External validation of a lung cancer-based prediction model for two-year mortality in esophageal cancer patient cohorts.

PURPOSE/OBJECTIVE: Chemo-radiotherapy can improve the oncological outcome of esophageal cancer (EC) patients, but may cause long term radiation-induced toxicity, including an increased risk of non-cancer related death. For lung cancer patients, a model to predict 2-year total mortality using mean heart dose (MHD) and gross tumor volume (GTV) has previously been developed and validated. This project aimed to externally validate this model in EC patients. METHODS: Five EC patient cohorts from 3 different Dutch centres were used for model validation. External validity of the model was assessed separately in definitive (n = 170) and neo-adjuvant (n = 568) chemoradiotherapy (dCRT and nCRT) patients. External validity was assessed in terms of calibration by calibration plots, calibration-in-the-large (CITL) and calibration slope (CS), and discrimination by assessment of the c-statistic. If suboptimal model performance was observed, the model was further updated accordingly. RESULTS: For the dCRT patients, good calibration was found after adjustment of the intercept (CITL 0.00; CS 1.08). The c-statistic of the adjusted model was 0.67 (95%CI: 0.58 to 0.75). For nCRT patients the model needed adjustment of both the slope and the intercept because of initial miscalibration in the validation population (CITL 0.00; CS 1.72). After recalibration, the model showed perfect calibration (i.e., CITL 0, CS 1), as is common after recalibration. The c-statistic of the recalibrated model equaled 0.62 (95%CI: 0.57 to 0.67). CONCLUSION: The existing model for 2-year mortality prediction in lung cancer patients, based on the predictive factors MHD and GTV, showed good performance in EC patients after updating the intercept and/or slope of the original model.

Patterns of recurrence following definitive chemoradiation for patients with proximal esophageal cancer.

INTRODUCTION: The aim of this retrospective study was to determine the patterns of recurrence and overall survival (OS) in patients achieving clinical complete response after treatment with definitive chemoradiation (CRT) for proximal esophageal cancer. MATERIALS AND METHODS: Patients with proximal esophageal cancer treated with CRT between 2004 and 2014 in 11 centers in the Netherlands were included. OS and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Cumulative incidence of first recurrence (locoregional or distant) and locoregional recurrence (LRR) were assessed using competing risk analyses. RESULTS: In 197 of the 200 identified patients, response was evaluated, 133 (68%) showed a complete response. In complete responders, median OS, three-year OS, and PFS were 45.0 months (95% CI 34.8-61.5 months), 58% (95% CI 48-66), and 49% (95% CI 40-57), respectively. Three- and five-year risk of recurrence were respectively 40% (95% CI 31-48), and 45% (95% CI 36-54). Three- and five-year risk of LRR were 26% (95% CI 19-33), and 30% (95% CI 22-38). Eight of 32 patients with an isolated LRR underwent salvage surgery, with a median OS of 32.0 months (95% CI 6.8-not reached). CONCLUSION: In patients with a complete response after definitive CRT for proximal esophageal cancer, most recurrences were locoregional and developed within the first three years after CRT. These findings suggest to shorten locoregional follow-up from five to three years.

Diagnostic performance of MRI for assessment of response to neoadjuvant chemoradiotherapy in oesophageal cancer.

BACKGROUND: Patients with a pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) for oesophageal cancer may benefit from non-surgical management. The aim of this study was to determine the diagnostic performance of visual response assessment of the primary tumour after nCRT on T2-weighted (T2W) and diffusion-weighted (DW) MRI. METHODS: Patients with locally advanced oesophageal cancer who underwent T2W- and DW-MRI (1·5 T) before and after nCRT in two hospitals, between July 2013 and September 2017, were included in this prospective study. Three radiologists evaluated T2W images retrospectively using a five-point score for the assessment of residual tumour in a blinded manner and immediately rescored after adding DW-MRI. Histopathology of the resection specimen was used as the reference standard; ypT0 represented a pCR. Sensitivity, specificity, area under the receiver operating characteristic (ROC) curve (AUC) and interobserver agreement were calculated. RESULTS: Twelve of 51 patients (24 per cent) had a pCR. The sensitivity and specificity of T2W-MRI for detection of residual tumour ranged from 90 to 100 and 8 to 25 per cent respectively. Respective values for T2W + DW-MRI were 90-97 and 42-50 per cent. AUCs for the three readers were 0·65, 0·66 and 0·68 on T2W-MRI, and 0·71, 0·70 and 0·70 on T2W + DW-MRI (P = 0·441, P = 0·611 and P = 0·828 for readers 1, 2 and 3 respectively). The κ value for interobserver agreement improved from 0·24-0·55 on T2W-MRI to 0·55-0·71 with DW-MRI. CONCLUSION: Preoperative assessment of residual tumour on MRI after nCRT for oesophageal cancer is feasible with high sensitivity, reflecting a low chance of missing residual tumour. However, the specificity was low; this results in overstaging of complete responders as having residual tumour and, consequently, overtreatment.

