Watanabe M, Tachimori Y, Oyama T, Toh Y, Matsubara H, Ueno M, Kono K, Uno T, Ishihara R, Muro K, Numasaki H, Tanaka K, Ozawa S, Murakami K, Usune S, Takahashi A, Miyata H; Registration Committee for Esophageal Cancer of the Japan Esophageal Society.
Comprehensive registry of esophageal cancer in Japan, 2013.
Esophagus. 2021 Jan;18(1):1-24. doi: 10.1007/s10388-020-00785-y. Epub 2020 Oct 13.
Abstract/Text
BACKGROUND: Esophageal cancer is the eighth most common cause of cancer mortality in Japan. More than 11,000 people had died from esophageal cancer in 2018. The Japan Esophageal Society has collected the data on patients' characteristics, performed treatment, and outcomes annually.
METHODS: We analyzed the data of patients who had first visited the participating hospitals in 2013. In 2019, the data collection method was changed from an electronic submission to a web-based data collection using the National Clinical Database (NCD). Japanese Classification of Esophageal Cancer 10th by the Japan Esophageal Society (JES) and UICC TNM Classification 7th were used for cancer staging RESULTS: A total of 8019 cases were registered from 334 institutions in Japan. Squamous cell carcinoma and adenocarcinoma accounted for 87.8% and 6.3%, respectively. The 5-year survival rates of patients treated using endoscopic resection, concurrent chemoradiotherapy, radiotherapy alone, or esophagectomy were 88.3%, 32.4%, 24.4%, and 59.3%, respectively. Esophagectomy was performed in 4910 cases. The operative and the hospital mortality rates were 0.77% and 1.98%, respectively. The survival curves showed a good discriminatory ability both in the clinical and pathologic stages by the JES system. The 5-year survival rate of patients with pStage IV in the UICC classification that included patients with supraclavicular node metastasis was better than that of patients with pStage IVb in JES classification.
CONCLUSION: We hope this report contributes to improving all aspects of the diagnosis and treatment of esophageal cancer in Japan.
Steevens J, Schouten LJ, Goldbohm RA, van den Brandt PA.
Alcohol consumption, cigarette smoking and risk of subtypes of oesophageal and gastric cancer: a prospective cohort study.
Gut. 2010 Jan;59(1):39-48. doi: 10.1136/gut.2009.191080.
Abstract/Text
OBJECTIVE: Alcohol consumption and cigarette smoking may be differentially associated with oesophageal squamous cell carcinoma (OSCC), oesophageal adenocarcinoma (OAC), gastric cardia adenocarcinoma (GCA) and gastric non-cardia adenocarcinoma (GNCA). However, because this was based on retrospective studies, these hypotheses were examined in a prospective cohort.
METHODS: The prospective Netherlands Cohort Study consists of 120 852 participants who completed a baseline questionnaire on diet and other cancer risk factors in 1986. After 16.3 years of follow-up, 107 OSCC, 145 OAC, 164 GCA and 491 GNCA cases were available for analysis using Cox proportional hazards models and the case-cohort approach.
RESULTS: The multivariable adjusted incidence rate ratio (RR) for OSCC was 4.61 (95% CI 2.24 to 9.50) for > or = 30 g ethanol/day compared with abstainers (p trend <0.001), while no associations with alcohol were found for OAC, GCA or GNCA. Compared with never smokers, current smokers had RRs varying from 1.60 for GCA to 2.63 for OSCC, and were statistically significant or borderline statistically significant. Frequency, duration and pack-years of smoking were independently associated with risk of all four cancers. A positive interaction was found between alcohol consumption and smoking status regarding OSCC risk. The RR for current smokers who consumed >15 g/day of ethanol was 8.05 (95% CI 3.89 to 16.60; p interaction = 0.65), when compared with never smokers who consumed <5 g/day of ethanol.
CONCLUSIONS: This prospective study found alcohol consumption to be associated with increased risk of only OSCC. Cigarette smoking was associated with risk of all four cancers.
Sakata K, Hoshiyama Y, Morioka S, Hashimoto T, Takeshita T, Tamakoshi A; JACC Study Group.
Smoking, alcohol drinking and esophageal cancer: findings from the JACC Study.
J Epidemiol. 2005 Jun;15 Suppl 2(Suppl II):S212-9. doi: 10.2188/jea.15.s212.
Abstract/Text
BACKGROUND: Using a large-scale cohort of about 110,000 people established in 45 areas throughout Japan from 1988 through 1990, the study attempted to uncover the joint effects of combined smoking and alcohol intake on esophageal cancer mortality.
METHODS: A cohort established from 1988 through 1990 included 46,465 men and 64,327 women aged 40 years and older and younger than 80. The number of female smokers and drinkers was low, and women were excluded from the analysis for that reason. In addition, 308 people with histories of malignant neoplasm, and 3,579 with unclear smoking and drinking data were also excluded, resulting in 42,578 people available for analysis. A follow-up of these individuals was conducted until 1999. Cox proportional hazards model was used for the analysis.
RESULTS: The joint effects of number of cigarettes and amount of alcohol consumed per day were compared with non-smokers and non-drinkers or those consuming less than one unit of alcohol per day. An increased synergistic esophageal cancer mortality risk (3.88) for both smoking and drinking was observed for those smoking 20 cigarettes or less per day and drinking one unit of alcohol or more but less than three units per day, with the risk rising (6.30) for those smoking at least 21 cigarettes and drinking at least three units of alcohol per day. Even in non-smokers with increased alcohol consumption, and in non-drinkers or those drinking at most one drink per day with increased smoking, no increased risk was observed.
CONCLUSIONS: In this cohort study of a Japanese population, increased esophageal cancer mortality risk was observed only when both factors of alcohol and tobacco intake were present simultaneously.
Ishiguro S, Sasazuki S, Inoue M, Kurahashi N, Iwasaki M, Tsugane S; JPHC Study Group.
Effect of alcohol consumption, cigarette smoking and flushing response on esophageal cancer risk: a population-based cohort study (JPHC study).
Cancer Lett. 2009 Mar 18;275(2):240-6. doi: 10.1016/j.canlet.2008.10.020. Epub 2008 Nov 25.
Abstract/Text
We examined the effect of alcohol consumption, cigarette smoking and flushing response on esophageal squamous cell carcinoma (ESCC) in a large-scale population-based cohort study. 44,970 middle-aged and older Japanese men were followed. A total of 215 cases of ESCC were newly diagnosed. Alcohol consumption and cigarette smoking are strongly associated with the incidence of ESCC. Heavy alcohol consumption increased the risk of ESCC especially among heavy smokers with the flushing response (HR = 3.41, 95% CI = 2.10-5.51). Strong effect modification was detected in heavy smokers. Our results suggest that heavy alcohol consumption together with heavy smoking may increase the risk of ESCC particularly in individuals with the flushing response.
Yokoyama A, Ohmori T, Muramatsu T, Higuchi S, Yokoyama T, Matsushita S, Matsumoto M, Maruyama K, Hayashida M, Ishii H.
Cancer screening of upper aerodigestive tract in Japanese alcoholics with reference to drinking and smoking habits and aldehyde dehydrogenase-2 genotype.
Int J Cancer. 1996 Nov 4;68(3):313-6. doi: 10.1002/(SICI)1097-0215(19961104)68:3<313::AID-IJC8>3.0.CO;2-4.
Abstract/Text
In this study, 1,000 Japanese male alcoholics were consecutively screened by upper gastrointestinal endoscopy with esophageal iodine staining. Associations among cancer-detection rates, drinking and smoking habits, and aldehyde dehydrogenase-2 (ALDH2) genotypes were evaluated. A total of 53 patients (5.3%) had histologically confirmed cancer. Esophageal cancer was diagnosed in 36, gastric cancer in 17, and oropharyngolaryngeal cancer in 9 patients: 8 of the esophageal-cancer patients were multiple-cancer patients, with additional cancer(s) in the stomach and/or oropharyngolaryngeal region. Multiple logistic regression revealed that use of stronger alcoholic beverages (whisky or shochu) in contrast with lighter beverages (sake or beer) and smoking of 50 pack-years or more increased the risks for esophageal (odds ratio 3.2 and 2.8 respectively), oropharyngolaryngeal (4.8 and 5.1 respectively) and multiple cancer (10.5 and 11.8 respectively). The inactive form of ALDH2, encoded by the gene ALDH2*1/2*2 prevalent in Orientals, exposes them to higher blood levels of acetaldehyde, a recognized animal carcinogen, after drinking. This inactive ALDH2 was detected in 19/36 (52.8%) patients with esophageal cancer, in 5/9 (55.6%) patients with oropharyngolaryngeal cancer, and in 7/8 (87.5%) patients with multiple cancer. All of these gene frequencies far exceeded that in a large alcoholic cohort (80/655, 12.2%). The triple combination of the risk factors of the inactive ALDH2, stronger alcoholic beverages and heavy smoking was more commonly associated with multiple-cancer patients than with patients with esophageal cancer alone (62.5% vs. 7.1%). These results show that the 3 risk factors are important for the development of upper-aerodigestive-tract cancer in Japanese alcoholics. For these high-risk drinkers, regimented screening appears to be indicated.
