International Expert Consensus on Semantics of Multimodal Esophageal Cancer Treatment: Delphi Study.

BACKGROUND: Recent developments in esophageal cancer treatment, including studies exploring active surveillance following chemoradiotherapy, have led to a need for clear terminology and definitions regarding different multimodal treatment options. OBJECTIVE: The aim of this study was to reach worldwide consensus on the definitions and semantics of multimodal esophageal cancer treatment. METHODS: In total, 72 experts working in the field of multimodal esophageal cancer treatment were invited to participate in this Delphi study. The study comprised three Delphi surveys sent out by email and one online meeting. Input for the Delphi survey consisted of terminology obtained from a systematic literature search. Participants were asked to respond to open questions and to indicate whether they agreed or disagreed with different statements. Consensus was reached when there was ≥75% agreement among respondents. RESULTS: Forty-nine of 72 invited experts (68.1%) participated in the first online Delphi survey, 45 (62.5%) in the second survey, 21 (46.7%) of 45 in the online meeting, and 39 (86.7%) of 45 in the final survey. Consensus on neoadjuvant and definitive chemoradiotherapy with or without surgery was reached for 27 of 31 items (87%). No consensus was reached on follow-up after treatment with definitive chemoradiotherapy. CONCLUSION(S): Consensus was reached on most statements regarding terminology and definitions of multimodal esophageal cancer treatment. Implementing uniform criteria facilitates comparison of studies and promotes international research collaborations.

Overall survival after definitive chemoradiotherapy for patients with esophageal cancer: a retrospective cohort study.

Definitive chemoradiotherapy (dCRT) is a potentially curative therapy for esophageal cancer. As indications for dCRT differ widely, it is challenging to draw conclusions on outcomes and survival. The aim of this study was to evaluate overall survival (OS) and recurrence patterns according to indications for treatment. Patients who underwent dCRT (50.4 Gy concomitant with carboplatin/paclitaxel) for esophageal cancer between 2012 and 2022 were identified. Indications for dCRT were: cervical tumor, irresectable disease, unfit for surgery, and patient and/or physician preference. The primary endpoint was OS calculated with the Kaplan-Meier method. Secondary endpoints included the proportion of patients that completed the dCRT regimen, 30- and 90-day mortality, and disease recurrence. One hundred and fifty-seven patients were included (72.6% esophageal squamous cell carcinoma) with a median follow-up of 20 months (IQR 10.0-43.9). The full dCRT regimen was completed by 116 patients (73.9%). Thirty- and 90-day mortality were 2.5% and 8.3%, respectively. Median and 5-year OS for all patients were 22.9 months (95% CI 18.0-27.9) and 31.4%, respectively. The median OS per indication was 23.7 months (95% CI 6.5-40.8) for patients with cervical tumors, 10.9 months (95% 0.0-23.2) for irresectable disease, 28.2 months (95% CI 12.3-44.0) for unfit patients, and 22.9 months (95% CI 15.4-30.5) for patients' preference for dCRT (P = 0.11). Disease recurrence was observed in 74 patients (46%), located locoregionally (46%), distant (19%), or combined (35%). Patients who underwent dCRT had a 5-year OS of 31.4%, but OS differed according to indications for treatment with patients who had irresectable disease having the worst prognosis.

Effectiveness and safety of combined nimotuzumab and S-1 chemotherapy with concurrent radiotherapy for locally advanced esophageal cancer in malnourished and elderly patients: A prospective phase II study.

Objective: Definitive chemoradiotherapy (dCRT) is the standard treatment for unresectable locally advanced esophageal cancer. However, this treatment is associated with substantial toxicity, and most malnourished or elderly patients are unable to complete this therapy. Therefore, there is a need for a more suitable radiotherapy combination regimen for this population. This study was aimed to evaluate the efficacy and safety of a combination regimen comprising chemotherapy with nimotuzumab and S-1 and concurrent radiotherapy for patients with fragile locally advanced esophageal cancer with a high Nutritional Risk Screening 2002 (NRS-2002) score. Methods: Eligible patients with unresectable esophageal carcinoma who had an NRS-2002 score of 2 or higher were enrolled. They were treated with S-1 and nimotuzumab with concurrent radiotherapy, followed by surgery or definitive radiotherapy. The primary endpoint was the locoregional control (LRC) rate. Results: A total of 55 patients who met the study criteria were enrolled. After completion of treatment, surgery was performed in 15 patients and radiotherapy was continued in 40 patients. The median follow-up period was 33.3 [95% confidence interval (95% CI), 31.4-35.1)] months. The LRC rate was 77.2% (95% CI, 66.6%-89.4%) at 1 year in the entire population. The overall survival (OS) rate and event-free survival (EFS) rate were 57.5% and 51.5% at 3 years, respectively. Surgery was associated with better LRC [hazard ratio (HR)=0.16; 95% CI, 0.04-0.70; P=0.015], OS (HR=0.19; 95% CI, 0.04-0.80; P=0.024), and EFS (HR=0.25; 95% CI, 0.08-0.75; P=0.013). Most adverse events were of grade 1 or 2, and no severe adverse events occurred. Conclusions: For malnourished or elderly patients with locally advanced esophageal cancer, radiotherapy combined with nimotuzumab and S-1 is effective and has a good safety profile.

