European clinical practice guidelines for the definition, diagnosis, and treatment of oligometastatic esophagogastric cancer (OMEC-4).

INTRODUCTION: The OligoMetastatic Esophagogastric Cancer (OMEC) project aims to provide clinical practice guidelines for the definition, diagnosis, and treatment of esophagogastric oligometastatic disease (OMD). METHODS: Guidelines were developed according to AGREE II and GRADE principles. Guidelines were based on a systematic review (OMEC-1), clinical case discussions (OMEC-2), and a Delphi consensus study (OMEC-3) by 49 European expert centers for esophagogastric cancer. OMEC identified patients for whom the term OMD is considered or could be considered. Disease-free interval (DFI) was defined as the time between primary tumor treatment and detection of OMD. RESULTS: Moderate to high quality of evidence was found (i.e. 1 randomized and 4 non-randomized phase II trials) resulting in moderate recommendations. OMD is considered in esophagogastric cancer patients with 1 organ with ≤ 3 metastases or 1 involved extra-regional lymph node station. In addition, OMD continues to be considered in patients with OMD without progression in number of metastases after systemic therapy. 18F-FDG PET/CT imaging is recommended for baseline staging and for restaging after systemic therapy when local treatment is considered. For patients with synchronous OMD or metachronous OMD and a DFI ≤ 2 years, recommended treatment consists of systemic therapy followed by restaging to assess suitability for local treatment. For patients with metachronous OMD and DFI > 2 years, upfront local treatment is additionally recommended. DISCUSSION: These multidisciplinary European clinical practice guidelines for the uniform definition, diagnosis and treatment of esophagogastric OMD can be used to standardize inclusion criteria in future clinical trials and to reduce variation in treatment.

TRIFLURIDINE/TIPIRACIL (FTD/TPI) with or without bevacizumab in previously treated patients with esophago-gastric adenocarcinoma, a randomised phase III trial.

Background: Trifluridine-tipiracil has shown a survival benefit compared with placebo in patients with chemorefractory metastatic esophago-gastric adenocarcinoma. We aimed to compare the efficacy of trifluridine-tipiracil plus bevacizumab vs trifluridine-tipiracil monotherapy in pre-treated patients with metastatic esophago-gastric adenocarcinoma. Methods: This investigator-initiated, open-label, randomized trial enrolled patients with metastatic esophago-gastric adenocarcinoma. The main inclusion criteria were patients with pre-treated metastatic esophago-gastric adenocarcinoma, and WHO performance status 0 or 1. Participants were randomly assigned (1:1) to receive oral trifluridine-tipiracil (35 mg/m2 twice daily on days 1-5 and 8-12 every 28 days) alone or combined with bevacizumab (5 mg/kg on days 1 and 15) until progression, unacceptable toxicity, or patient decision to withdraw. Randomisation was stratified by sex and treatment line. The primary endpoint was investigator-evaluated progression-free survival. All analyses were based on intention to treat. This trial is registered with EudraCT, 2018-004845-18. Findings: From Oct 1, 2019, to Sept 30, 2021, 103 patients were enrolled and randomly assigned to trifluridine-tipiracil (n = 53) or trifluridine-tipiracil plus bevacizumab (n = 50). The clinical cut-off date was March 1st, 2023, after a median follow-up of 36.6 months. Median progression-free survival was 3.1 months (95% CI 2.0-4.3) in the trifluridine-tipiracil group vs 3.9 months (3.0-6.3) in the trifluridine-tipiracil plus bevacizumab group (hazard ratio 0.68, 95% CI 0.46-1.02; p = 0.058). The most frequent grade 3 or worse adverse event was neutropenia, observed in 26 (49%) patients in the trifluridine-tipiracil group vs 23 patients (46%) in the trifluridine-tipiracil plus bevacizumab group. At least one hospitalization was observed in 21 patients (40%) in the trifluridine-tipiracil group and 22 patients (44%) in the trifluridine-tipiracil plus bevacizumab group. No deaths were deemed treatment related. Interpretation: In patients with pre-treated metastatic esophago-gastric cancer, trifluridine-tipiracil plus bevacizumab, compared to trifluridine-tipiracil monotherapy, did not significantly prolong progression-free survival. The combination of trifluridine-tipiracil with bevacizumab was well tolerated without increase in severe neutropenia and no new safety signals. Funding: Servier, Roche.

High Incidence of Cardiovascular Disease in Patients With Oesophageal Cancer-A Registry-Based Cohort Study.

