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.

Efficacy and safety analysis in metastatic cancer patients treated with multiple courses of repeat radiation therapy.

Background and purpose: Due to advances in oncology, a growing proportion of patients is treated with repetitive courses of radiotherapy. The aim of this study is to analyze whether radiotherapy maintains its safety and efficacy profile in patients treated with multiple repeat courses of irradiation. Material and methods: All patients treated between 2011 and 2019 at our institution were screened for a minimum of five repeat irradiation courses, to analyze treatment characteristics, survival, safety and efficacy. The type of re-irradiation was classified according to ESTRO-EORTC consensus guidelines. Results: A total of n = 112 patients receiving n = 660 radiotherapy courses were included in this retrospective cohort study. The most frequent primary tumors were lung cancer in 41.9 % (n = 47) and malignant melanoma in 8.9 % (n = 10). The most frequent re-irradiation types were repeat irradiation and Type 2 re-irradiation in 309 (46.8 %) and 113 (17.1 %) cases, respectively. Median survival after the first course of radiotherapy was 3.6 (0.3-13.4) years. Response to radiotherapy was observed in 548 (83.0 %) cases and CTCAE toxicity grade ≥ 3 was observed in 21 (3.2 %) cases. An increasing number of RT courses (HR: 1.30, p=<0.0001), Type 1 re-irradiation (HR 3.50, p = 0.008) and KPS ≤ 80 % (HR: 2.02, p = 0.002) were associated with significantly worse treatment responses. Toxicity rates remained stable with increasing numbers of RT courses. Conclusion: Multiple courses of repeat radiotherapy maintain a favorable therapeutic ratio of high response combined with reasonable safety profile.

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.

Recognition of and treatment recommendations for oligometastatic disease in multidisciplinary tumor boards.

Background and introduction: Growing evidence supports a combined modality treatment strategy for patients with oligometastatic disease. However, lack of phase III trial data and uncertainties around patient selection highlight the importance of multidisciplinary tumor boards (MDT) in therapeutic decision-making. This study aimed to analyze the recognition of and treatment recommendations for oligometastatic patients by MDTs at a large comprehensive cancer center in order to better understand current treatment patterns of oligometastasis. Materials and methods: For this retrospective single-center cross-sectional study, oligometastatic patients were identified by screening oncological PET and concurrent brain MRI scans conducted at our center in 2020. MDT discussions and recommendations within four weeks of the imaging diagnosis of oligometastasis were analyzed. Logistic regression analysis was used to identify predictors for the addition of local therapy to standard-of-care. Results: A total of 787 oligometastatic cases were identified. Lung cancer and mesothelioma, skin cancer, and prostate cancer were the most common histologies with 231 (29 %), 160 (20 %), and 84 (11 %) cases, respectively. Almost half of the cases (46 %) had one distant metastasis on imaging only. More than half (56 %) of all oligometastatic cases were discussed at an MDT. In 47 % of cases, for which a therapeutic recommendation was reached in an MDT, local therapy was part of the therapeutic strategy. On logistic regression analysis, oligometastatic skin cancer was significantly associated with a recommendation for local therapy (p < 0.05), whereas the number of oligometastases was not (p = 0.202). Conclusion: More than half of oligometastatic cases were discussed in MDTs, of which more than every second received a recommendation including the addition of local therapy. This frequency of MDT use underscores the importance of multidisciplinary decision-making, yet efforts should be increased to standardize reporting and use standard nomenclature on oligometastasis in MDTs to better frame multidisciplinary discussion.

Liver oligometastatic disease in synchronous metastatic gastric cancer patients: a nationwide population-based cohort study.