Association Between Lymphopenia and Survival Outcomes in Esophageal Carcinoma Patients Receiving Combined Immunotherapy and Chemoradiotherapy.

BACKGROUND: To investigate the association between absolute lymphocyte count (ALC) nadir and survival outcomes in esophageal squamous cell carcinoma (ESCC) patients who received definitive chemoradiotherapy (CRT) combined with anti-PD-1 immunotherapy, as well as to explore clinical characteristics and dosimetric parameters that affect ALC nadir during CRT. PATIENTS AND METHODS: Patients with ESCC (n = 602) who underwent definitive CRT were analyzed, of whom 166 received combined anti-PD-1 immunotherapy and CRT. Changes in ALC and survival were compared between patients with and without immunotherapy. Propensity score matching (PSM) was performed to minimize the effects of confounding factors. Low ALC was defined as nadir of <0.33 × 103 cells/µL during CRT (top tertile). Univariate and multivariate logistic regression were used to identify predictors of low ALC nadir. RESULTS: Patients with immunotherapy had significantly higher ALC in the first 3 weeks during CRT and higher ALC nadir than those without. Overall survival was more favorable in patients with immunotherapy both before and after PSM. After a median follow-up of 12.1 months, patients with low ALC during CRT had a worse progression-free survival (PFS) (P = .026). In multivariate analysis, low ALC remained a significant prognostic factor for PFS. Planning target volume (PTV) and heart V5 were revealed to be independent predictors of low ALC. CONCLUSIONS: The addition of anti-PD-1 immunotherapy to definitive CRT could mitigate the decline of ALC during radiotherapy and might prolong survival. Low ALC nadir was correlated to worse PFS, larger PTV, and higher heart V5 in patients receiving combined immunotherapy and CRT.

Nationwide survey of the follow-up practices for patients with esophageal carcinoma after radical treatment: historical changes and future perspectives in Japan.

BACKGROUND: No post-treatment follow-up methods have been established yet for patients with esophageal carcinoma who undergo radical esophagectomy (Surg) or who show complete response to definitive chemoradiotherapy (dCRT-CR). The purpose of this study was to investigate the current status of follow-up of the Surg and dCRT-CR patients in Japan, and understand the current reality and problems to establish an optimal follow-up method. METHODS: A questionnaire on the follow-up method adopted was sent by e-mail to 124 institutions approved by the Japan Esophageal Society as training institutions for board-certified esophageal surgeons; responses were received from 89 institutions. The data were compared with those obtained by a similar survey conducted in 2014. RESULTS: Follow-up methods markedly varied among institutions. Almost all institutions scheduled computed tomography and upper gastrointestinal endoscopy at least once a year up to postoperative year 5 for both the Surg and dCRT-CR groups. At least 70% of the institutions continued follow-up up to postoperative year 10, and this proportion had increased as compared to that reported from the 2014 survey. Only 25-30% of the institutions scheduled follow-up screening for metachronous head and neck cancer for both groups, and the health-related quality of life (HR-QOL) after the treatment were seldom assessed. These trends remained unchanged as compared to those reported from the 2014 survey. CONCLUSIONS: The results suggest that the consensus of follow-up protocol could not be established. More attention is required for detection of metachronous cancers and assessment of the HR-QOL. Establishment of a consensus-based follow-up system and verification of its effectiveness are required.

Lymphopenia During Definitive Chemoradiotherapy in Esophageal Squamous Cell Carcinoma: Association with Dosimetric Parameters and Patient Outcomes.