BACKGROUND: The cardiovascular disease (CVD) burden among patients with oesophageal cancer (EC) treated with curative intent is unclear. AIM: To determine CVD incidence and all-cause mortality in patients with EC. METHOD: Danish national health registries were used to identify patients diagnosed with primary EC between 2008 and 2018. Each EC patient was matched with 10 individuals from the general population. The primary endpoint was a CVD hospital contact (CVD-HC), either admission or outpatient contact. Cox proportional hazard regression models were used to compare the risk of incident CVD-HCs between the cohorts. RESULTS: The study included 1,525 patients with EC and 15,250 individuals from the general population. Patients with EC had a post-diagnosis one-year adjusted hazard ratio (HR) of CVD-HC of 6.1 (95% confidence intervals [CIs] 5.6-6.8) compared with the general population. During the next nine years, the risk of CVD-HC was comparable between the two cohorts, with an adjusted HR of 1.0 (95% CI 0.9-1.3). Patients with EC, and particularly those with prevalent CVD, had a high risk of atrial fibrillation, ischaemic heart disease, and venous thromboembolism within the first year after EC diagnosis. Prevalent CVD among patients with EC was not associated with higher mortality. CONCLUSIONS: CVD morbidity was transiently increased in the first year following EC diagnosis compared with the general population. All-cause mortality risks were high but did not appear to be affected by prevalent CVD. The very high risk of CVD in patients with primary EC to be treated with curative intent calls for healthcare initiatives to advance preventive and post-treatment strategies.

The impact of sex on treatment and outcome in relation to histological subtype in patients with resectable gastric cancer: Results from the randomized CRITICS trial.

BACKGROUND AND OBJECTIVE: This study aims to investigate the impact of sex on outcome measures stratified by histological subtype in patients with resectable gastric cancer (GC). METHODS: A post-hoc analysis of the CRITICS-trial, in which patients with resectable GC were treated with perioperative therapy, was performed. Histopathological characteristics and survival were evaluated for males and females stratified for histological subtype (intestinal/diffuse). Additionally, therapy-related toxicity and compliance were compared. RESULTS: Data from 781 patients (523 males) were available for analyses. Female sex was associated with a distal tumor localization in intestinal (p = 0.014) and diffuse tumors (p < 0.001), and younger age in diffuse GC (p = 0.035). In diffuse GC, tumor-positive resection margins were also more common in females than males (21% vs. 10%; p = 0.020), specifically at the duodenal margin. During preoperative chemotherapy, severe toxicity occurred in 327 (63%) males and 184 (71%) females (p = 0.015). Notwithstanding this, relative dose intensities were not significantly different between sexes. CONCLUSIONS: Positive distal margin rates were higher in females with diffuse GC, predominantly at the duodenal site. Females also experience more toxicity, but this neither impacts dose intensities nor surgical resection rates. Clinicians should be aware of these different surgical outcomes when treating males and females with GC.

Definition, diagnosis and treatment of oligometastatic oesophagogastric cancer: A Delphi consensus study in Europe.

BACKGROUND: Local treatment improves the outcomes for oligometastatic disease (OMD, i.e. an intermediate state between locoregional and widespread disseminated disease). However, consensus about the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer is lacking. The aim of this study was to develop a multidisciplinary European consensus statement on the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer. METHODS: In total, 65 specialists in the multidisciplinary treatment for oesophagogastric cancer from 49 expert centres across 16 European countries were requested to participate in this Delphi study. The consensus finding process consisted of a starting meeting, 2 online Delphi questionnaire rounds and an online consensus meeting. Input for Delphi questionnaires consisted of (1) a systematic review on definitions of oligometastatic oesophagogastric cancer and (2) a discussion of real-life clinical cases by multidisciplinary teams. Experts were asked to score each statement on a 5-point Likert scale. The agreement was scored to be either absent/poor (<50%), fair (50%-75%) or consensus (≥75%). RESULTS: A total of 48 experts participated in the starting meeting, both Delphi rounds, and the consensus meeting (overall response rate: 71%). OMD was considered in patients with metastatic oesophagogastric cancer limited to 1 organ with ≤3 metastases or 1 extra-regional lymph node station (consensus). In addition, OMD was considered in patients without progression at restaging after systemic therapy (consensus). For patients with synchronous or metachronous OMD with a disease-free interval ≤2 years, systemic therapy followed by restaging to consider local treatment was considered as treatment (consensus). For metachronous OMD with a disease-free interval >2 years, either upfront local treatment or systemic treatment followed by restaging was considered as treatment (fair agreement). CONCLUSION: The OMEC project has resulted in a multidisciplinary European consensus statement for the definition, diagnosis and treatment of oligometastatic oesophagogastric adenocarcinoma and squamous cell cancer. This can be used to standardise inclusion criteria for future clinical trials.

