Effectiveness of S-1-Based Chemoradiotherapy in Patients 70 Years and Older With Esophageal Squamous Cell Carcinoma: A Randomized Clinical Trial.

Importance: Double-agent intravenous chemotherapy concurrent with radiotherapy is the standard of care for patients with inoperable esophageal cancer. However, patients tend to tolerate intravenous chemotherapy less well with age and comorbidities. It is essential to find a better treatment modality that improves survival outcomes without reducing the quality of life. Objective: To evaluate the effectiveness of simultaneous integrated boost radiotherapy (SIB-RT) with concurrent and consolidated oral S-1 chemotherapy for patients aged 70 years and older with inoperable esophageal squamous cell carcinoma (ESCC). Design, Setting, and Participants: This multicenter, phase III randomized clinical trial was conducted between March 2017 and April 2020 in 10 centers in China. Patients with inoperable, locally advanced, clinical stage II to IV ESCC were enrolled and randomized to receive SIB-RT concurrent with and followed by oral S-1 chemotherapy (CRTCT group) or SIB-RT alone (RT group). Data analysis was completed on March 22, 2022. Interventions: In both groups, the planning gross tumor volume was administered with radiation dose of 59.92 Gy and the planning target volume was administered with radiation dose of 50.4 Gy, in 28 fractions each. In the CRTCT group, concurrent S-1 was administered on radiotherapy days, and consolidated S-1 was administered at 4 to 8 weeks after SIB-RT. Main Outcomes and Measures: The primary end point was overall survival (OS) of the intent-to-treat population. Secondary end points were progression-free survival (PFS) and toxicity profile. Results: A total of 330 patients (median [IQR] age, 75.5 [72-79] years; 220 [66.7%] male patients) were included, with 146 patients randomized to the RT group and 184 randomized to the CRTCT group. A total of 107 patients (73.3%) in the RT group and 121 patients (67.9%) in the CRTCT group were clinically diagnosed with stage III to IV disease. At the time of analysis of the 330 patients in the intent-to treat-population (March 22, 2022), OS was improved in the CRTCT group compared with the RT group at 1 year (72.2% vs 62.3%) and 3 years (46.2% vs 33.9%; log-rank P = .02). PFS was similarly improved in the CRTCT group compared with the RT group at 1 year (60.8% vs 49.3%) and 3 years (37.3% vs 27.9%; log-rank P = .04). There was no significant difference in the incidence of treatment-related toxic effects higher than grade 3 between the 2 groups. Grade 5 toxic effects occurred in each group, including 1 patient who experienced myelosuppression and 4 patients with pneumonitis in the RT group and 3 patients with pneumonitis and 2 patients with fever in the CRTCT group. Conclusions and Relevance: These findings suggest that oral S-1 chemotherapy administered with SIB-RT should be considered as an alternative treatment option for patients aged 70 years and older with inoperable ESCC, since it improved survival outcomes without additional treatment-related toxic effects compared with SIB-RT alone. Trial Registration: ClinicalTrials.gov Identifier: NCT02979691.

High-Dose Versus Standard-Dose Intensity-Modulated Radiotherapy With Concurrent Paclitaxel Plus Carboplatin for Patients With Thoracic Esophageal Squamous Cell Carcinoma: A Randomized, Multicenter, Open-Label, Phase 3 Superiority Trial.

PURPOSE: The standard dose (SD) of definitive concurrent chemoradiotherapy (dCRT) remains 50.4 Gy in patients with esophageal cancer; a higher dose, when applied with conventional radiation therapy techniques, increases toxicities without improving survival. We investigated whether a high dose of 59.4 Gy using intensity-modulated radiation therapy (IMRT) would improve survival without increasing toxicities. METHODS: Patients with inoperable thoracic esophageal squamous cell carcinoma (SCC) referred for dCRT were randomly assigned (1:1) to high-dose (HD) IMRT (59.4 Gy) or SD IMRT (50.4 Gy). Chemotherapy consisted of 6 cycles of concurrent weekly paclitaxel and carboplatin and a maximum of 2 cycles of consolidation chemotherapy. Nutritional intervention was implemented for patients with malnutrition on the basis of nutritional screening. The primary endpoint was median overall survival (mOS). Analyses were by modified intention to treat. RESULTS: Between April 30, 2016, and April 30, 2019, 167 patients were enrolled at 9 participating centers in China. Seventy-one patients in the HD and 73 patients in the SD groups were included in the analysis; 86.8% of the patients completed radiation therapy and 70.1% received 5 or 6 cycles of concurrent chemotherapy. The median follow-up was 36.0 months. The mOS was 28.1 and 26.0 months in the HD and SD arms, respectively (P = .54). A total of 7 treatment-related deaths were observed. Grade 3 or worse treatment-related toxicities were observed in 62% and 68.5% of the patients in the HD and SD arms, respectively (P = .675). CONCLUSIONS: For patients with inoperable thoracic esophageal SCC, a dose of 59.4 Gy did not improve survival compared with the SD of dCRT using IMRT.