BACKGROUND: The objective of this study was to investigate the relationship between clinical characteristics, as well as dosimetric parameters, and the risk of treatment-related lymphopenia in esophageal squamous cell carcinoma (ESCC) treated with definitive chemoradiotherapy (CRT). MATERIALS AND METHODS: Clinical characteristics and dosimetric parameters were collected from 436 patients with ESCC who received definitive CRT from 2010 through 2017. Absolute lymphocyte counts (ALCs) were obtained before, during, and 1 month after CRT. Grade 4 (G4) lymphopenia was defined as ALC <0.2 × 109 /L during CRT. Logistic regression analysis was used to evaluate the effect of each factor on predicting G4 lymphopenia. The relationship between lymphopenia and overall survival (OS) was examined, and a nomogram was developed to predict OS. RESULTS: G4 lymphopenia was observed in 103 patients (23.6%) during CRT. Multivariate analysis indicated that planning target volume (PTV), lung V10 , heart V10 , performance status, and pretreatment lymphopenia were significant risk factors for G4 lymphopenia. Patients with G4 lymphopenia had significantly worse survival than those without. Based on multivariate analysis, clinical TNM stage, radiotherapy modality, pretreatment ALC, and G4 lymphopenia were predictive of OS and were incorporated into the nomogram, yielding a concordance index of 0.71. CONCLUSIONS: G4 lymphopenia during definitive CRT was associated with larger PTVs, higher lung V10 and heart V10 , and worse survival. IMPLICATIONS FOR PRACTICE: The purpose of this study was to investigate the relationship between clinical characteristics, as well as dosimetric parameters, and the risk of treatment-related lymphopenia in 436 patients with esophageal squamous cell carcinoma who received definitive chemoradiotherapy. Grade 4 (G4) lymphopenia was observed in 23.6% of patients during radiotherapy. G4 lymphopenia was associated with larger planning target volumes, higher lung V10 and heart V10 , and worse survival. Then, a nomogram was built based on multivariate analysis, yielding excellent performance to predict overall survival. Prospective studies are needed to investigate potential approaches for mitigating severe lymphopenia, which may ultimately convert into survival benefits.

Phase II study of definitive chemoradiation for locally advanced squamous cell cancer of the vulva: An efficacy study.

OBJECTIVE: To evaluate feasibility of chemoradiation as alternative for extensive surgery in patients with locally advanced vulvar cancer and to report on locoregional control, toxicity and survival. METHODS: In a multicenter, prospective phase II trial patients with locally advanced vulvar cancer were treated with locoregional radiotherapy combined with sensitizing chemotherapy (capecitabine). Treatment feasibility, percentage locoregional control, survival and toxicity were evaluated. RESULTS: 52 patients with mainly T2/T3 disease were treated according to the study protocol in 10 centers in the Netherlands from 2007 to 2019. Full dose radiotherapy (tumor dose of 64.8Gy) was delivered in 92% and full dose capecitabine in 69% of patients. Most prevalent acute ≥ grade 3 toxicities were regarding skin/mucosa and pain (54% and 37%). Late ≥grade 3 toxicity was reported for skin/mucosa (10%), fibrosis (4%), GI incontinence (4%) and stress fracture or osteoradionecrosis (4%). Twelve weeks after treatment, local clinical complete response (cCR) and regional control (RC) rates were 62% and 75%, respectively. After 2 years, local cCR persisted in 22 patients (42%) and RC was 58%. Thirty patients (58%) had no evidence of disease at end of follow-up (median 35 months). In 9 patients (17%) extensive surgery with stoma formation was needed. Progression free survival was 58%, 51% and 45% and overall survival was 76%, 66%, 52% at 1,2, and 5 years. CONCLUSIONS: Definitive capecitabine-based chemoradiation as alternative for extensive surgery is feasible in locally advanced vulvar cancer and results in considerable locoregional control with acceptable survival rates with manageable acute and late toxicity.

Long-term outcomes of patients with recurrent squamous cell carcinoma of the esophagus undergoing salvage endoscopic resection after definitive chemoradiotherapy.

