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Visual Abstract. Concurrent Chemoradiotherapy With S-1 for Older Patients With Esophageal Cancer
Concurrent Chemoradiotherapy With S-1 for Older Patients With Esophageal Cancer
Figure 1.  Patient Flowchart
Patient Flowchart
Figure 2.  Survival in the Intention-to-Treat Population
Survival in the Intention-to-Treat Population

A, Overall survival (hazard ratio, 0.63; 95% CI, 0.47-0.85; P = .002). B, Progression-free survival (hazard ratio, 0.66; 95% CI, 0.50-0.87; P = .003). CCRT indicates concurrent chemoradiotherapy; RT, radiotherapy.

Figure 3.  Subgroup Analyses of Overall Survival in the Intention-to-Treat Population
Subgroup Analyses of Overall Survival in the Intention-to-Treat Population

AJCC indicates American Joint Committee on Cancer; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CCRT, concurrent chemoradiotherapy; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; NRS-2002, Nutritional Risk Screening-2002; and RT, radiotherapy;.

Table 1.  Baseline Characteristics of the Intention-to-Treat Population
Baseline Characteristics of the Intention-to-Treat Population
Table 2.  Adverse Events in Each Group
Adverse Events in Each Group
1.
Sung  H, Ferlay  J, Siegel  RL,  et al.  Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.   CA Cancer J Clin. 2021;71(3):209-249. doi:10.3322/caac.21660 PubMedGoogle ScholarCrossref
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National Cancer Institute. SEER cancer stat facts: esophageal cancer. Accessed January 20, 2021. https://seer.cancer.gov/statfacts/html/esoph.html
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Vlacich  G, Samson  PP, Perkins  SM,  et al.  Treatment utilization and outcomes in elderly patients with locally advanced esophageal carcinoma: a review of the National Cancer Database.   Cancer Med. 2017;6(12):2886-2896. doi:10.1002/cam4.1250 PubMedGoogle ScholarCrossref
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van Groeningen  CJ, Peters  GJ, Schornagel  JH,  et al.  Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors.   J Clin Oncol. 2000;18(14):2772-2779. doi:10.1200/JCO.2000.18.14.2772 PubMedGoogle ScholarCrossref
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Ji  Y, Qiu  G, Sheng  L,  et al.  A phase I dose escalation study of S-1 with concurrent radiotherapy in elderly patients with esophageal cancer.   J Thorac Dis. 2016;8(3):451-458. doi:10.21037/jtd.2016.02.70 PubMedGoogle ScholarCrossref
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Ji  Y, Du  X, Tian  Y,  et al.  A phase II study of S-1 with concurrent radiotherapy in elderly patients with esophageal cancer.   Oncotarget. 2017;8(47):83022-83029. doi:10.18632/oncotarget.20938 PubMedGoogle ScholarCrossref
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Charlson  ME, Pompei  P, Ales  KL, MacKenzie  CR.  A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.   J Chronic Dis. 1987;40(5):373-383. doi:10.1016/0021-9681(87)90171-8 PubMedGoogle ScholarCrossref
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Therasse  P, Arbuck  SG, Eisenhauer  EA,  et al.  New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.   J Natl Cancer Inst. 2000;92(3):205-216. doi:10.1093/jnci/92.3.205 PubMedGoogle ScholarCrossref
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National Cancer Institute.  Common Terminology Criteria for Adverse Events. National Cancer Institute; 2009.
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Cooper  JS, Guo  MD, Herskovic  A,  et al; Radiation Therapy Oncology Group.  Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01).   JAMA. 1999;281(17):1623-1627. doi:10.1001/jama.281.17.1623 PubMedGoogle ScholarCrossref
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Semrau  R, Herzog  SL, Vallböhmer  D, Kocher  M, Hölscher  A, Müller  RP.  Radiotherapy in elderly patients with inoperable esophageal cancer. ss there a benefit?   Strahlenther Onkol. 2012;188(3):226-232. doi:10.1007/s00066-011-0039-2 PubMedGoogle ScholarCrossref
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Lv  S, Fang  M, Yang  J,  et al.  Long-term results of definitive concurrent chemoradiotherapy using S-1 in the treatment of geriatric patients with esophageal cancer.   Onco Targets Ther. 2016;9:5389-5397. doi:10.2147/OTT.S107668 PubMedGoogle Scholar
21.
Walter  F, Böckle  D, Schmidt-Hegemann  NS,  et al.  Clinical outcome of elderly patients (≥70 years) with esophageal cancer undergoing definitive or neoadjuvant radio(chemo)therapy: a retrospective single center analysis.   Radiat Oncol. 2018;13(1):93. doi:10.1186/s13014-018-1044-8 PubMedGoogle ScholarCrossref
22.
Fukushima  M, Sakamoto  K, Sakata  M, Nakagawa  F, Saito  H, Sakata  Y.  Gimeracil, a component of S-1, may enhance the antitumor activity of X-ray irradiation in human cancer xenograft models in vivo.   Oncol Rep. 2010;24(5):1307-1313. doi:10.3892/or_00000987 PubMedGoogle ScholarCrossref
23.
Takagi  M, Sakata  K, Someya  M,  et al.  Gimeracil sensitizes cells to radiation via inhibition of homologous recombination.   Radiother Oncol. 2010;96(2):259-266. doi:10.1016/j.radonc.2010.05.020 PubMedGoogle ScholarCrossref
