Interval Metastases After Neoadjuvant Chemoradiotherapy for Patients with Locally Advanced Esophageal Cancer: A Multicenter Observational Cohort Study.

BACKGROUND: Despite trimodality treatment, 10% to 20% of patients with esophageal cancer experience interval metastases after surgery. Restaging may identify patients who should not proceed to surgery, as well as a subgroup with limited metastases for whom long-term disease-control can be obtained. This study aimed to determine the proportion of patients with interval metastases after neoadjuvant chemoradiotherapy (nCRT) and to evaluate treatment and survival. METHODS: Patients who had cT2-4aN0-3M0 esophageal cancer treated with nCRT were identified from a trial database. Metastases detected up to 14 weeks after nCRT on 18F-FDG-PET/CT or during surgery were categorized as oligometastases (≤3 lesions located in one single organ or one extra-regional lymph node station) or as non-oligometastases. The primary outcome was the proportion of patients with metastases after nCRT. The secondary outcomes were overall survival (OS) and the site and treatment of metastases. RESULTS: Between 2013 and 2021, 973 patients received nCRT, and 10.3% had interval metastases. Of 100 patients, 30 (30%) had oligometastases, located mostly in non-regional lymph nodes (33.3%) or bones (26.7%). The median OS of this group was 13.8 months (95% confidence interval [CI] 9.2-27.1 months). Of 30 patients, 12 (40%) with oligometastases underwent potentially curative treatment, with a median OS of 22.8 months (95% CI 10.4-NA). The patients with non-oligometastases underwent mostly systemic therapy or BSC and had a median OS of 9 months (95% CI 7.4-10.9 months). CONCLUSIONS: Interval metastases were detected in about 10% of patients after nCRT, underscoring the importance of re-staging with 18F-FDG-PET/CT for those who proceed to surgery. A favorable survival might be accomplished for a subgroup of patients with oligometastases.

Prognostic value of Mandard score and nodal status for recurrence patterns and survival after multimodal treatment of oesophageal adenocarcinoma.

BACKGROUND: This study evaluated the association of pathological tumour response (tumour regression grade, TRG) and a novel scoring system, combining both TRG and nodal status (TRG-ypN score; TRG1-ypN0, TRG>1-ypN0, TRG1-ypN+ and TRG>1-ypN+), with recurrence patterns and survival after multimodal treatment of oesophageal adenocarcinoma. METHODS: This Dutch nationwide cohort study included patients treated with neoadjuvant chemoradiotherapy followed by oesophagectomy for distal oesophageal or gastro-oesophageal junctional adenocarcinoma between 2007 and 2016. The primary endpoint was the association of Mandard score and TRG-ypN score with recurrence patterns (rate, location, and time to recurrence). The secondary endpoint was overall survival. RESULTS: Among 2746 inclusions, recurrence rates increased with higher Mandard scores (TRG1 30.6%, TRG2 44.9%, TRG3 52.9%, TRG4 61.4%, TRG5 58.2%; P < 0.001). Among patients with recurrent disease, the distribution (locoregional versus distant) was the same for the different TRG groups. Patients with TRG1 developed more brain recurrences (17.7 versus 9.8%; P = 0.001) and had a longer mean overall survival (44 versus 35 months; P < 0.001) than those with TRG>1. The TRG>1-ypN+ group had the highest recurrence rate (64.9%) and worst overall survival (mean 27 months). Compared with the TRG>1-ypN0 group, patients with TRG1-ypN+ had a higher risk of recurrence (51.9 versus 39.6%; P < 0.001) and worse mean overall survival (33 versus 41 months; P < 0.001). CONCLUSION: Improved tumour response to neoadjuvant therapy was associated with lower recurrence rates and higher overall survival rates. Among patients with recurrent disease, TRG1 was associated with a higher incidence of brain recurrence than TRG>1. Residual nodal disease influenced prognosis more negatively than residual disease at the primary tumour site.

Trends in best-case, typical and worst-case survival scenarios of patients with non-metastatic esophagogastric cancer between 2006 and 2020: A population-based study.

New treatment options and centralization of surgery have improved survival for patients with non-metastatic esophageal or gastric cancer. It is unknown, however, which patients benefitted the most from treatment advances. The aim of this study was to identify best-case, typical and worst-case scenarios in terms of survival time, and to assess if survival associated with these scenarios changed over time. Patients with non-metastatic potentially resectable esophageal or gastric cancer diagnosed between 2006 and 2020 were selected from the Netherlands Cancer Registry. Best-case (20th percentile), upper-typical (40th percentile), typical (median), lower-typical (60th percentile) and worst-case (80th percentile) survival scenarios were defined, and regression analysis was used to investigate the change in survival time for each scenario across years. For patients with esophageal cancer (N = 24 352) survival time improved on average 12.0 (until 2011), 1.5 (until 2018), 0.7, 0.4 and 0.2 months per year for the best-case, upper-typical, median, lower-typical and worst-case scenario, respectively. For patients with gastric cancer (N = 9993) survival time of the best-case scenario remained constant, whereas the upper-typical, median, lower-typical and worst-case scenario improved on average with 1.0 (until 2018), 0.5, 0.2 and 0.2 months per year, respectively. Subgroup analyses showed that, survival scenarios improved for nearly all patients across treatment groups and for patients with squamous cell carcinomas or adenocarcinomas. Survival improved for almost all patients suggesting that in clinical practice the vast majority of patients benefitted from treatment advances. The clinically most meaningful survival advantage was observed for the best-case scenario of esophageal cancer.