Progression-free survival as surrogate endpoint of overall survival in esophageal squamous cell carcinoma: a real-world data and literature-based analysis.

Background: The surrogacy of progression-free survival (PFS) for overall survival (OS) in esophageal squamous cell carcinoma (ESCC) remains unelucidated. This study aimed to determine the validity of PFS as a surrogate endpoint for OS in ESCC patients treated with definitive radiotherapy or definitive chemoradiotherapy (dRT/dCRT), as well as characterize the prognostic factors and survival of such patients. Methods: A total of 3662 patients from 10 cancer centers were enrolled. One-, 2-, and 3-year PFS (PFS12, PFS24, and PSF36, respectively) were used as time points for analysis. At each time point, ESCC-specific mortality and OS were characterized using competing risk and conditional survival models, while correlation between PFS and OS was evaluated by linear regression. Results: At PFS12, PFS24, and PFS36, a progressive decrease in 5-year ESCC-specific mortality (35.2%-13.4%) and increase in 5-year OS (46.6%-62.9%) were observed. Regardless, the OS of patients remained markedly lower than those of the age- and sex-matched Chinese general population. TNM stage remained a significant prognostic factor at PFS36. Strong correlation was found between 3-year PFS and 5-year OS, which was further externally validated. Conclusions: Three-year PFS may act as a potential surrogate endpoint for 5-year OS. TNM stage was considered a significant prognostic factor for OS, and may represent the optimal prognostic tool to guide clinical decision-making and post-treatment follow-up.

Interobserver variability in target volume delineation in definitive radiotherapy for thoracic esophageal cancer: a multi-center study from China.

PURPOSE: To investigate the interobserver variability (IOV) in target volume delineation of definitive radiotherapy for thoracic esophageal cancer (TEC) among cancer centers in China, and ultimately improve contouring consistency as much as possible to lay the foundation for multi-center prospective studies. METHODS: Sixteen cancer centers throughout China participated in this study. In Phase 1, three suitable cases with upper, middle, and lower TEC were chosen, and participants were asked to contour a group of gross tumor volume (GTV-T), nodal gross tumor volume (GTV-N) and clinical target volume (CTV) for each case based on their routine experience. In Phase 2, the same clinicians were instructed to follow a contouring protocol to re-contour another group of target volume. The variation of the target volume was analyzed and quantified using dice similarity coefficient (DSC). RESULTS: Sixteen clinicians provided routine volumes, whereas ten provided both routine and protocol volumes for each case. The IOV of routine GTV-N was the most striking in all cases, with the smallest DSC of 0.37 (95% CI 0.32-0.42), followed by CTV, whereas GTV-T showed high consistency. After following the protocol, the smallest DSC of GTV-N was improved to 0.64 (95% CI 0.45-0.83, P = 0.005) but the DSC of GTV-T and CTV remained constant in most cases. CONCLUSION: Variability in target volume delineation was observed, but it could be significantly reduced and controlled using mandatory interventions.

Clinical practice and outcome of radiotherapy for advanced esophageal squamous cell carcinoma between 2002 and 2018 in China: the multi-center 3JECROG Survey.

PURPOSE: To determine the survival and prognostic factors of esophageal squamous cell carcinoma (ESCC) patients undergoing radical (chemo)radiotherapy in the era of three-dimensional conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT) in China. MATERIAL AND METHODS: The Jing-Jin-Ji Esophageal and Esophagogastric Cancer Radiotherapy Oncology Group (3JECROG) conducted the first nationwide survey of nine institutions. Detailed information was accumulated on 5185 patients with ESCC who received definitive 3DCRT/IMRT between 2002 and 2018. Relevant prognostic factors were evaluated to assess their influence on overall and progression-free survivals. RESULTS: After a median follow-up time of 47.0 (0.9-157.4) months, the 1-year, 2-year, 3-year and 5-year overall survival rates of the whole group were 69.8%, 46.6%, 37.9% and 30.1%. The 1-year, 2-year, 3-year, and 5-year progression-free survival rates were 54.1%, 36.6%, 30.5% and 24.9%. Multivariate analysis demonstrated that sex, clinical stage, treatment modality and radiation dose were prognostic factors for OS. The survival of patients who received concurrent chemoradiotherapy (CCRT) was better than that of patients who received radiotherapy alone or sequential chemoradiotherapy. Patients receiving adjuvant chemotherapy after CCRT had a better OS than patients receiving CCRT alone. Patients receiving higher radiation dose had a better OS than those patients receiving low-dose radiotherapy. CONCLUSIONS: The survival of ESCC patients undergoing radical (chemo)radiotherapy was relatively satisfactory in the era of 3DCRTand IMRT. As the largest-scale multicenter research on esophageal cancer radiotherapy conducted in China, this study establishes national benchmarks and helps to provide references for subsequent related researches.

