Locally Advanced Esophageal Cancer Research Articles

Clinical mechanism of muscle mass loss during neoadjuvant chemotherapy in older patients with esophageal cancer: a prospective cohort study.

In older patients with locally advanced esophageal cancer (LAEC), loss of skeletal muscle mass during neoadjuvant chemotherapy (NAC) is associated with poor clinical outcomes. This study aimed to investigate factors associated with loss of skeletal muscle mass during NAC in older patients with LAEC. This was a single-center exploratory prospective cohort study. Consecutive patients aged ≥65years with LAEC scheduled for curative esophagectomy after NAC were enrolled between October 2021 and December 2023. As a primary endpoint, loss of skeletal muscle mass index (ΔSMI: pre-NAC minus post-NAC value) was calculated from computed tomography images before and after NAC. Significant pre-NAC and during-NAC factors with ΔSMI were detected with a multivariate regression model. Statistical significance was considered as two-tailed P <0.05. A total of 69 patients were analyzed. The mean age was 72.9years, and 53 (77%) were male. Mean SMI before and after NAC was 43.1 and 40.9cm2/m2, and mean ΔSMI was 2.2cm2/m2. In multivariate analysis, ΔSMI was associated with increased sitting time during NAC (per 1min/day, adjusted coefficient 0.007, 95% confidence interval [CI] 0.001 to 0.013, P = 0.016), decreased Geriatric Nutritional Risk Index during NAC (per 1 score, adjusted coefficient -0.146, 95% CI -0.213 to -0.013, P = 0.002), and worsening decreased appetite during NAC (vs. no worsening, adjusted coefficient 1.571, 95% CI 0.279 to 2.862, P = 0.018). It was hypothesized that the inactivity-related mechanism and malnutrition-related mechanism are important for skeletal muscle mass loss during NAC in older patients with LAEC.

Skeletal muscle mass recovery after oesophagectomy and neoadjuvant chemotherapy in oesophageal cancer: retrospective cohort study

ObjectiveSkeletal muscle mass (SMM) is an important biomarker for prognosis and health in older patients with cancer. Limited information is available on the recovery course of SMM after oesophagectomy following...

MRI-based Tumor Habitat Analysis for Treatment Evaluation of Radiotherapy on Esophageal Cancer

Introduction: We aim to evaluate the performance of pre-treatment MRI-based habitat imaging to segment tumor micro-environment and its potential to identify patients with esophageal cancer who can achieve pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT). Material and methods: A total of 18 patients with locally advanced esophageal cancer (LAEC) were recruited into this retrospective study. All patients underwent MRI before nCRT and surgery using a 3.0 T scanner (Ingenia 3.0 CX, Philips Healthcare). A series of MR sequences including T2-weighted (T2), diffusion-weighted imaging (DWI), and Contrast Enhance-T1 weighted (CE-T1) were performed. A clustering algorithm using a two-stage hierarchical approach groups MRI voxels into separate clusters based on their similarity. The t-test and receiver operating characteristic (ROC) analysis were used to evaluate the predictive effect of pCR on habitat imaging results. Cross-validation of 18 folds is used to test the accuracy of predictions. Results: A total of 9 habitats were identified based on structural and physiologic features. The predictive performance of habitat imaging based on these habitat volume fractions (VFs) was evaluated. Students’ t-tests identified 2 habitats as good classifiers for pCR and non-pCR patients. ROC analysis shows that the best classifier had the highest AUC (0.82) with an average prediction accuracy of 77.78%. Conclusion: We demonstrate that MRI-based tumor habitat imaging has great potential for predicting treatment response in LAEC. Spatialized habitat imaging results can also be used to identify tumor non-responsive sub-regions for the design of focused boost treatment to potentially improve nCRT efficacy.

Age and body composition of patients receiving treatment for locally advanced esophageal cancer.