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Xu  D, Li  G, Li  H, Jia  F.  Comparison of IMRT versus 3D-CRT in the treatment of esophagus cancer: a systematic review and meta-analysis.   Medicine (Baltimore). 2017;96(31):e7685-e7692. doi:10.1097/MD.0000000000007685 PubMedGoogle ScholarCrossref
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Siewert  JR, Ott  K.  Are squamous and adenocarcinomas of the esophagus the same disease?   Semin Radiat Oncol. 2007;17(1):38-44. doi:10.1016/j.semradonc.2006.09.007 PubMedGoogle ScholarCrossref
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Xu  C, Xi  M, Moreno  A,  et al.  Definitive chemoradiation therapy for esophageal cancer in the elderly: clinical outcomes for patients exceeding 80 years old.   Int J Radiat Oncol Biol Phys. 2017;98(4):811-819. doi:10.1016/j.ijrobp.2017.02.097 PubMedGoogle ScholarCrossref
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Boku  N, Yamamoto  S, Fukuda  H,  et al; Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group.  Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study.   Lancet Oncol. 2009;10(11):1063-1069. doi:10.1016/S1470-2045(09)70259-1 PubMedGoogle ScholarCrossref
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Nokihara  H, Lu  S, Mok  TSK,  et al.  Randomized controlled trial of S-1 versus docetaxel in patients with non–small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer).   Ann Oncol. 2017;28(11):2698-2706. doi:10.1093/annonc/mdx419 PubMedGoogle ScholarCrossref
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Sakuramoto  S, Sasako  M, Yamaguchi  T,  et al; ACTS-GC Group.  Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine.   N Engl J Med. 2007;357(18):1810-1820. doi:10.1056/NEJMoa072252 PubMedGoogle ScholarCrossref
30.
Huang  J, Cao  Y, Wu  L, Liao  C, He  Y, Gao  F.  S-1–based therapy versus 5-FU–based therapy in advanced gastric cancer: a meta-analysis.   Med Oncol. 2011;28(4):1004-1011. doi:10.1007/s12032-010-9594-0 PubMedGoogle ScholarCrossref
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Lees  J, Chan  A.  Polypharmacy in elderly patients with cancer: clinical implications and management.   Lancet Oncol. 2011;12(13):1249-1257. doi:10.1016/S1470-2045(11)70040-7 PubMedGoogle ScholarCrossref
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Popa  MA, Wallace  KJ, Brunello  A, Extermann  M, Balducci  L.  Potential drug interactions and chemotoxicity in older patients with cancer receiving chemotherapy.   J Geriatr Oncol. 2014;5(3):307-314. doi:10.1016/j.jgo.2014.04.002 PubMedGoogle ScholarCrossref
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Conroy  T, Galais  MP, Raoul  JL,  et al; Fédération Francophone de Cancérologie Digestive and UNICANCER-GI Group.  Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial.   Lancet Oncol. 2014;15(3):305-314. doi:10.1016/S1470-2045(14)70028-2 PubMedGoogle ScholarCrossref
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Chen  M, Shen  M, Lin  Y,  et al.  Adjuvant chemotherapy does not benefit patients with esophageal squamous cell carcinoma treated with definitive chemoradiotherapy.   Radiat Oncol. 2018;13(1):150. doi:10.1186/s13014-018-1086-y PubMedGoogle ScholarCrossref
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Luo  H, Jiang  W, Ma  L,  et al.  Icotinib with concurrent radiotherapy vs radiotherapy alone in older adults with unresectable esophageal squamous cell carcinoma: a phase II randomized clinical trial.   JAMA Netw Open. 2020;3(10):e2019440. doi:10.1001/jamanetworkopen.2020.19440 PubMedGoogle Scholar
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Crosby  T, Hurt  CN, Falk  S,  et al.  Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, phase 2/3 randomised trial.   Lancet Oncol. 2013;14(7):627-637. doi:10.1016/S1470-2045(13)70136-0 PubMedGoogle ScholarCrossref
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Suntharalingam  M, Winter  K, Ilson  D,  et al.  Effect of the addition of cetuximab to paclitaxel, cisplatin, and radiation therapy for patients with esophageal cancer: the NRG oncology RTOG 0436 phase 3 randomized clinical trial.   JAMA Oncol. 2017;3(11):1520-1528. doi:10.1001/jamaoncol.2017.1598 PubMedGoogle ScholarCrossref
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Ruhstaller  T, Thuss-Patience  P, Hayoz  S,  et al; Swiss Group for Clinical Cancer Research (SAKK); German Esophageal Cancer Study Group; Austrian ‘Arbeitsgemeinschaft Medikamentöse Tumortherapie’ (AGMT); Fédération Francophone de Cancérologie Digestive (FFCD)/Fédération de Recherche en Chirurgie (FRENCH).  Neoadjuvant chemotherapy followed by chemoradiation and surgery with and without cetuximab in patients with resectable esophageal cancer: a randomized, open-label, phase III trial (SAKK 75/08).   Ann Oncol. 2018;29(6):1386-1393. doi:10.1093/annonc/mdy105 PubMedGoogle ScholarCrossref
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Verma  V, Haque  W, Zheng  D, Osayande  F, Lin  C.  Patterns of care and outcomes of elderly esophageal cancer patients not meeting age-based criteria of the CROSS trial.   Am J Clin Oncol. 2019;42(1):67-74. doi:10.1097/COC.0000000000000481 PubMedGoogle ScholarCrossref
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    Original Investigation
    August 5, 2021