Study protocol for the OligoMetastatic Esophagogastric Cancer (OMEC) project: A multidisciplinary European consensus project on the definition and treatment for oligometastatic esophagogastric cancer.

BACKGROUND: A uniform definition and treatment for oligometastatic esophagogastric cancer is currently lacking. However, a comprehensive definition of oligometastatic esophagogastric cancer is necessary to initiate studies on local treatment strategies (e.g. metastasectomy or stereotactic radiotherapy) and new systemic therapy agents in this group of patients. For this purpose, the OligoMetastatic Esophagogastric Cancer (OMEC) project was established. The OMEC-project aims to develop a multidisciplinary European consensus statement on the definition, diagnosis, and treatment for oligometastatic esophagogastric cancer and provide a framework for prospective studies to improve outcomes of these patients. METHODS: The OMEC-project consists of five studies, including 1) a systematic review on definitions and outcomes of oligometastatic esophagogastric cancer; 2) real-life clinical scenario discussions in multidisciplinary expert teams to determine the variation in the definition and treatment strategies; 3) Delphi consensus process through a starting meeting, two Delphi questionnaire rounds, and a consensus meeting; 4) publication of a multidisciplinary European consensus statement; and 5) a prospective clinical trial in patients with oligometastatic esophagogastric cancer. DISCUSSION: The OMEC project aims to establish a multidisciplinary European consensus statement for oligometastatic esophagogastric cancer and aims to initiate a prospective clinical trial to improve outcomes for these patients. Recommendations from OMEC can be used to update the relevant guidelines on treatment for patients with (oligometastatic) esophagogastric cancer.

Triplet Chemotherapy with Cisplatin versus Oxaliplatin in the CRITICS Trial: Treatment Compliance, Toxicity, Outcomes and Quality of Life in Patients with Resectable Gastric Cancer.

(1) Background: Perioperative chemotherapy is the current standard treatment for patients with resectable gastric cancer. Based on studies in patients with metastatic gastric cancer, oxaliplatin has replaced cisplatin in the curative setting as well. However, evidence to prefer oxaliplatin over cisplatin in the curative setting is limited. (2) Methods: We compared patient-related and tumor-related outcomes for cisplatin versus oxaliplatin in patients with resectable gastric cancer treated with perioperative chemotherapy in the CRITICS trial. (3) Results: Preoperatively, 632 patients received cisplatin and 149 patients received oxaliplatin. Preoperative severe toxicity was encountered in 422 (67%) patients who received cisplatin versus 89 (60%) patients who received oxaliplatin (p = 0.105). Severe neuropathy was observed in 5 (1%) versus 6 (4%; p = 0.009) patients, respectively. Postoperative severe toxicity occurred in 109 (60%) versus 26 (51%) (p = 0.266) patients; severe neuropathy in 2 (1%) versus 2 (4%; p = 0.209) for patients who received cisplatin or oxaliplatin, respectively. Diarrhea impacted the quality of life more frequently in patients who received oxaliplatin compared to cisplatin. Complete or near-complete pathological response was achieved in 94 (21%) versus 16 (15%; p = 0.126) patients who received cisplatin or oxaliplatin, respectively. Overall survival was not significantly different in both groups (p = 0.300). (4) Conclusions: Both cisplatin and oxaliplatin are legitimate options as part of systemic treatment in patients with resectable gastric cancer.

Treatment planning comparison in the PROTECT-trial randomising proton versus photon beam therapy in oesophageal cancer: Results from eight European centres.

PURPOSE: To compare dose distributions and robustness in treatment plans from eight European centres in preparation for the European randomized phase-III PROTECT-trial investigating the effect of proton therapy (PT) versus photon therapy (XT) for oesophageal cancer. MATERIALS AND METHODS: All centres optimized one PT and one XT nominal plan using delineated 4DCT scans for four patients receiving 50.4 Gy (RBE) in 28 fractions. Target volume receiving 95% of prescribed dose (V95%iCTVtotal) should be >99%. Robustness towards setup, range, and respiration was evaluated. The plans were recalculated on a surveillance 4DCT (sCT) acquired at fraction ten and robustness evaluation was performed to evaluate the effect of respiration and inter-fractional anatomical changes. RESULTS: All PT and XT plans complied with V95%iCTVtotal >99% for the nominal plan and V95%iCTVtotal >97% for all respiratory and robustness scenarios. Lung and heart dose varied considerably between centres for both modalities. The difference in mean lung dose and mean heart dose between each pair of XT and PT plans was in median [range] 4.8 Gy [1.1;7.6] and 8.4 Gy [1.9;24.5], respectively. Patients B and C showed large inter-fractional anatomical changes on sCT. For patient B, the minimum V95%iCTVtotal in the worst-case robustness scenario was 45% and 94% for XT and PT, respectively. For patient C, the minimum V95%iCTVtotal was 57% and 72% for XT and PT, respectively. Patient A and D showed minor inter-fractional changes and the minimum V95%iCTVtotal was >85%. CONCLUSION: Large variability in dose to the lungs and heart was observed for both modalities. Inter-fractional anatomical changes led to larger target dose deterioration for XT than PT plans.