Trends in Distal Esophageal and Gastroesophageal Junction Cancer Care: The Dutch Nationwide Ivory Study.

OBJECTIVE: This study evaluated the nationwide trends in care and accompanied postoperative outcomes for patients with distal esophageal and gastro-esophageal junction cancer. SUMMARY OF BACKGROUND DATA: The introduction of transthoracic esophagectomy, minimally invasive surgery, and neo-adjuvant chemo(radio)therapy changed care for patients with esophageal cancer. METHODS: Patients after elective transthoracic and transhiatal esophagectomy for distal esophageal or gastroesophageal junction carcinoma in the Netherlands between 2007-2016 were included. The primary aim was to evaluate trends in both care and postoperative outcomes for the included patients. Additionally, postoperative outcomes after transthoracic and tran-shiatal esophagectomy were compared, stratified by time periods. RESULTS: Among 4712 patients included, 74% had distal esophageal tumors and 87% had adenocarcinomas. Between 2007 and 2016, the proportion of transthoracic esophagectomy increased from 41% to 81%, and neo-adjuvant treatment and minimally invasive esophagectomy increased from 31% to 96%, and from 7% to 80%, respectively. Over this 10-year period, postoperative outcomes improved: postoperative morbidity decreased from 66.6% to 61.8% ( P = 0.001), R0 resection rate increased from 90.0% to 96.5% (P <0.001), median lymph node harvest increased from 15 to 19 ( P <0.001), and median survival increased from 35 to 41 months ( P = 0.027). CONCLUSION: In this nationwide cohort, a transition towards more neo-adju-vant treatment, transthoracic esophagectomy and minimally invasive surgery was observed over a 10-year period, accompanied by decreased postoperative morbidity, improved surgical radicality and lymph node harvest, and improved survival.

A comparison between real-time intraoperative voice dictation and the operative report in laparoscopic cholecystectomy: a multicenter prospective observational study.

PURPOSE: The current operative report often inadequately reflects events occurring during laparoscopic cholecystectomy (LC). The addition of intraoperative video recording to the operative report has already proven to add important information. It was hypothesized that real-time intraoperative voice dictation (RIVD) can provide an equal or more complete overview of the operative procedure compared to the narrative operative report (NR) produced postoperatively. METHODS: SONAR is a multicenter prospective observational trial, conducted at four surgical centers in the Netherlands. Elective LCs of patients aged 18 years and older were included. Participating surgeons were requested to dictate the essential steps of LC during surgery. RIVDs and NRs were reviewed according to the stepwise LC guideline of the Dutch Society for Surgery. The cumulative adequacy rates for RIVDs were compared with those of the postoperatively written NR. RESULTS: 79 of 90 cases were eligible for inclusion and available for further analysis. RIVD resulted in a significantly higher adequacy rate compared to NR for the circumferential dissection of the cystic duct and artery (NR 32.5% vs. RIVD 61.0%, P = 0.016). NR had higher adequacy rates in reporting the transection of the cystic duct (NR 100% vs. RIVD 77.9%, P = < 0.001) and the removal of the gallbladder from the liver bed (NR 98.7% vs. RIVD 68.8%, P < 0.001). The total adequacy was not significantly different between the two reporting methods (NR 78.0% vs. RIVD 76.4%, P = 1.00). CONCLUSION: Overall, the adequacy of RIVD is comparable to the postoperatively written NR in reporting surgical steps in LC. However, the most essential surgical step, the circumferential dissection of the cystic duct and artery, was reported more adequately in RIVD.

Outcomes after hybrid minimally invasive treatment of Boerhaave syndrome: a single-institution experience.