e16094 Background: Standard of care for locally advanced esophageal cancer consists of chemoradiation (chemoRT) followed by esophagectomy. Fewer patients in older populations with locally advanced esophageal cancer undergo esophagectomy when compared to their younger counterparts. Furthermore, frail patients frequently forgo surgery after chemoRT. The current study examined the relationship between age, body composition, and treatment decision-making in locally advanced esophageal cancer. Methods: Patients with clinical stage T2-4, N0-2, and M0 adenocarcinoma or squamous cell carcinoma of the mid or distal esophagus diagnosed between 2010-2021 were included from 11 hospitals across our healthcare system. Treatment decision-points included receipt of chemoRT versus non-curative therapy, unresectable disease after chemoRT defined by metastatic disease or upper mediastinal lymphadenopathy, and receipt of surgery stratified by histology. Sociodemographic data including age, race, sex, insurance status, socioeconomic status, body composition data from CT imaging (skeletal muscle gauge [SMG]), and outcome data were collected. Skeletal Muscle Gauge was calculated as the product of skeletal muscle cross-sectional area at L3 normalized for height and muscle density. Fisher's exact test was used for categorical variables and Kruskal-Wallis for continuous variables. Results: 513 patients were included in the analysis, of which 399 (78%) had adenocarcinoma and 114 (22%) had squamous cell carcinoma. Median age was 66. Of the 513 patients, 472 (92%) underwent chemoRT (366 [78%] adenocarcinoma, 106 [22%] squamous cell carcinoma). Patients who were over the age of 75 were less likely to undergo chemoRT when compared to their younger counterparts (85% vs. 94%, p = 0.002). After the completion of chemoRT, 419 (89%) patients were deemed resectable, 330 adenocarcinoma and 89 with squamous cell carcinoma. Among resectable patients with adenocarcinoma, those &gt; 75 years old and lower SMG were less likely to receive surgery (p &lt; 0.001 and p =0.001). Age and body composition associated with lower receipt of surgery in locally advanced esophageal cancer patients was significant on both univariate and multivariate analyses. Conclusions: Patients over 75 are less likely to undergo chemoRT and surgical resection for locally advanced esophageal cancer. Among patients with resectable disease who have completed chemoRT, those with unfavorable body composition as measured by low SMG on CT imaging are also less likely to undergo surgical resection. These measures may be helpful in surgical decision-making in patients with locally-advanced esophageal cancer. Further study is warranted to more precisely define the relationship between age, body composition, and risk of surgery in esophageal cancer.

Prognostic impact of muscle mass loss in elderly patients with oesophageal cancer receiving neoadjuvant chemoradiation therapy.

We aimed to identify the impact of muscle mass on locally advanced oesophageal cancer (LAEC) in elderly patients receiving neoadjuvant chemoradiation therapy (NACRT). We reviewed the medical records of 345 patients diagnosed with LAEC who underwent NACRT and surgery. Physical variables, including height, weight, skeletal muscle mass, and laboratory values, were obtained before and after NACRT. Body mass index (BMI, kg/m2), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index (PNI) were calculated as height/(weight)2, ANC/ALC, platelet count/ALC, and (10×albumin+0.05×ALC), respectively. The cutoff for low muscle mass was 43.0cm2/m2 for BMI below 25kg/m2 and 53.0cm2/m2 for BMI 25kg/m2 or higher. The skeletal muscle index (SMI) was defined as skeletal muscle area/(height)2 (cm2/m2). The ΔSMI (%/50days) was defined as (SMI after NACRT-SMI before NACRT)/interval (days)×50 (days) to compare changes over the same period. The excessive muscle loss (EML) group was defined as patients with ΔSMI ≤-10% following NACRT. An elderly patient was defined as aged ≥65years. The primary outcome measure was overall survival (OS). During a median follow-up of 32.8months (range, 2.0-176.2), 192 patients died, with a median OS of 50.2months. Elderly patients did not show inferior OS (young vs. elderly, 57.7% vs. 54.0% at 3years, P=0.247). 71.0% and 87.2% of all patients had low muscle mass before and after NACRT, respectively, which was not associated with OS (P=0.270 and P=0.509, respectively). Inflammatory (NLR and PLR) and nutritional index (PNI) values or their changes did not correlate with OS. However, the EML group had worse OS (41.6% vs. 63.2% at 3years, P<0.0001). In the multivariate analysis, EML was also a significant prognostic factor for OS. In the subgroup analysis by age, EML was a strong prognostic factor for OS in the elderly group. The 3-year OS was 36.8% in the EML group and 64.9% in the non-EML group (P<0.0001) in elderly patients, and 47.4% and 62.1% (P=0.063) in the young patients. In multivariate analysis of each subgroup, EML remained prognostic only in the elderly group (P=0.008). EML may be strongly associated with a deteriorated OS in elderly patients undergoing NACRT, followed by surgery for LAEC. The strategies for decreasing muscle loss in these patients should be investigated.

