 patients. Furthermore, using SOURCE under these cut-off scores, seven patients were incorrectly predicted to not survive three months compared to 18 patients using the Steyerberg model. Conclusions: Results showed that the SOURCE and Steyerberg models could have improved survival predictions compared to clinical judgement alone. The SOURCE model was found to be a more useful decision aid than the Steyerberg model as it was more accurate. Accepting that a small proportion of patients are incorrectly predicted not to survive three months and are not considered for EBRT treatment, we recommend using the SOURCE model for patients that are considered for palliative treatment of dysphagia caused by esophageal cancer.

TPS4154 Background: Esophageal cancer is the 6th leading cause of mortality worldwide, with an overall 5-year survival rate of 10%. This is in part due to more than 50% of patients presenting with irresectable or metastatic disease. With the introduction of definitive chemoradiation, 3-year survival rates of patients with irresectable tumors have risen to up to 40% (Hulshof et al., ASCO GI Oral Presentation, 2020). However, treatment still fails in the majority of patients due to locoregional recurrences or development of metastatic disease. Recently, it has been shown that addition of TGF-β inhibition to chemoradiation may improve treatment efficacy (Steins et al., Int J Cancer, 2019). Additionally, PD-L1 inhibition has emerged as a relevant therapeutic strategy in specific patient subgroups, such as squamous cell carcinoma (Kato et al., The Lancet Oncology, 2019). In this phase II study, we will investigate the feasibility of addition of bintrafusp alfa, a bifunctional fusion protein blocking TGF-β and PD-L1, to definitive chemoradiation in patients with esophageal squamous cell carcinoma. Methods: To assess feasibility, 52 patients will receive definitive chemoradiation combined with three doses of bintrafusp alfa at week 1, 4 and 7 (Table). Feasibility is defined as ≥80% of patients completing 2 cycles of bintrafusp alfa and will be tested with a one-sample test for a binomial proportion, comparing the observed percentage to the fixed reference value of unfeasibility (62%). Secondary endpoints are toxicity, progression-free survival, overall survival and quality of life. Additionally, exploratory endpoints include development of biomarkers to predict treatment response. Eligible for inclusion are patients with surgically irresectable (T1-4a N+ M0) squamous cell carcinoma of the esophagus or gastro-esophageal junction, or patients with resectable tumors refraining from radical surgery. Patients with M1 disease solely on the basis of supraclavicular metastasis are eligible. Patients with locoregional recurrences are eligible, provided that full dose of radiation can be safely delivered. Currently, 2 of planned 52 patients have been enrolled. Clinical trial information: NCT04595149. [Table: see text]

OBJECTIVE: Delineation variation of esophageal tumors remains a large source of geometric uncertainty. In the present study, we investigated the inter- and intra-observer variation in esophageal gross tumor volume (GTV) delineation and the impact of endoscopically implanted fiducial markers on these variations.MATERIAL/METHODS: Ten esophageal cancer patients with at least two markers endoscopically implanted at the cranial and caudal tumor borders and visible on the planning computed tomography (pCT) were included in this study. Five dedicated gastrointestinal radiation oncologists independently delineated GTVs on the pCT without markers and with markers. The GTV was first delineated on pCTs where markers were digitally removed and next on the original pCT with markers. Both delineation series were executed twice to determine intra-observer variation. For both the inter- and intra-observer analyses, the generalized conformity index (CIgen), and the standard deviation (SD) of the distances between delineated surfaces (i.e., overall, longitudinal, and radial SDs) were calculated. Linear mixed-effect models were used to compare the without and with markers series (α = 0.05).RESULTS: Both the inter- and intra-observer CIgen were significantly larger in the series with markers than in the series without markers (p CONCLUSION: The presence of markers at the cranial and caudal tumor borders significantly reduced both inter- and intra-observer GTV delineation variation, especially in the longitudinal direction. Our results endorse the use of markers in GTV delineation for esophageal cancer patients.