BACKGROUND: Spontaneous esophageal perforation or Boerhaave syndrome is a life-threatening emergency, associated with significant morbidity and mortality. In this retrospective series we describe our single-center experience with a hybrid minimally invasive treatment approach for the treatment of Boerhaave syndrome. METHODS: Clinical data of all patients who presented with spontaneous esophageal rupture between January 2009 and December 2019 were analyzed. All patients underwent esophageal endoscopic stenting to seal the perforation and debridement of the contaminated mediastinal and pleural cavity through video-assisted thoracoscopic surgery (VATS). Primary outcome measure was defined as in-hospital death and 30-day mortality. RESULTS: Twelve patients were included with a median age of 63 years (interquartile range [IQR] 51-74 years) of whom 58% (n = 7) were male. The median Pittsburg perforation severity score was 6.5 (IQR 6-9). Endoscopic reintervention was required in 8 patients (67%), primarily due to stent dislocation. In addition, 5 patients (42%) required re-VATS due to empyema formation. Thirty-day mortality and in-hospital mortality were respectively 17% (n = 2) and 25% (n = 3). CONCLUSION: Endoscopic stenting in combination with thoracoscopic debridement is an effective and safe minimally invasive hybrid approach for the treatment of Boerhaave syndrome. This is depicted by the relatively low mortality rates, even among patients with high perforation severity scores. The relatively low mortality rates may be attributed to the combined approach of rapidly sealing the defect and decontamination of the thorax. Future studies should aim to corroborate this evidence which is limited by its sample size and retrospective nature.

Learning Curves of Ivor Lewis Totally Minimally Invasive Esophagectomy by Hospital and Surgeon Characteristics: A Retrospective Multinational Cohort Study.

OBJECTIVE: To describe the pooled learning curves of Ivor Lewis totally minimally invasive esophagectomy (TMIE) in hospitals stratified by predefined hospital- and surgeon-related factors. BACKGROUND: Ivor Lewis (TMIE is known to have a long learning curve which is associated with considerable learning associated morbidity. It is unknown whether hospital and surgeon characteristics are associated with more efficient learning. METHODS: A retrospective analysis of prospectively collected data of consecutive Ivor Lewis TMIE patients in 14 European hospitals was performed. Outcome parameters used as proxy for efficient learning were learning curve length, learning associated morbidity, and the plateau level regarding anastomotic leakage and textbook outcome. Pooled incidences were plotted for the factor-based subgroups using generalized additive models and 2-phase models. Casemix predicted outcomes were plotted and compared with observed outcomes. The investigated factors included annual volume, TMIE experience, clinic visits, courses and fellowships followed, and proctor supervision. RESULTS: This study included 2121 patients. The length of the learning curve was shorter for centers with an annual volume >50 compared to centers with an annual volume <50. Analysis with an annual volume cut-off of 30 cases showed similar but less pronounced results. No outcomes suggesting more efficient learning were found for longer experience as consultant, visiting an expert clinic, completing a minimally invasive esophagectomy fellowship or implementation under proctor supervision. CONCLUSIONS: More efficient learning was observed in centers with higher annual volume. Visiting an expert clinic, completing a fellowship, or implementation under a proctor's supervision were not associated with more efficient learning.

Recurrent Disease After Esophageal Cancer Surgery: A Substudy of The Dutch Nationwide Ivory Study.

OBJECTIVE: This study investigated the patterns, predictors, and survival of recurrent disease following esophageal cancer surgery. BACKGROUND: Survival of recurrent esophageal cancer is usually poor, with limited prospects of remission. METHODS: This nationwide cohort study included patients with distal esophageal and gastroesophageal junction adenocarcinoma and squamous cell carcinoma after curatively intended esophagectomy in 2007 to 2016 (follow-up until January 2020). Patients with distant metastases detected during surgery were excluded. Univariable and multivariable logistic regression were used to identify predictors of recurrent disease. Multivariable Cox regression was used to determine the association of recurrence site and treatment intent with postrecurrence survival. RESULTS: Among 4626 patients, 45.1% developed recurrent disease a median of 11 months postoperative, of whom most had solely distant metastases (59.8%). Disease recurrences were most frequently hepatic (26.2%) or pulmonary (25.1%). Factors significantly associated with disease recurrence included young age (≤65 y), male sex, adenocarcinoma, open surgery, transthoracic esophagectomy, nonradical resection, higher T-stage, and tumor positive lymph nodes. Overall, median postrecurrence survival was 4 months [95% confidence interval (95% CI): 3.6-4.4]. After curatively intended recurrence treatment, median survival was 20 months (95% CI: 16.4-23.7). Survival was more favorable after locoregional compared with distant recurrence (hazard ratio: 0.74, 95% CI: 0.65-0.84). CONCLUSIONS: This study provides important prognostic information assisting in the surveillance and counseling of patients after curatively intended esophageal cancer surgery. Nearly half the patients developed recurrent disease, with limited prospects of survival. The risk of recurrence was higher in patients with a higher tumor stage, nonradical resection and positive lymph node harvest.

Active Surveillance Versus Immediate Surgery in Clinically Complete Responders After Neoadjuvant Chemoradiotherapy for Esophageal Cancer: A Multicenter Propensity Matched Study.