INTRODUCTION: This population-based cohort study analysed treatment, overall survival (OS), and independent prognostic factors for OS in gastric cancer patients with liver metastases. METHODS: Between 2015 and 2017, patients with synchronous metastatic gastric or gastroesophageal junction adenocarcinoma limited to the liver were included from the prospectively maintained population-based Netherlands Cancer Registry. Liver oligometastatic disease (OMD) was defined as ≤3 liver metastases. The primary outcome was OS. Independent prognostic factors for OS were analysed using multivariable Cox regression analysis. RESULTS: A total 295 patients with metastases limited to the liver were included. The primary tumour was resected in four patients (1.4%). Treatment for liver metastases consisted of chemotherapy alone (28.1%), trastuzumab plus chemotherapy (4.7%), surgery (1.0%), or best supportive care (67.5%). Median OS across all included patients was 4.0 months (95% confidence interval [CI]: 3.1-4.5). Liver OMD was detected in 77 patients (26%). Treatment for liver OMD consisted of chemotherapy alone (24.6%), trastuzumab plus chemotherapy (5.2%), surgery (3.9%), or best supportive care (67.5%). Median OS among patients with liver OMD was 5.7 months (95% CI: 4.8-7.5). Across all patients, better OS was independently associated with liver OMD (hazard ratio [HR] 0.66, 95% CI: 0.50-0.87), trastuzumab (HR 0.41, 95% CI: 0.23-0.72) but not with triplet compared with doublet chemotherapy (HR 0.94, 95% CI: 0.57-2.87). Worse OS was independently associated with unknown nodal stage versus cN0 (HR 1.74, 95% CI: 1.17-2.60), diffuse-type versus intestinal-type adenocarcinoma (HR 2.06, 95% CI: 1.32-3.20), and monotherapy or best supportive care versus doublet chemotherapy (HR 1.72, 95% CI: 1.03-2.87, and HR 3.61, 95% CI: 2.55-5.10, respectively). CONCLUSION: In this population-based cohort study, liver OMD was detected in 26% of patients. Liver OMD and trastuzumab treatment were independently associated with better OS while triplet as compared with doublet chemotherapy was not. OS among patients with liver OMD nevertheless remained poor. The concept of OMD and the benefit of resection of liver OMD may still have been relatively unknown in this disease type during the study inclusion years.

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.

Stereotactic radiotherapy or metastasectomy for oligometastatic esophagogastric cancer: A nationwide population-based cohort study.

Background and purpose: This nationwide population-based study analyzed the outcomes of local treatment (i.e. stereotactic body radiotherapy [SBRT] or metastasectomy) or systemic therapy for oligometastatic disease (OMD) in patients with esophagogastric cancer in The Netherlands. Materials and methods: Between 2015 and 2016, all patients in The Netherlands with esophagogastric cancer and synchronous or metachronous OMD were eligible for inclusion. Patients who underwent local treatment of OMD (SBRT or metastasectomy) and/or systemic therapy were included. OMD was defined as distant metastases in 1 organ or 1 extra-regional lymph node region. The primary outcomes were overall survival (OS) and independent prognostic factors for OS. OS was calculated from diagnosis of OMD. Prognostic factors for OS were analyzed using a multivariable Cox proportional hazard model. Results: A total of 594 patients were included, of whom 83 underwent local treatment for OMD alone, 22 local treatment plus systemic therapy, and 489 systemic therapy alone. Median OS after local treatment for OMD alone was 16.0 months, local treatment plus systemic therapy 22.7 months, and after systemic therapy alone 8.5 months. Improved OS was independently associated with local treatment for OMD alone or combined with systemic therapy as compared with systemic therapy alone (hazard ratio [HR] 0.52, 95% CI: 0.31-0.90 and HR 0.42, 95% CI: 0.22-0.82, respectively) and a controlled primary tumor(HR 0.48, 95% CI: 0.27-0.86). Worse OS was independently associated with worse performance scores (HR 1.41, 95%: 1.32-1.75), poorly or undiffertumor as compared with good or moderadifferentiated tumor (HR 1.37, 95% CI: 1.06-1.76), and peritoneal as compared with lymph mode metastases (HR 1.39, 95% CI: 1.00-1.93). Conclusion: Local treatment of OMD alone or combined with systemic therapy was independently associated with improved OS as compared with systemic therapy alone in this population-based cohort study in The Netherlands. Randomized controlled trials are warranted to confirm these results.

Incidence and survival of patients with oligometastatic esophagogastric cancer: A multicenter cohort study.