Reduction in myocardial function and oxygen consumption after chemoradiotherapy in patients with esophageal cancer.

BACKGROUND: Chemoradiotherapy (CRT) may induce myocardial dysfunction, congestive heart failure, and impaired physical performance in patients with esophageal cancer (EC). We aimed to investigate left ventricular (LV) function at rest and during stress, using echocardiography (echo) and a cardiopulmonary exercise (CPX) test both before and immediately after completing CRT. MATERIAL AND METHODS: Consecutive EC patients referred for curative treatment were enrolled. Patients attended either definitive CRT or neoadjuvant CRT with subsequent surgery. The evaluation included cardiac biomarkers, electrocardiogram, echo, and CPX test. The primary endpoint was changes in left ventricular (LV) global longitudinal strain (GLS) at rest. Secondary endpoints were LV ejection fraction (LVEF), LV diastolic function, LVEF and GLS at peak exercise, and maximal oxygen consumption (VO2max). The trial was registered with ClinicalTrials.gov (NCT03619317). RESULTS: Among 47 patients enrolled (94% male; median age 67 years, range 50-86 years), cardiac examinations were performed a median of three days [Interquartile range (IQR (1-5))] before CRT and one day [IQR (0-6)] after CRT. At rest, GLS and LVEF decreased, 17.6 vs. 16.4% and 56.4 vs. 55.1%, respectively (p = 0.004; p = 0.030). Furthermore, an absolute decrease of at least 5% in LVEF and 2.5% in GLS was noted in 21% of the patients. Signs of LV diastolic dysfunction increased from 13 to 21% (p = ns). VO2max significantly decreased; 21.2 ml/kg/min vs. 18.8 ml/kg/min (p < 0.001). CONCLUSION: LV function and physical performance decreased in EC patients after CRT, and the LV systolic reserve capacity declined. This study highlighted that EC treatment was associated with early cardiac side effects, which may have clinical and prognostic implications.

Definitions and treatment of oligometastatic oesophagogastric cancer according to multidisciplinary tumour boards in Europe.

BACKGROUND: Consensus about the definition and treatment of oligometastatic oesophagogastric cancer is lacking. OBJECTIVE: To assess the definition and treatment of oligometastatic oesophagogastric cancer across multidisciplinary tumour boards (MDTs) in Europe. MATERIAL AND METHODS: European expert centers (n = 49) were requested to discuss 15 real-life cases in their MDT with at least a medical, surgical, and radiation oncologist present. The cases varied in terms of location and number of metastases, histology, timing of detection (i.e. synchronous versus metachronous), primary tumour treatment status, and response to systemic therapy. The primary outcome was the agreement in the definition of oligometastatic disease at diagnosis and after systemic therapy. The secondary outcome was the agreement in treatment strategies. Treatment strategies for oligometastatic disease were categorised into upfront local treatment (i.e. metastasectomy or stereotactic radiotherapy), systemic therapy followed by restaging to consider local treatment or systemic therapy alone. The agreement across MDTs was scored to be either absent/poor (<50%), fair (50%-75%), or consensus (≥75%). RESULTS: A total of 47 MDTs across 16 countries fully discussed the cases (96%). Oligometastatic disease was considered in patients with 1-2 metastases in either the liver, lung, retroperitoneal lymph nodes, adrenal gland, soft tissue or bone (consensus). At follow-up, oligometastatic disease was considered after a median of 18 weeks of systemic therapy when no progression or progression in size only of the oligometastatic lesion(s) was seen (consensus). If at restaging after a median of 18 weeks of systemic therapy the number of lesions progressed, this was not considered as oligometastatic disease (fair agreement). There was no consensus on treatment strategies for oligometastatic disease. CONCLUSION: A broad consensus on definitions of oligometastatic oesophagogastric cancer was found among MDTs of oesophagogastric cancer expert centres in Europe. However, high practice variability in treatment strategies exists.