Muto M, Minashi K, Yano T, Saito Y, Oda I, Nonaka S, Omori T, Sugiura H, Goda K, Kaise M, Inoue H, Ishikawa H, Ochiai A, Shimoda T, Watanabe H, Tajiri H, Saito D.
Early detection of superficial squamous cell carcinoma in the head and neck region and esophagus by narrow band imaging: a multicenter randomized controlled trial.
J Clin Oncol. 2010 Mar 20;28(9):1566-72. doi: 10.1200/JCO.2009.25.4680. Epub 2010 Feb 22.
Abstract/Text
PURPOSE: Most of the esophageal squamous cell carcinomas (ESCCs) and cancers of the head and neck (H&N) region are diagnosed at later stages. To achieve better survival, early detection is necessary. We compared the real-time diagnostic yield of superficial cancer in these regions between conventional white light imaging (WLI) and narrow band imaging (NBI) in high-risk patients.
PATIENTS AND METHODS: In a multicenter, prospective, randomized controlled trial, 320 patients with ESCC were randomly assigned to primary WLI followed by NBI (n = 162) or primary NBI followed by WLI (n = 158) in a back-to-back fashion. The primary aim was to compare the real-time detection rates of superficial cancer in the H&N region and the esophagus between WLI and NBI. The secondary aim was to evaluate the diagnostic accuracy of these techniques.
RESULTS: NBI detected superficial cancer more frequently than did WLI in both the H&N region and the esophagus (100% v 8%, P < .001; 97% v 55%, P < .001, respectively). The sensitivity of NBI for diagnosis of superficial cancer was 100% and 97.2% in the H&N region and the esophagus, respectively. The accuracy of NBI for diagnosis of superficial cancer was 86.7% and 88.9% in these regions, respectively. The sensitivity and accuracy were significantly higher using NBI than WLI in both regions (P < .001 and P = .02 for the H&N region; P < .001 for both measures for the esophagus, respectively).
CONCLUSION: NBI could be the standard examination for the early detection of superficial cancer in the H&N region and the esophagus.
Chatterton BE, Ho Shon I, Baldey A, Lenzo N, Patrikeos A, Kelley B, Wong D, Ramshaw JE, Scott AM.
Positron emission tomography changes management and prognostic stratification in patients with oesophageal cancer: results of a multicentre prospective study.
Eur J Nucl Med Mol Imaging. 2009 Mar;36(3):354-61. doi: 10.1007/s00259-008-0959-y. Epub 2008 Oct 18.
Abstract/Text
OBJECTIVES: The aims of this study were (1) to determine the incremental information provided by (18)F-FDG positron emission tomography (PET) in staging patients with oesophageal cancer, and (2) to determine the impact of PET staging on post-PET clinical management of oesophageal cancer, and on prognosis.
METHODS: In a multicentre, single-arm open study, patients with proved oesophageal cancer without definite distant metastases and regarded as suitable for potentially curative treatment were examined by PET. Clinicians were requested to supply a management plan before and another plan after being supplied with the PET scan results. Patients were followed for at least 1 year for outcome analysis.
RESULTS: A total of 129 patients (104 men, mean age 67 y) were recruited. PET detected additional sites of disease in 53 patients (41%). Significant changes in management (high or medium impact) were observed in 38% of patients, primarily as a result of identifying additional sites of disease and/or confirming previously equivocal regional and distant metastases. Progression-free survival was significantly shorter in patients found to have additional lesions on PET (p < 0.05), but was not related to SUV(max).
CONCLUSION: These findings demonstrate the significant impact of PET on the clinical management of patients with newly diagnosed oesophageal carcinoma, and on prognostic stratification of these patients.
van Westreenen HL, Westerterp M, Sloof GW, Groen H, Bossuyt PM, Jager PL, Comans EF, van Dullemen HM, Fockens P, Stoker J, van der Jagt EJ, van Lanschot JJ, Plukker JT.
Limited additional value of positron emission tomography in staging oesophageal cancer.
Br J Surg. 2007 Dec;94(12):1515-20. doi: 10.1002/bjs.5708.
Abstract/Text
BACKGROUND: The detection of distant metastases in patients with oesophageal cancer may be improved with [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET), preventing unnecessary surgical explorations. The aim of this study was to assess the additional value of FDG-PET after a state-of-the-art preoperative staging protocol.
METHODS: All patients in this prospective cohort study were staged with multidetector computed tomography, endoscopic ultrasonography and external ultrasonography of the neck, both combined with selective fine-needle aspiration cytology. Patients considered eligible for curative surgery after these investigations underwent FDG-PET.
RESULTS: FDG-PET revealed suspicious hot spots in 30 (15.1 per cent) of 199 patients. Metastases were confirmed in eight (4.0 per cent). In six of these, distant metastases were confirmed before surgery, but exploratory surgery was necessary for histological confirmation in the other two. All eight upstaged patients had clinical stage III-IV disease before FDG-PET (6.6 per cent of 122 with stage III-IV disease). In seven patients (3.5 per cent) hot spots appeared to be synchronous neoplasms, mainly colonic polyps. However, those in the remaining 15 (7.5 per cent) were false positive, leading to unnecessary additional investigations.
CONCLUSION: FDG-PET improves the selection of patients with oesophageal cancer for potentially curative surgery, especially in stages III-IV. However, the diagnostic benefit is limited after state-of-the-art staging, and so broad implementation in daily clinical practice is questionable.
Copyright (c) 2007 British Journal of Surgery Society Ltd.
Goda K, Tajiri H, Ikegami M, Yoshida Y, Yoshimura N, Kato M, Sumiyama K, Imazu H, Matsuda K, Kaise M, Kato T, Omar S.
Magnifying endoscopy with narrow band imaging for predicting the invasion depth of superficial esophageal squamous cell carcinoma.
Dis Esophagus. 2009;22(5):453-60. doi: 10.1111/j.1442-2050.2009.00942.x. Epub 2009 Feb 13.
Abstract/Text
The invasion depth of superficial esophageal squamous cell carcinoma is important in determining therapeutic strategy. The aim of this study was to prospectively investigate the clinical utility of magnifying endoscopy with narrow band imaging compared with that of non-magnifying high-resolution endoscopy or high-frequency endoscopic ultrasonography in predicting the depth of superficial esophageal squamous cell carcinoma. The techniques were carried out in 72 patients with 101 superficial esophageal squamous cell carcinomas, which were then resected by either endoscopic mucosal resection or esophagectomy. The histological invasion depth was divided into two: mucosal or submucosal carcinoma. We investigated the relationship between endoscopic staging and histology of tumor depth. Non-magnifying high-resolution endoscopy, magnifying endoscopy with narrow band imaging, and high-frequency endoscopic ultrasonography had overestimation/underestimation rates of 7/5, 4/4 and 8/3%, respectively. The sensitivity rates for the three techniques were 72, 78, and 83%, respectively, and the specificity rates were 92, 95, and 89%, respectively. There were no statistically significant differences among the three endoscopic techniques. Clinical utility of magnifying endoscopy with narrow band imaging does not seem to be significantly different from that of non-magnifying high-resolution endoscopy or high-frequency endoscopic ultrasonography in predicting the depth of superficial esophageal squamous cell carcinoma. Magnifying endoscopy with narrow band imaging may have potential to reduce overestimation risks of non-magnifying high-resolution endoscopy or high-frequency endoscopic ultrasonography.
Ishihara R, Mizusawa J, Kushima R, Matsuura N, Yano T, Kataoka T, Fukuda H, Hanaoka N, Yoshio T, Abe S, Yamamoto Y, Nagata S, Ono H, Tamaoki M, Yoshida N, Takizawa K, Muto M.
Assessment of the Diagnostic Performance of Endoscopic Ultrasonography After Conventional Endoscopy for the Evaluation of Esophageal Squamous Cell Carcinoma Invasion Depth.
JAMA Netw Open. 2021 Sep 1;4(9):e2125317. doi: 10.1001/jamanetworkopen.2021.25317. Epub 2021 Sep 1.
Abstract/Text
IMPORTANCE: Distinguishing between mucosal and submucosal cancers is important for selecting the optimal treatment for patients with esophageal squamous cell carcinoma (ESCC); however, standard procedures for diagnosing cancer invasion depth have not yet been determined.
OBJECTIVE: To evaluate the diagnostic performance of endoscopic ultrasonography (EUS) after conventional endoscopy for the evaluation of ESCC invasion depth.
DESIGN, SETTING, AND PARTICIPANTS: This prospective single-arm confirmatory diagnostic study comprising 372 patients with T1 esophageal cancer was conducted at 41 secondary or tertiary hospitals in Japan. Enrollment began on July 20, 2017; patients were enrolled in 2 steps, with the first registration occurring from August 4, 2017, to December 11, 2019, and the second from August 9, 2017, to December 11, 2019. After the completion of all first and second registration examinations, patients received treatment and were followed up for 30 days, with follow-up ending on February 14, 2020. Patients were eligible for inclusion if they had pathologically or endoscopically diagnosed esophageal cancer with T1 clinical depth of invasion.
INTERVENTIONS: In the first registration, nonmagnifying endoscopy (non-ME) and magnifying endoscopy (ME) were used to diagnose cancer invasion depth. In the second registration, patients from the first registration who had cancers invading the muscularis mucosa or submucosa were enrolled and received EUS. After completion of the protocol examinations, patients received treatment with endoscopic resection or esophagectomy. The pathological results of the resected specimens were used as the reference standard for evaluating cancer invasion depth.