Patients with complete clinical response after neoadjuvant chemoradiotherapy for locally advanced esophageal cancer: A Markov decision analysis of esophagectomy versus active surveillance

ObjectiveChemoradiation followed by esophagectomy is a standard treatment option for patients with locally advanced esophageal cancer (LAEC). Esophagectomy is a high-risk procedure, and recent evidence suggests select patients may benefit from omitting or delaying surgery. This study aims to compare surgery versus active surveillance for LAEC patients with complete clinical response (cCR) after neoadjuvant chemoradiotherapy (nCRT). MethodsDecision analysis with Markov modeling was used. The base case was a 60-year-old man with T3N0M0 esophageal cancer with cCR after nCRT. The decision was modeled for a 5-year time horizon. Primary outcomes were life-years and quality-adjusted life-years (QALY). Probabilities and utilities were derived through the literature. Deterministic sensitivity analyses were performed using ranges from the literature with consideration for clinical plausibility. ResultsSurgery was favored for survival with an expected life-years of 2.89 versus 2.64. After incorporating quality of life, active surveillance was favored, with an expected QALY of 1.70 versus 1.56. The model was sensitive to probability of recurrence on active surveillance (threshold value 0.598), probability of recurrence being resectable (0.318), and disutility of previous esophagectomy (−0.091). The model was not sensitive to perioperative morbidity and mortality. ConclusionsOur study finds that surgery increases life expectancy but decreases QALY. Although the incremental change in QALY for either modality is insufficient to make broad clinical recommendations, our study demonstrates that either approach is acceptable. As probabilities of key factors are further defined in the literature, treatment decisions for patients with LAEC and a cCR after nCRT should consider histology, patient values, and quality of life.

Application of neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy in curative surgery for esophageal cancer: A meta-analysis.

The effectiveness of neoadjuvant therapy in esophageal cancer (EC) treatment is still a subject of debate. To compare the clinical efficacy and toxic side effects between neoadjuvant chemoradiotherapy (nCRT) and neoadjuvant chemotherapy (nCT) for locally advanced EC (LAEC). A comprehensive search was conducted using multiple databases, including PubMed, EMBASE, MEDLINE, Science Direct, The Cochrane Library, China National Knowledge Infrastructure, Wanfang Database, Chinese Science and Technology Journal Database, and Chinese Biomedical Literature Database Article. Studies up to December 2022 comparing nCRT and nCT in patients with EC were selected. The analysis revealed significant differences between nCRT and nCT in terms of disease-free survival. The results indicated that nCRT provided better outcomes in terms of the 3-year overall survival rate (OSR) [odds ratio (OR) = 0.95], complete response rate (OR = 3.15), and R0 clearance rate (CR) (OR = 2.25). However, nCT demonstrated a better 5-year OSR (OR = 1.02) than nCRT. Moreover, when compared to nCRT, nCT showed reduced risks of cardiac complications (OR = 1.15) and pulmonary complications (OR = 1.30). Overall, both nCRT and nCT were effective in terms of survival outcomes for LAEC. However, nCT exhibited better performance in terms of postoperative complications.

Advancing Esophageal Cancer Treatment: Immunotherapy in Neoadjuvant and Adjuvant Settings.

Locally advanced esophageal cancer (LAEC) poses a significant and persistent challenge in terms of effective treatment. Traditionally, the primary strategy for managing LAEC has involved concurrent neoadjuvant chemoradiation followed by surgery. However, achieving a pathologic complete response (pCR) has proven to be inconsistent, and despite treatment, roughly half of patients experience locoregional recurrence or metastasis. Consequently, there has been a paradigm shift towards exploring the potential of immunotherapy in reshaping the landscape of LAEC management. Recent research has particularly focused on immune checkpoint inhibitors, investigating their application in both neoadjuvant and adjuvant settings. These inhibitors, designed to block specific proteins in immune cells, are meant to enhance the immune system's ability to target and combat cancer cells. Emerging evidence from these studies suggests the possibility of a mortality benefit, indicating that immunotherapy may contribute to improved overall survival rates for individuals grappling with esophageal cancer. This manuscript aims to meticulously review the existing literature surrounding neoadjuvant and adjuvant immunotherapy in the context of LAEC management. The intention is to thoroughly examine the methodologies and findings of relevant studies, providing a comprehensive synthesis of the current understanding of the impact of immunotherapy on esophageal cancer.

Cost-utility analysis of proton beam therapy for locally advanced esophageal cancer in Japan.