Response to neoadjuvant chemotherapy and survival in molecular subtypes of resectable gastric cancer: a post hoc analysis of the D1/D2 and CRITICS trials.

BACKGROUND: Epstein-Barr virus positivity (EBV+) and microsatellite instability (MSI-high) are positive prognostic factors for survival in resectable gastric cancer (GC). However, benefit of perioperative treatment in patients with MSI-high tumors remains topic of discussion. Here, we present the clinicopathological outcomes of patients with EBV+, MSI-high, and EBV-/MSS GCs who received either surgery only or perioperative treatment. METHODS: EBV and MSI status were determined on tumor samples collected from 447 patients treated with surgery only in the D1/D2 trial, and from 451 patients treated perioperatively in the CRITICS trial. Results were correlated to histopathological response, morphological tumor characteristics, and survival. RESULTS: In the D1/D2 trial, 5-year cancer-related survival was 65.2% in 47 patients with EBV+, 56.7% in 47 patients with MSI-high, and 47.6% in 353 patients with EBV-/MSS tumors. In the CRITICS trial, 5-year cancer-related survival was 69.8% in 25 patients with EBV+, 51.7% in 27 patients with MSI-high, and 38.6% in 402 patients with EBV-/MSS tumors. Interestingly, all three MSI-high tumors with moderate to complete histopathological response (3/27, 11.1%) had substantial mucinous differentiation. No EBV+ tumors had a mucinous phenotype. 115/402 (28.6%) of EBV-/MSS tumors had moderate to complete histopathological response, of which 23/115 (20.0%) had a mucinous phenotype. CONCLUSIONS: In resectable GC, MSI-high had favorable outcome compared to EBV-/MSS, both in patients treated with surgery only, and in those treated with perioperative chemo(radio)therapy. Substantial histopathological response was restricted to mucinous MSI-high tumors. The mucinous phenotype might be a relevant parameter in future clinical trials for MSI-high patients.

Oncological results and morbidity following intended curative resection and free jejunal graft reconstruction of cervical esophageal cancer: a retrospective Danish consecutive cohort study.

BACKGROUND: The role of surgery in treatment of locally advanced cervical esophageal cancer (CEC) remains debated. In the European and American treatment guidelines, definitive chemoradiotherapy (dCRT) is preferred over surgery, while in the Danish guidelines, the two treatment modalities are equally recommended. Surgical treatment of CEC is centralized at our center in Denmark. We present our outcomes following neoadjuvant chemoradiotherapy (nCRT) when possible and resection as first-line therapy for CEC and compare with recent published dCRT results. METHOD: We retrospectively reviewed the medical charts of patients treated for cervical esophageal cancer at Aarhus University Hospital from 2001-2018 with nCRT when possible and pharyngolaryngectomy followed by reconstruction with a free jejunal graft. RESULTS: Forty consecutive patients were included. About, 45% received nCRT. The median survival was 21 months. The overall, disease-specific and disease-free 5-year survival was 43.6%, 53.2%, and 47.4%, respectively. The rate of microscopically radical resection was 85%. The recurrence rate was 47% and 81% of recurrences were locoregional. The in-hospital and 30-day mortality rate was 0%. Major complications occurred in 27.9%. Anastomotic leakage, graft failure, fistulas and strictures occurred in 10%, 7.5%, 30%, and 30%, respectively. CONCLUSION: Our treatment offers equal oncological results compared to the best internationally published results for dCRT for CEC. Results vary considerably between dCRT studies. Morbidity appears more pronounced following surgery. Future studies are warranted to investigate the Danish national outcomes following dCRT as first-line treatment for curable locally advanced CEC.

Prognostic value of tumor markers and ctDNA in patients with resectable gastric cancer receiving perioperative treatment: results from the CRITICS trial.