PURPOSE/OBJECTIVE: This multicenter study assessed the incidence and survival of patients with esophagogastric cancer and oligometastatic disease (OMD) in two tertiary referral cancer centers in The Netherlands and Switzerland. MATERIALS/METHODS: Between 2010 and 2021, patients with metastatic esophagogastric cancer were identified. Patients with de-novo OMD were included (first-time diagnosis of ≤5 distant metastases on 18F-FDG-PET/CT). Control of the primary tumor was considered in patients who underwent primary tumor resection or definitive chemoradiotherapy without locoregional recurrence. Treatment of OMD was categorized into (1) systemic therapy, (2) local treatment (stereotactic body radiotherapy or metastasectomy), (3) local plus systemic therapy, or (4) best supportive care. The primary outcomes were overall survival (OS) and independent prognostic factors for OS. Independent prognostic factors for OS were analyzed using multivariable Cox proportional hazard models. RESULTS: In total, 830 patients with metastatic esophagogastric cancer were identified of whom 200 patients with de-novo OMD were included (24%). The majority of included patients had esophageal cancer (73%) with adenocarcinoma histology (79%) and metachronous OMD (52%). The primary tumor was controlled in 68%. Treatment of OMD was systemic therapy (25%), local treatment (43%), local plus systemic therapy (13%), or best supportive care (18%). Median follow-up was 14 months (interquartile range: 7-27). Median OS was 16 months (95% CI: 13-21). Improved OS was independently associated with local plus systemic therapy compared with systemic therapy alone (hazard ratio [HR] 0.47, 95% confidence interval [CI]: 0.25-0.87). Worse OS was independently associated with squamous cell carcinoma (HR 1.70, 95% CI: 1.07-2.74), bone oligometastases (HR 2.44, 95% CI: 1.28-4.68), brain oligometastases (HR 1.98, 95% CI: 1.05-4.69), and two metastatic locations (HR 2.07, 95% CI: 1.04-4.12). Median OS after local plus systemic therapy was 35 months (95% CI: 22-NA) as compared with 13 months (95% CI: 9-21, p < 0.001) after systemic therapy alone for OMD. CONCLUSION: Patients with metastatic esophagogastric cancer present in 25% with de-novo OMD. Local treatment of OMD plus systemic therapy was independently associated with long-term OS and independently improved OS when compared with systemic therapy alone. Randomized controlled trials are warranted to confirm these results.

Detecting Interval Distant Metastases With 18F-FDG PET/CT After Neoadjuvant Chemoradiotherapy for Locally Advanced Esophageal Cancer.

PURPOSE: Patients with esophageal cancer can develop distant metastases between the start of neoadjuvant chemoradiotherapy (nCRT) and planned surgery (ie, interval distant metastases). 18F-FDG PET/CT restaging after nCRT detects interval distant metastases in ~8% of patients. This study aimed to identify patients for whom 18F-FDG PET/CT restaging after nCRT could be omitted using an existing prediction model predicting for interval distant metastases or by using clinical stage groups. PATIENTS AND METHODS: Patients with locally advanced esophageal cancer who underwent baseline and restaging 18F-FDG PET/CT, nCRT, and were planned for esophagectomy between 2017 and 2021 were eligible for inclusion in this retrospective study. The primary outcome was the existing model's external performance (ie, discrimination and calibration) for predicting interval distant metastases. The existing model predictors included tumor length, cN status, squamous cell carcinoma histology, and baseline SUVmax. The secondary outcome determined the clinical stage groups (AJCC/UICC eighth edition) for adenocarcinoma and squamous cell carcinoma for which the incidence of interval distant metastases was <10%. RESULTS: In total, 127 patients were included, of whom 17 patients developed interval distant metastases (13%; 95% confidence interval [CI], 8%-21%) and 9 patients were deemed to have false-positive lesions on 18F-FDG PET/CT (7%; 95% CI, 2%-11%). Applying the existing model to this cohort yielded a discriminatory c-statistic of 0.56 (95% CI, 0.40-0.72). The calibration of the existing model was poor (ie, mostly underestimating the actual risk). The incidence of true-positive versus false-positive interval distant metastases for patients with clinical stage II disease was 5% versus 0%; clinical stage III, 14% versus 8%; and clinical stage IVa, 22% versus 9%. CONCLUSIONS: The existing prediction model cannot reliably identify patients at risk for developing interval distant metastases after nCRT for esophageal cancer. Omission of 18F-FDG PET/CT restaging after nCRT could be considered in patients with clinical stage II esophageal cancer.

Metastasectomy or Stereotactic Body Radiation Therapy With or Without Systemic Therapy for Oligometastatic Esophagogastric Cancer.