    Efficacy of Concurrent Chemoradiotherapy With S-1 vs Radiotherapy Alone for Older Patients With Esophageal Cancer: A Multicenter Randomized Phase 3 Clinical Trial

    Author Affiliations
    • 1Department of Radiation Oncology, Cancer Hospital of the University of Chinese Academy of Science/Institute of Cancer and Basic Medicine, Chinese Academy of Science, Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China
    • 2The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Nanjing, China
    • 3Nantong Tumor Hospital, Nantong, China
    • 4Anhui Provincial Hospital, Hefei, China
    • 5Chongqing Sanxia Central Hospital, Chongqing, China
    • 6Fujian Provincial Cancer Hospital, Fuzhou, China
    • 7Jiangsu Cancer Hospital, Nanjing, China
    • 8Huaian Second People's Hospital, Huaian, China
    • 9Taizhou Hospital of Zhejiang Province, Taizhou, China
    • 10The First People's Hospital of Changzhou, Changzhou, China
    • 11The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
    • 12Lishui Municipal Central Hospital, Lishui, China
    • 13Xinghua City People's Hospital, Xinghua, China
    • 14Henan Cancer Hospital, Zhengzhou, China
    • 15Maoming People's Hospital, Maoming, China
    • 16The First Hospital of Jiaxing, Jiaxing, China
    • 17Sichuan Provincial People's Hospital, Chengdu, China
    • 18The Fifth Affiliated Hospital Sun Yat-sen University, Guangzhou, China
    • 19Shangrao People's Hospital, Shangrao, China
    • 20Lianshui County People's Hospital, Lianshui, China
    • 21Yinzhou People's Hospital, Ningbo, China
    • 22Jinhua Municipal Central Hospital, Jinhua, China
    • 23Shanghai Key Laboratory of Artificial Intelligence for Medical Image and Knowledge Graph, Shanghai, China
    • 24The First People's Hospital of Foshan, Foshan, China
    • 25Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
    JAMA Oncol. 2021;7(10):1459-1466. doi:10.1001/jamaoncol.2021.2705
    Key Points

    Question  Is concurrent chemoradiotherapy with S-1 an effective and tolerable treatment for older patients with esophageal cancer?

    Findings  In this randomized phase 3 clinical trial that included 298 older patients with esophageal cancer, concurrent chemoradiotherapy with S-1 significantly improved 2-year overall survival compared with radiotherapy alone (53.2% vs 35.8%). The incidence of grade 3 or higher toxic effects was not significantly higher except for leukopenia (9.5% vs 2.7%).

    Meaning  The findings of this trial indicate that concurrent chemoradiotherapy with S-1 is an effective and tolerable treatment for older patients with esophageal cancer.

    Abstract

    Importance  Most older patients with esophageal cancer cannot complete the standard concurrent chemoradiotherapy (CCRT). An effective and tolerable chemoradiotherapy regimen for older patients is needed.

    Objective  To evaluate the efficacy and toxic effects of CCRT with S-1 vs radiotherapy (RT) alone in older patients with esophageal cancer.

    Design, Setting, and Participants  A randomized, open-label, phase 3 clinical trial was conducted at 23 Chinese centers between June 1, 2016, and August 31, 2018. The study enrolled 298 patients aged 70 to 85 years. Eligible participants had histologically confirmed esophageal cancer, stage IB to IVB disease based on the 6th edition of the American Joint Committee on Cancer (stage IVB: only metastasis to the supraclavicular/celiac lymph nodes) and an Eastern Cooperative Oncology Group performance status of 0 to 1. Data analysis was performed from August 1, 2020, to March 10, 2021.