MAIN OUTCOMES AND MEASURES: The primary end point was the proportion of overdiagnosis of submucosal cancer (defined as invasion depth >200 μm) after receipt of non-ME and ME, with or without the addition of EUS. The secondary end points were underdiagnosis, sensitivity, and specificity.
RESULTS: Among 372 patients enrolled in the first registration, 371 received non-ME and ME. Of those, 300 patients were enrolled in the second registration, and 293 patients received EUS. A total of 269 patients (217 men [80.7%]; median age, 69 years; interquartile range, 62-75 years) were included in the final analysis. The addition of EUS was associated with a 6.6% increase in the proportion of overdiagnosis (from 16 of 74 patients [21.6%; 95% CI, 12.9%-32.7%] after non-ME and ME to 29 of 103 patients [28.2%; 95% CI, 19.7%-37.9%] after the addition of EUS; 1-sided P = .93). All subgroup analyses found similar increases in overdiagnosis of submucosal cancer. The addition of EUS was associated with a 4.5% reduction in the proportion of underdiagnosis (from 57 of 195 patients [29.2%; 95% CI, 23.0%-36.2%] after non-ME and ME to 41 of 166 patients [24.7%; 95% CI, 18.3%-32.0%] after the addition of EUS). After non-ME and ME, diagnostic sensitivity was 50.4% (95% CI, 41.0%-59.9%), specificity was 89.6% (95% CI, 83.7%-93.9%), and accuracy was 72.9% (95% CI, 67.1%-78.1%). After the addition of EUS, diagnostic sensitivity was 64.3% (95% CI, 54.9%-73.1%), specificity was 81.2% (95% CI, 74.1%-87.0%), and accuracy was 74.0% (95% CI, 68.3%-79.1%).
CONCLUSIONS AND RELEVANCE: This study found that the addition of EUS was not associated with improvements in the diagnostic accuracy of cancer invasion depth. These findings do not support the routine use of EUS after conventional endoscopy for evaluating the invasion depth among patients with T1 ESCC.
Katada C, Muto M, Momma K, Arima M, Tajiri H, Kanamaru C, Ooyanagi H, Endo H, Michida T, Hasuike N, Oda I, Fujii T, Saito D.
Clinical outcome after endoscopic mucosal resection for esophageal squamous cell carcinoma invading the muscularis mucosae--a multicenter retrospective cohort study.
Endoscopy. 2007 Sep;39(9):779-83. doi: 10.1055/s-2007-966761.
Abstract/Text
BACKGROUND AND STUDY AIMS: Endoscopic mucosal resection (EMR) is now commonly indicated for esophageal squamous cell carcinoma (ESCC) within the lamina propria mucosa. However, EMR for ESCC that has invaded the muscularis mucosa is controversial because the risk of lymph node metastasis is not negligible. We conducted a multicenter retrospective cohort study to investigate the incidence of lymph node metastasis and survival after EMR for ESCC invading the muscularis mucosa.
PATIENTS AND METHODS: A total of 104 patients with 111 lesions invading the muscularis mucosa, were retrospectively studied at eight institutes. No patients exhibited evidence of metastasis of lymph nodes or distant organs prior to EMR. Overall and cause-specific survival rates were calculated from the date of EMR to the date of death or the most recent follow-up visit. Survival curves were plotted according to the Kaplan-Meier method.
RESULTS: In total, 86 patients (82.7%) who did not receive further treatment such as chemotherapy, irradiation therapy, chemoradiotherapy, or esophagectomy after EMR were followed up. Only two patients (1.9%) developed lymph node metastasis after EMR. With a median follow-up period of 43 months (range, 8-134 months), overall and cause-specific survival rates at 5 years after EMR were 79.5% and 95.0%, respectively.
CONCLUSIONS: EMR for ESCC that invades the muscularis mucosa has curative potential as a minimally invasive treatment option.
Shimizu Y, Tsukagoshi H, Fujita M, Hosokawa M, Kato M, Asaka M.
Long-term outcome after endoscopic mucosal resection in patients with esophageal squamous cell carcinoma invading the muscularis mucosae or deeper.
Gastrointest Endosc. 2002 Sep;56(3):387-90. doi: 10.1016/s0016-5107(02)70043-6.
Abstract/Text
BACKGROUND: Endoscopic mucosal resection is recommended for squamous cell carcinoma of the esophagus confined to the lamina propria. However, endoscopic mucosal resection is often performed in patients with tumors that invade the muscularis mucosa or upper submucosa to minimize surgical invasiveness, despite the increased risk of lymph node metastasis. This study prospectively evaluated long-term outcome in such patients.
METHODS: Twenty-six consecutive patients with squamous cell esophageal carcinoma invading the muscularis mucosa or submucosa who underwent endoscopic mucosal resection from June 1992 through March 2000 (extended endoscopic mucosal resection group) were studied. As control group, 44 consecutive patients with esophageal carcinoma invading the muscularis mucosae or upper third of the submucosa and no preoperative evidence of lymph node metastasis who underwent esophagectomy during the same period (surgical resection group) were studied.
RESULTS: Overall survival rates at 5 years in the extended endoscopic mucosal resection group and surgical resection group were, respectively, 77.4% and 84.5%. There was no significant difference between survival distributions. Cause-specific survival rates at 5 years in extended endoscopic mucosal resection and surgical resection groups were, respectively, 95.0% and 93.5%. Survival curves for the groups were similar.
CONCLUSION: Although patients were not randomized to extended endoscopic mucosal resection or surgical resection in this study, the results suggest that endoscopic mucosal resection may be safe and effective for management of squamous cell esophageal carcinoma invading the muscularis mucosae or upper submucosa.
Mizuta H, Nishimori I, Kuratani Y, Higashidani Y, Kohsaki T, Onishi S.
Predictive factors for esophageal stenosis after endoscopic submucosal dissection for superficial esophageal cancer.
Dis Esophagus. 2009;22(7):626-31. doi: 10.1111/j.1442-2050.2009.00954.x. Epub 2009 Mar 6.
Abstract/Text
Endoscopic submucosal dissection (ESD) has been utilized as an alternative treatment to endoscopic mucosal resection for superficial esophageal cancer. We aimed to evaluate the complications associated with esophageal ESD and elucidate predictive factors for post-ESD stenosis. The study enrolled a total of 42 lesions of superficial esophageal cancer in 33 consecutive patients who underwent ESD in our department. We retrospectively reviewed ESD-associated complications and comparatively analyzed regional and technical factors between cases with and without post-ESD stenosis. The regional factors included location, endoscopic appearance, longitudinal and circumferential tumor sizes, depth of invasion, and lymphatic and vessel invasion. The technical factors included longitudinal and circumferential sizes of mucosal defects, muscle disclosure and cleavage, perforation, and en bloc resection. Esophageal stenosis was defined when a standard endoscope (9.8 mm in diameter) failed to pass through the stenosis. The results showed no cases of delayed bleeding, three cases of insidious perforation (7.1%), two cases of endoscopically confirmed perforation followed by mediastinitis (4.8%), and seven cases of esophageal stenosis (16.7%). Monovalent analysis indicated that the longitudinal and circumferential sizes of the tumor and mucosal defect were significant predictive factors for post-ESD stenosis (P < 0.005). Receiver operating characteristic analysis showed the highest sensitivity and specificity for a circumferential mucosal defect size of more than 71% (100 and 97.1%, respectively), followed by a circumferential tumor size of more than 59% (85.7 and 97.1%, respectively). It is of note that the success rate of en bloc resection was 95.2%, and balloon dilatation was effective for clinical symptoms in all seven patients with post-ESD stenosis. In conclusion, the most frequent complication with ESD was esophageal stenosis, for which the sizes of the tumor and mucosal defect were significant predictive factors. Although ESD enables large en bloc resection of esophageal cancer, practically, in cases with a lesion more than half of the circumference, great care must be taken because of the high risk of post-ESD stenosis.
Katada C, Muto M, Manabe T, Boku N, Ohtsu A, Yoshida S.
Esophageal stenosis after endoscopic mucosal resection of superficial esophageal lesions.
Gastrointest Endosc. 2003 Feb;57(2):165-9. doi: 10.1067/mge.2003.73.
Abstract/Text
BACKGROUND: Although bleeding and perforation are generally recognized major complications of endoscopic mucosal resection, esophageal stricture after endoscopic mucosal resection has not been well studied. Factors associated with the occurrence and severity of esophageal stenosis after endoscopic mucosal resection were investigated.
METHODS: Two hundred sixteen superficial esophageal lesions in 137 consecutive patients who underwent endoscopic mucosal resection from February 1993 through March 2001 were retrospectively studied. The circumferential extent of the mucosal defect after endoscopic mucosal resection was classified into 4 groups: under one fourth, one fourth to one half, one half to three fourths, and over three fourths. The longitudinal length of the mucosal defect was also evaluated. Stenosis was diagnosed when a standard endoscope (11-mm diameter) could not be passed through the stricture.
RESULTS: Esophageal stenosis developed after endoscopic mucosal resection of 13 lesions (6.0%). In all these cases endoscopic mucosal resection resulted in a mucosal defect that involved over three fourths of the luminal circumference. In the subgroup of patients with mucosal defects involving over three fourths of the circumference, those with a mucosal defect over 30 mm long required more frequent balloon dilatation (mean 8 [4.3] times) and the stenosis was of longer duration (mean 16 [17.7] months) than those with defects 30 mm or less in length (respectively, 1 [0.6] times and 2 [1.9] months).