BACKGROUND: The primary goal of this study was to determine overall survival (OS) in patients who underwent local treatment (metastasectomy or stereotactic body radiotherapy [SBRT]) or systemic therapy (chemotherapy or targeted therapy) for oligometastatic esophagogastric cancer. The secondary goal was to determine prognostic factors for OS. METHODS: Patients with synchronous or metachronous oligometastatic esophagogastric cancer who underwent local treatment or systemic therapy were included in this single-center, retrospective cohort study. Oligometastatic disease (OMD) included 1 organ or 1 extraregional lymph node station with ≤ 3 lesions. OS was determined after OMD detection. Treatment for OMD was categorized as (1) local treatment, (2) local plus systemic, (3) systemic therapy. The primary tumor was controlled after resection or definitive chemoradiotherapy. RESULTS: In total, 85 patients were included. Treatment for OMD was local treatment (58%), local plus systemic (14%), or systemic therapy (28%). The primary tumor was controlled in 68% of patients. Most patients were diagnosed with distal esophageal cancer (61%), with adenocarcinoma histology (76%), and presented with synchronous OMD (51%). OS after local treatment was 17 months (95% confidence interval [CI] 12-40), after local plus systemic therapy 35 months (95% CI 29-NA), and after systemic therapy 16 months (95% CI 11-NA). Better OS was independently associated with local plus systemic compared with local treatment (hazard ratio [HR] 2.11, 95% CI 1.05-5.07) or systemic therapy (HR 2.28, 95% CI 1.04-6.07). CONCLUSIONS: Local plus systemic therapy for oligometastatic esophagogastric cancer was independently associated with improved OS and better OS compared with either systemic therapy or local treatment.

Definition of oligometastatic esophagogastric cancer and impact of local oligometastasis-directed treatment: A systematic review and meta-analysis.

BACKGROUND: Local treatment (metastasectomy or stereotactic radiotherapy) for oligometastatic disease (OMD) in patients with esophagogastric cancer may improve overall survival (OS). The primary aim was to identify definitions of esophagogastric OMD. A secondary aim was to perform a meta-analysis of OS after local treatment versus systemic therapy alone for OMD. METHODS: Studies and study protocols reporting on definitions or OS after local treatment for esophagogastric OMD were included. The primary outcome was the maximum number of organs/lesions considered OMD and the maximum number of lesions per organ (i.e. 'organ-specific' OMD burden). Agreement was considered to be either absent/poor (< 50%), fair (50%-75%), or consensus (≥ 75%). The secondary outcome was the pooled adjusted hazard ratio (aHR) for OS after local treatment versus systemic therapy alone. The ROBINS tool was used for quality assessment. RESULTS: A total of 97 studies, including 7 study protocols, and 2 prospective studies, were included. OMD was considered in 1 organ with ≤ 3 metastases (consensus). 'Organ-specific' OMD burden could involve bilobar ≤ 3 liver metastases, unilateral ≤ 2 lung metastases, 1 extra-regional lymph node station, ≤ 2 brain metastases, or bilateral adrenal gland metastases (consensus). Local treatment for OMD was associated with improved OS compared with systemic therapy alone based on 6 non-randomized studies (pooled aHR 0.47, 95% CI: 0.30-0.74) and for liver oligometastases based on 5 non-randomized studies (pooled aHR 0.39, 95% CI: 0.22-0.59). All studies scored serious risk of bias. CONCLUSIONS: Current literature considers esophagogastric cancer spread limited to 1 organ with ≤ 3 metastases or 1 extra-regional lymph node station to be OMD. Local treatment for OMD appeared associated with improved OS compared with systemic therapy alone. Prospective randomized trials are warranted.

A population-based study on treatment and outcomes in patients with gastric adenocarcinoma diagnosed with distant interval metastases.

BACKGROUND: In patients with gastric or gastroesophageal junction (GEJ) cancer treated with curative intent, distant interval metastases may be detected after start of neoadjuvant chemotherapy or during surgery. The aim of this study was to explore characteristics, allocated treatment and overall survival (OS) in gastric/GEJ cancer patients with interval metastases, and to compare OS with synchronous metastatic gastric/GEJ cancer patients who started palliative chemotherapy. METHODS: Patients with interval metastases were selected from the Netherlands Cancer Registry by including patients with potentially curable gastric/GEJ adenocarcinoma (2010-2018) who started chemotherapy without concurrent radiotherapy. The OS since start of neoadjuvant treatment of patients with interval metastases was compared with a propensity score-matched cohort of patients with synchronous metastases who received palliative systemic treatment. RESULTS: 164 patients with interval metastases diagnosed in 2010-2018 were included. Metastases were most frequently detected during surgery (83%) and most frequently located in the peritoneum (77%). Peritoneal interval metastases were observed in 63% and 80% of the patients who did and did not have a diagnostic laparoscopy prior to neoadjuvant treatment, respectively (P = 0.041). Median OS was 8.9 months (IQR 5.5-13.4), compared to 8.0 months (IQR 4.1-14.1) in matched synchronous metastatic patients calculated from start of neoadjuvant and palliative systemic treatment, respectively (P = 0.848). CONCLUSION: This population-based study shows that gastric/GEJ cancer patients who started neoadjuvant treatment and were diagnosed with interval metastases most frequently suffered from peritoneal metastases detected during (exploratory) surgery, even when a diagnostic laparoscopy was performed before start of treatment. OS was comparable to patients with synchronous metastatic gastric/GEJ cancer.