Proton beam therapy (PBT) has recently been included in Japan's health insurance benefit package for certain cancer types. This study aimed to determine the cost-effectiveness of PBT as a replacement for conventional three-dimensional conformal radiotherapy (3D-CRT) for locally advanced esophageal cancer (LAEC) that is not covered by social insurance. We estimated the incremental cost-effectiveness ratio (ICER) of PBT as a replacement for 3D-CRT, using clinical evidence from the literature and expert opinions. We used an economic model, decision tree, and Markov model to illustrate the courses followed by patients with LAEC. Effectiveness was estimated as quality-adjusted life years (QALY) using utility weights for the health state. Social insurance fees were calculated as costs. We assumed two base cases depending on the two existing levels of fees for PBT in social insurance: 2,735,000 Japanese yen (US$20,652) or 1,600,000 yen (US$13,913). The stability of the ICER against these assumptions was appraised using sensitivity analysis. The effectiveness of PBT and 3D-CRT was 2.62 and 2.51 QALY, respectively. The estimated ICER was 14,025,268 yen (US$121,958) per QALY for the higher fee level and 7,026,402 yen (US$61,099) for the lower fee level. According to the Japanese threshold for cost-effectiveness of anticancer therapy of 7,500,000 yen (US$65,217) per QALY gain, the inclusion of PBT for LAEC in the benefit package of social insurance is cost-effective if a lower fee is applied. PBT is a cost-effective alternative to 3D-CRT for LAEC and making it available to patients under social insurance could be justifiable.

Involved-field irradiation or elective-nodal irradiation in neoadjuvant chemo-radiotherapy for locally-advanced esophageal cancer: comprehensive analysis for dosimetry, treatment-related complications, impact on lymphocyte, patterns of failure and survival.

To compare the differences between involved-field irradiation (IFI) and elective nodal irradiation (ENI) in selecting the optimal target area for neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC). We retrospectively analyzed 267 patients with LA-ESCC, of whom 165 underwent ENI and 102 underwent IFI. Dosimetry, treatment-related complications, pathological responses, recurrence/metastasis patterns, and survival were compared between the two groups. The median follow-up duration was 27.9 months. The R0 resection rates in the IFI and ENI groups were 95.1% and 92.7%, respectively (p=0.441), while the pathological complete response (pCR) rates were 42.2% and 34.5%, respectively (p=0.12). The ENI group received higher radiation doses to the heart (HV30:23.9% vs. 18%, p=0.033) and lungs (LV30:7.7% vs. 4.9%, p<0.001) than the IFI group. Consequently, the ENI group showed a higher incidence of grade 2 or higher radiation pneumonitis (30.3% vs. 17.6%, p=0.004) and pericardial effusion (26.7% vs. 11.8%, p=0.021) than the IFI group. Post-operation fistulas were observed in 3 (2.9%) and 17 cases (10.3%) in the IFI and ENI groups, respectively (p=0.026). In the multivariate analysis, smoking, positive lymph node involvement (pN+), and anastomotic fistula were independent predictors of overall survival (OS). The pN+ patients exhibited a greater propensity for recurrence compared to pN- patients, especially in the first year of follow-up (6.67% vs. 0.56%, p=0.003). The ENI group had a higher incidence of radiation-induced adverse events compared to the IFI group, likely due to the higher radiation doses to normal tissues. Considering the similar disease-free survival (DFS) and OS rates in the two groups, IFI may be suitable for nCRT in patients with LA-ESCC, although further prospective studies are warranted.

Grade 4 Lymphopenia Might Associate with Pericardial Irradiation Dose and Worse Prognosis in Patients with Locally Advanced Esophageal Cancer Receiving Concurrent Chemo-Radiotherapy

The immune system may influence prognosis, and lymphopenia is a frequent side effect of concurrent chemo-radiotherapy (CCRT). Radical irradiation for locally advanced esophageal cancer (LA-EC) exposes significant vascular and heart volumes, and we hypothesized that lymphopenia is linked to cardiac and pericardial doses and affects patient prognosis. We identified 190 LA-EC patients who received radical CCRT between 2011 and 2019. Cardiac, pericardial, and lung dosimetric parameters were obtained and multivariate analysis (MVA) was performed to correlate clinical factors and dosimetric parameters with overall survival (OS). Absolute lymphocyte count (ALC), absolute platelet count (PLT), absolute white blood cell count (WBC), absolute neutrophil count (ANC), neutrophil-lymphocyte ratio (NLR = ANC/ALC), and platelet-lymphocyte ratio (PLR = PLT/ALC) were collected before and during CRT. Grade 4 (G4) lymphopenia was defined as Lymphocyte count nadir <0.2 103/mL during CRT and it was used to dichotomize the lymphocyte count nadir. MVA was performed to correlate hematologic toxicity with OS. Logistic stepwise regression was performed to determine the relationship between dosimetric parameters and G4 lymphopenia. Finally, a nomogram of G4 lymphopenia was developed and validated externally. Median follow-up time for all patients was 27.5 months (range 12-118 months). On MVA for OS (n = 190), higher pericardial V30 (PV30) was linked to worse survival (HR = 1.013, 95% CI 1.001-1.026, p = 0.039). The median OS stratified by PV30>55.3% and PV30≤55.3% was 24 months and 54 months, respectively (p = 0.004). G4 lymphopenia was shown to be linked with worse OS in the MVA of hematological toxicity (n = 161) with OS (HR = 2.042, 95% CI 1.335-3.126, p = 0.001). 24 (24%) of the 100 patients in the training set had G4 lymphopenia. Our final model comprised Stage-IVA (p = 0.017), PLR during CRT (p = 0.008), Heart V50 (p = 0.046), and PV30 (p = 0.048). External validation 26 of 90 patients (29%) had grade 4 lymphocytopenia. The ROC curve displays an AUC for internal validation of 0.775 and external validation of 0.843. Higher doses of pericardial radiation might affect LA-EC patients' prognosis by inducing G4 lymphopenia in CCRT process. Further prospective studies are warranted to confirm these findings, especially in the era of immune-checkpoint inhibitor treatment.