    Interventions  Patients were stratified according to age (<80 vs ≥80 years) and tumor length (<5 vs ≥5 cm) and randomly assigned (1:1) to receive either CCRT with S-1 or RT alone.

    Main Outcomes and Measures  The primary end point was the 2-year overall survival rate using intention-to-treat analysis.

    Results  Of the 298 patients enrolled, 180 (60.4%) were men. The median age was 77 (interquartile range, 74-79) years in the CCRT group and 77 (interquartile range, 74-80) years in the RT alone group. A total of 151 patients (50.7%) had stage III or IV disease. The CCRT group had a significantly higher complete response rate than the RT group (41.6% vs 26.8%; P = .007). Surviving patients had a median follow-up of 33.9 months (interquartile range: 28.5-38.2 months), and the CCRT group had a significantly higher 2-year overall survival rate (53.2% vs 35.8%; hazard ratio, 0.63; 95% CI, 0.47-0.85; P = .002). There were no significant differences in the incidence of grade 3 or higher toxic effects between the CCRT and RT groups except that grade 3 or higher leukopenia occurred in more patients in the CCRT group (9.5% vs 2.7%; P = .01). Treatment-related deaths were observed in 3 patients (2.0%) in the CCRT group and 4 patients (2.7%) in the RT group.

    Conclusions and Relevance  In this phase 3 randomized clinical trial, CCRT with S-1 was tolerable and provided significant benefits over RT alone in older patients with esophageal cancer.

    Trial Registration  ClinicalTrials.gov Identifier: NCT02813967

    Introduction

    Esophageal cancer is the sixth leading global cause of cancer-related deaths.1 The median age at diagnosis is 68 years, and more than 40% of the patients are aged 70 years or older.2,3 With the greater life expectancy and population aging, it has become increasingly important to investigate appropriate treatments for older patients with esophageal cancer.

    At present, concurrent chemoradiotherapy (CCRT) with fluorouracil and cisplatin is the standard treatment for inoperable, locally advanced esophageal cancer in patients with a good performance status.4,5 However, CCRT has substantial toxic effects, and a large number of older patients cannot tolerate CCRT.3,4,6 In a study on patients aged 75 years or older diagnosed with potentially curable esophageal cancer, less than 15% of these patients underwent CCRT, and more than 70% of these patients were treated with radiotherapy (RT) alone or other palliative care or received no treatment.6 Furthermore, adherence to CCRT with fluorouracil and cisplatin is poor even among the selected older patients, and only 9% to 38.5% of patients completed their planned treatment.7-9 In addition, it remains unclear whether CCRT is superior to RT alone in older patients with esophageal cancer. Few prospective trials have assessed the risks and benefits of CCRT in this population. A recent multicenter retrospective analysis noted no significant difference in survival between CCRT and RT alone among older patients (≥70 years) with esophageal cancer (hazard ratio [HR], 1.02; 95% CI, 0.81-1.29; P = .85).10 Therefore, an effective and tolerable CCRT regimen for older patients is needed.

    As an oral fluoropyrimidine, S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate) is designed to have enhanced anticancer activity and reduced toxicity.11 Our phase 1 and 2 trials have suggested that CCRT with S-1 provides promising outcomes and mild toxic effects in older patients with esophageal cancer.12,13 In the phase 1 trial, the median overall survival was 29 months. The dose-limiting toxic effects included grade 3 esophagitis, pneumonitis, and thrombocytopenia.12 In the subsequent phase 2 trial, the median overall survival was 24 months. The most common grade 3 toxic effects included esophagitis (16.7%), leukopenia (13.3%), and neutropenia (10%). No grade 4 toxic effects or treatment-related deaths occurred.13 Against this background, this phase 3 trial aimed to further evaluate the efficacy and toxic effects of CCRT with S-1 (herinafter referred to as the CCRT group) vs RT alone in older patients with esophageal cancer.

    Methods
    Study Design and Participants

    This study was designed as a multicenter, randomized, open-label, phase 3 trial. The main eligibility criteria were histologically confirmed esophageal cancer, stage IB to IVB disease (based on the 6th edition of the American Joint Committee on Cancer14; stage IVB included only supraclavicular/celiac lymph node metastasis and not any other distant metastasis), age 70 to 85 years, Eastern Cooperative Oncology Group performance status of 0 to 1, and adequate bone marrow, hepatic, and kidney function. Patients were excluded if they had tracheoesophageal fistula, active infection, interstitial pneumonia, severe cardiovascular disease, malignant pleural effusion or pericardial effusion, or other concomitant cancers. The comorbidities before the diagnosis of esophageal cancer were assessed according to the Charlson Comorbidity Index.15 All patients provided written informed consent before enrollment. The study protocol was approved by the clinical research ethics committee of Zhejiang Cancer Hospital and is available in Supplement 1. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for randomized clinical trials.