BACKGROUND: Salvage endoscopic resection (ER) has been reported to be effective for patients with local failure of esophageal squamous cell carcinoma (ESCC) after definitive chemoradiotherapy (dCRT). This study aimed to evaluate the long-term outcomes of salvage ER for patients with local failure of ESCC and to identify risk factors associated with disease recurrence after salvage ER. METHODS: This study included 45 patients undergoing salvage ER after dCRT during 2000 to 2017. After ER, all patients were required to undergo surveillance esophagogastroduodenoscopy (EGD) once or twice every year, and a computed tomography (CT) examination was repeated every 3 to 6 months. We assessed short-term outcomes and long-term outcomes. RESULTS: Of the 45 patients in this study, the baseline clinical T stage before dCRT was T1 in 80%, 66% of the patients did not have nodal metastasis. The median time from CRT to the detection of local failure was 11 months (range 2-130 months). The en-bloc resection rate was 46%, and the R0 resection rate was 38%, respectively. Stricture occurred after salvage ER for one case, while adverse events such as bleeding or perforation and ER-related death did not occur. After a median observation period of 57 months, recurrence free survival at 3 years was 58%, overall survival was 72%, and disease specific survival was 81%. In multivariate analysis, clinical N stage before CRT was the only independent risk factor of recurrence after salvage ER (p = 0.04). CONCLUSIONS: Salvage ER might be effective local treatment in patients with local failure after dCRT. For the patients with clinical N stage, frequent surveillance should be performed.

Modeling the risk of radiation pneumonitis in esophageal squamous cell carcinoma treated with definitive chemoradiotherapy.

BACKGROUND: To develop and validate a nomogram for the prediction of symptomatic radiation pneumonitis (RP) in patients with esophageal squamous cell carcinoma (ESCC) who received definitive concurrent chemoradiotherapy. METHODS: Clinical factors, dose-volume histogram parameters, and pulmonary function parameters were collected from 402 ESCC patients between 2010 and 2017, including 321 patients in the primary cohort and 81 in the validation cohort. The end-point was the occurrence of symptomatic RP (grade ≥ 2) within the first 12 months after radiotherapy. Univariate and multivariate logistic regression analyses were applied to evaluate the predictive value of each factor for RP. A prediction model was generated in the primary cohort, which was internally validated to assess its performance. RESULTS: In the primary cohort, 31 patients (9.7%) experienced symptomatic RP. Based on logistic regression model, patients with larger planning target volumes (PTVs) or higher lung V20 had a higher predictive risk of RP, whereas the overall risk was substantially higher for three-dimensional conformal radiotherapy (3DCRT) than intensity-modulated radiotherapy. On multivariate analysis, independent predictive factors for RP were smoking history (P = 0.035), radiotherapy modality (P < 0.001), PTV (P = 0.039), and lung V20 (P < 0.001), which were incorporated into the nomogram. The areas under the receiver operating characteristic curve of the nomogram in the primary and validation cohorts were 0.772 and 0.900, respectively, which were superior to each predictor alone. CONCLUSIONS: Non-smoking status, 3DCRT, lung V20 (> 27.5%), and PTV (≥ 713.0 cc) were significantly associated with a higher risk of RP. A nomogram was built with satisfactory prediction ability.

A multicenter prospective phase III clinical randomized study of simultaneous integrated boost intensity-modulated radiotherapy with or without concurrent chemotherapy in patients with esophageal cancer: 3JECROG P-02 study protocol.

BACKGROUND: Since the development of three-dimensional conformal radiotherapy and intensity-modulated radiotherapy (IMRT), no prospective study has investigated whether concurrent chemoradiotherapy (SIB-IMRT with 60 Gy) remains superior to radiotherapy (SIB-IMRT) alone for unresectable esophageal cancer (EC). Furthermore, the optimal therapeutic regimen for patients who cannot tolerate concurrent chemoradiotherapy is unclear. We recently completed a phase I/II radiation dose-escalation trial using simultaneous integrated boost (SIB), elective nodal irradiation, and concurrent chemotherapy for unresectable EC. We now intend to conduct a prospective, phase III, randomized study of SIB-IMRT with or without concurrent chemotherapy. We aim to find a safe, practical, and effective therapeutic regimen to replace the conventional segmentation (1.8-2.0 Gy) treatment mode (radiotherapy ± chemotherapy) for unresectable EC. METHODS: This two-arm, open, randomized, multicenter, phase III trial will recruit esophageal squamous cell carcinoma patients (stage IIA-IVB [UICC 2002]; IVB only with metastasis to the supraclavicular or celiac lymph nodes). In all, 164 patients will be randomized using a 1:1 allocation ratio, and stratified by study site and disease stage, especially the extent of lymph node metastasis. Patients in the SIB arm will receive definitive SIB radiotherapy (95% planning target volume/planning gross tumor volume, 50.4 Gy/59.92 Gy/28 f, equivalent dose in 2-Gy fractions = 60.62 Gy). Patients in the SIB + concurrent chemotherapy arm will receive definitive SIB radiotherapy with weekly paclitaxel and a platinum-based drug (5-6 weeks). Four cycles of consolidated chemoradiotherapy will also be recommended. The primary objective is to compare the 1-year, 2-year, and 3-year overall survival of the SIB + chemotherapy group and SIB groups. Secondary objectives include progression-free survival, local recurrence-free rate, completion rate, and adverse events. Detailed radiotherapy protocol and quality-assurance procedures have been incorporated into this trial. DISCUSSION: In unresectable, locally advanced EC, a safe and effective total radiotherapy dose and reasonable segmentation doses are required for the clinical application of SIB-IMRT + two-drug chemotherapy. Whether this protocol will replace the standard treatment regimen will be prospectively investigated. The effects of SIB-IMRT in patients with poor physical condition who cannot tolerate definitive chemoradiotherapy will also be investigated. TRIAL REGISTRATION: clinicaltrials.gov ( NCT03308552 , November 1, 2017).