A Machine Learning Method to Predict Pathological Complete Response of Esophageal Cancer after Neoadjuvant Chemoradiotherapy with Clinicohematological Markers and MR Radiomics: A Multi-Center Study

Nearly 30% of patients with local advanced esophageal cancer achieved pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT), who may benefit from organ-preservation strategy under accurate prediction of pCR. We aimed to develop and validate machine learning models based on clinicohematological markers and MR radiomics to accurately predict pCR of esophageal cancer after nCRT. In this multi-center study, eligible patients with esophageal cancer who received baseline MR scan (T2-weighted image) and nCRT plus surgery were enrolled between September 2014 and September 2022 at institution 1 (training set) and between December 2017 and August 2021 at institution 2 (testing set). Pre-nCRT and post-nCRT blood test results were collected to calculate hematological markers. Models were constructed by machine learning based on clinicohematological markers and MR radiomics to predict pCR. Area under the curve (AUC) and cut-off analysis were used to evaluate model performances. Totally 154 patients (81 in the training set and 73 in the testing set) were enrolled. The combined model integrating pre-nCRT monocyte-to-lymphocyte ratio and 6 radiomics features achieved AUC of 0.800 (95% CI 0.671-0.918) in the testing set, with sensitivity of 79.2% (95% CI 62.5%-95.8%), specificity of 83.7% (95% CI 73.5%-93.9%), positive predictive value of 76.0% (95% CI 62.5%-90.0%), and negative predictive value of 89.6% (95% CI 82.0%-95.8%). A machine learning model based on clinicohematological markers and MR radiomics to predict pCR after nCRT for patients with esophageal cancer was developed and validated, providing a novel tool for personalized treatment. It is necessary to further validate in more large datasets.

Interim position emission tomography-computed tomography during multimodality treatment of locally advanced esophageal cancer: a scoping review.

Among cancers, esophageal cancer (EC) has one of the highest incidences and mortality in Asia. As recognized in many national guidelines, functional imaging performed with position emission tomography is recommended for patients with locally advanced disease. This review evaluated evidence for the use of fluorodeoxyglucose (FDG) interim positron emission tomography (PETint) in bimodality (chemoradiation) and trimodality (chemoradiation followed by surgery) management of locally advanced esophageal cancer (LAEC), with a focus on its prognostic and predictive value. The MEDLINE database was searched from January 1, 2001, to January 1, 2022, as part of a scoping review. References of selected articles were manually checked to identify other articles meeting the inclusion criteria; only original articles were included, and reviews, guidelines, letters, editorials, and case reports were excluded. A total of 63 articles were included in this review. PET-computed tomography (PET-CT) is recognized as having a significant role in the assessment of treatment response. Studies on the predictive PETint suggest that it has a certain value, particularly for early response. Identification of poor responders or nonresponders soon after commencement of multimodality treatment allows for treatment modification. The scoping review indicated variable utility for the prognostic value of PETint. There is a need to improve its accuracy, which can likely be achieved through greater standardization of measurements and reporting and testing as well as combination with other promising measures of response to residual disease.

143. NEOADJUVANT CHEMORADIOTHERAPY VERSUS CHEMOTHERAPY FOR THE TREATMENT OF LOCALLY ADVANCED ESOPHAGEAL ADENOCARCINOMA IN THE EUROPEAN MULTICENTER ENSURE STUDY