AIM: To evaluate the prognostic value of tumor markers in a European cohort of patients with resectable gastric cancer. METHODS: We performed a post hoc analysis of the CRITICS trial, in which 788 patients received perioperative therapy. Association between survival and pretreatment CEA, CA 19-9, alkaline phosphatase, neutrophils, hemoglobin and lactate dehydrogenase were explored in uni- and multivariable Cox regression analyses. Likelihoods to receive potentially curative surgery were investigated for patients without elevated tumor markers versus one of the tumor markers elevated versus both tumor markers elevated. The association between tumor markers and the presence of circulating tumor DNA (ctDNA) was explored in 50 patients with available ctDNA data. RESULTS: In multivariable analysis, in which we corrected for allocated treatment and other baseline characteristics, elevated pretreatment CEA (HR 1.43; 95% CI 1.11-1.85, p < 0.001) and CA 19-9 (HR 1.79; 95% CI 1.42-2.25, p < 0.001) were associated with worse OS. Likelihoods to receive potentially curative surgery were 86%, 77% and 60% for patients without elevated tumor marker versus either elevated CEA or CA 19-9 versus both elevated, respectively (p < 0.001). Although both preoperative presence of ctDNA and tumor markers were prognostic for survival, no association was found between these two parameters. CONCLUSION: CEA and CA 19-9 were independent prognostic factors for survival in a large cohort of European patients with resectable gastric cancer. No relationship was found between tumor markers and ctDNA. These factors could potentially guide treatment choices and should be included in future trials to determine their definitive position. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT00407186. EudraCT number: 2006-00413032.

Prognostic significance of T-cell-inflamed gene expression profile and PD-L1 expression in patients with esophageal cancer.

PURPOSE: The ability of the T-cell-inflamed gene expression profile (GEP) to predict clinical outcome in esophageal cancer (EC) is unknown. This retrospective observational study assessed the prognostic value of GEP and programmed death ligand 1 (PD-L1) expression in patients with EC treated in routine clinical practice. METHODS: Tumor samples of 294 patients from three centers in Denmark, South Korea, and the United States, collected between 2005 and 2017, were included. T-cell-inflamed GEP score was defined as non-low or low using a cutoff of -1.54. A combined positive score (CPS) ≥10 was defined as PD-L1 expression positivity. Associations between overall survival (OS) and GEP status and PD-L1 expression were explored by Cox proportional hazards models adjusting for age, sex, histology, stage, and performance status. RESULTS: Median age was 65 years; 63% of patients had adenocarcinoma (AC) and 37% had squamous cell carcinoma (SCC). Thirty-six percent of tumors were GEP non-low, with higher prevalence in AC (46%) than SCC (18%). Twenty-one percent were PD-L1-positive: 32% in South Korean samples versus 16% in non-Asian samples and 26% in SCC versus 18% in AC. GEP scores and PD-L1 CPS were weakly correlated (Spearman's R = 0.363). OS was not significantly associated with GEP status (non-low vs low; adjusted hazard ratio, 0.91 [95% CI, 0.69-1.19]) or PD-L1 expression status. CONCLUSION: Neither GEP nor PD-L1 expression was a prognostic marker in Asian and non-Asian patients with EC.

Treatment and Survival in Advanced Non-Small Cell Lung Cancer, Urothelial, Ovarian, Gastric and Kidney Cancer: A Nationwide Comprehensive Evaluation.

PURPOSE: Few studies have described real-world treatment patterns and survival before the widespread use of immune checkpoint inhibitors (ICIs). We aimed to describe anti-cancer treatment including the use of programmed cell death-1 and ligand-1 (PD-1/PD-L1) ICIs and overall survival (OS) in advanced cancer patients as a benchmarking real-world standard before widespread use of ICIs. PATIENTS AND METHODS: Using nationwide Danish medical registries, we assembled cohorts of Danish patients with advanced non-small cell lung cancer (NSCLC) (n=12,283), urothelial carcinoma (n=2504), epithelial ovarian cancer (n=1466), gastric adenocarcinoma (n=1457), and renal cell carcinoma (RCC) (n=1261) diagnosed between 1/1/2013 and 31/12/2017. We describe anti-cancer treatment and OS using proportions, medians, and Kaplan-Meier methods. RESULTS: Between 9% (ovarian cancer) and 25% (gastric adenocarcinoma) of patients did not receive anti-cancer treatment. The remaining patients received surgery, radiation therapy, and/or medical therapy. Chemotherapy was the most frequent medical therapy in all cohorts except for RCC (tyrosine kinase inhibitors). PD-L1/PD-1 ICIs were used in 7-8% of the NSCLC and RCC cohorts-mainly as second or higher line treatments. OS was longest in patients starting treatment with surgery (eg 25.6 months [95%-confidence interval (CI)=21.9-29.4] for NSCLC and 21.4 months [95%-CI=19.8-23.5] for urothelial carcinoma) and shortest for radiation therapy (eg 3.9 months [95%-CI=3.6-4.2] for NSCLC and 12.6 months [95%-CI=9.2-17.5] for urothelial carcinoma). NSCLC patients starting with medical therapy had OS between these limits. Median OS for NSCLC patients starting treatment with PD-L1/PD-1 ICIs was 21.4 months (95%-CI=13.9-not estimable). CONCLUSION: Most patients with advanced NSCLC, urothelial carcinoma, epithelial ovarian cancer, gastric adenocarcinoma and RCC had poor OS in an era where only a minority received PD-L1/PD-1 ICIs. This information on treatment patterns and survival is important as a benchmarking real-world standard before widespread use of ICIs.