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.

Contributing factors to lymph node recovery with esophagectomy by thoracic surgeons: an analysis of the Society of Thoracic Surgeons General Thoracic Surgery Database.

Given the association between lymphadenectomy and survival after esophagectomy, and the ongoing development of effective adjuvant protocols for identified residual disease, we determined factors contributing to lymph node yield and effects on postoperative morbidity following esophagectomy by thoracic surgeons. Using the Society of Thoracic Surgeons General Thoracic Surgery Database, all patients who underwent esophagectomy for primary esophageal cancer with gastric conduit reconstruction from 2012 to 2016 were identified. Patient demographics, technical factors, and tumor characteristics associated with lymph node yield were determined using a multivariable multilevel mixed-effects regression model. Associations between lymph node yield and perioperative morbidity and mortality were similarly assessed. A total of 8480 patients were included. The median number of nodes harvested was 16 [Interquartile Range 11-22]. Factors associated with fewer nodes included female gender (b=-0.53, P=0.032), body mass index <18.5 (b=-1.46, P=0.012), prior cardiothoracic surgery (b=-0.73, P=0.015), intraoperative blood transfusion (b=-1.43, P<0.001), squamous cell histology (b=-0.86, P=0.006), and neoadjuvant treatment (b=-1.41, P<0.001). Operative approach significantly affected lymph node yield, with minimally invasive approaches demonstrating higher lymph node counts, and open transhiatal esophagectomy recovering the fewest nodes. Findings were independent of clinical center. There was no association of higher lymph node yield with 30-day mortality, with only slightly increased risk for chyle leak (odds ratio [OR] 1.02, P=0.012). In conclusion, several patient and tumor factors affect lymph node recovery with esophagectomy, independent of hospital center. Technical aspects, specifically minimally invasive approach, play a significant role in quantified lymph node yield. Higher operative lymph node yield was associated with minimal increased morbidity.

Prognosis of Interval Distant Metastases After Neoadjuvant Chemoradiotherapy for Esophageal Cancer.

BACKGROUND: In esophageal cancer patients, distant metastases develop between the start of neoadjuvant chemoradiotherapy and planned surgery, so-called interval metastases. The primary aim of this study was to assess management, overall survival (OS), and prognostic factors for OS in these patients. A secondary aim was to compare OS with synchronous metastatic patients. METHODS: Esophageal cancer patients with interval distant metastases were identified from the Netherlands Cancer Registry (2010 to 2017). Management was categorized into metastasis-directed therapy (MDT), primary tumor resection, or best supportive care (BSC). The OS was calculated from the diagnosis of the primary tumor. Prognostic factors affecting OS were studied using Cox proportional hazard models. Propensity score-matching (1:3) generated matched cases with synchronous distant metastases. RESULTS: In all, 208 patients with interval metastases were identified: in 87 patients (42%) MDT was initiated; in 10%, primary tumor resection only; in 7%, primary tumor resection plus MDT; and in 41%, BSC. Median OS was 10 months (interquartile range, 8.6 to 11.1). Compared with BSC, superior OS was independently associated with MDT (hazard ratio [HR] 0.36; 95% confidence interval [CI], 0.26 to 0.49), primary tumor resection (HR 0.55; 95% CI, 0.33 to 0.94), and primary tumor resection plus MDT (HR 0.20; 95% CI, 0.10 to 0.38). Worse OS was independently associated with signet ring cell carcinoma (HR 1.92; 95% CI, 1.12 to 3.28) and poor differentiation grade (HR 1.96; 95% CI, 1.35 to 2.83). The OS was comparable between matched patients with interval and synchronous distant metastases (10.2 versus 9.4 months, P = .760). CONCLUSIONS: In esophageal cancer patients treated with neoadjuvant chemoradiotherapy with interval distant metastases, the OS was poor and comparable to that of synchronous metastatic patients.