Age plays an important role in the decision of definitive concurrent chemoradiotherapy (CCRT) for esophageal squamous cell carcinoma (ESCC): a propensity-score matched analysis of multicenter data (3JECROG R-02A).

BACKGROUND: To examine the survival benefit of definitive concurrent chemoradiotherapy (CCRT) compared to radiotherapy alone in patients with esophageal squamous cell carcinoma (ESCC) using a real-world patient population. METHODS: This retrospective study included 2,762 patients with ESCC across ten medical centers in China from 2001 to 2017. A total of 1,133 patients received radiotherapy alone and 815 patients were treated with CCRT. The patient survival rates were assessed by propensity-score matching (PSM) and subgroup analysis. RESULTS: The baseline characteristics were significantly different between the two groups, with the CCRT group showing a higher proportion of males, younger patients, cervical/upper thoracic cancers, and worse T and N stages. There were no significant differences in the clinical characteristics between the two groups after PSM. Before PSM, the median overall survival (OS) rates were 31.2 and 24.1 months in the CCRT and RT alone groups, respectively, demonstrating the superior therapeutic effects (TEs) of the CCRT. However, the median OS rates were not significantly different between the two groups after PSM (32.6 and 39.4 months in the CCRT and radiotherapy alone groups, respectively). The subgroup analyses revealed that the median OS was significantly better in the CCRT group compared to the radiotherapy alone group (37.5 vs. 25.1 months, respectively) in patients less than 70 years of age [hazard ratio (HR) 0.782, 95% confidence interval (CI): 0.657 to 0.932]. In contrast, in patients 70 years of age and older, the 5-year survival rate was poorer in the CCRT group (34.8%) compared to the radiotherapy alone group (73.4%). Therefore, CCRT was an independent poor prognostic risk factor (HR 3.206, 95% CI: 2.168 to 4.740). CONCLUSIONS: CCRT may not be suitable for all patients with localized ESCC. Younger patients less than 70 years of age might benefit significantly from CCRT. However, in patients aged 70 years and older, the potential survival benefit of CCRT and the optimal combination treatment regimens require further investigation.

Dose escalation of 3D radiotherapy is effective for esophageal squamous cell carcinoma: a multicenter retrospective analysis (3JECROG R-03).

BACKGROUND: To evaluate the impact of radiation dose escalation on overall survival (OS) in patients with non-metastatic esophageal squamous cell carcinoma (ESCC) treated with radical radiotherapy. METHODS: The clinical data of ESCC patients treated with three-dimensional (3D) radiotherapy alone or chemoradiotherapy were collected from multiple institutes and retrospectively analyzed. Patients who received radiation dose ≥40 Gy were included. Radiation dose as a continuous variable was entered into the Cox regression model by using penalized spline regression to allow for a nonlinear relationship between radiation dose and OS to be identified. Patients were stratified into five groups according to EQD2. The Kaplan-Meier method was used to assess the OS in different dose groups. Univariate and multivariate analyses were performed to evaluate the factors associated with OS. RESULTS: A total of 2,469 patients were included from 10 institutes across China. The median follow-up time was 58.3 months [95% confidence interval (CI): 56.4-60.2 months]. The median OS and PFS time were 24.3 months (95% CI: 22.5-26.2 months) and 18.0 months (95% CI: 16.4-19.6 months), respectively. The risk of death decreased sharply with a dose up to 60 to 62 Gy, before increasing slightly after the dose was elevated beyond 62 Gy. Multivariate analysis indicated that the chance of death was significantly decreased in patients who received radiotherapy doses of 60-62 Gy [P=0.028, hazard ratio (HR) 0.85, 95% CI: 0.73-0.98)], compared with those who received radiotherapy doses of 40-60 Gy. CONCLUSIONS: Our results reveal radiation dose is a significant prognostic factor of survival for ESCC patients. Higher radiation dose contributes to much more favorable survival outcomes for ESCC patients receiving radical radiotherapy by modern techniques, and 60 Gy or above might be the most optimal radiation dose.

Stage III Esophageal Squamous Cell Carcinoma Patients With Three-Dimensional Conformal or Intensity-Modulated Radiotherapy: A Multicenter Retrospective Study.