CONCLUSIONS: A circumferential mucosal defect involving over three fourths the circumference of the esophagus after endoscopic mucosal resection was significantly associated with the subsequent development of esophageal stenosis. In addition, mucosal defects longer than 30 mm were associated with greater severity of stenosis. When endoscopic mucosal resection is performed for superficial esophageal lesions, removal of excess mucosa should be avoided.
日本食道学会編：食道癌診療ガイドライン 2022年版、金原出版,2022.
小山恒男、宮田佳典、島谷茂樹、友利彰寿、堀田欣一、吉田操: 【食道m3・sm1癌の診断と遠隔成績】第46回食道色素研究会アンケート調査報告、転移のあったm3・sm1食道癌の特徴．胃と腸．2002;37(1):71-74．.
日本消化器内視鏡学会：食道癌に対する ESD/EMR ガイドライン.日本消化器内視鏡学会雑誌 2020:62(2):221-271.
Minashi K, Nihei K, Mizusawa J, Takizawa K, Yano T, Ezoe Y, Tsuchida T, Ono H, Iizuka T, Hanaoka N, Oda I, Morita Y, Tajika M, Fujiwara J, Yamamoto Y, Katada C, Hori S, Doyama H, Oyama T, Nebiki H, Amagai K, Kubota Y, Nishimura K, Kobayashi N, Suzuki T, Hirasawa K, Takeuchi T, Fukuda H, Muto M.
Efficacy of Endoscopic Resection and Selective Chemoradiotherapy for Stage I Esophageal Squamous Cell Carcinoma.
Gastroenterology. 2019 Aug;157(2):382-390.e3. doi: 10.1053/j.gastro.2019.04.017. Epub 2019 Apr 20.
Abstract/Text
BACKGROUND & AIMS: Esophagectomy is the standard treatment for stage I esophageal squamous cell carcinoma (ESCC). We conducted a single-arm prospective study to confirm the efficacy and safety of selective chemoradiotherapy (CRT) based on findings from endoscopic resection (ER).
METHODS: We performed a prospective study of patients with T1b (SM1-2) N0M0 thoracic ESCC from December 2006 through July 2012; 176 patients underwent ER. Based on the findings from ER, patients received the following: no additional treatment for patients with pT1a tumors with a negative resection margin and no lymphovascular invasion (group A); prophylactic CRT with 41.4 Gy delivered to locoregional lymph nodes for patients with pT1b tumors with a negative resection margin or pT1a tumors with lymphovascular invasion (group B); or definitive CRT (50.4 Gy) with a 9-Gy boost to the primary site for patients with a positive vertical resection margin (group C). Chemotherapy comprised 5-fluorouracil and cisplatin. The primary end point was 3-year overall survival in group B, and the key secondary end point was 3-year overall survival for all patients. If lower limits of 90% confidence intervals for the primary and key secondary end points exceeded the 80% threshold, the efficacy of combined ER and selective CRT was confirmed.
RESULTS: Based on the results from pathology analysis, 74, 87, and 15 patients were categorized into groups A, B, and C, respectively. The 3-year overall survival rates were 90.7% for group B (90% confidence interval, 84.0%-94.7%) and 92.6% in all patients (90% confidence interval, 88.5%-95.2%).
CONCLUSIONS: In a prospective study of patients with T1b (SM1-2) N0M0 thoracic ESCC, we confirmed the efficacy of the combination of ER and selective CRT. Efficacy is comparable to that of surgery, and the combination of ER and selective CRT should be considered as a minimally invasive treatment option. UMIN-Clinical Trials Registry no.: UMIN000000553.
Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
Kato K, Ito Y, Nozaki I, Daiko H, Kojima T, Yano M, Ueno M, Nakagawa S, Takagi M, Tsunoda S, Abe T, Nakamura T, Okada M, Toh Y, Shibuya Y, Yamamoto S, Katayama H, Nakamura K, Kitagawa Y; Japan Esophageal Oncology Group of the Japan Clinical Oncology Group.
Parallel-Group Controlled Trial of Surgery Versus Chemoradiotherapy in Patients With Stage I Esophageal Squamous Cell Carcinoma.
Gastroenterology. 2021 Dec;161(6):1878-1886.e2. doi: 10.1053/j.gastro.2021.08.007. Epub 2021 Aug 10.
Abstract/Text
BACKGROUND & AIMS: Surgery is the standard of care for T1bN0M0 esophageal squamous cell carcinoma (ESCC), whereas chemoradiotherapy (CRT) is a treatment option. This trial aimed to investigate the noninferiority of CRT relative to surgery for T1bN0M0 ESCC.
METHODS: Clinical T1bN0M0 ESCC patients were eligible for enrollment in this prospective nonrandomized controlled study of surgery versus CRT. The primary endpoint was overall survival, which was determined using inverse probability weighting with propensity scoring. Surgery consisted of an esophagectomy with 2- or 3-field lymph node dissection. CRT consisted of 2 courses of 5-fluorouracil (700 mg/m2) on days 1-4 and cisplatin (70 mg/m2) on day 1 every 4 weeks with concurrent radiation (60 Gy).
RESULTS: From December 20, 2006 to February 5, 2013, a total of 368 patients were enrolled in the nonrandomized portion of the study. The patient characteristics in surgery arm and CRT arm, respectively, were as follows: median age, 62 and 65 years; proportion of males, 82.8% and 88.1%; and proportion of performance status 0, 99.5% and 98.1%. Comparisons were made using the nonrandomized groups. The 5-year overall survival rate was 86.5% in the surgery arm and 85.5% in the CRT arm (adjusted hazard ratio, 1.05; 95% confidence interval, 0.67-1.64 [<1.78]). The complete response rate in the CRT arm was 87.3% (95% confidence interval, 81.1-92.1). The 5-year progression-free survival rate was 81.7% in the surgery arm and 71.6% in the CRT arm. Treatment-related deaths occurred in 2 patients in the surgery arm and none in the CRT arm.
CONCLUSIONS: CRT is noninferior to surgery and should be considered for the treatment of T1bN0M0 ESCC.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Marubashi S, Takahashi A, Kakeji Y, Hasegawa H, Ueno H, Eguchi S, Endo I, Goi T, Saiura A, Sasaki A, Takiguchi S, Takeuchi H, Tanaka C, Hashimoto M, Hiki N, Horiguchi A, Masaki T, Yoshida K, Gotoh M, Konno H, Yamamoto H, Miyata H, Seto Y, Kitagawa Y; National Clinical Database.
Surgical outcomes in gastroenterological surgery in Japan: Report of the National Clinical Database 2011-2019.
Ann Gastroenterol Surg. 2021 Sep;5(5):639-658. doi: 10.1002/ags3.12462. Epub 2021 Apr 9.
Abstract/Text
BACKGROUND: We aimed to present the 2019 annual report of the gastroenterological section of the National Clinical Database (NCD).
METHODS: We reviewed 609,589 cases recorded in 2019 and 5,029,764 cases registered from 2011 to 2019 for the 115 selected gastroenterological surgical procedures.
RESULTS: The main features of gastroenterological surgery in Japan were similar to those described in the 2018 annual report, namely, that 1) operative numbers gradually increased in all procedures, except gastrectomy and hepatectomy, which decreased in these years; 2) in all eight major gastroenterological surgeries, the age distribution tended toward older patients; 3) the morbidity of esophagectomy, hepatectomy, and pancreaticoduodenectomy increased, but mortality was minimized in all procedures; 4) all eight major gastroenterological procedures have increasingly been performed under laparoscopy; and 5) board-certified surgeons were increasingly involved. These trends in recent years were more prominent in 2019.
CONCLUSIONS: Thanks to the continuous cooperation and dedication of the surgeons, medical staff, and surgical clinical reviewers who registered the clinical data into the NCD, it is possible to understand the comprehensive landscape of surgery in Japan and to disclose new evidence in this field. The Japanese Society of Gastroenterological Surgery will continue to promote the value of this database and encourage the use of feedback and clinical studies using the NCD, now and in the future. Generating further approaches to surgical quality improvement are important directions for future research.
© 2021 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterology.
Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, Nakamura T, Yabusaki H, Aoyama N, Kurita A, Ikeda K, Kanda T, Tsujinaka T, Nakamura K, Fukuda H.
A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907).
Ann Surg Oncol. 2012 Jan;19(1):68-74. doi: 10.1245/s10434-011-2049-9. Epub 2011 Aug 31.
Abstract/Text
BACKGROUND: Patients with esophageal carcinoma receiving postoperative chemotherapy showed superior disease-free survival than those receiving surgery alone in a Japan Clinical Oncology Group trial (JCOG9204). The purpose of this study was to evaluate optimal perioperative timing-that is, before or after surgery-for providing chemotherapy in patients with locally advanced esophageal squamous cell carcinoma.
METHODS: Eligible patients with clinical stage II or III, excluding T4, squamous cell carcinoma were randomized to undergo surgery followed (group 1) or preceded (group 2) by chemotherapy consisting of two courses of cisplatin plus 5-fluorouracil. The primary end point was progression-free survival.