OBJECTIVE: This study compared outcomes of patients with esophageal cancer and clinically complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT) undergoing active surveillance or immediate surgery. BACKGROUND: Since nearly one-third of patients with esophageal cancer show pathologically complete response after nCRT according to CROSS regimen, the oncological benefit of immediate surgery in cCR is topic of debate. METHODS: Patients with cCR based on endoscopic biopsies and endoscopic ultrasonography with fine-needle aspiration initially declining or accepting immediate surgery after nCRT were identified between 2011 and 2018. Primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), rate and timing of distant dissemination, and postoperative outcomes. RESULTS: Some 98 patients with cCR were identified: 31 in the active surveillance- and 67 in the immediate surgery group with median followup of survivors of 27.7 and 34.8 months, respectively. Propensity score matching resulted in 2 comparable groups (n = 29 in both groups). Patients undergoing active surveillance or immediate surgery had a 3-year OS of 77% and 55% (HR 0.41; 95% CI 0.14-1.20, P = 0.104), respectively. The 3-year PFS was 60% and 54% (HR 1.08; 95% CI 0.44-2.67, P = 0.871), respectively. Patients undergoing active surveillance or immediate surgery had a comparable distant dissemination rate (both groups 28%), radical resection rate (both groups 100%), and severity of postoperative complications (Clav- ien-Dindo grade ≥ 3: 43% vs 45%, respectively). CONCLUSION: In this retrospective study, OS and PFS in patients with cCR undergoing active surveillance or immediate surgery were not significantly different. Active surveillance with postponed surgery for recurrent disease was not associated with a higher distant dissemination rate or more severe adverse postoperative outcomes.

High CD8+ tumour-infiltrating lymphocyte density associates with unfavourable prognosis in oesophageal adenocarcinoma following poor response to neoadjuvant chemoradiotherapy.

AIMS: Determining prognosis following poor response to neoadjuvant chemoradiotherapy (nCRT) in oesophageal adenocarcinoma (OAC) remains challenging. An immunosuppressive tumour microenvironment (TME) as well as immune infiltrate density and composition are considered to play a critical role in the immune interaction between host and tumour and can predict therapy response and survival in many cancers, including gastrointestinal malignancies. The aim of this study was to establish the TME characteristics associated with survival following a poor response to nCRT. METHODS AND RESULTS: The prognostic significance of OAC-associated CD3+ , CD4+ , CD8+ , forkhead box protein 3 (FoxP3+ ) and programmed cell death ligand 1 (PD-L1) expression was studied by immunohistochemistry and quantified by automated image analysis in 123 patients who underwent nCRT and curative resection. Results from good and poor responders were contrasted and immune infiltration was related to disease course in both groups. Subsequently a cohort of 57 patients with a moderate response to nCRT was analysed in a similar fashion. Tumour cell percentage positively correlated to immune infiltration markers. In good and moderate responders, none of the immune infiltrate parameters was associated with survival; in poor responders CD8+ was an independent negative predictor of OS in univariate analysis (P = 0.03) and high CD8+ infiltration was associated with worse OS (15 versus 32 months, P = 0.042). CONCLUSION: A high CD8+ density is an independent biomarker of poor OS in poor responders to nCRT, but not in good and moderate responders. Our results suggest that patients with a poor response to nCRT but concomitant high CD8+ counts in the resection specimen require adjuvant therapy.

The Introduction of Laparoscopic Colorectal Surgery: Can It Improve Hospital Economics?

INTRODUCTION: Clinical benefits of laparoscopic surgery are well established, but evidence for financial benefits is limited. This study aimed to compare the financial impact of the introduction of laparoscopic colorectal surgery. METHODS: This study included patients who underwent colorectal surgery between January 2010 and 2015. We collected a range of financial data and divided the patients into 2 groups. Primary outcome was total cost defined by surgical-related costs. RESULTS: A total of 1,246 patients were included, of which 440 surgeries were performed laparoscopically. The total median cost of laparoscopy was higher compared to open surgery (EUR 4,665 vs. EUR 4,268, p = 0.001). Laparoscopy was associated with higher equipment costs (EUR 857 vs. EUR 232, p < 0.001), longer operating time (3.2 vs. 2.5 hours, p < 0.001), and more readmissions (10.9 vs. 8.5%, p < 0.001). However, after adjusting for heterogeneity, no difference was found in total cost. Surgical-related costs were counterbalanced by lower costs associated with shorter median hospital stay (6 vs. 9 days, p < 0.001), less morbidity (37.3 vs. 55.1%, p < 0.001), and less mortality (1.8 vs. 5.6%, p = 0.013) for laparoscopy. CONCLUSION: During the introduction of laparoscopy for colorectal surgery, no significant differences were found in total cost between laparoscopic and open colorectal surgery. However, favorable postoperative outcomes were achieved with laparoscopic surgery.

Lymph node response to chemoradiotherapy in oesophageal cancer patients: relationship with radiotherapy fields.