Aim: To evaluate long-term outcome and prognostic factors of stage III esophageal cancer after definitive radiotherapy using three dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT) techniques. Methods: Patients with T3N1M0/T4N0-1M0 esophageal squamous cell carcinoma (ESCC) treated with definitive radiotherapy from 2002 to 2016 in 10 Chinese medical centers were retrospectively analyzed. Overall survival (OS) and progression-free survival (PFS) rates were calculated. Prognostic factors were analyzed by Log-rank test and multivariable Cox model. Results: Survival data of 1,450 patients were retrospectively collected. With a median follow-up time of 65.9 months, 1-, 3-, and 5-year OS rates were 69.3, 36.7, and 27.7%, respectively, and PFS rates were 58.6, 32.7, and 27.4%, respectively. Univariable analyses showed that gender, age, lesion location, lesion length, largest tumor diameter, lymph node metastasis, gross tumor volume, EQD2, short-term response, and concurrent chemotherapy were prognostic factors for OS. Multivariable analyses showed that lesion location, T-classification, GTV size, EQD2, and short-term response to RT were independent prognostic factors for OS, and tumor diameter, GTV size, and short-term response were independent prognostic factors for PFS. Conclusions: This study demonstrated that definitive radiotherapy using 3DCRT and IMRT provides promising outcomes for locally advanced ESCC.

S-1-Based Chemoradiotherapy Followed by Consolidation Chemotherapy With S-1 in Elderly Patients With Esophageal Squamous Cell Carcinoma: A Multicenter Phase II Trial.

Introduction: Intensive treatments can often not be administered to elderly patients with esophageal squamous cell carcinoma (ESCC), leading to a poorer prognosis. This multi-center phase II trial aimed to determine the toxicity profile and efficiency of S-1-based simultaneous integrated boost radiotherapy (SIB-RT) followed by consolidation chemotherapy with S-1 in elderly ESCC patients and to evaluate the usefulness of comprehensive geriatric assessment (CGA). Patients and Methods: We prospectively enrolled 46 elderly patients (age ≥ 70 years) with histopathologically proven ESCC. The patients underwent pretreatment CGA followed by SIB-RT (dose, 59.92 Gy/50.4 Gy) in 28 daily fractions administered using intensity-modulated radiotherapy or volumetric-modulated arc therapy. S-1 was orally administered (40-60 mg/m2) concurrently with radiotherapy and 4-8 weeks later, for up to four 3-week cycles at the same dose. Results: The median survival time was 22.6 months. The 1- and 2-year overall survival rates were 80.4 and 47.8%, respectively. The overall response rate was 78.3% (36/46). The incidence of grade 3-4 toxicities was 28% (13/46). The most common grade 3-4 toxicities were radiation esophagitis (5/46, 10.9%), nausea (4/46, 8.7%), anorexia (3/46, 6.5%), and radiation pneumonitis (3/46, 6.5%). There were no grade 5 toxicities. CGA identified that 48.8% of patients were at risk for depression and 65.5% had malnutrition. Conclusion: Concurrent S-1 treatment with SIB-RT followed by 4 cycles of S-1 monotherapy yielded satisfactory tumor response rates and manageable toxicities in selected elderly patients with ESCC. Pretreatment CGA uncovered numerous health problems and allowed the provision of appropriate supportive care. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02979691.

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).

Does chemoradiotherapy benefit elderly patients with esophageal squamous cell cancer? A propensity-score matched analysis on multicenter data (3JECROG R-03A).

BACKGROUND: The aim of the present study was to assess the efficacy of concurrent chemoradiotherapy (CRT) or radiotherapy alone (RT-alone) in elderly patients with esophageal squamous cell carcinoma (ESCC). METHODS: The clinical data of patients with ESCC treated with RT-alone or CRT were collected and retrospectively reviewed. The 1-, 3- and 5-year overall survival (OS) rates and the clinical characteristics correlated with survival were analyzed statistically. Propensity score matching (PSM) analyses were used to compensate for differences in baseline characteristics between the CRT and RT-alone groups to confirm the survival difference. RESULTS: A total of 729 patients fulfilling the inclusion criteria were reviewed. Diabetes, primary tumor volume (pTV), primary tumor location (pTLo), clinical T stage,(cT) clinical N stage (cN), clinical M stage (cM) and short-term response to RT were independent factors influencing OS (P = 0.002-0.044). The 5-year OS rate was 26.6, 26.0 and 30.1% in the whole cohort, RT-alone and CRT groups, respectively. The survival difference between RT alone and CRT was not significant before or following PSM. Compared with the corresponding subgroups treated with RT alone, CRT significantly benefited patients with diabetes (P = 0.003), cT4 (P = 0.030) and cN0 (P = 0.049), whereas no benefit was identified between CRT and RT alone in the other subgroups, including cT1-3, cN1, cM, pTLo, pTV, age and gender. CONCLUSIONS: CRT with the current chemotherapy regimens may not improve the survival of elderly ESCC patients compared to RT-alone, except in patients with cT4 stage, cN0 stage or diabetes. However, due to the limitation of the retrospective nature of the current study, further clinical trials are required for confirmation.

Correction to: 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.

Following publication of the original article [1], the authors reported that an error in the Methods/Design, Study design and objectives section (third sentence).

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.