Radiation-Induced Lymphopenia Is a Causal Mediator of Survival After Chemoradiation Therapy for Esophagus Cancer

PURPOSE: Radiation-induced lymphopenia (RIL) is common during chemoradiation therapy. Severe lymphopenia is associated with reduced survival. Proton beam therapy (PBT), with its substantially more compact dose distributions, spares circulating lymphocytes and immune organs at risk to a greater extent than photon therapy. Recent studies comparing PBT to photon radiation therapy, specifically intensity-modulated radiation therapy (IMRT) for esophageal cancer (EC), showed that the incidence of grade 4 RIL (G4RIL) is significantly reduced among patients receiving PBT for EC. However, whether the extent of this reduction has a direct causative link with improved survival is unknown. This study applies causal mediation analysis to answer this question. METHODS AND MATERIALS: We retrospectively assessed 734 patients treated with concurrent chemoradiation therapy for biopsy-proven EC from 2004 to 2017. To address the potential for bias in the choice of radiation modality, propensity score analysis was used to evaluate and reduce imbalances between the PBT and IMRT cohorts. Causal mediation analysis was applied to decompose the total effect of radiation modality on overall survival (OS) into indirect (mediated through G4RIL) and direct effects. RESULTS: We found that PBT was associated with a significantly lower incidence of G4RIL and prolonged OS compared with IMRT (odds ratio, 0.41; 95% CI, 0.28-0.60; CONCLUSIONS: G4RIL was found to mediate survival; however, a statistically significant direct effect of PBT on survival was not observed. In other words, the statistical significance of survival benefit from protons over photons in this EC cohort was lost in the absence of G4RIL risk reduction

Long-term survival after sequential local treatments for oligometastatic esophageal squamous cell carcinoma: A case report

Introduction and importance: Patients with metastatic esophageal cancer generally have a poor prognosis. In patients with oligometastatic disease (OMD), local treatment of metastases may improve overall survival (OS). Case presentation: This case report describes a 57-year-old female with a cT4bN2M1 mid-esophageal squamous cell carcinoma with ingrowth in the aorta and pathologic para-aortic lymph node metastases in the left thorax (i.e. synchronous OMD). The patient first underwent a robot-assisted thoracoscopic para-aortic lymph node dissection (R1, aorta). After response to definitive chemoradiotherapy (ycT4aN1), a salvage robot-assisted minimally-invasive esophagectomy was performed (ypT0N1, R0). During follow-up, metastasectomy and repeated cryoablations for pulmonary metastases were performed (repeat OMD). The patient is currently alive in very good condition without evidence of disease 4.5 years after the first diagnosis of OMD and free of systemic therapy. Discussion: Clinical decision-making, local treatment options, and favorable biological tumor behavior in OMD are discussed. Conclusion: In this case of oligometastatic esophageal squamous cancer with favorable biological behavior, sequential local treatment of OMD (i.e. metastasectomy and cryoablations) combined with primary tumor resection was associated with long-term OS

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

urpose/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. Keywords: Esophageal neoplasms; Gastric neoplasms; Lymphatic metastasis; Metastasectomy; Neoplasm metastasis; Radiosurgery

Comparing 90-Day Postoperative Mortality After Neoadjuvant Proton-Based Versus Photon-Based Chemoradiotherapy for Esophageal Cancer

PURPOSE: Evidence suggests that proton-beam therapy (PBT) results in less toxicity and postoperative complications compared to photon-based radiotherapy in patients who receive chemoradiotherapy followed by esophagectomy for cancer. Ninety-day mortality (90DM) is an important measure of the postoperative (nononcologic) outcome as proxy of quality-of-care. We hypothesize that PBT could reduce 90DM compared to photon-based radiotherapy. MATERIALS AND METHODS: From a single-center retrospective database patients treated with chemoradiotherapy before esophagectomy for cancer were selected (1998-2022). Univariable logistic regression was used to study the association of radiotherapy modality with 90DM. Three separate methods were applied to adjust for confounding bias, including multivariable logistic regression, propensity score matching, and inverse probability of treatment weighting. Stratified analysis for the age threshold that maximized the difference in 90DM (ie, ≥67 vs \u3c67 \u3eyears) was performed. RESULTS: A total of 894 eligible patients were included and 90DM was 5/202 (2.5%) in the PBT versus 29/692 (4.2%) in the photon-based radiotherapy group ( CONCLUSION: No statistically significant difference was observed in postoperative 90DM after esophagectomy for cancer between PBT and photon-based neoadjuvant chemoradiotherapy. However, among older patients a signal was observed that PBT may reduce 90DM risk