Abstract Background nCT and nCRT are the standard of care for locally advanced esophageal cancer (LAEC) treated with curative intent. However, no published randomized controlled trial to date has demonstrated superiority of either approach. This study aimed to compare clinicopathologic, oncologic and health-related quality of life (HRQL) outcomes following neoadjuvant chemoradiation (nCRT) and chemotherapy (nCT) in the ENSURE international multicenter study. Methods ENSURE is an international multicenter study of consecutive patients undergoing surgery for LAEC (2009–2015) across 20 high-volume centers (NCT03461341). The primary outcome measure was overall survival (OS), secondary outcomes included histopathologic response, recurrence pattern, oncologic outcome, and HRQL in survivorship. Results 2211 patients were studied (48% nCT, 52% nCRT). pCR was observed in 4.9% and 14.7% (P &amp;lt; 0.001), with R0 in 78.2% and 94.2% (P &amp;lt; 0.001) post nCT and nCRT, respectively. Postoperative morbidity was equivalent, but in-hospital mortality was independently increased (HR 2.73, 95%CI 1.43–5.21, P = 0.002) following nCRT vs nCT. Probability of local recurrence was reduced (OR 0.71, 956% CI 0.54–0.93, P = 0.012), and distant recurrence free survival time reduced (HR 1.18, 95% CI 1.02–1.37, P = 0.023) after nCRT vs nCT, with no difference in OS among all patients (HR 1.10, 95% CI 0.98–1.25, P = 0.113). On subgroup analysis, patients who underwent R0 resection following nCT as compared with nCRT had improved OS (median 60.7, 95% CI 49.5–71.8 months, vs 40.8, 95% CI 42.8–53.4, P &amp;lt; 0.001). Conclusion In this European multicenter study, nCRT compared with nCT was associated with reduced probability of local recurrence but reduced distant recurrence free survival for patients with LAEC, without differences in overall survival. These data support tailored patient-specific decision-making in the overall approach to achieving optimum outcomes in LAEC.

Pericardial irradiation dose may be strongly associated with grade 4 lymphopenia and affect prognosis in patients with locally advanced esophageal cancer receiving definitive concurrent chemoradiotherapy.

The immune system may influence prognosis, and lymphopenia is a frequent side effect of concurrent chemoradiotherapy (CCRT). Radical irradiation for locally advanced esophageal cancer (LA-EC) exposes significant vascular and heart volumes. In this study, we hypothesized that lymphopenia is linked to cardiac and pericardial doses and affects patient prognosis. We identified 190 LA-EC patients who received radical CCRT. Multivariate analysis (MVA) was performed to correlate clinical factors and dosimetric parameters with overall survival (OS). We collected lymphocyte-related variables and ratios before and during CCRT. MVA was performed to correlate hematologic toxicity with OS. The relationship between dosimetric parameters and G4 lymphopenia was determined using logistic stepwise regression. Finally, a nomogram of G4 lymphopenia was developed and validated externally. Median follow-up time for all patients was 27.5 months. On MVA for OS, higher pericardial V30 (PV30 ) was linked to worse survival (HR: 1.013, 95% CI: 1.001-1.026, p = 0.039). The median OS stratified by PV30 > 55.3% and PV30 ≤ 55.3% was 24.0 months and 54.0 months, respectively (p = 0.004). G4 lymphopenia was shown to be linked with worse OS in the MVA of hematological toxicity with OS (HR: 2.042, 95% CI: 1.335-3.126, p = 0.001). Thirty of the 100 patients in the training set had G4 lymphopenia. Logistic stepwise regression was used to identify variables associated with G4 lymphopenia, and the final model consisted of stage-IVA (p = 0.017), platelet-to-lymphocyte ratio during CCRT (p = 0.008), Heart V50 (p = 0.046), and PV30 (p = 0.048). Finally, a nomogram predicting G4 lymphocytopenia were constructed and externally validated. The ROC curve showed an AUC for internal validation of 0.775 and external validation of 0.843. Higher doses of pericardial radiation might affect LA-EC patients' prognosis by inducing G4 lymphopenia during CCRT. Further prospective studies are warranted to confirm these findings, especially in the era of immune-checkpoint inhibitor treatment.

Association of sarcopenia with relative dose intensity of neoadjuvant chemotherapy in older patients with locally advanced esophageal cancer: A retrospective cohort study

IntroductionSarcopenia impacts the toxicity of chemotherapy in patients with cancer, but there is little information on the association of sarcopenia with the relative dose intensity (RDI) of chemotherapy. We investigated the association of sarcopenia with RDI of neoadjuvant chemotherapy (NAC) in older patients with locally advanced esophageal cancer (LAEC). Materials and MethodsThis was a single-center retrospective cohort study of patients aged ≥65 years who underwent curative esophagectomy after NAC for LAEC between 2016 and 2020. Skeletal muscle mass index (SMI) was calculated from computed tomography images at the L3 level. Sarcopenia was defined using the Youden index of SMI. Average RDI was calculated from delivered-dose intensity and standard-dose intensity of all drugs. The cutoff point of low average RDI was defined as <85%. The multivariate logistic regression model was used for the endpoint. ResultsWe analyzed 188 patients with a mean age of 71.3 years. The cutoff points of sarcopenia for low average RDI were defined as 42.81 cm2/m2 in males and 37.48 cm2/m2 in females. Sarcopenia significantly affected low average RDI, adjusted for age, sex, body mass index, drug regimen, clinical stage, and creatinine clearance (adjusted odds ratio: 2.195, 95% confidence interval: 1.107–4.411, p = 0.024). Compared with the non-sarcopenia patients, the sarcopenia patients with low average RDI had a higher rate of dose reduction, delayed, or discontinuation after the first cycle because of neutropenia (45% vs. 38%), and decreased performance status (11% vs. 0%). DiscussionSarcopenia predicted low average RDI (<85%) of NAC in older patients with LAEC. In the future, the information about the mechanism of association of sarcopenia with RDI will progress the development of intervention strategy and novel supportive care.