BACKGROUND: The presence of lymph node metastasis (LNmets) is a poor prognostic factor in oesophageal cancer (OeC) patients treated with neoadjuvant chemoradiotherapy (nCRT) followed by surgery. Tumour regression grade (TRG) in LNmets has been suggested as a predictor for survival. The aim of this study was to investigate whether TRG in LNmets is related to their location within the radiotherapy (RT) field. METHODS: Histopathological TRG was retrospectively classified in 2565 lymph nodes (LNs) from 117 OeC patients treated with nCRT and surgery as: (A) no tumour, no signs of regression; (B) tumour without regression; (C) viable tumour and regression; and (D) complete response. Multivariate survival analysis was used to investigate the relationship between LN location within the RT field, pathological TRG of the LN and TRG of the primary tumour. RESULTS: In 63 (54%) patients, viable tumour cells or signs of regression were seen in 264 (10.2%) LNs which were classified as TRG-B (n = 56), C (n = 104) or D (n = 104) LNs. 73% of B, C and D LNs were located within the RT field. There was a trend towards a relationship between LN response and anatomical LN location with respect to the RT field (p = 0.052). Multivariate analysis showed that only the presence of LNmets within the RT field with TRG-B is related to poor overall survival. CONCLUSION: Patients have the best survival if all LNmets show tumour regression, even if LNmets are located outside the RT field. Response in LNmets to nCRT is heterogeneous which warrants further studies to better understand underlying mechanisms.

Pulmonary levels of biomarkers for inflammation and lung injury in protective versus conventional one-lung ventilation for oesophagectomy: A randomised clinical trial.

BACKGROUND: It is uncertain whether protective ventilation reduces ventilation-induced pulmonary inflammation and injury during one-lung ventilation. OBJECTIVE: To compare intra-operative protective ventilation with conventional during oesophagectomy with respect to pulmonary levels of biomarkers for inflammation and lung injury. DESIGN: Randomised clinical trial. SETTING: Tertiary centre for oesophageal diseases. PATIENTS: Twenty-nine patients scheduled for one-lung ventilation during oesophagectomy. INTERVENTIONS: Low tidal volume (VT) of 6 ml kg predicted body weight (pbw) during two-lung ventilation and 3 ml kgpbw during one-lung ventilation with 5 cmH2O positive end expired pressure versus intermediate VT of 10 ml kgpbw during two-lung ventilation and 5 ml kgpbw body weight during one-lung ventilation with no positive end-expiratory pressure. OUTCOME MEASURES: The primary outcome was the change in bronchoalveolar lavage (BAL) levels of preselected biomarkers for inflammation (TNF-α, IL-6 and IL-8) and lung injury (soluble Receptor for Advanced Glycation End-products, surfactant protein-D, Clara Cell protein 16 and Krebs von den Lungen 6), from start to end of ventilation. RESULTS: Median [IQR] VT in the protective ventilation group (n = 13) was 6.0 [5.7 to 7.8] and 3.1 [3.0 to 3.6] ml kgpbw during two and one-lung ventilation; VT in the conventional ventilation group (n = 16) was 9.8 [7.0 to 10.1] and 5.2 [5.0 to 5.5] ml kgpbw during two and one-lung ventilation. BAL levels of biomarkers for inflammation increased from start to end of ventilation in both groups; levels of soluble Receptor for Advanced Glycation End-products, Clara Cell protein 16 and Krebs von den Lungen 6 did not change, while levels of surfactant protein-D decreased. Changes in BAL biomarkers levels were not significantly different between the two ventilation strategies. CONCLUSION: Intra-operative protective ventilation compared with conventional ventilation does not affect changes in pulmonary levels of biomarkers for inflammation and lung injury in patients undergoing one-lung ventilation for oesophagectomy. TRIAL REGISTRATION: The 'Low versus Conventional tidal volumes during one-lung ventilation for minimally invasive oesophagectomy trial' (LoCo) was registered at the Netherlands Trial Register (study identifier NTR 4391).

Distribution of lymph node metastases in esophageal carcinoma [TIGER study]: study protocol of a multinational observational study.

BACKGROUND: An important parameter for survival in patients with esophageal carcinoma is lymph node status. The distribution of lymph node metastases depends on tumor characteristics such as tumor location, histology, invasion depth, and on neoadjuvant treatment. The exact distribution is unknown. Neoadjuvant treatment and surgical strategy depends on the distribution pattern of nodal metastases but consensus on the extent of lymphadenectomy has not been reached. The aim of this study is to determine the distribution of lymph node metastases in patients with resectable esophageal or gastro-esophageal junction carcinoma in whom a transthoracic esophagectomy with a 2- or 3-field lymphadenectomy is performed. This can be the foundation for a uniform worldwide staging system and establishment of the optimal surgical strategy for esophageal cancer patients. METHODS: The TIGER study is an international observational cohort study with 50 participating centers. Patients with a resectable esophageal or gastro-esophageal junction carcinoma in whom a transthoracic esophagectomy with a 2- or 3-field lymphadenectomy is performed in participating centers will be included. All lymph node stations will be excised and separately individually analyzed by pathological examination. The aim is to include 5000 patients. The primary endpoint is the distribution of lymph node metastases in esophageal and esophago-gastric junction carcinoma specimens following transthoracic esophagectomy with at least 2-field lymphadenectomy in relation to tumor histology, tumor location, invasion depth, number of lymph nodes and lymph node metastases, pre-operative diagnostics, neo-adjuvant therapy and (disease free) survival. DISCUSSION: The TIGER study will provide a roadmap of the location of lymph node metastases in relation to tumor histology, tumor location, invasion depth, number of lymph nodes and lymph node metastases, pre-operative diagnostics, neo-adjuvant therapy and survival. Patient-tailored treatment can be developed based on these results, such as the optimal radiation field and extent of lymphadenectomy based on the primary tumor characteristics. TRIAL REGISTRATION: NCT03222895 , date of registration: July 19th, 2017.