Severe lymphopenia acquired during chemoradiotherapy for esophageal cancer: Incidence and external validation of a prediction model.

BACKGROUND: The incidence of grade 4 lymphopenia in patients treated with chemoradiotherapy (CRT) according to Chemoradiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) regimen is unclear. The primary aim was to determine the incidence of grade 4 lymphopenia during CROSS for esophageal cancer. Secondary aims were to externally validate a prediction model for grade 4 lymphopenia and compare overall survival between patients with and without grade 4 lymphopenia. METHODS: Patients who underwent CRT for esophageal cancer between 2014 and 2019 were eligible for inclusion. Patients with a planned radiation dose of 41.4 Gy (CROSS) or 50.4 Gy ("extended-CROSS") and concurrent carboplatin and paclitaxel were included. The primary outcome was the incidence of grade 4 lymphopenia during CRT defined according to Common Terminology Criteria for Adverse Events version 5.0 (i.e. lymphocyte count nadir < 0.2 µL). The secondary outcome measures were the prediction model's external performance (i.e. discrimination and calibration). Overall survival for patients with versus without grade 4 lymphopenia was compared using Kaplan-Meier analysis. RESULTS: A total of 219 patients were included of whom 176 patients (80%) underwent CROSS and 43 patients (20%) extended-CROSS. The incidence of grade 4 lymphopenia was 11% in CROSS and 33% in extended-CROSS (p < 0.001). External discrimination yielded a c-statistic of 0.80 (95% confidence interval: 0.70-0.89). External calibration of the model was poor in CROSS but fair in extended-CROSS. Adjusted calibration using intercept correction (adjusted for the lower a-priori risk for grade 4 lymphopenia in CROSS) showed fair agreement between the observed and predicted risk for grade 4 lymphopenia. Median overall survival in patients with versus without grade 4 lymphopenia was 12.7 versus 42.5 months (p = 0.045). CONCLUSION: The incidence of grade 4 lymphopenia is significantly higher in esophageal cancer patients receiving extended-CROSS compared to those receiving CROSS. The prediction model demonstrated good external performance in the setting of the CROSS-regimen and could be used to identify patients at high-risk for grade 4 lymphopenia who might be eligible for lymphopenia-mitigating strategies.

The Influence of Severe Radiation-Induced Lymphopenia on Overall Survival in Solid Tumors: A Systematic Review and Meta-Analysis.

PURPOSE: Emerging evidence suggests a detrimental prognostic association between radiation-induced lymphopenia (RIL) and pathologic response, progression-free survival, and overall survival (OS) in patients who undergo radiation therapy for cancer. The aim of this study was to systematically review and meta-analyze the prognostic impact of RIL on OS in patients with solid tumors. METHODS AND MATERIALS: PubMed/MEDLINE and Embase were systematically searched. The analysis included intervention and prognostic studies that reported on the prognostic relationship between RIL and survival in patients with solid tumors. An overall pooled adjusted hazard ratio (aHR) was calculated using a random-effects model. Subgroup analyses for different patient-, tumor-, treatment-, and study-related characteristics were performed using meta-regression. RESULTS: Pooling of 21 cohorts within 20 eligible studies demonstrated a statistically significant association between OS and grade ≥3 versus grade 0-2 RIL (n = 16; pooled aHR, 1.65; 95% confidence interval [CI], 1.43-1.90) and grade 4 RIL versus grade 0-3 (n = 5; aHR, 1.53; 95% CI, 1.24-1.90). Moderate heterogeneity among aHRs was observed, mostly attributable to overestimated aHRs in 7 studies likely subject to model-overfitting. Subgroup analysis showed significant prognostic impact of grade ≥3 RIL in 4 brain tumor (aHR, 1.63; 95% CI, 1.06-2.51), 4 lung cancer (aHR, 1.52; 95% CI, 1.01-2.29), and 3 pancreatic cancer (aHR, 1.92; 95% CI, 1.10-3.36) cohorts. CONCLUSIONS: This meta-analysis demonstrates a significant detrimental prognostic association between grade ≥3 lymphopenia and OS in patients receiving radiation therapy for solid tumors. This finding appears consistent for tumors of the brain, thorax, and upper abdomen and provides an imperative to further elucidate the potential survival benefit of lymphopenia-mitigating strategies.