    Eligible patients were randomly assigned in a 1:1 ratio either to the CCRT group or the RT group using a stratified permuted block method. Random assignments were stratified according to age (<80 vs ≥80 years) and tumor length (<5 vs ≥5 cm) by a statistician (H.L.) at a randomization center (Zhejiang Cancer Center, Hangzhou, China). Assignment results were provided to the investigators via telephone. Patients and physicians were not blinded to the group assignments.

    Treatment and Outcomes

    Eligible patients in the CCRT group were treated with RT (54 Gy in 30 fractions, 1.8 Gy/d 5 days per week) with concurrent S-1 administration, 70 mg/m2 per day, orally on days 1 to 14 and 29 to 42 (Shandong New Time Pharmaceutical Ltd). Because S-1 was only available in 20-mg capsules at the time of this trial, individual doses were rounded down to the nearest capsule if the calculated dose would have required a fraction of a capsule. Patients who were unable to swallow the capsules were provided with a powdered form of S-1 for oral administration. Patients assigned to the RT group were treated with 60 Gy in 30 fractions, 2.0 Gy/d 5 days per week.

    Three-dimensional conformal RT or intensity-modulated RT was delivered using a linear accelerator with 6- to 10-MV photons. The gross tumor volume was defined as the primary tumor and the involved lymph nodes, which were determined using all available information (eg, physical examination, endoscopy, ultrasonography endoscopy, neck-thorax-abdomen computed tomography, and positron emission computed tomography). The clinical tumor volume was defined as the primary tumor plus 3-cm superior and inferior expansion margins and a 1-cm radial expansion margin. The nodal clinical tumor volume was defined as the metastatic lymph node plus a 0.5- to 1.0-cm expansion margin. Patients who were aged 70 to 79 years were eligible to receive elective nodal irradiation, which included the supraclavicular lymph nodes if the primary tumor was located in the upper third of the esophagus and the celiac lymph nodes if the primary tumor was located in the lower third of the esophagus. Patients who were aged 80 years or older were not eligible to receive prophylactic irradiation of the lymph node drainage regions. The planning target volume was defined as a 0.5- to 1-cm margin around the clinical tumor volume to account for tumor motion and setup variations.

    The primary outcome was the 2-year overall survival (OS) rate, which was calculated from the date of randomization to the first date of all-cause death or the last follow-up. The secondary outcomes were treatment response rates, progression-free survival (PFS), and toxicity profile. Treatment response was assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.0.16 The PFS interval was calculated from the date of randomization to the first date of disease progression or death. Toxic effects were assessed according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.17

    Statistical Analysis

    This trial was designed to have 90% power to detect an improvement of 14% in the 2-year OS rate (from 16% in the RT group to 30% in the CCRT group) using the log-rank test with 2-sided α = .05.4,18,19 The required sample size was calculated to be 298 patients (149 per group) accrued over 3 years, with 2 years of follow-up and 10% loss during follow-up.

    Efficacy outcomes were analyzed using the intention-to-treat population. The Kaplan-Meier method was used to compare the curves for OS and PFS. Hazard ratios and 95% CIs were calculated using Cox proportional hazards regression analysis. Pearson χ2 test or Fisher exact test was used to compare the groups in terms of treatment responses, toxic effects, and other categorical variables. Differences were considered statistically significant at P < .05. All analyses were performed using R, version 3.6.1 (R Core Team), and data analysis was performed from August 1, 2020, to March 10, 2021.

    Results

    Between June 31, 2016, and August 31, 2018, this trial enrolled 298 patients aged 70 to 85 years who were scheduled for esophageal cancer treatment at 23 Chinese centers (eTable 1 in Supplement 2). The patients were randomly assigned to be treated with either CCRT with S-1 (n = 149) or RT alone (n = 149), which was defined as the intention-to-treat population (Figure 1). One patient in the CCRT group refused CCRT and received RT alone and was removed from the safety population. The 2 treatment groups had well-balanced baseline characteristics (Table 1). The population included 180 men (60.4%) and 118 women (39.6%). The median age was 77 (interquartile range, 74-79) years in the CCRT group and 77 (interquartile range, 74-80) years in the RT group. A total of 151 patients (50.7%) had stage III or IV disease, 296 (99.3%) had squamous cell carcinoma, and 178 (59.7%) had a tumor length greater than or equal to 5 cm.

    Treatment adherence is reported in eTable 2 in Supplement 2. In the CCRT group, 133 patients (89.3%) completed the prescribed RT, 117 (78.5%) completed the prescribed chemotherapy, and 115 (77.2%) completed the prescribed CCRT. Thirty-three patients (22.1%) discontinued CCRT because of adverse events (n = 24), comorbidities (n = 3), or patient refusal (n = 6). In the RT group, 134 patients (89.9%) completed the prescribed RT and 15 (10.1%) discontinued RT because of adverse events (n = 5), comorbidities (n = 1), or patient refusal (n = 9). The radiation doses to healthy tissues are reported in eTable 3 in Supplement 2.