281 Background: To analyze the effect of radiation dose escalation to the primary tumor on local control, locoregional control, survival and toxicity in definitive chemoradiation for esophageal cancer. Methods: Patients with clinical stage T2-4, N0-3, M0 carcinoma of the esophagus were randomized between a standard dose of 50.4 Gy/1.8 Gy/5,5 weeks to the tumor and regional lymph nodes (SD) versus the same dose combined with an integrated boost of 0,4 Gy per fraction (total 61,6 Gy) to the primary tumor (HD). Chemotherapy consisted of 6 weekly concurrent carboplatin (AUC 2) and paclitaxel (50 mg/m2) in both arms. The primary endpoint was local progression free survival (LPFS) and 260 patients were needed to detect a difference of 15% (power: 80%). Secondary endpoints were locoregional progression free survival (LRPFS), overall survival (OS) and toxicity. Patients were stratified for histological subtype. Results: Between September 2012 and June 2018, 260 patients were included. Reasons for inoperability were proximal localization and patient preference (44%), comorbidity (30%), unresectable lymph nodes (11%), T4 (5%), local recurrence 2% and combinations (7%). 61% of the patients had a squamous cell carcinoma (SCC) and 39% had an adenocarcinoma (AC). 94% completed radiation treatment and 85% had at least 5 courses chemotherapy. Median follow up time was 45 months. 3-year LPFS was 70% in the SD arm versus 76% in the HD arm (ns). LPFS for SCC and AC was 74% versus 81% and 62% versus 65% for SD and HD, resp. (ns). 3-year LRPFS was 53% and 63% for the SD and HD arm resp. (p = 0.08). 1 year any progression free survival was 60% for SCC and 50% for AC, without a significant difference between SD and HD (p = 0,5). 3-year OS was 41% versus 40% for SD and HD resp. Overall grade 4 and 5 CTC toxicity was 12% and 4% in the SD arm versus 14% and 10% in the HD arm, resp. Conclusions: In definitive chemoradiation for esophageal cancer, radiation dose escalation up to 61,6 Gy to the primary tumor did not result in a significant increase in local control over 50,4 Gy. Numerical improvement of locoregional control after HD was observed with an increase in toxicity and without improving OS. Clinical trial information: NL38343.018.11.

Purpose To analyze recurrence patterns in patients with cancer of the esophagus or gastroesophageal junction treated with either preoperative chemoradiotherapy (CRT) plus surgery or surgery alone. Patients and Methods Recurrence pattern was analyzed in patients from the previously published CROSS I and II trials in relation to radiation target volumes. CRT consisted of five weekly courses of paclitaxel and carboplatin combined with a concurrent radiation dose of 41.4 Gy in 1.8-Gy fractions to the tumor and pathologic lymph nodes with margin. Results Of the 422 patients included from 2001 to 2008, 418 were available for analysis. Histology was mostly adenocarcinoma (75%). Of the 374 patients who underwent resection, 86% were allocated to surgery and 92% to CRT plus surgery. On January 1, 2011, after a minimum follow-up of 24 months (median, 45 months), the overall recurrence rate in the surgery arm was 58% versus 35% in the CRT plus surgery arm. Preoperative CRT reduced locoregional recurrence (LRR) from 34% to 14% (P < .001) and peritoneal carcinomatosis from 14% to 4% (P < .001). There was a small but significant effect on hematogenous dissemination in favor of the CRT group (35% v 29%; P = .025). LRR occurred in 5% within the target volume, in 2% in the margins, and in 6% outside the radiation target volume. In 1%, the exact site in relation to the target volume was unclear. Only 1% had an isolated infield recurrence after CRT plus surgery. Conclusion Preoperative CRT in patients with esophageal cancer reduced LRR and peritoneal carcinomatosis. Recurrence within the radiation target volume occurred in only 5%, mostly combined with outfield failures.

Postoperative chemoradiotherapy in gastric cancer improves locoregional control and survival. Reports on late toxicity, however, have been scarce thus far. Because renal toxicity is one of the most serious late complications in upper abdominal radiotherapy, we prospectively analyzed kidney function in patients who underwent postoperative chemoradiotherapy for gastric cancer.In 44 patients, Tc99m-thiatide renography was performed before and at regular intervals after postoperative chemoradiotherapy. The left-to-right (L/R) ratio was used as an index of the relative kidney function. Mean L/R values were calculated for four follow-up time intervals. For all patients, kidney V20 (percentage of the volume of the kidney that received more than 20 Gy) and mean dose of both kidneys were retrieved from the three-dimensional dose-volume histograms.We observed a progressive decrease in left renal function of 11% (p = 0.012) after 6 months, up to 52% (p0.001) after18 months. The V20 (left kidney) and mean left kidney dose were identified as parameters associated with decreased kidney function. Mean serum creatinine was increased from 74.6 micromol/L before treatment to 86.1 micromol/L at 1 year after chemoradiotherapy (p0.001). In patients with a follow-up of 18-28 months, one case of severe renovascular hypertension was observed.A progressive relative functional impairment of the left kidney in patients after postoperative chemoradiotherapy for gastric cancer is demonstrated. To optimize the survival benefit that can be established with adjuvant regimens, strategies to minimize the dose to the kidneys and other critical organs should be explored.