Pre-operative chemoradiotherapy with or without induction chemotherapy for operable locally-advanced esophageal cancer.

For patients with operable locally advanced esophageal carcinoma (LA-EC), we hypothesized that pre-operative induction chemotherapy followed by chemoradiotherapy (IC-CRT) would improve progression-free survival (PFS) and overall survival (OS) when compared to chemoradiotherapy (CRT). This was a single institution retrospective cohort study including patients with LA-EC who received preoperative-intent IC-CRT vs. CRT between 2013-2019. The Kaplan-Meier method was used to estimate OS and PFS. Cox proportional hazards regression was used to assess for variables associated with survival. The impact of treatment group on pathologic response was assessed by chi-square. Ninty-five patients were included for analysis (IC-CRT n=59; CRT n=36) and the median follow-up was 37.7 months (IQR: 16.8-56.1). There was no difference in median PFS or OS for IC-CRT or CRT, 22 months (95% CI: 12-59) vs. 32 months (95% CI: 10-57) (P=0.64) and 39 months (95% CI: 23-not reached) vs. 56.5 months (95% CI: 38-not reached) (P=0.36), respectively. Amongst the subset of patients with adenocarcinoma histology, there was no difference in median PFS or OS, nor was there when analyses were further restricted to those who received ≥3 cycles of induction 5-fluorouracil and platinum, or for those who underwent esophagectomy. Pathologic complete response occurred in 45% vs. 29% (P=0.24) and N-stage regression occurred in 72% vs. 58% (P=0.28) of patients in the IC-CRT and CRT cohorts, respectively. Distant metastasis occurred in 44% of patients in each treatment cohort. For patients with LA-EC, preoperative-intent IC-CRT was not associated with improved PFS or OS when compared with CRT.

Computed tomography-based radiomic analysis for predicting pathological response and prognosis after neoadjuvant chemotherapy in patients with locally advanced esophageal cancer.

Accurate prediction of prognosis and pathological response to neoadjuvant chemotherapy (NAC) is crucial for optimizing treatment strategies for patients with locally advanced esophageal cancer (LA-EC). This study aimed to investigate the use of radiomics for pretreatment CT in predicting the pathological response of patients with LA-EC to NAC. Overall, 144 patients (145 lesions) with LA-EC who underwent pretreatment contrast-enhanced CT and then received NAC followed by surgery with pathological tumor regression grade (TRG) analysis were enrolled. The obtained dataset was randomly divided into training and validation cohorts using fivefold cross-validation. CT-based radiomic features were extracted followed by the feature selection process using the variance threshold, SelectKBest, and least absolute shrinkage and selection operator methods. The radiomic model was constructed using six machine learning classifiers, and predictive performance was evaluated using ROC curve analysis in the training and validation cohorts. All patients were divided into responders (n = 40, 28%) and non-responders (n = 104, 72%) based on the TRG results and a statistically significant split by overall survival analysis (0.899 [0.754-0.961] vs. 0.630 [0.510-0.729], respectively). There were no significant differences between responders and non-responders in terms of age, sex, tumor size, tumor location, or histopathology. The mean AUC of fivefold in the validation cohort was 0.720 (confidence interval [CI]: 0.594-0.982), and the best AUC of the radiomic model using logistic regression to predict the non-responders was 0.815 (CI: 0.626-1.000, sensitivity 0.620, specificity 0.860). A radiomic model derived from contrast-enhanced CT may help stratify chemotherapy effect prediction and improve clinical decision-making.