Risk Factors for Metachronous Isolated Peritoneal Metastasis after Preoperative Chemotherapy and Potentially Curative Gastric Cancer Resection: Results from the CRITICS Trial.

Gastric cancer (GC) patients at high risk of developing peritoneal metastasis (PM) as a single site of metastasis after curative treatment may be candidates for adjuvant prophylactic strategies. Here we investigated risk factors for metachronous isolated PM in patients who were treated in the CRITICS trial (NCT00407186). Univariable and multivariable analyses on both metachronous isolated PM and 'other events', i.e., (concurrent) distant metastasis, locoregional recurrence or death, were performed using a competing risk model and summarized by cumulative incidences. Isolated PM occurred in 64 of the 606 (11%) included patients. Diffuse or mixed histological subtype, ypT4 tumor stage and LNhigh (ypN3 lymph node stage or a lymph node ratio >20%) were independent risk factors for isolated PM in both univariable and multivariable analyses. Likewise, LNhigh was an independent risk factor for 'other events'. Patients with tumors who were positive for all three independent risk factors had the highest two-year cumulative incidence of 43% for isolated PM development. In conclusion, diffuse or mixed histological subtype, ypT4 and LNhigh were identified as independent risk factors for isolated PM in patients treated with preoperative chemotherapy followed by surgical resection. The combination of these factors may identify a subgroup that may benefit from PM-preventing treatment strategies.

Strategies for Motion Robust Proton Therapy With Pencil Beam Scanning for Esophageal Cancer.

PURPOSE: Proton therapy of esophageal cancer is superior to photon radiation therapy in terms of normal tissue sparing. However, respiratory motion and anatomical changes may compromise target dose coverage owing to density changes, geometric misses, and interplay effects. Here we investigate the combined effect on clinical target volume (CTV) coverage and compare proton therapy with intensity modulated radiation therapy (IMRT). METHODS AND MATERIALS: This study includes 26 patients with esophageal cancer previously treated with IMRT planned on 4-dimensional computed tomography (4D-CT). For each patient, 7 proton pencil beam scanning (PBS) plans were created with different field configurations and optimization strategies. The effect of respiration was investigated by calculating the phase doses, 4D dose, and 4D dynamic dose (including interplay effects). The effect of anatomical changes was investigated by recalculating all plans on all phases of a 4D-CT surveillance scan. RESULTS: The most robust PBS plans were achieved using 2 posterior beams requiring coverage of planning target volume (PTV) and simultaneously using robust optimization (RO) of CTV (2PAPTVRO), resulting in only 1 patient showing V95%CTV <97% in 1 or more phases of the planning CT. For the least robust PBS plans obtained using lateral + posterior beams and CTV-RO, but not requiring PTV coverage (2LPRO), 10 patients showed underdosage. For IMRT, 2 patients showed underdosage. Interplay effects reduced V95%CTV significantly when delivering only 1 fraction, but the effects generally averaged out after 10 fractions. The effect of interplay was significantly larger for RO-only plans compared with plans optimized with RO combined with PTV coverage. Combining the effect of anatomical changes and respiration on the 4D-CT surveillance scan resulted in V95%CTV <97% for 3 2PAPTVRO, 16 2LPRO, and 8 IMRT patients. CONCLUSIONS: PBS using posterior beam angles was more robust to anatomical changes and respiration than IMRT. The effect of respiration was enhanced when anatomical changes were present. Single fraction interplay effects deteriorated the dose distribution but were averaged out after 10 fractions.

The impact of a tailored follow-up intervention on comprehensive geriatric assessment in older patients with cancer - a randomised controlled trial.