Patient selection for salvage surgery after definitive chemoradiotherapy in esophageal squamous cell carcinoma.

PURPOSE: With the widespread use of definitive chemoradiotherapy (dCRT) for esophageal squamous cell carcinoma (ESCC), salvage surgery for recurrence/residual patients became prevalent. However, survival impact of salvage surgery remains obscure at present. METHODS: The updated clinical outcomes of salvage surgery were investigated to know its survival impact. Of the 155 ESCC patients who underwent dCRT between 2009 and 2016, we included 85 patients with recurrence or residual disease. The median follow-up was 65 months. RESULTS: Of the 85 patients with progression disease, there were 42 and 43 patients of recurrence and residual disease, respectively. Salvage surgery was performed in 27 patients after dCRT, including 15 patients who underwent salvage esophagectomy. The 5-year overall survival (OS) of salvage surgery and otherwise patients was 66.1% and 14.5%, and the patients with salvage surgery had a significantly better prognosis (p < 0.0001). In the 15 patients who underwent salvage esophagectomy, residual disease, lymph node metastasis-positive (ycN+) after dCRT, and pathological lymph node metastasis-positive (ypN+) were significantly associated with poor prognosis (p = 0.0492, p = 0.0006, p = 0.0276), and the 5-year OS rates for the ycN/ypN combinations were 90%, 33.3%, and 0% in ycN-/ypN-, ycN+/ypN-, and ycN+/ypN+ patients, respectively (p = 0.0026). In a multivariate analysis, ycN+ was an independent poor prognostic factor (HR 13.6, 95% CI 1.65-286.8, p = 0.0154). CONCLUSIONS: Survival impact of salvage surgery after dCRT is robust, and lymph node metastasis after dCRT may help determine the indication for salvage esophagectomy.

Long-term outcomes of multimodal therapy combining definitive chemoradiotherapy and salvage surgery for T4 esophageal squamous cell carcinoma.

BACKGROUND: Survival outcomes of patients with cT4 esophageal squamous cell carcinoma (ESCC) remain extremely poor. We aimed to investigate long-term outcomes and identify prognostic factors in patients treated by definitive chemoradiotherapy (dCRT) alone or with dCRT plus salvage surgery (SALV) for cT4 ESCC. PATIENTS AND METHODS: In total, 73 patients completing dCRT were analyzed. Patients achieving clinical complete response (CR) received follow-up evaluations thereafter. For patients diagnosed with clinical partial response (PR), potentially curative SALV was generally performed. Possible prognostic factors included demographic data, tumor staging, blood chemistry profiles, and esophageal stenosis. RESULTS: The 1- and 3-year overall survival (OS) rates of the 73 patients were 67.1% and 40.8%, respectively. Twenty-one patients (29%) achieved clinical CR with dCRT alone. Among 35 patients (48%) with clinical PR, 31 underwent SALV and 4 opted for non-surgical treatments. In the dCRT-alone group (n = 42), patients with clinical CR-PR (n = 25) showed significantly better 3-year OS than those who responded poorly to dCRT (stable or progressive) (n = 17) (67.5% vs. 0%, P < 0.001). In the SALV group (n = 31), curative SALV (n = 22, 73%) provided significantly better 3-year OS than non-curative SALV (58.7% vs. 0%, P < 0.001). Multivariable analysis revealed stenosis before dCRT (P = 0.02) and pretreatment elevated CRP (P = 0.02) to be independently associated with poor outcomes. CONCLUSIONS: The multimodal treatment strategy combining dCRT and SALV is rational for treating cT4 ESCC patients. When curative resection is feasible, SALV can provide good long-term survival outcome for patients who responded to dCRT but did not achieve clinical CR with dCRT alone.