Neoadjuvant PD-1 blockade combined with chemotherapy is not superior to neoadjuvant chemotherapy alone in resectable locally advanced esophageal carcinoma

BackgroundNeoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy followed by surgery has been recommended as standard treatment in patients with locally advanced esophageal cancer (LAEC). But the risk of tumor recurrence still remained, and many patients refused or abandoned radiotherapy because of the intolerable adverse effects in China. Neoadjuvant immunochemotherapy (nICT) followed by surgery has become an emerging treatment in patients with esophageal cancer. There was still no consensus on whether nICT was superior to nCT alone in patients with esophageal cancer.MethodsIn this retrospective study, patients with resectable esophageal cancer who received surgery after nICT (n=26, 40%) or nCT alone (n=39, 60%) were included. The patients were classified as nICT or nCT arm. The primary endpoints were pathological tumor response (PTR) and event-free survival (EFS). The different clinic-pathological features were compared by the Kruskal-Wallis test for continuous variables and the Chi-square (χ2) test for categorical variables. Kaplan-Meier curves were used to estimate EFS from the date of treatment to recurrence or death. All tests were 2-sided with a significative P-value defined <.05.ResultsThree (11.5%) of the 26 patients achieved pathological complete remission (pCR) in the nICT group, and four (10.3%) of the 39 patients achieved pCR in the nCT group, respectively (P=1.000). Six (23.1%) of the 26 patients achieved major pathological response (MPR) in the nICT group, and 11 (28.2%) of the 39 patients achieved MPR in the nCT group, respectively (P=0.645). Downstaging was achieved in 13 (44.8%) patients in the nICT group and 16 (55.2%) patients in the nCT group, respectively (P=0.732). To verify the tumor regression grade (TRG) results, we compared them with MPR and pCR, which showed a significant dependency (P< 0.001). Patients who achieved downgrading showed better MPR and pCR rates (P<0.001 and P =0.010). There was no significant difference in EFS between the nICT and nCT groups (HR=1.011, 95% CI: 0.421–2.425, P = 0.981).ConclusionsNeoadjuvant PD-1 blockade combined with chemotherapy was not superior to chemotherapy alone for patients with resectable locally advanced esophageal carcinoma. However, more studies with long-term follow-up were needed to confirm this result.

Treatment selection and outcomes of locally advanced esophageal cancer in octo- and nonagenarians: Is a curative intent multimodal approach feasible?

333 Background: Neoadjuvant therapy followed by en bloc surgical resection affords the highest rates of survival from locally advanced esophageal cancer (LAEC) and represents the standard of care. However, patients of advanced age may not be offered this approach due to concerns over toxicity/tolerability. The outcomes of different treatment modalities for patients aged 80 and above with LAEC are not well described. Methods: A retrospective, single center, cohort analysis was performed on a prospectively maintained comprehensive esophageal cancer database. Between 2010-20, all patients ≥80yrs with locally advanced esophageal/GEJ cancer (cT2-4a, Nany, M0) were identified and outcomes stratified according to the following treatment categories: Neoadjuvant chemotherapy (nCT) or chemoradiotherapy (nCRT) followed by surgery; definitive CRT (dCRT); upfront surgery; palliative CT or RT; or best supportive care (BSC). Data presented as median(range). Univariate analysis used for clinicopathological data (*p&lt;0.05). Survival was compared with log rank analysis (Mantel Cox). Results: 79 patients ≥80 yrs with LAEC were identified. Median age was 83yr (80-97) and Charlson comorbidity index=7 (6-10). Most were cT3 (73%), cN- (56%) and adenocarcinoma (62%). Treatment approaches included: neoadjuvant (nCT(n=11)/nCRT(N=5)) + surgery (16/79(20%)); surgery alone (19/79 (24%)); dCRT (12/29(15%)); palliative RT or CT (24 + 3/79(34%)); BSC (5/79(6%)). Neoadjuvant consisted of nCT (FLOT=4; carbo-taxol =4; FOLFOX=2; CP+pembro=1) and nCRT (CROSS=5) and most received the intended full treatment/cycles (10/16:63%). Surgery was performed in 35 (age=82(80-96)), with major complications (grade 3-5) in 13/35 (37%) and 90-day mortality in 3/35(8.5%). Overall Survival for the entire cohort was 58% (1yr) and 19% (3yr), but highest with nCT/nCRT+surgery (94%/46%)*, followed by surgery alone (68%/39%), dCRT (58%/8%), palliative treatment (40%/4%), and BSC (0%/0%). Curative intent treatment (nCT/nCRT/surgery/dCRT) had significantly increased 1 and 3-yr survival compare to palliative treatment (76%/31% vs 34%/3.3%)*. Conclusions: Multimodal standard of care treatment, including surgical resection, of locally advanced esophageal cancer in octo/nonagenarians is feasible and safe in a subset of this high-risk population and associated with improved outcomes compared to other approaches. Age alone should not bias against curative-intent treatment in elderly patients with esophageal cancer.