Gross tumour delineation on computed tomography and positron emission tomography-computed tomography in oesophageal cancer: A nationwide study.

BACKGROUND AND PURPOSE: Accurate delineation of the primary tumour is vital to the success of radiotherapy and even more important for successful boost strategies, aiming for improved local control in oesophageal cancer patients. Therefore, the aim was to assess delineation variability of the gross tumour volume (GTV) between CT and combined PET-CT in oesophageal cancer patients in a multi-institutional study. MATERIALS AND METHODS: Twenty observers from 14 institutes delineated the primary tumour of 6 cases on CT and PET-CT fusion. The delineated volumes, generalized conformity index (CIgen) and standard deviation (SD) in position of the most cranial/caudal slice over the observers were evaluated. For the central delineated region, perpendicular distance between median surface GTV and each individual GTV was evaluated as in-slice SD. RESULTS: After addition of PET, mean GTVs were significantly smaller in 3 cases and larger in 1 case. No difference in CIgen was observed (average 0.67 on CT, 0.69 on PET-CT). On CT cranial-caudal delineation variation ranged between 0.2 and 1.5 cm SD versus 0.2 and 1.3 cm SD on PET-CT. After addition of PET, the cranial and caudal variation was significantly reduced in 1 and 2 cases, respectively. The in-slice SD was on average 0.16 cm in both phases. CONCLUSION: In some cases considerable GTV delineation variability was observed at the cranial-caudal border. PET significantly influenced the delineated volume in four out of six cases, however its impact on observer variation was limited.

Preoperative image-guided identification of response to neoadjuvant chemoradiotherapy in esophageal cancer (PRIDE): a multicenter observational study.

BACKGROUND: Nearly one third of patients undergoing neoadjuvant chemoradiotherapy (nCRT) for locally advanced esophageal cancer have a pathologic complete response (pCR) of the primary tumor upon histopathological evaluation of the resection specimen. The primary aim of this study is to develop a model that predicts the probability of pCR to nCRT in esophageal cancer, based on diffusion-weighted magnetic resonance imaging (DW-MRI), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and 18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET-CT). Accurate response prediction could lead to a patient-tailored approach with omission of surgery in the future in case of predicted pCR or additional neoadjuvant treatment in case of non-pCR. METHODS: The PRIDE study is a prospective, single arm, observational multicenter study designed to develop a multimodal prediction model for histopathological response to nCRT for esophageal cancer. A total of 200 patients with locally advanced esophageal cancer - of which at least 130 patients with adenocarcinoma and at least 61 patients with squamous cell carcinoma - scheduled to receive nCRT followed by esophagectomy will be included. The primary modalities to be incorporated in the prediction model are quantitative parameters derived from MRI and 18F-FDG PET-CT scans, which will be acquired at fixed intervals before, during and after nCRT. Secondary modalities include blood samples for analysis of the presence of circulating tumor DNA (ctDNA) at 3 time-points (before, during and after nCRT), and an endoscopy with (random) bite-on-bite biopsies of the primary tumor site and other suspected lesions in the esophagus as well as an endoscopic ultrasonography (EUS) with fine needle aspiration of suspected lymph nodes after finishing nCRT. The main study endpoint is the performance of the model for pCR prediction. Secondary endpoints include progression-free and overall survival. DISCUSSION: If the multimodal PRIDE concept provides high predictive performance for pCR, the results of this study will play an important role in accurate identification of esophageal cancer patients with a pCR to nCRT. These patients might benefit from a patient-tailored approach with omission of surgery in the future. Vice versa, patients with non-pCR might benefit from additional neoadjuvant treatment, or ineffective therapy could be stopped. TRIAL REGISTRATION: The article reports on a health care intervention on human participants and was prospectively registered on March 22, 2018 under ClinicalTrials.gov Identifier: NCT03474341 .

Using textbook outcome as a measure of quality of care in oesophagogastric cancer surgery.