A retrospective study of definitive chemoradiotherapy in patients with resectable small cell neuroendocrine carcinoma of the esophagus.

BACKGROUND: Standard treatment for resectable small cell neuroendocrine carcinoma of the esophagus (SCNEC-E) remains to be established. METHODS: We retrospectively studied 7 consecutive patients with resectable SCNEC-E who received definitive chemoradiotherapy (dCRT) to evaluate the safety and efficacy. Treatment consisted of two courses of chemotherapy with cisplatin (80 mg/m2 on day 1) and etoposide (100 mg/m2 on days 1-3) or carboplatin (AUC 5 on day 1) and etoposide (80 mg/m2 on days 1-3) given every 4 weeks during dCRT. The total radiation dose was 50.4 Gy (28 fractions). RESULTS: The clinical stage was IA in 1 patient, IB in 2 patients, IIA in 3 patients, and IIB in 1 patient. Definitive CRT was completed in all patients. The median overall treatment time of radiotherapy was 44 days. The chemotherapy regimen included in dCRT was cisplatin and etoposide in 3 patients and carboplatin and etoposide in 4 patients. Acute adverse events of grade 3 or 4 were neutropenia 100%, thrombocytopenia 43%, febrile neutropenia 43%, and nausea 14%. There were no late grade 3 or 4 adverse events. The median survival time was 32 months. The complete response rate was 100%. The recurrence rate was 43%. The median survival of the 4 patients without recurrence was 56 months. CONCLUSIONS: Definitive CRT with cisplatin and etoposide or carboplatin and etoposide is a feasible treatment for the resectable SCNEC-E, and long-term survival can be achieved in some patients.

A multicenter phase III study comparing Simultaneous Integrated Boost (SIB) radiotherapy concurrent and consolidated with S-1 versus SIB alone in elderly patients with esophageal and esophagogastric cancer - the 3JECROG P-01 study protocol.

BACKGROUND: The importance of definitive radiotherapy for elderly patients with esophageal and esophagogastric-junction cancer is pronounced. However, little is known in terms of the best way to combine radiotherapy with other treatment options. This study aims to compare the efficiency of SIB radiotherapy alone with SIB radiotherapy concurrent and consolidated with S-1 for elderly patients. Comprehensive geriatric assessment is also incorporated in the procedure of treatment. METHODS/DESIGN: The study is a two arm, open, randomized multicenter Phase III trial with patients over 70 years old with stage IIA-IVB (UICC 2002, IVB only with metastasis to supraclavicular or celiac lymph nodes) squamous cell carcinoma or adenocarcinoma of esophagus or gastroesophageal junction. A total of 300 patients will be randomized using a 1:1 allocation ratio stratified by disease stage and study site. Patients allocated to the SIB arm will receive definitive SIB radiotherapy (95%PTV/PGTV 50.4Gy/59.92Gy/28f) while those randomized to SIB + S-1 arm will receive definitive SIB radiotherapy concurrent and consolidated with S-1. The primary endpoint of the trial is 1-year overall survival. Secondary objectives include progression-free survival, recurrence-free survival (local-regional and distant), disease failure pattern, toxicity profile as well as quality of life. Besides, detailed radiotherapy protocol and quality assurance procedure have been incorporated into this trial. DISCUSSION: The proportion of elderly patients in esophageal cancer is now growing, but there is a lack of evidence in term of treatment standard for this group of patients, which is what we aim to obtain through this prospective phase III study. TRIAL REGISTRATION: clinicaltrials.gov NCT02979691 . Registered November 22, 2016.

Pre-treatment magnetic resonance-based texture features as potential imaging biomarkers for predicting event free survival in anal cancer treated by chemoradiotherapy.

AIM: To assess regular MRI findings and tumour texture features on pre-CRT imaging as potential predictive factors of event-free survival (disease progression or death) after chemoradiotherapy (CRT) for anal squamous cell carcinoma (ASCC) without metastasis. MATERIALS AND METHODS: We retrospectively included 28 patients treated by CRT for pathologically proven ASCC with a pre-CRT MRI. Texture analysis was carried out with axial T2W images by delineating a 3D region of interest around the entire tumour volume. First-order analysis by quantification of the histogram was carried out. Second-order statistical texture features were derived from the calculation of the grey-level co-occurrence matrix using a distance of 1 (d1), 2 (d2) and 5 (d5) pixels. Prognostic factors were assessed by Cox regression and performance of the model by the Harrell C-index. RESULTS: Eight tumour progressions led to six tumour-specific deaths. After adjusting for age, gender and tumour grade, skewness (HR = 0.131, 95% CI = 0-0.447, p = 0.005) and cluster shade_d1 (HR = 0.601, 95% CI = 0-0.861, p = 0.027) were associated with event occurrence. The corresponding Harrell C-indices were 0.846, 95% CI = 0.697-0.993, and 0.851, 95% CI = 0.708-0.994. CONCLUSION: ASCC MR texture analysis provides prognostic factors of event occurrence and requires additional studies to assess its potential in an "individual dose" strategy for ASCC chemoradiation therapy. KEY POINTS: • MR texture features help to identify tumours with high progression risk. • Texture feature maps help to identify intra-tumoral heterogeneity. • Texture features are a better prognostic factor than regular MR findings.