Detection of residual disease after neoadjuvant chemoradiotherapy for oesophageal cancer (preSANO): a prospective multicentre, diagnostic cohort study.

BACKGROUND: After neoadjuvant chemoradiotherapy for oesophageal cancer, roughly half of the patients with squamous cell carcinoma and a quarter of those with adenocarcinoma have a pathological complete response of the primary tumour before surgery. Thus, the necessity of standard oesophagectomy after neoadjuvant chemoradiotherapy should be reconsidered for patients who respond sufficiently to neoadjuvant treatment. In this study, we aimed to establish the accuracy of detection of residual disease after neoadjuvant chemoradiotherapy with different diagnostic approaches, and the optimal combination of diagnostic techniques for clinical response evaluations. METHODS: The preSANO trial was a prospective, multicentre, diagnostic cohort study at six centres in the Netherlands. Eligible patients were aged 18 years or older, had histologically proven, resectable, squamous cell carcinoma or adenocarcinoma of the oesophagus or oesophagogastric junction, and were eligible for potential curative therapy with neoadjuvant chemoradiotherapy (five weekly cycles of carboplatin [area under the curve 2 mg/mL per min] plus paclitaxel [50 mg/m2 of body-surface area] combined with 41·4 Gy radiotherapy in 23 fractions) followed by oesophagectomy. 4-6 weeks after completion of neoadjuvant chemoradiotherapy, patients had oesophagogastroduodenoscopy with biopsies and endoscopic ultrasonography with measurement of maximum tumour thickness. Patients with histologically proven locoregional residual disease or no-pass during endoscopy and without distant metastases underwent immediate surgical resection. In the remaining patients a second clinical response evaluation was done (PET-CT, oesophagogastroduodenoscopy with biopsies, endoscopic ultrasonography with measurement of maximum tumour thickness, and fine-needle aspiration of suspicious lymph nodes), followed by surgery 12-14 weeks after completion of neoadjuvant chemoradiotherapy. The primary endpoint was the correlation between clinical response during clinical response evaluations and the final pathological response in resection specimens, as shown by the proportion of tumour regression grade (TRG) 3 or 4 (>10% residual carcinoma in the resection specimen) residual tumours that was missed during clinical response evaluations. This study was registered with the Netherlands Trial Register (NTR4834), and has been completed. FINDINGS: Between July 22, 2013, and Dec 28, 2016, 219 patients were included, 207 of whom were included in the analyses. Eight of 26 TRG3 or TRG4 tumours (31% [95% CI 17-50]) were missed by endoscopy with regular biopsies and fine-needle aspiration. Four of 41 TRG3 or TRG4 tumours (10% [95% CI 4-23]) were missed with bite-on-bite biopsies and fine-needle aspiration. Endoscopic ultrasonography with maximum tumour thickness measurement missed TRG3 or TRG4 residual tumours in 11 of 39 patients (28% [95% CI 17-44]). PET-CT missed six of 41 TRG3 or TRG4 tumours (15% [95% CI 7-28]). PET-CT detected interval distant histologically proven metastases in 18 (9%) of 190 patients (one squamous cell carcinoma, 17 adenocarcinomas). INTERPRETATION: After neoadjuvant chemoradiotherapy for oesophageal cancer, clinical response evaluation with endoscopic ultrasonography, bite-on-bite biopsies, and fine-needle aspiration of suspicious lymph nodes was adequate for detection of locoregional residual disease, with PET-CT for detection of interval metastases. Active surveillance with this combination of diagnostic modalities is now being assessed in a phase 3 randomised controlled trial (SANO trial; Netherlands Trial Register NTR6803). FUNDING: Dutch Cancer Society.

Organ Preservation in Rectal Cancer After Chemoradiation: Should We Extend the Observation Period in Patients with a Clinical Near-Complete Response?