    At the time of analysis (August 2020), the surviving patients had a median follow-up of 33.9 months (interquartile range, 28.5-38.2). A total of 13 patients were lost to follow-up, including 8 (5.4%) in the CCRT group and 5 (3.4%) in the RT group. A total of 186 deaths (62.4%) were identified, including 81 (54.4%) in the CCRT group and 105 (70.5%) in the RT group. The CCRT group had significantly better OS than the RT group (HR, 0.63; 95% CI, 0.47-0.85; P = .002) (Figure 2A). The CCRT group had significantly better OS rates than the RT group at 1 year (74.3% vs 59.7%), 2 years (53.2% vs 35.8%), and 3 years (43.4% vs 28.4%). The median OS interval was 24.9 months in the CCRT group (95% CI, 16.7-33.2 months) and 15.4 months in the RT group (95% CI, 12.4-18.3 months). The subgroup analyses revealed favorable OS outcomes in the CCRT arm for most subgroups based on the patient demographic and baseline clinical characteristics, such as age (eg, 70-79 y: 0.66; 95% CI, 0.47-0.93), sex (eg, men: HR, 0.64; 0.44-0.92), Eastern Cooperative Oncology Group performance status (eg, level 1: HR, 0.66; 95% CI, 0.48-0.90), body mass index (eg, <18.5: HR, 0.63; 95% CI, 0.45-0.88), Charlson Comorbidity Index score (eg, 0: HR, 0.62; 95% CI, 0.44-0.89), tumor length (eg, <5 cm: HR, 0.62; 95% CI, 0.39-1.00), and clinical stage (eg, stage II: HR, 0.60; 95% CI, 0.39-0.94) (Figure 3). eTable 4 in Supplement 2 presents the multivariable analysis of OS: CCRT, age 70 to 79 years, and stage II were associated with improved OS.

    The tumor responses to treatment, judged according to the Response Evaluation Criteria in Solid Tumors, version 1.0 criteria are reported in eTable 5 in Supplement 2. The CCRT group had a significantly higher clinical complete response rate (41.6% vs 26.8%; P = .007). At the time of analysis (August 2020), disease progression was noted in 80 patients (53.7%) in the CCRT group and 98 patients (65.8%) in the RT group (P = .03). The first sites of disease progression are presented in eTable 6 in Supplement 2. Treatment using CCRT with S-1 was associated with a significantly lower frequency of locoregional progression (28.2% vs 40.9%; P = .02). The median PFS intervals were 18.7 months (95% CI, 12.1-25.3 months) in the CCRT group and 9.5 months (95% CI, 6.9-12.1 months) in the RT group, and CCRT was associated with significantly prolonged PFS (HR, 0.66; 95% CI, 0.50-0.87; P = .003) (Figure 2B). The multivariable analysis revealed that CCRT and stage II disease were associated with improved PFS (eTable 4 in Supplement 2). Two patients in the CCRT group underwent salvage surgery after local progression, and 1 patient experienced anastomotic leakage.

    Table 2 lists the adverse events (grade 1-2 adverse events that affected >10% of patients in either group and all grade 3-5 adverse events). The CCRT group showed more frequent all-grade neutropenia vs the RT group (33.8% vs 22.1%; P = .04), thrombocytopenia (25.7% vs 12.8%; P = .007), and constipation (15.5% vs 7.4%; P = .04). There were no significant differences in the incidence of grade 3 or higher toxic effects between the CCRT and RT group except for grade 3 or higher leukopenia (9.5% vs 2.7%; P = .01). Treatment-related death was noted for 3 patients (2.0%) in the CCRT group and 4 patients (2.7%) in the RT group. Radiation-associated pneumonitis at 1 to 4 months after completing RT was the most common cause of death (3 cases in the CCRT group and 2 cases in the RT group). The 2 other deaths in the RT group involved 1 patient who died due to pneumonia (6 months after completing RT) and 1 who developed bacterial pneumonia that required stopping RT (total dose, 24 Gy) who subsequently died of pneumonia 27 days later. Six of the 7 treatment-related deaths occurred in patients aged 75 years or older, including 3 patients aged 80 years or older.

    Discussion

    To our knowledge, this is the first randomized phase 3 trial that aimed to assess the efficacy of an optimized CCRT regimen for older patients with esophageal cancer. Our results indicate that CCRT with S-1 was tolerable and significantly improved survival over RT alone among older patients. In addition, the survival benefit associated with CCRT was observed in most subgroups, including patients who were older than 80 years.