Minimally Invasive Salvage Operations for Esophageal Cancer after Definitive Chemoradiotherapy.

BACKGROUND/AIMS: Because salvage surgery after definitive chemoradiotherapy for esophageal cancer is associated with high postoperative mortality and morbidity, minimally invasive methods are desirable. We analyzed the validity of minimally invasive salvage operations (MISO). METHODS: Twenty-five patients underwent salvage operation between 2010 and 2016 in our institution, 10 having undergone right transthoracic salvage esophagectomy (TTSE group), 6 transhiatal salvage esophagectomy (THSE), 6 salvage lymphadenectomy (SLA), and 3 salvage endoscopic submucosal dissection (SESD). Patients who had undergone THSE, SLA, or SESD were categorized as the MISO group. Short- and long-term outcomes were assessed. RESULTS: The mean duration of surgery was significantly shorter in the SLA groups than in the TTSE group (p = 0.0248). Blood loss was significantly less in the SLA than the TTSE group (p = 0.0340). Intensive care unit stay was shorter in the THSE than the TTSE group (p = 0.0412). There was no significant difference in postoperative mortality between the MISO and THSE groups. Postoperative hospital stay was significantly shorter in the SLA than the TTSE group (p = 0.0061). Patients' survivals did not differ significantly between the MISO and TTSE groups (p = 0.752). Multivariate analysis revealed that residual disease (R0; HR 4.872, 95% CI 1.387-17.110, p = 0.013) was the only independent factor influencing overall survival. CONCLUSION: MISO is preferable because short-term outcomes are better and long-term outcomes do not differ from those of TTSE.

The role of definitive chemoradiotherapy versus surgery as initial treatments for potentially resectable esophageal carcinoma.

BACKGROUND: We performed a meta-analysis to compare the efficacy of definitive chemoradiotherapy (dCRT) and esophagectomy as initial treatments for potentially resectable esophageal cancer. METHODS: To assess both strategies, the combined odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Thirteen studies (N = 2071; dCRT = 869 and surgery = 1202) were included. In all, 90.39% of the patients were diagnosed with esophageal squamous cell carcinoma (ESCC). RESULTS: The 2-year (OR = 1.199, 95% CI 0.922-1.560; P = 0.177) and 5-year overall survival (OS) rates (OR = 0.947, 95% CI 0.628-1.429; P = 0.796) were not significantly different. No significant differences were identified in the 2-year OS among patients with stage I disease (OR = 1.397, 95% CI 0.740-2.638; P = 0.303) or stage II-III (OR = 0.418, 95% CI 0.022-7.833; P = 0.560). Patients with lymph node metastases tended to have a better 5-year OS when treated with dCRT than with surgery (OR = 0.226, 95% CI 0.044-1.169; P = 0.076); however, the difference between the two methods was not significant. Western patients who received dCRT had poorer prognoses than patients who underwent surgery (OR = 1.522, 95% CI 1.035-2.238; P = 0.033). dCRT and surgery led to similar 5-year progression-free survival rates (OR = 1.06, 95% CI 0.79-1.42; P = 0.70). CONCLUSIONS: dCRT and surgery are equally effective as initial treatments for potentially resectable esophageal cancer. These results apply primarily to Asian populations as they have an increased incidence of ESCC.

Revisiting Milan cervical cancer study: Do the original findings hold in the era of chemotherapy?