PURPOSE: Comprehensive Geriatric Assessment (CGA) can identify health problems in older persons. In addition, CGA includes intervention towards the identified problems. With follow up, more problems may be identified and the interventions can be adjusted. We wanted to compare CGA with or without tailored follow-up in a randomised design. PATIENTS AND METHODS: Patients 70+ years referred for oncology treatment with four primary tumour sites. Participants were randomised 1:1 to either control group with no follow-up or intervention group with a tailored follow-up by a multidisciplinary team. Primary outcome was adherence to cancer treatment. Secondary outcomes were daily life activities, physical performance and hospitalisation. RESULTS: In total, 363 participants were randomised. After randomisation only 301 were planned to receive specific cancer treatment. Median age was 75 years. Among the 301 participants, 52% of control group vs. 61% of intervention group completed treatment. Risk Rate (RR): 1.16 (95% Confidence Interval (CI): 0.95-1.42), p = .14. The impact varied between the included tumour-sites, p < .01. We found no difference in 90 days physical performance or daily life activities between groups. During the study period, 55% of controls vs. 47% in the intervention group were admitted to hospital, RR: 0.86 (95%CI: 0.69-1.07), p = .19. CONCLUSION: In frail and vulnerable patients with cancer, a tailored follow-up on CGA showed no differences in ability to complete initially planned cancer treatment. The impact varied between the included tumour sites. We did not find any impact of tailored follow-up on daily life activities, physical performance or hospitalisation.

Cardiovascular Burden and Adverse Events in Patients With Esophageal Cancer Treated With Chemoradiation for Curative Intent.

OBJECTIVES: The aim of this study was to characterize the cardiovascular disease (CVD) profile and describe the incidence and characteristics of cardiovascular (CV) events in patients with esophageal cancer (EC) following chemoradiation and surgery. BACKGROUND: Underlying CVD is a concern in patients with EC receiving curative treatment with chemoradiation and surgery. METHODS: Consecutive patients with EC referred for curative treatment were enrolled. Clinical CVD status, ongoing CVD treatment, cardiac function, and physical performance were assessed before chemoradiation. During a 90-day follow-up period, all CV events were noted and classified after in-depth medical record review. CV events were defined by major adverse CV events (transient ischemic attack, imaging-verified new stroke, unstable angina, heart failure or cardiomyopathy) or by Common Terminology Criteria for Adverse Events grade ≥3 (arrhythmia, thromboembolic events, or pericardial effusion requiring pericardiocentesis). RESULTS: Among 55 patients enrolled (median age 67 years; range: 50-86 years; 89% men), 22% had CVD prior to chemoradiation, and 11% with pre-existing CVD were inadequately treated according to current CV guidelines. Thirteen patients (24%) developed 15 events during follow-up. Pre-existing atrial fibrillation and a dilated left atrium were significantly associated with subsequent CV events. Left ventricular (LV) systolic dysfunction was frequently noted; 51% had impaired LV global longitudinal strain (<18%), and 16% had LV ejection fraction <50%. CONCLUSIONS: A systematic cardiac evaluation prior to chemoradiation in patients with EC revealed a high prevalence of undetected CVD, inadequately treated pre-existing CVD, and a high incidence of CV events after chemoradiation. These findings highlight the need for a systematic baseline cardiac examination in patients with EC to optimize CVD treatment. (Impact of Cancer Therapy on Myocardial Function in Patients With Esophagus Cancer [Heartcheck]; NCT03619317).

Proposal for the delineation of neoadjuvant target volumes in oesophageal cancer.

PURPOSE: To define instructions for delineation of target volumes in the neoadjuvant setting in oesophageal cancer. MATERIALS AND METHODS: Radiation oncologists of five European centres participated in the following consensus process: [1] revision of published (MEDLINE) and national/institutional delineation guidelines; [2] first delineation round of five cases (patient 1-5) according to national/institutional guidelines; [3] consensus meeting to discuss the results of step 1 and 2, followed by a target volume delineation proposal; [4] circulation of proposed instructions for target volume delineation and atlas for feedback; [5] second delineation round of five new cases (patient 6-10) to peer review and validate (two additional centres) the agreed delineation guidelines and atlas; [6] final consensus on the delineation guidelines depicted in an atlas. Target volumes of the delineation rounds were compared between centres by Dice similarity coefficient (DSC) and maximum/mean undirected Hausdorff distances (Hmax/Hmean). RESULTS: In the first delineation round, the consistency between centres was moderate (CTVtotal: DSC = 0.59-0.88; Hmean = 0.2-0.4 cm). Delineations in the second round were much more consistent. Lowest variability was obtained between centres participating in the consensus meeting (CTVtotal: DSC: p < 0.050 between rounds for patients 6/7/8/10; Hmean: p < 0.050 for patients 7/8/10), compared to validation centres (CTVtotal: DSC: p < 0.050 between validation and consensus meeting centres for patients 6/7/8; Hmean: p < 0.050 for patients 7/10). A proposal for delineation of target volumes and an atlas were generated. CONCLUSION: We proposed instructions for target volume delineation and an atlas for the neoadjuvant radiation treatment in oesophageal cancer. These will enable a more uniform delineation of patients in clinical practice and clinical trials.