RESULTS: We randomized 330 patients, with 166 assigned to group 1 and 164 to group 2, between May 2000 and May 2006. The planned interim analysis was conducted after completion of patient accrual. Progression-free survival did not reach the stopping boundary, but overall survival in group 2 was superior to that of group 1 (P = 0.01). Therefore, the Data and Safety Monitoring Committee recommended early publication. Updated analyses showed the 5-year overall survival to be 43% in group 1 and 55% in group 2 (hazard ratio 0.73, 95% confidence interval 0.54-0.99, P = 0.04), where the median follow-up of censored patients was 61.6 months. Concerning operative morbidity, renal dysfunction after surgery in group 2 was slightly higher than in group 1.
CONCLUSIONS: Preoperative chemotherapy with cisplatin plus 5-fluorouracil can be regarded as standard treatment for patients with stage II/III squamous cell carcinoma.
Committee for Scientific Affairs, The Japanese Association for Thoracic Surgery; Shimizu H, Endo S, Natsugoe S, Doki Y, Hirata Y, Kobayashi J, Motomura N, Nakano K, Nishida H, Okada M, Saiki Y, Saito A, Sato Y, Tanemoto K, Toh Y, Tsukihara H, Wakui S, Yokomise H, Masuda M, Yokoi K, Okita Y.
Thoracic and cardiovascular surgery in Japan in 2016 : Annual report by The Japanese Association for Thoracic Surgery.
Gen Thorac Cardiovasc Surg. 2019 Apr;67(4):377-411. doi: 10.1007/s11748-019-01068-9.
Abstract/Text
Smithers BM, Gotley DC, Martin I, Thomas JM.
Comparison of the outcomes between open and minimally invasive esophagectomy.
Ann Surg. 2007 Feb;245(2):232-40. doi: 10.1097/01.sla.0000225093.58071.c6.
Abstract/Text
OBJECTIVE: We report patient outcomes from esophageal resection with respect to morbidity and cancer survival comparing open thoracotomy and laparotomy (Open), with a thoracoscopic/laparotomy approach (Thoracoscopic-Assisted) and a total thoracoscopic/laparoscopic approach (Total MIE).
METHODS: From a prospective database of all patients managed with cancer of the esophagus or esophagogastric junction, patients who had a resection using one of three techniques were analyzed to assess postoperative variables, adequacy of cancer clearance, and survival.
RESULTS: The number of patients for each procedure was as follows: Open, 114; Thoracoscopic-Assisted, 309; and Total MIE, 23. The groups were comparable with respect to preoperative variables. The differences in the postoperative variables were: less median blood loss in the Thoracoscopic-Assisted (400 mL) and Total MIE (300 mL) groups versus Open (600 mL); longer time for Total MIE (330 minutes) versus Thoracoscopic-Assisted (285 minutes) and Open (300 minutes); longer median time in hospital for Open (14 days) versus Thoracoscopic-Assisted (13 days), Total MIE (11 days) and less stricture formation in the Open (6.1%) versus Thoracoscopic-Assisted (21.6%), Total MIE (36%). There were no differences in lymph node retrieval for each of the approaches. Open had more stage III patients (65.8%) versus Thoracoscopic-Assisted (34.4%), Total MIE (52.1%). There was no difference in survival when the groups were compared stage for stage for overall median or 3-year survival.
CONCLUSION: Minimally invasive techniques to resect the esophagus in patients with cancer were confirmed to be safe and comparable to an open approach with respect to postoperative recovery and cancer survival.
Luketich JD, Alvelo-Rivera M, Buenaventura PO, Christie NA, McCaughan JS, Litle VR, Schauer PR, Close JM, Fernando HC.
Minimally invasive esophagectomy: outcomes in 222 patients.
Ann Surg. 2003 Oct;238(4):486-94; discussion 494-5. doi: 10.1097/01.sla.0000089858.40725.68.
Abstract/Text
OBJECTIVE: To assess our outcomes after minimally invasive esophagectomy (MIE).
SUMMARY BACKGROUND DATA: Esophagectomy has traditionally been performed by open methods. Results from most series include mortality rates in excess of 5% and hospital stays frequently greater than 10 days. MIE has the potential to improve these results, but only a few small series have been reported. This report summarizes our experience of 222 cases.
METHODS: From 1996 to 2002, MIE was performed in 222 patients. Indications for operation included high-grade dysplasia (n = 47) and cancer (n = 175). Neoadjuvant chemotherapy was used in 78 (35.1%) and radiation in 36 (16.2%). Initially, a laparoscopic transhiatal approach was used (n = 8), but subsequently our approach evolved to include thoracoscopic mobilization (n = 214).
RESULTS: There were 186 men and 36 women. Median age was 66.5 years (range, 39-89). Nonemergent conversion to open procedure was required in 16 patients (7.2%). MIE was successfully completed in 206 (92.8%) patients. The median intensive care unit stay was 1 day (range, 1-30); hospital stay was 7 days (range, 3-75). Operative mortality was 1.4% (n = 3). Anastomotic leak rate was 11.7% (n = 26). At a mean follow-up of 19 months (range, 1-68), quality of life scores were similar to preoperative values and population norms. Stage specific survival was similar to open series.
CONCLUSIONS: MIE offers results as good as or better than open operation in our center with extensive minimally invasive and open experience. In this single institution experience, we observed a lower mortality rate (1.4%) and shorter hospital stay (7 days) than most open series. Given these results, we are now developing an intergroup trial (ECOG 2202) to assess MIE in a multicenter setting.
Zingg U, McQuinn A, DiValentino D, Esterman AJ, Bessell JR, Thompson SK, Jamieson GG, Watson DI.
Minimally invasive versus open esophagectomy for patients with esophageal cancer.
Ann Thorac Surg. 2009 Mar;87(3):911-9. doi: 10.1016/j.athoracsur.2008.11.060.
Abstract/Text
BACKGROUND: Minimally invasive esophagectomy (MIE) compared with open esophagectomy (OE) has been shown to have clinical advantages, but selection bias is present.
METHODS: All patients undergoing MIE or OE for cancer between 1999 and 2007 were eligible for analysis. To minimize selection bias, only patients who also met the selection criteria for the thoracoscopic approach were included in the open esophagectomy group.
RESULTS: Fifty-six patients underwent MIE and 98 OE. No significant differences in demographics or pathologic data between groups occurred, with the exception of thoracic epidural analgesia (OE 98%, MIE 71.1%, p < 0.001), and neoadjuvant treatment (OE 50.5%, MIE 71.4%, p = 0.016). Morbidity and in-hospital death were not significantly different. Duration of surgery was longer in MIE (250 vs 209 minutes, p < 0.001) and blood loss less (320 mL vs 857 mL, p < 0.001). Intensive care unit stay was shorter in MIE (3.0 vs 6.8 days, p = 0.022). The relative risk (RR) for in-hospital death was 0.57 (p = 0.475) if the patients underwent MIE. After adjusting for thoracic epidural analgesia, the RR was 0.29 (p = 0.213) for the MIE group. The RR for surgical morbidity was 1.47 (p = 0.154) for patients undergoing MIE. Neoadjuvant treatment increased the RR for surgical morbidity to 1.78 (p = 0.028). No difference between the two groups concerning survival occurred.
CONCLUSIONS: The MIE is comparable with the OE. In MIE, neoadjuvant treatment increased the risk of surgical morbidity. Thoracic epidural analgesia in MIE reduced the risk of in-hospital death and should be considered for all patients undergoing esophagectomy.
Osugi H, Takemura M, Higashino M, Takada N, Lee S, Ueno M, Tanaka Y, Fukuhara K, Hashimoto Y, Fujiwara Y, Kinoshita H.
Learning curve of video-assisted thoracoscopic esophagectomy and extensive lymphadenectomy for squamous cell cancer of the thoracic esophagus and results.
Surg Endosc. 2003 Mar;17(3):515-9. doi: 10.1007/s00464-002-9075-4. Epub 2002 Oct 29.
Abstract/Text
BACKGROUND: The efficacy of thoracoscopic radical esophagectomy for cancer of the thoracic esophagus and the learning curve required have yet to be clearly established.
METHODS: Eighty treatment-naive patients with esophageal cancer without contiguous spread underwent esophageal mobilization and extensive mediastinal lymphadenectomy through a 5-cm minithoracotomy and four trocar ports. The outcomes in the first 34 patients (group 1) and the last 46 patients (group 2) were compared.
RESULTS: There were no differences in background or clinicopathologic factors between the two groups. The duration of the thoracoscopic procedure and blood loss were less (p <0.0001), the incidence of postoperative pulmonary infection was less (p = 0.0127), and the number of mediastinal nodes retrieved was greater (p = 0.0076) in group 2. Multivariate analysis demonstrated that surgical experience (number of cases performed) predicted the risk of pulmonary infection (p = 0.0331).
CONCLUSION: Video-assisted thoracoscopic radical esophagectomy can be performed with safety and efficacy comparable to those of open esophagectomy. Morbidity decreases with the surgeon's experience.
Kataoka K, Takeuchi H, Mizusawa J, Ando M, Tsubosa Y, Koyanagi K, Daiko H, Matsuda S, Nakamura K, Kato K, Kitagawa Y; Japan Esophageal Oncology Group/Japan Clinical Oncology Group.