BACKGROUND: To assess whether extending the observation period in patients with a near clinical complete response (near cCR) after chemoradiation (CRT) leads to an impaired oncological outcome. METHODS: Patients who had a clinical complete response (cCR) 8-10 weeks after CRT restaging with magnetic resonance imaging and endoscopy were offered a watch-and-wait strategy (W&W1), while patients with a near cCR were offered to undergo local excision or a second restaging 6-12 weeks later. Patients who achieved a cCR at the second restaging were also offered a watch-and-wait strategy (W&W2). RESULTS: Overall, 102 patients with a cCR at the first restaging immediately entered the W&W1, while the remaining 68 patients had a near cCR: 19 patients underwent transanal endoscopic microsurgery and 49 patients opted for a second restaging. Additionally, 44/49 (90%) patients showed a cCR at the second restaging and entered the W&W2. Patients in the W&W1 group had a 2-year local regrowth-free rate (LRFR) of 84% and 2-year overall survival (OS) of 99%, while patients in the W&W2 group had a 2-year LRFR of 73% and OS of 98% (p > 0.05). Multivariable Cox regression analyses showed that late inclusion was not a significant predictive factor for higher risk of LR or lower non-regrowth disease-free survival. CONCLUSIONS: Overall, 90% of patients with a near cCR 8-10 weeks after CRT will proceed to a cCR 6-12 weeks later; therefore, it seems logical to extend the observation period rather than to proceed to surgery. Although there is a non-significant increase in local regrowth rate in these patients, it does not seem to impact the oncological outcome.

Neoadjuvant chemoradiotherapy plus surgery versus active surveillance for oesophageal cancer: a stepped-wedge cluster randomised trial.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard treatment for locally advanced oesophageal cancer. With this treatment, 29% of patients have a pathologically complete response in the resection specimen. This provides the rationale for investigating an active surveillance approach. The aim of this study is to assess the (cost-)effectiveness of active surveillance vs. standard oesophagectomy after nCRT for oesophageal cancer. METHODS: This is a phase-III multi-centre, stepped-wedge cluster randomised controlled trial. A total of 300 patients with clinically complete response (cCR, i.e. no local or disseminated disease proven by histology) after nCRT will be randomised to show non-inferiority of active surveillance to standard oesophagectomy (non-inferiority margin 15%, intra-correlation coefficient 0.02, power 80%, 2-sided α 0.05, 12% drop-out). Patients will undergo a first clinical response evaluation (CRE-I) 4-6 weeks after nCRT, consisting of endoscopy with bite-on-bite biopsies of the primary tumour site and other suspected lesions. Clinically complete responders will undergo a second CRE (CRE-II), 6-8 weeks after CRE-I. CRE-II will include 18F-FDG-PET-CT, followed by endoscopy with bite-on-bite biopsies and ultra-endosonography plus fine needle aspiration of suspected lymph nodes and/or PET- positive lesions. Patients with cCR at CRE-II will be assigned to oesophagectomy (first phase) or active surveillance (second phase of the study). The duration of the first phase is determined randomly over the 12 centres, i.e., stepped-wedge cluster design. Patients in the active surveillance arm will undergo diagnostic evaluations similar to CRE-II at 6/9/12/16/20/24/30/36/48 and 60 months after nCRT. In this arm, oesophagectomy will be offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant dissemination. The main study parameter is overall survival; secondary endpoints include percentage of patients who do not undergo surgery, quality of life, clinical irresectability (cT4b) rate, radical resection rate, postoperative complications, progression-free survival, distant dissemination rate, and cost-effectiveness. We hypothesise that active surveillance leads to non-inferior survival, improved quality of life and a reduction in costs, compared to standard oesophagectomy. DISCUSSION: If active surveillance and surgery as needed after nCRT leads to non-inferior survival compared to standard oesophagectomy, this organ-sparing approach can be implemented as a standard of care.

Pre-treatment CT radiomics to predict 3-year overall survival following chemoradiotherapy of esophageal cancer.

BACKGROUND: Radiomic features retrieved from standard CT-images have shown prognostic power in several tumor sites. In this study, we investigated the prognostic value of pretreatment CT radiomic features to predict overall survival of esophageal cancer patients after chemoradiotherapy. MATERIAL AND METHODS: Two datasets of independent centers were analyzed, consisting of esophageal cancer patients treated with concurrent chemotherapy (Carboplatin/Paclitaxel) and 41.4Gy radiotherapy, followed by surgery if feasible. In total, 1049 radiomic features were calculated from the primary tumor volume. Recursive feature elimination was performed to select the 40 most relevant predictors. Using these 40 features and six clinical variables as input, two random forest (RF) models predicting 3-year overall survival were developed. RESULTS: In total 165 patients from center 1 and 74 patients from center 2 were used. The radiomics-based RF model yielded an area under the curve (AUC) of 0.69 (95%CI 0.61-0.77), with the top-5 most important features for 3-year survival describing tumor heterogeneity after wavelet filtering. In the validation dataset, the RF model yielded an AUC of 0.61 (95%CI 0.47-0.75). Kaplan Meier plots were significantly different between risk groups in the training dataset (p = .027) and borderline significant in the validation dataset (p = .053). The clinical RF model yielded AUCs of 0.63 (95%CI 0.54-0.71) and 0.62 (95%CI 0.49-0.76) in the training and validation dataset, respectively. Risk groups did not reach a significant correlation with pathological response in the primary tumor. CONCLUSIONS: A RF model predicting 3-year overall survival based on pretreatment CT radiomic features was developed and validated in two independent datasets of esophageal cancer patients. The radiomics model had better prognostic power compared to the model using standard clinical variables.