    The present study showed a 2-year OS rate of 53.2% and a median OS interval of 24.9 months after CCRT with S-1, which was consistent with the results from previous phase 1/2 trials and a retrospective analysis of CCRT with S-1.12,13,20 Several retrospective studies have reported a 2-year OS rate of 26.0% to 35.5% and median OS interval of 8.6 to 15.2 months among older patients who were treated with the standard CCRT with fluorouracil and cisplatin.7-9,21 In a review of the US National Cancer Database, the median OS was 14 months among older patients (age ≥70 years) with stage II to III disease who underwent CCRT.3 We cannot directly compare our results with those of retrospective studies. Our favorable survival outcomes may be partly due to the differences between prospective trials and retrospective studies and among histologic types, as well as the improvements made in RT technology and supportive treatment.22,23 However, it is also possible that S-1 may have a superior radiosensitizing effect than fluorouracil24 because the plasma half-life of fluorouracil during S-1 treatment is prolonged vs intravenously administered fluorouracil, which favors radiosensitization.11 Moreover, 5-chloro-2,4-dihydroxypyridine, a component of S-1, may enhance radiosensitivity by inhibiting DNA repair after radiation-induced damage.25 In addition, adherence to CCRT with S-1 treatment was good, considering that CCRT with fluorouracil and cisplatin frequently requires dose reduction and treatment discontinuation.7-9,21

    Older patients with esophageal cancer generally have an increased risk of toxic effects due to reduced physiologic reserves, especially in terms of bone marrow and kidney function, as well as a higher prevalence of comorbidities and malnutrition.7,8,21,26 Although some single-arm retrospective studies have reported that the toxic effects of CCRT with fluorouracil and cisplatin were not more severe in older patients,9 participants in these retrospective studies were highly selected, and most of them were administered lower doses of chemotherapy or RT. However, a retrospective comparison of older patients (aged 71-79 years) and somewhat younger patients (≤70 years) with esophageal cancer who were administered CCRT with fluorouracil and cisplatin revealed that older patients had a higher incidence of grade 3 or higher leukopenia (70.0% vs 49.7%), anemia (51.5% vs 17.9%), and thrombocytopenia (33.3% vs 18.6%).7 Some studies have reported that treatment-related death occurred in up to 13% to 18% of older patients who underwent CCRT.8,21 Therefore, less-toxic options, such as CCRT with a single agent, are likely to be more suitable for older patients. S-1 has shown favorable toxicity profiles in patients with gastric cancer and non–small cell lung cancer.27-30 In the present trial, toxic effects of grade 3 or higher were infrequent (<10% of patients) in both groups, and CCRT with S-1 did not increase the incidence of grade 3 toxic effects except for leukopenia (9.5% vs 2.7%). Thus, our results suggest that CCRT with S-1 is tolerable for older patients with esophageal cancer.

    Compared with intravenously administered chemotherapy, S-1 has several advantages, including convenient oral administration that does not necessitate the use of corticosteroids, antiemetics, and hydration. The use of these drugs in older patients may interact with their comorbidities, such as diabetes, hypertension, and cardiovascular disease, and increase the risk of drug interactions.31,32

    In the previous studies on CCRT for non–age-selected patients with esophageal cancer, 2 cycles of consolidation chemotherapy were administered after CCRT.4,5,18,33 However, consolidation chemotherapy was not administered in the present study because it has poor adherence among older patients.7-9 Moreover, the benefit of consolidation chemotherapy remains unclear for older patients with esophageal cancer.8,34

    A recent randomized phase 2 trial showed that, compared with RT alone, concurrent RT with icotinib (oral epidermal growth factor receptor tyrosine kinase inhibitor) improved survival among older patients with esophageal squamous cell carcinoma (median OS, 16.3 vs 24.0 months; P = .008) and was associated with a similar rate of grade 3 to 4 toxic effects (22.2% vs 26.6%).35 However, some phase 3 trials have indicated that there was no benefit of adding epidermal growth factor receptor inhibitors to CCRT for patients with esophageal cancer.36-38 For example, the SCOPE1 trial randomized 258 patients with local esophageal cancer to be treated with CCRT with or without cetuximab, which revealed that the addition of cetuximab was associated with inferior OS (median OS, 22.1 vs 25.4 months; P = .04) and increased grade 3 to 4 nonhematologic toxic effects (79% vs 63%; P = .004).36 Therefore, further studies are needed to better establish the efficacy of a combination of epidermal growth factor receptor inhibition and RT for patients with esophageal cancer.