A randomized Phase III trial of thoracoscopic versus open esophagectomy for thoracic esophageal cancer: Japan Clinical Oncology Group Study JCOG1409.
Jpn J Clin Oncol. 2016 Feb;46(2):174-7. doi: 10.1093/jjco/hyv178. Epub 2016 Jan 4.
Abstract/Text
A randomized Phase III study was commenced in May 2015 to confirm the non-inferiority of thoracoscopic esophagectomy to open esophagectomy in terms of overall survival for clinical Stage I-III esophageal cancer. A total of 300 patients will be accrued from Japanese institutions over 6 years. The primary endpoint is overall survival. The secondary endpoints are relapse-free survival, proportion of patients with R0 resection, proportion of patients who underwent re-operation, adverse events, postoperative respiratory function change, postoperative quality-of-life score (EORTC QLQ-C30), and proportion of patients who need conversion from thoracoscopic surgery to open surgery. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000017628.
© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Takeuchi H, Ando M, Tsubosa Y, et al. A randomized controlled phase III trial comparing thoracoscopic esophagectomy and open esophagectomy for thoracic esophageal cancer: JCOG1409 (MONET trial). Journal of Clinical Oncology2024. p. 249-.
Kato K, Ito Y, Daiko H, Ozawa S, Ogata T, Hara H, Kojima T, Abe T, Bamba T, Watanabe M, Kawakubo H, Shibuya Y, Tsubosa Y, Takegawa N, Kajiwara T, Baba H, Ueno M, Machida R, Nakamura K, Kitagawa Y. A randomized controlled phase III trial comparing two chemotherapy regimen and chemoradiotherapy regimen as neoadjuvant treatment for locally advanced esophageal cancer, JCOG1109 NExT study. https://doi.org/101200/JCO2022404_suppl238. American Society of Clinical Oncology; 2022 Jan 19;40(4_suppl):238–238.
Kelly RJ, Ajani JA, Kuzdzal J, Zander T, Van Cutsem E, Piessen G, Mendez G, Feliciano J, Motoyama S, Lièvre A, Uronis H, Elimova E, Grootscholten C, Geboes K, Zafar S, Snow S, Ko AH, Feeney K, Schenker M, Kocon P, Zhang J, Zhu L, Lei M, Singh P, Kondo K, Cleary JM, Moehler M; CheckMate 577 Investigators.
Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer.
N Engl J Med. 2021 Apr 1;384(13):1191-1203. doi: 10.1056/NEJMoa2032125.
Abstract/Text
BACKGROUND: No adjuvant treatment has been established for patients who remain at high risk for recurrence after neoadjuvant chemoradiotherapy and surgery for esophageal or gastroesophageal junction cancer.
METHODS: We conducted CheckMate 577, a global, randomized, double-blind, placebo-controlled phase 3 trial to evaluate a checkpoint inhibitor as adjuvant therapy in patients with esophageal or gastroesophageal junction cancer. Adults with resected (R0) stage II or III esophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy and had residual pathological disease were randomly assigned in a 2:1 ratio to receive nivolumab (at a dose of 240 mg every 2 weeks for 16 weeks, followed by nivolumab at a dose of 480 mg every 4 weeks) or matching placebo. The maximum duration of the trial intervention period was 1 year. The primary end point was disease-free survival.
RESULTS: The median follow-up was 24.4 months. Among the 532 patients who received nivolumab, the median disease-free survival was 22.4 months (95% confidence interval [CI], 16.6 to 34.0), as compared with 11.0 months (95% CI, 8.3 to 14.3) among the 262 patients who received placebo (hazard ratio for disease recurrence or death, 0.69; 96.4% CI, 0.56 to 0.86; P<0.001). Disease-free survival favored nivolumab across multiple prespecified subgroups. Grade 3 or 4 adverse events that were considered by the investigators to be related to the active drug or placebo occurred in 71 of 532 patients (13%) in the nivolumab group and 15 of 260 patients (6%) in the placebo group. The trial regimen was discontinued because of adverse events related to the active drug or placebo in 9% of the patients in the nivolumab group and 3% of those in the placebo group.
CONCLUSIONS: Among patients with resected esophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy, disease-free survival was significantly longer among those who received nivolumab adjuvant therapy than among those who received placebo. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 577 ClinicalTrials.gov number, NCT02743494.).
Copyright © 2021 Massachusetts Medical Society.
Ishikura S, Nihei K, Ohtsu A, Boku N, Hironaka S, Mera K, Muto M, Ogino T, Yoshida S.
Long-term toxicity after definitive chemoradiotherapy for squamous cell carcinoma of the thoracic esophagus.
J Clin Oncol. 2003 Jul 15;21(14):2697-702. doi: 10.1200/JCO.2003.03.055.
Abstract/Text
PURPOSE: To assess the long-term toxicity after definitive chemoradiotherapy (CRT) for squamous cell carcinoma (SCC) of the esophagus.
PATIENTS AND METHODS: Patients newly diagnosed with SCC of the esophagus and treated with definitive CRT between 1992 and 1999 in our institution were recruited from our database on the basis of the following criteria: age RESULTS: A total of 139 patients were recruited, and their characteristics were as follows: median age, 62 years (range, 38 to 75 years); 121 males and 18 females; 96 patients PS 0, 42 patients PS 1, and one patient PS 2; 15 patients T1, 11 patients T2, 60 patients T3, and 53 patients T4; and 101 patients M0, 38 patients M1a. With a median follow-up of 53 months, the median survival time and 5-year survival rate were 21 months and 29%, respectively. Of 78 patients with complete remission, two patients died as a result of acute myocardial infarction. Grade 2, 3, and 4 late toxicities occurred with the following incidences: pericarditis in eight patients, seven patients, and one patient, respectively; heart failure in zero, zero, and two patients; pleural effusion in seven, eight, and zero patients; and radiation pneumonitis in one patient, three patients, and zero patients, respectively.
CONCLUSION: Definitive CRT for SCC of the esophagus is effective with substantial toxicities. Additional investigation to minimize the normal tissue toxicities is warranted.
Kato K, Muro K, Minashi K, Ohtsu A, Ishikura S, Boku N, Takiuchi H, Komatsu Y, Miyata Y, Fukuda H; Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group (JCOG).
Phase II study of chemoradiotherapy with 5-fluorouracil and cisplatin for Stage II-III esophageal squamous cell carcinoma: JCOG trial (JCOG 9906).
Int J Radiat Oncol Biol Phys. 2011 Nov 1;81(3):684-90. doi: 10.1016/j.ijrobp.2010.06.033. Epub 2010 Oct 6.
Abstract/Text
PURPOSE: In this Phase II study, we evaluated the efficacy and toxicity of chemoradiotherapy (CRT) with cisplatin (CDDP) and 5-fluorouracil (5-FU) for Stage II-III esophageal squamous cell carcinoma (ESCC).
PATIENTS AND METHODS: Patients with clinical Stage II-III (T1N1M0 or T2-3N0-1M0) thoracic ESCC were enrolled between April 2000 and March 2002. Chemotherapy comprised two courses of protracted infusion of 5-FU (400 mg/m(2)/day) on Days 1-5 and 8-12, and 2-h infusion of CDDP (40 mg/m(2)) on Days 1 and 8; this regimen was repeated every 5 weeks. Concurrent radiotherapy involved 60-Gy irradiation (30 fractions) for 8 weeks with a 2-week break. Responders received two courses of 5-FU (800 mg/m(2)/day) on Days 1-5 and CDDP (80 mg/m(2)) on Day 1. Final analysis was conducted in March 2007. Survival and late toxicities were monitored for 5 years.
RESULTS: The characteristics of the 76 patients enrolled were as follows: median age, 61 years; male/female, 68/8; performance status 0/1, 59/17 patients; Stage IIA/IIB/III, 26/12/38 patients. Of the 74 eligible patients, 46 (62.2%) achieved complete response. Median survival time was 29 months, with 3- and 5-year survival rates of 44.7% and 36.8%, respectively. Acute toxicities included Grade 3/4 esophagitis (17%), nausea (17%), hyponatremia (16%), and infection without neutropenia (12%). Late toxicities comprised Grade 3/4 esophagitis (13%), pericardial (16%) and pleural (9%) effusion, and radiation pneumonitis (4%), causing 4 deaths.
CONCLUSIONS: CRT is effective for Stage II-III ESCC with manageable acute toxicities and can provide a nonsurgical treatment option. However, further improvement is required for reduction in late toxicity.
Copyright © 2011 Elsevier Inc. All rights reserved.
Zenda S, Hironaka S, Taku K, Sato H, Hashimoto T, Hasuike N, Boku N, Tsubosa Y, Ono H, Nishimura T.
Optimal timing of endoscopic evaluation of the primary site of esophageal cancer after chemoradiotherapy or radiotherapy: a retrospective analysis.
Dig Endosc. 2009 Oct;21(4):245-51. doi: 10.1111/j.1443-1661.2009.00900.x.
Abstract/Text
BACKGROUND: Although use of gastrointestinal endoscopy for response evaluation in patients with esophageal cancer undergoing chemoradiotherapy or radiotherapy (CRT/RT) treatment is widely accepted, optimal timing for evaluation has not been sufficiently investigated. Here, we investigated optimal timing of primary site response evaluation in esophageal cancer patients treated with CRT/RT.