BACKGROUND: The primary treatment of early stage cervical carcinoma (IB-IIA) is either surgery or radiation therapy based on the pivotal Milan randomized study published twenty years ago. In the presence of high-risk features, the gold standard treatment is concurrent chemotherapy and radiation therapy (CRT) whether it is the in the postoperative or the definitive setting. Using the National Cancer Data Base (NCDB), the goal of our study is to compare the outcomes of surgery and radiation therapy in the chemotherapy era. METHODS: Between 2004 and 2013, 5478 patients diagnosed with early stage cervical cancer were divided into 2 groups based on their primary treatment: non-surgical (n=1980) and surgical groups (n=3498). The distribution of patient/tumor characteristics and treatment variables with their relation to overall survival and proportional regression models were assessed to investigate the superiority of one approach over the other. Propensity score analysis adjusted for imbalance of covariates to create a well-matched-patient cohort. FINDINGS: At 46months median follow-up, the 5-year overall survival was similar between both groups (73·8% vs. 75.7%; p=0.619) after applying propensity score analysis. On multivariate analysis, high Charlson comorbidity score, stage IIA disease, larger tumor size, positive lymph nodes and high-grade disease were significant predictors of poor outcome while older age and treatment approach were not. INTERPRETATION: Our analysis suggests that surgery (followed by adjuvant RT or CRT) and definitive radiotherapy (with or without chemotherapy) result in equivalent survival. Prospective studies are warranted to establish this paradigm in the chemotherapy era.

Response evaluation with endoscopic ultrasound and computed tomography in esophageal squamous cell carcinoma treated by definitive chemoradiotherapy.

BACKGROUND AND AIM: We assessed the feasibility of combined endoscopic ultrasound and computed tomography on response evaluation in patients with esophageal squamous cell carcinoma treated by definitive chemoradiotherapy, and the impact of response on prognosis. METHODS: Sixty patients treated by definitive chemoradiotherapy were followed by miniprobe endoscopic ultrasound and computed tomography. The post-treatment esophageal wall thickness was measured by miniprobe endoscopic ultrasound. Metastatic tumors were evaluated by computed tomography. The correlation between post-treatment image findings and prognosis was evaluated. RESULTS: Twenty-four patients (40%) had esophageal stricture after chemoradiotherapy, which limited complete evaluation by endoscopy. Miniprobe successfully penetrated all strictures to measure post-treatment esophageal wall thickness. Both post-treatment esophageal wall thickness < 8 mm measured by endoscopic ultrasound and no enlargement of metastatic tumor foci on computed tomography predicted good prognosis (P = 0.001). Combined evaluation with these two modalities improved survival prediction (P < 0.001). Patients who met the above two criteria after chemoradiotherapy had the longest survival compared with those who met only one or none of the criteria. The corresponding median survivals were > 30 months, 16.8 months and 7.1 months, respectively (P < 0.001). On multivariate analysis, treatment response is the strongest independent prognostic factor (hazard ratio 3.65, P = 0.006) regardless of baseline tumor-node-metastasis staging and chemoradiation regimen. CONCLUSIONS: Response evaluation by miniprobe endoscopic ultrasound and computed tomography can predict the prognosis of esophageal squamous cell carcinoma patients treated by definitive chemoradiotherapy. Those who were judged as poor responder should receive additional treatment to improve outcome.

Survival outcome of esophagectomy and chemoradiotherapy for resectable esophageal squamous cell carcinoma in patients >75 years of age.

BACKGROUND: The gold standard for resectable, locally advanced esophageal squamous cell carcinoma (ESCC) is surgery-based treatment; however, it is unclear whether esophagectomy or chemoradiotherapy is suitable for older patients. This retrospective study aimed to identify the treatment outcomes of surgery-based therapy versus definitive chemoradiotherapy (dCRT) as an initial treatment for older patients with resectable, locally advanced ESCC. METHODS: Data from 434 patients who received radical treatment for resectable, locally advanced ESCC were collected from January 2011 to December 2020. Of the patients >75 years of age, 49 underwent radical esophagectomy and 26 received dCRT. Survival was compared between the surgery and dCRT groups. RESULTS: The mean ages of the surgery and chemoradiotherapy groups were 77.3 and 78.8 years, respectively. Differences in overall survival (OS) between the two groups were not statistically significant (3-year OS: surgery 66.2%, dCRT 55.7%, p = 0.236). Multivariate analysis for OS showed a hazard ratio of 1.229 for dCRT versus surgery (90% confidence interval 0.681-2.217). OS did not differ between the groups in any of the performance statuses. For patients who were able to receive chemotherapy using fluorouracil and cisplatin, OS tended to be better in the surgery group, but the difference was not statistically significant (3-year OS: surgery 68.1%, dCRT 51.8%, p = 0.117). CONCLUSIONS: There was no clear difference in survival outcome between surgery-based therapy and dCRT as an initial treatment for esophageal cancer in older patients. Either treatment may be an option for older patients.