Influence of gray level discretization on radiomic feature stability for different CT scanners, tube currents and slice thicknesses: a comprehensive phantom study.

BACKGROUND: Radiomic analyses of CT images provide prognostic information that can potentially be used for personalized treatment. However, heterogeneity of acquisition- and reconstruction protocols influences robustness of radiomic analyses. The aim of this study was to investigate the influence of different CT-scanners, slice thicknesses, exposures and gray-level discretization on radiomic feature values and their stability. MATERIAL AND METHODS: A texture phantom with ten different inserts was scanned on nine different CT-scanners with varying tube currents. Scans were reconstructed with 1.5 mm or 3 mm slice thickness. Image pre-processing comprised gray-level discretization in ten different bin widths ranging from 5 to 50 HU and different resampling methods (i.e., linear, cubic and nearest neighbor interpolation to 1 × 1 × 3 mm3 voxels) were investigated. Subsequently, 114 textural radiomic features were extracted from a 2.1 cm3 sphere in the center of each insert. The influence of slice thickness, exposure and bin width on feature values was investigated. Feature stability was assessed by calculating the concordance correlation coefficient (CCC) in a test-retest setting and for different combinations of scanners, tube currents and slice thicknesses. RESULTS: Bin width influenced feature values, but this only had a marginal effect on the total number of stable features (CCC > 0.85) when comparing different scanners, slice thicknesses or exposures. Most radiomic features were affected by slice thickness, but this effect could be reduced by resampling the CT-images before feature extraction. Statistics feature 'energy' was the most dependent on slice thickness. No clear correlation between feature values and exposures was observed. CONCLUSIONS: CT-scanner, slice thickness and bin width affected radiomic feature values, whereas no effect of exposure was observed. Optimization of gray-level discretization to potentially improve prognostic value can be performed without compromising feature stability. Resampling images prior to feature extraction decreases the variability of radiomic features.

A phase 1 'window-of-opportunity' trial testing evofosfamide (TH-302), a tumour-selective hypoxia-activated cytotoxic prodrug, with preoperative chemoradiotherapy in oesophageal adenocarcinoma patients.

BACKGROUND: Neo-adjuvant chemoradiotherapy followed by surgery is the standard treatment with curative intent for oesophageal cancer patients, with 5-year overall survival rates up to 50 %. However, patients' quality of life is severely compromised by oesophagectomy, and eventually many patients die due to metastatic disease. Most solid tumours, including oesophageal cancer, contain hypoxic regions that are more resistant to chemoradiotherapy. The hypoxia-activated prodrug evofosfamide works as a DNA-alkylating agent under these hypoxic conditions, which directly kills hypoxic cancer cells and potentially minimizes resistance to conventional therapy. This drug has shown promising results in several clinical studies when combined with chemotherapy. Therefore, in this phase I study we investigate the safety of evofosfamide added to the chemoradiotherapy treatment of oesophageal cancer. METHODS/DESIGN: A phase I, non-randomized, single-centre, open-label, 3 + 3 trial with repeated hypoxia PET imaging, will test the safety of evofosfamide in combination with neo-adjuvant chemoradiotherapy in potentially resectable oesophageal adenocarcinoma patients. Investigated dose levels range from 120 mg/m2 to 340 mg/m2. Evofosfamide will be administered one week before the start of chemoradiotherapy (CROSS-regimen) and repeated weekly up to a total of six doses. PET/CT acquisitions with hypoxia tracer (18)F-HX4 will be made before and after the first administration of evofosfamide, allowing early assessment of changes in hypoxia, accompanied with blood sampling to measure hypoxia blood biomarkers. Oesophagectomy will be performed according to standard clinical practice. Higher grade and uncommon non-haematological, haematological, and post-operative toxicities are the primary endpoints according to the CTCAEv4.0 and Clavien-Dindo classifications. Secondary endpoints are reduction in hypoxic fraction based on (18)F-HX4 imaging, pathological complete response, histopathological negative circumferential resection margin (R0) rate, local and distant recurrence rate, and progression free and overall survival. DISCUSSION: This is the first clinical trial testing evofosfamide in combination with chemoradiotherapy. The primary objective is to determine the dose limiting toxicity of this combined treatment and herewith to define the maximum tolerated dose and recommended phase 2 dose for future clinical studies. The addition of non-invasive repeated hypoxia imaging ('window-of-opportunity') enables us to identify the biologically effective dose. We believe this approach could also be used for other hypoxia targeted drugs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02598687 .