PATIENTS AND METHODS: This study examined esophageal cancer patients who underwent CRT/RT between September 2002 and December 2004. Time to complete response (CR) at the primary site was assessed in patients designated as CR at the primary site, while progression-free survival at the primary site (PFSp) was assessed in patients designated as incomplete response at the primary site.
RESULTS: Eighty-three patients were enrolled in this study. Median total RT dose was 60 Gy (range, 50-60 Gy), and median RT duration was 53 days (range, 35-74 days). Mean time to CR at the primary site was 97 days (range, 52-201 days). In four patients, although initial examination of biopsy specimens found evidence of viable cancer cells within 75 days of treatment initiation, subsequent examination found no such evidence, and the patients were thus designated as CR. Median PFSp was 149 days (range, 67-399 days), and PFSp rate at 90 days was 97%. Median interval between the previous examination and initial primary progressive disease was 37 days.
CONCLUSION: Recommended time of first response evaluation for esophageal cancer following initiation of CRT/RT was found to be between 75 and 90 days. Subsequent evaluation should be carried out approximately one month following non-CR/non-progressive disease declassification.
Yano T, Muto M, Hattori S, Minashi K, Onozawa M, Nihei K, Ishikura S, Ohtsu A, Yoshida S.
Long-term results of salvage endoscopic mucosal resection in patients with local failure after definitive chemoradiotherapy for esophageal squamous cell carcinoma.
Endoscopy. 2008 Sep;40(9):717-21. doi: 10.1055/s-2008-1077480. Epub 2008 Sep 4.
Abstract/Text
BACKGROUND AND STUDY AIMS: Local failure after definitive chemoradiotherapy (CRT) in patients with esophageal cancer remains one of the major problems in finding a cure. Endoscopic mucosal resection (EMR) is one treatment option when failure lesions are superficial. However, there are no relevant long-term survival data. The aim of this study was to clarify the long-term survival of salvage EMR.
PATIENTS AND METHODS: Between January 1998 and March 2004, 289 patients with esophageal squamous cell carcinoma were treated with definitive CRT at the National Cancer Center Hospital East, Japan. Of these 289 patients, 21 patients with local failure without lymph-node or distant metastases were treated with salvage EMR. The technique of salvage EMR involved a strip biopsy method. We retrospectively analyzed the long-term survival data for the patients who underwent salvage EMR.
RESULTS: At a median follow-up period of 54 months (range, 16-108 months), eight of 21 patients (38%) were alive with no recurrence and two patients had died from another disease but with no recurrence of esophageal cancer. Local recurrence after EMR was detected in four patients, with local and lymph-node recurrence in two patients, and lymph-node and/or distant metastases in five patients. The 5-year survival rate from the initiation of salvage EMR was 49.1%. There were no severe complications associated with EMR.
CONCLUSION: EMR is one of the curative salvage treatment options for local failure after definitive CRT, if the failure lesion is superficial and there are no lymph-node or distant metastases.
Tachimori Y, Kanamori N, Uemura N, Hokamura N, Igaki H, Kato H.
Salvage esophagectomy after high-dose chemoradiotherapy for esophageal squamous cell carcinoma.
J Thorac Cardiovasc Surg. 2009 Jan;137(1):49-54. doi: 10.1016/j.jtcvs.2008.05.016.
Abstract/Text
OBJECTIVE: Chemoradiotherapy is a popular definitive therapy for esophageal carcinoma among many patients and oncologists. Although the complete response rates are high and short-term survival is favorable after chemoradiotherapy, persistent or recurrent locoregional disease is frequent. Salvage surgery is the sole curative intent treatment option for this course of the disease. The present study evaluates the safety and value of salvage esophagectomy for locoregional failure after high-dose definitive chemoradiotherapy for esophageal squamous cell carcinoma.
METHODS: We reviewed 59 consecutive patients with thoracic esophageal squamous cell carcinoma who underwent salvage esophagectomy after definitive chemoradiotherapy. All patients received more than 60 Gy of radiation plus concurrent chemotherapy for curative intent. The data were compared with those of patients who received esophagectomy without preoperative therapy.
RESULTS: Postoperative morbidity and mortality rates were increased among patients who underwent salvage esophagectomy compared with those who underwent esophagectomy without preoperative therapy (mean hospital stay, 38 vs 33 days; anastomotic leak rates, 31% vs 25%; respiratory complication rates, 31% vs 20%; reintubation within 1 week, 2% vs 2%; hospital mortality rates, 8% vs 2%). Tracheobronchial necrosis and gastric conduit necrosis were highly lethal complications after salvage esophagectomy; 3-year postoperative survivals were 38% and 58%, respectively.
CONCLUSION: Patients who underwent salvage esophagectomy after definitive high-dose chemoradiotherapy had increased morbidity and mortality. Nevertheless, this is acceptable in view of the potential long-term survival after salvage esophagectomy. Such treatment should be considered for carefully selected patients at specialized centers.
Takeuchi H, Saikawa Y, Oyama T, Ozawa S, Suda K, Wada N, Takahashi T, Nakamura R, Shigematsu N, Ando N, Kitajima M, Kitagawa Y.
Factors influencing the long-term survival in patients with esophageal cancer who underwent esophagectomy after chemoradiotherapy.
World J Surg. 2010 Feb;34(2):277-84. doi: 10.1007/s00268-009-0331-9.
Abstract/Text
BACKGROUND: Salvage esophagectomy is potentially the only treatment available that can offer a chance of long-term survival when definitive chemoradiotherapy (CRT) fails to achieve local control for patients with esophageal squamous cell carcinoma (ESCC). However, salvage esophagectomy is a highly invasive procedure with various postoperative complications compared to planned esophagectomy after neoadjuvant chemoradiotherapy (CRT). We hypothesize that severe postoperative complications may affect not only surgical mortality but also tumor recurrence and long-term survival for patients with salvage esophagectomy after definitive CRT.
METHODS: For the present study we reviewed the surgical procedures, postoperative complications, and the prognosis of 65 consecutive patients with thoracic ESCC who underwent the esophagectomy after neoadjuvant (neoadjuvant group: n = 40) or definitive (salvage group: n = 25) CRT.
RESULTS: Most patients underwent right-transthoracic extended esophagectomy and reconstruction using gastric conduit by way of subcutaneous route with left cervical anastomosis. The incidence of postoperative pneumonia was found to be higher in the salvage group than in the neoadjuvant group. In both groups, the survival of patients with R0 resection was significantly better than those with R1/R2 resection. Moreover, in the salvage group, the postoperative survival rate of patients with pneumonia or bacteremia/sepsis was significantly lower than that for patients who did not suffer the same complications. In the neoadjuvant group, R0 resection was selected to be the only independent prognostic factor in univariate and multivariate analysis. In contrast, in the salvage group, R0 resection and bacteremia/sepsis remained significant and were independent of the other factors in multivariate analysis.
CONCLUSIONS: This study reveals that postoperative morbidity affects not only the perioperative mortality but also the long-term survival of patients with ESCC who undergo salvage esophagectomy after definitive CRT.
Takeuchi H, Ito Y, Machida R, Kato K, Onozawa M, Minashi K, Yano T, Nakamura K, Tsushima T, Hara H, Okuno T, Hironaka S, Nozaki I, Ura T, Chin K, Kojima T, Seki S, Sakanaka K, Fukuda H, Kitagawa Y; Japan Esophageal Oncology Group of the Japan Clinical Oncology Group.
A Single-Arm Confirmatory Study of Definitive Chemoradiation Therapy Including Salvage Treatment for Clinical Stage II/III Esophageal Squamous Cell Carcinoma (JCOG0909 Study).
Int J Radiat Oncol Biol Phys. 2022 Nov 1;114(3):454-462. doi: 10.1016/j.ijrobp.2022.07.007. Epub 2022 Aug 4.
Abstract/Text
PURPOSE: Definitive chemoradiotherapy (CRT) is the standard treatment for patients with locally advanced esophageal cancer (EC) who refuse surgery as the initial therapy. However, poor survival, a high incidence of late toxicities, and severe complications after salvage surgery remain issues to be resolved. This single-arm multicenter trial (JCOG0909) aimed to confirm the efficacy of CRT modifications, including salvage treatment for reducing CRT-related toxicities and facilitating salvage treatment for improved survival.
METHODS AND MATERIALS: Patients with clinical stage II/III EC (International Union Against Cancer sixth edition, non-T4) were eligible. Chemotherapy comprised cisplatin (75 mg/m2 on days 1 and 29) and 5-fluorouracil (1000 mg/m2/d on days 1-4 and 29-32). Radiation therapy was administered at a total dose of 50.4 Gy. Good responders received 1 to 2 additional cycles of chemotherapy. For residual or recurrent disease, salvage endoscopic resection or salvage surgery was performed based on specific criteria. The primary endpoint was 3-year overall survival (OS). The calculated sample size was 95 patients, with a 1-sided alpha of 5% and a power of 80%. The expected and threshold 3-year OS were 55% and 42%, respectively.
RESULTS: Overall, 96 patients were enrolled, and 94 were included in the efficacy analysis. A complete response was achieved in 55 patients (59%). Salvage endoscopic resection and salvage surgery were performed in 5 (5%) and 25 patients (27%), respectively. R0 resection by salvage surgery was achieved in 19 patients (76%). Five patients (20%) showed grade 3 or 4 early operative complications, and 9 patients (9.6%) showed grade 3 late toxicities during the long-term follow-up. The 3-year OS was 74.2% (90% confidence interval, 65.9%-80.8%).