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

Clinical Translation of a Deep Learning Model of Radiation-Induced Lymphopenia for Esophageal Cancer

PURPOSE: Radiation-induced lymphopenia is a common immune toxicity that adversely impacts treatment outcomes. We report here our approach to translate a deep-learning (DL) model developed to predict severe lymphopenia risk among esophageal cancer into a strategy for incorporating the immune system as an organ-at-risk (iOAR) to mitigate the risk. MATERIALS AND METHODS: We conducted virtual clinical trials utilizing retrospective data for 10 intensity-modulated radiation therapy (IMRT) and 10 passively-scattered proton therapy (PSPT) esophageal cancer patients. For each patient, additional treatment plans of the modality other than the original were created employing standard-of-care (SOC) dose constraints. Predicted values of absolute lymphocyte count (ALC) nadir for all plans were estimated using a previously-developed DL model. The model also yielded the relative magnitudes of contributions of iOARs dosimetric factors to ALC nadir, which were used to compute iOARs dose-volume constraints, which were incorporated into optimization criteria to produce IMRT-enhanced and intensity-modulated proton therapy (IMPT)-enhanced plans. RESULTS: Model-predicted ALC nadir for the original IMRT (IMRT-SOC) and PSPT plans agreed well with actual values. IMPT-SOC showed greater immune sparing vs IMRT and PSPT. The average mean body doses were 13.10 Gy vs 7.62 Gy for IMRT-SOC vs IMPT-SOC for patients treated with IMRT-SOC; and 8.08 Gy vs 6.68 Gy for PSPT vs IMPT-SOC for patients treated with PSPT. For IMRT patients, the average predicted ALC nadir of IMRT-SOC, IMRT-enhanced, IMPT-SOC, and IMPT-enhanced was 281, 327, 351, and 392 cells/µL, respectively. For PSPT patients, the average predicted ALC nadir of PSPT, IMPT-SOC, and IMPT-enhanced was 258, 316, and 350 cells/µL, respectively. Enhanced plans achieved higher predicted ALC nadir, with an average improvement of 40.8 cells/µL (20.6%). CONCLUSION: The proposed DL model-guided strategy to incorporate the immune system as iOAR in IMRT and IMPT optimization has the potential for radiation-induced lymphopenia mitigation. A prospective clinical trial is planned

The impact of para-aortic lymph node irradiation on disease-free survival in patients with cervical cancer: A systematic review and meta-analysis

Background: Patients with locally advanced cervical cancer without para-aortic lymph node metastases (PAO-LNM) at diagnosis who undergo concurrent chemoradiotherapy are at 4-11% risk of developing PAO-LNM during follow-up. Some studies suggest a beneficial influence of elective para-aortic radiotherapy (PAO-RT) on disease-free survival (DFS) in these patients. The aim of this study was to systematically review and meta-analyse literature on the impact of PAO-RT on DFS in cervical cancer patients. Methods: A systematic search of PubMed/MEDLINE and EMBASE databases was performed. The analysis included intervention studies that reported on DFS in patients with cervical cancer who received chemotherapy and pelvic radiotherapy with or without PAO-RT. From each included study, relevant study characteristics and outcome data including the hazard ratio (HR) adjusted for potential confounders were extracted. An overall pooled adjusted hazard ratio (aHR) for DFS after PAO-RT versus no PAO-RT was calculated using a random-effects model. Results: A total of 2,016 articles were evaluated. Eleven articles were included in the systematic review, of which 3 were appropriate for quantitative meta-analysis. Pooling of these 3 cohorts (including 1,113 patients) demonstrated a statistically significant association between PAO-RT and DFS (pooled aHR 0.87, 95% confidence interval: 0.79-0.97). No significant heterogeneity among reported aHRs was observed (I 2 = 0.0%). Conclusions: This meta-analysis suggests a modest but significant beneficial impact of elective para-aortic radiotherapy on DFS in patients with locally advanced cervical cancer who undergo concurrent chemoradiotherapy. This finding based on non-randomized studies provides an imperative for further investigation in prospective controlled trials

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

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