BACKGROUND: Textbook outcome is a multidimensional measure representing an ideal course after oesophagogastric cancer surgery. It comprises ten perioperative quality-of-care parameters and has been developed recently using population-based data. Its association with long-term outcome is unknown. The objectives of this study were to validate the clinical relevance of textbook outcome at a hospital level, and to assess its relation with long-term survival after treatment for oesophagogastric cancer. METHODS: All patients with oesophageal or gastric cancer scheduled for surgery with curative intent between January 2009 and June 2015 were selected from an institutional database. A Cox model was used to study the association between textbook outcome and survival. RESULTS: A textbook outcome was achieved in 58 of 144 patients (40·3 per cent) with oesophageal cancer and in 48 of 105 (45·7 per cent) with gastric cancer. Factors associated with not achieving a textbook outcome were failure to achieve a lymph node yield of at least 15 (after oesophagectomy) and postoperative complications of grade II or more. After oesophagectomy, median overall survival was longer for patients with a textbook outcome than for patients without (median not reached versus 33 months; P = 0·012). After gastrectomy, median survival was 54 versus 33 months respectively (P = 0·018). In multivariable analysis, textbook outcome was associated with overall survival after oesophagectomy (hazard ratio 2·38, 95 per cent c.i. 1·29 to 4·42) and gastrectomy (hazard ratio 2·58, 1·25 to 5·32). CONCLUSION: Textbook outcome is a clinically relevant measure in patients undergoing oesophagogastric cancer surgery as it can identify underperforming parameters in a hospital setting. Overall survival in patients with a textbook outcome is better than in patients without a textbook outcome.

Factors contributing to variation in the use of multimodality treatment in patients with gastric cancer: A Dutch population based study.

BACKGROUND: Substantial variation in the use of (neo) adjuvant treatment in patients with gastric cancer exists. The aim of this study was to identify underlying (organizational and process) factors associated with the use of perioperative therapy. PATIENTS AND METHODS: Patients with resectable gastric cancer who underwent surgery between 2012 and 2014 were selected from the Dutch Upper gastrointestinal Cancer Audit (DUCA). The proportion of perioperatively treated patients was defined per hospital. Five hospitals with the lowest percentage (LP group) and 5 hospitals with the highest percentage (HP group) of perioperative therapy were identified. In the selected hospitals additional information was obtained from patients' medical records using a structured list with predefined variables. RESULTS: In total, 429 patients (231 in LP group, 198 in HP group) from 9 different hospitals were included. Perioperative therapy was given in 16.0% of patients in the LP group compared to 40.4% in the HP group. In the LP group, patients were enrolled in a clinical trial less frequently (10.8% versus 26.8%, P<.001), and a higher percentage grade III-IV toxicity was observed during neoadjuvant treatment (25.7% versus 46.3%, P=.007). Multivariable analysis showed that, besides known casemix factors, consultation with ≥3 upper GI specialists prior to treatment decision was positively associated with initiating perioperative therapy (OR 2.08, 95% CI 1.19-3.66). CONCLUSION: Results of this study confirm considerable hospital variation in the use of perioperative therapy in patients with gastric cancer. Besides known casemix factors, use of perioperative therapy was associated with the level of involvement of multidisciplinary care.

Degree of tumor shrinkage following neoadjuvant chemoradiotherapy: a potential predictor for complete pathological response in esophageal cancer?

Neoadjuvant chemoradiotherapy (CRT) before surgery results in a pathological complete response (pCR) rate in about 1/3 of the patients, which is correlated with survival. It was hypothesized that volumetric tumor response to CRT would correlate with outcomes. Patients who completed trimodality therapy, where planning, pre-, and post-CRT computed tomography scans were available, and pathology was reviewed by a central pathologist, were eligible for analysis. Absolute and relative tumor volume change pretreatment and post-treatment were correlated with pCR, locoregional recurrence (LRR), disease-free survival, and overall survival. Fifty-six patients were analyzed. pCR was observed in 30% of patients. Median follow up was 20.3 (range 4-89) months. The 2- and 4-year overall survival was 61.3% (95% confidence interval [CI]: 45-74) and 25.0% (95%CI: 11-41); proportion disease free was 32.1% (95% CI: 19-46) and 20.6% (9-36) at 2 and 4 years, respectively. The median relative volume reduction was 17% (95% CI: -24, -3%). Using 20% as the criteria, the proportion of patients with pCR of ≥20% versus <20% was 13/25 (52%) versus 4/31 (13%) for those who did not (odds ratio 7.3; 95% CI: 2-27). The LRR at 2 and 4 years were 29.5% (95% CI: 16-43) and 36.2% (95% CI: 23-50). The relative tumor reduction ≥20% was significantly correlated with LRR (hazard ratio 0.24; 95% CI: 0.07-0.8; p 0.02) at 2 and 4 years, respectively. Relative tumor volume reduction following CRT is correlated with pCR and LRR. Further investigations are warranted to examine the effect of volume change, alone or in conjunction with other factors as potential predictors for pathological response.