    Limitations

    This study is limited by the lack of comprehensive geriatric assessment and quality-of-life assessment, although we evaluated the patients’ functional status, comorbidities, and nutritional status. Furthermore, most of the patients in the present study had squamous cell carcinoma, which is the predominant histologic type in China. Whether these results are applicable to patients with adenocarcinoma requires additional investigation. Older patients with adenocarcinoma are more likely to receive surgical treatment compared with those with squamous cell carcinoma.3,39

    Conclusions

    In this trial, CCRT with S-1 provided significant benefits over RT alone among older patients with esophageal cancer, with tolerable toxic effects and convenient oral administration. Thus, S-1 administered with RT can be considered as a preferred regimen for this population.

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    Article Information

    Accepted for Publication: April 29, 2021

    Published Online: August 5, 2021. doi:10.1001/jamaoncol.2021.2705

    Corresponding Author: Ming Chen, MD, Department of Radiation Oncology, Cancer Hospital of the University of Chinese Academy of Science/Institute of Cancer and Basic Medicine, Chinese Academy of Science, Zhejiang Key Laboratory of Radiation Oncology, 1 E Banshan Rd, Hangzhou 310022, China. Department of Radiation Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng E Rd, Guangzhou 510060, China (chenming@zjcc.org.cn).

    Author Contributions: Drs Ming Chen and Yongling Ji had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Yongling Ji, Xianghui Du, Weiguo Zhu, Yanguang Yang, Ma, Zhang, Jiancheng Li, and Hua Tao contributed equally to this work.

    Concept and design: Y. Ji, X. Du, X. Hu, H. Li, R. Huang, M. Chen.

    Acquisition, analysis, or interpretation of data: Y. Ji, W. Zhu, Y. Yang, Ma, Zhang, J. Li, H. Tao, Xia, H. Yang, J. Huang, Bao, D. Du, D. Liu, X. Wang, C. Li, X. Yang, Zeng, Z. Liu, W. Zheng, Pu, Jun Chen, W. Hu, P. Li, J. Wang, Y. Xu, X. Zheng, Jianxiang Chen, W. Wang, G. Tao, Cai, Zhao, J. Zhu, Jiang, Yan, G. Xu, Bu, Song, Xie, S. Huang, Y. Zheng, Sheng, Lai, Y. Chen, Cheng, W. Ji, Fang, Kong, Yu, R. Li, Shi, Shen, C. Zhu, Lv, He.

    Drafting of the manuscript: Y. Ji, J. Wang, X. Zheng, Fang, H. Li, M. Chen.

    Critical revision of the manuscript for important intellectual content: X. Du, W. Zhu, Y. Yang, Ma, Zhang, J. Li, H. Tao, Xia, H. Yang, J. Huang, Bao, D. Du, D. Liu, X. Wang, C. Li, X. Yang, Zeng, Z. Liu, W. Zheng, Pu, Jun Chen, W. Hu, P. Li, Y. Xu, Jianxiang Chen, W. Wang, G. Tao, Cai, Zhao, J. Zhu, Jiang, Yan, G. Xu, Bu, Song, Xie, S. Huang, Y. Zheng, Sheng, Lai, Y. Chen, Cheng, X. Hu, W. Ji, Kong, Yu, R. Li, Shi, Shen, C. Zhu, Lv, R. Huang, He, M. Chen.

    Statistical analysis: X. Hu, H. Li, R. Li, Shi, C. Zhu, Lv, R. Huang.

    Obtained funding: Y. Ji, W. Zhu.

    Administrative, technical, or material support: X. Du, W. Zhu, Y. Yang, Ma, J. Li, Bao, Zeng, Y. Xu, X. Hu.

    Supervision: Y. Ji, X. Du, W. Zhu, D. Du, M. Chen.

    Other: H. Tao, Bao, Jun Chen, Zhao, Jiang, G. Xu, Xie, S. Huang, Y. Chen, W. Ji.

    Conflict of Interest Disclosures: Dr Y. Ji reported receiving grants from the Chinese Society of Clinical Oncology-Innovent Biologics Inc Immunotherapy Research Foundation outside the submitted work. No other disclosures were reported.

    Funding/Support: This study was supported by the Zhejiang Basic Public Welfare Research Project LGF19H160008 and the National Natural Science Foundation of China grant 81602118.

    Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Meeting Presentation: Parts of the results of this study were presented at the Virtual MD Anderson Cancer Center Global Academic Programs 2020; November 18, 2020.

    Data Sharing Statement: See Supplement 3.

    Additional Contributions: We thank all of the patients and their families for their participation in this study. Ji Zhu, MD (Cancer Hospital of the University of Chinese Academy of Science), Jun Ma, MD (Sun Yat-sen University Cancer Center), Yuan Zhang, MD (Sun Yat-sen University Cancer Center), and Zhengbo Song, MD (Cancer Hospital of the University of Chinese Academy of Science), provided critical review of the manuscript without compensation. Ning Yang, MD (Cancer Hospital of the University of Chinese Academy of Science), assisted with the medical writing without compensation and Vikas Narang (Editage) assisted with and received compensation for English language editing.

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