CONCLUSION: The combination of definitive CRT and salvage treatment has lower CRT-related toxicities and yields good OS, thus making it a promising novel treatment option for patients with locally advanced EC.
Copyright © 2022 Elsevier Inc. All rights reserved.
日本食道学会：食道癌に対するオキサリプラチンの使用について [Internet]. Available from: https://www.esophagus.jp/private/information/news_20191213.html
Kato K, Cho BC, Takahashi M, Okada M, Lin CY, Chin K, Kadowaki S, Ahn MJ, Hamamoto Y, Doki Y, Yen CC, Kubota Y, Kim SB, Hsu CH, Holtved E, Xynos I, Kodani M, Kitagawa Y.
Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial.
Lancet Oncol. 2019 Nov;20(11):1506-1517. doi: 10.1016/S1470-2045(19)30626-6. Epub 2019 Sep 30.
Abstract/Text
BACKGROUND: Chemotherapy for patients with advanced oesophageal squamous cell carcinoma offers poor long-term survival prospects. We report the final analysis from our study of the immune checkpoint PD-1 inhibitor nivolumab versus chemotherapy in patients with previously treated advanced oesophageal squamous cell carcinoma.
METHODS: We did a multicentre, randomised, open-label, phase 3 trial (ATTRACTION-3) at 90 hospitals and cancer centres in Denmark, Germany, Italy, Japan, South Korea, Taiwan, the UK, and the USA. We enrolled patients aged 20 years and older with unresectable advanced or recurrent oesophageal squamous cell carcinoma (regardless of PD-L1 expression), at least one measurable or non-measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a baseline Eastern Cooperative Oncology Group performance status of 0-1, and who were refractory or intolerant to one previous fluoropyrimidine-based and platinum-based chemotherapy and had a life expectancy of at least 3 months. Patients were randomly assigned (1:1) to either nivolumab (240 mg for 30 min every 2 weeks) or investigator's choice of chemotherapy (paclitaxel 100 mg/m2 for at least 60 min once per week for 6 weeks then 1 week off; or docetaxel 75 mg/m2 for at least 60 min every 3 weeks), all given intravenously. Treatment continued until disease progression assessed by the investigator per RECIST version 1.1 or unacceptable toxicity. Randomisation was done using an interactive web response system with a block size of four and stratified according to geographical region (Japan vs rest of the world), number of organs with metastases, and PD-L1 expression. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival, defined as the time from randomisation until death from any cause, in the intention-to-treat population that included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT02569242, and follow-up for long-term outcomes is ongoing.
FINDINGS: Between Jan 7, 2016, and May 25, 2017, we assigned 419 patients to treatment: 210 to nivolumab and 209 to chemotherapy. At the time of data cutoff on Nov 12, 2018, median follow-up for overall survival was 10·5 months (IQR 4·5-19·0) in the nivolumab group and 8·0 months (4·6-15·2) in the chemotherapy group. At a minimum follow-up time (ie, time from random assignment of the last patient to data cutoff) of 17·6 months, overall survival was significantly improved in the nivolumab group compared with the chemotherapy group (median 10·9 months, 95% CI 9·2-13·3 vs 8·4 months, 7·2-9·9; hazard ratio for death 0·77, 95% CI 0·62-0·96; p=0·019). 38 (18%) of 209 patients in the nivolumab group had grade 3 or 4 treatment-related adverse events compared with 131 (63%) of 208 patients in the chemotherapy group. The most frequent grade 3 or 4 treatment-related adverse events were anaemia (four [2%]) in the nivolumab group and decreased neutrophil count (59 [28%]) in the chemotherapy group. Five deaths were deemed treatment-related: two in the nivolumab group (one each of interstitial lung disease and pneumonitis) and three in the chemotherapy group (one each of pneumonia, spinal cord abscess, and interstitial lung disease).
INTERPRETATION: Nivolumab was associated with a significant improvement in overall survivaland a favourable safety profile compared with chemotherapy in previously treated patients with advanced oesophageal squamous cell carcinoma, and might represent a new standard second-line treatment option for these patients.
FUNDING: ONO Pharmaceutical Company and Bristol-Myers Squibb.
Copyright © 2019 Elsevier Ltd. All rights reserved.
Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, Doi T, Moriwaki T, Kim SB, Lee SH, Bennouna J, Kato K, Shen L, Enzinger P, Qin SK, Ferreira P, Chen J, Girotto G, de la Fouchardiere C, Senellart H, Al-Rajabi R, Lordick F, Wang R, Suryawanshi S, Bhagia P, Kang SP, Metges JP; KEYNOTE-181 Investigators.
Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer.
J Clin Oncol. 2020 Dec 10;38(35):4138-4148. doi: 10.1200/JCO.20.01888. Epub 2020 Oct 7.
Abstract/Text
PURPOSE: Patients with advanced esophageal cancer have a poor prognosis and limited treatment options after first-line chemotherapy.
PATIENTS AND METHODS: In this open-label, phase III study, we randomly assigned (1:1) 628 patients with advanced/metastatic squamous cell carcinoma or adenocarcinoma of the esophagus, that progressed after one prior therapy, to pembrolizumab 200 mg every 3 weeks for up to 2 years or chemotherapy (investigator's choice of paclitaxel, docetaxel, or irinotecan). Primary end points were overall survival (OS) in patients with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 10, in patients with squamous cell carcinoma, and in all patients (one-sided α 0.9%, 0.8%, and 0.8%, respectively).
RESULTS: At final analysis, conducted 16 months after the last patient was randomly assigned, OS was prolonged with pembrolizumab versus chemotherapy for patients with CPS ≥ 10 (median, 9.3 v 6.7 months; hazard ratio [HR], 0.69 [95% CI, 0.52 to 0.93]; P = .0074). Estimated 12-month OS rate was 43% (95% CI, 33.5% to 52.1%) with pembrolizumab versus 20% (95% CI, 13.5% to 28.3%) with chemotherapy. Median OS was 8.2 months versus 7.1 months (HR, 0.78 [95% CI, 0.63 to 0.96]; P = .0095) in patients with squamous cell carcinoma and 7.1 months versus 7.1 months (HR, 0.89 [95% CI, 0.75 to 1.05]; P = .0560) in all patients. Grade 3-5 treatment-related adverse events occurred in 18.2% of patients with pembrolizumab versus 40.9% in those who underwent chemotherapy.
CONCLUSION: Pembrolizumab prolonged OS versus chemotherapy as second-line therapy for advanced esophageal cancer in patients with PD-L1 CPS ≥ 10, with fewer treatment-related adverse events.
Sun JM, Shen L, Shah MA, Enzinger P, Adenis A, Doi T, Kojima T, Metges JP, Li Z, Kim SB, Cho BC, Mansoor W, Li SH, Sunpaweravong P, Maqueda MA, Goekkurt E, Hara H, Antunes L, Fountzilas C, Tsuji A, Oliden VC, Liu Q, Shah S, Bhagia P, Kato K; KEYNOTE-590 Investigators.
Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study.
Lancet. 2021 Aug 28;398(10302):759-771. doi: 10.1016/S0140-6736(21)01234-4.
Abstract/Text
BACKGROUND: First-line therapy for advanced oesophageal cancer is currently limited to fluoropyrimidine plus platinum-based chemotherapy. We aimed to evaluate the antitumour activity of pembrolizumab plus chemotherapy versus chemotherapy alone as first-line treatment in advanced oesophageal cancer and Siewert type 1 gastro-oesophageal junction cancer.
METHODS: We did a randomised, placebo-controlled, double-blind, phase 3 study across 168 medical centres in 26 countries. Patients aged 18 years or older with previously untreated, histologically or cytologically confirmed, locally advanced, unresectable or metastatic oesophageal cancer or Siewert type 1 gastro-oesophageal junction cancer (regardless of PD-L1 status), measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, and Eastern Cooperative Oncology Group performance status of 0-1, were randomly assigned (1:1) to intravenous pembrolizumab 200 mg or placebo, plus 5-fluorouracil and cisplatin (chemotherapy), once every 3 weeks for up to 35 cycles. Randomisation was stratified by geographical region, histology, and performance status. Patients, investigators, and site staff were masked to group assignment and PD-L1 biomarker status. Primary endpoints were overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 combined positive score (CPS) of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients. This trial is registered with ClinicalTrials.gov, NCT03189719, and is closed to recruitment.
FINDINGS: Between July 25, 2017, and June 3, 2019, 1020 patients were screened and 749 were enrolled and randomly assigned to pembrolizumab plus chemotherapy (n=373 [50%]) or placebo plus chemotherapy (n=376 [50%]). At the first interim analysis (median follow-up of 22·6 months), pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more (median 13·9 months vs 8·8 months; hazard ratio 0·57 [95% CI 0·43-0·75]; p<0·0001), oesophageal squamous cell carcinoma (12·6 months vs 9·8 months; 0·72 [0·60-0·88]; p=0·0006), PD-L1 CPS of 10 or more (13·5 months vs 9·4 months; 0·62 [0·49-0·78]; p<0·0001), and in all randomised patients (12·4 months vs 9·8 months; 0·73 [0·62-0·86]; p<0·0001). Pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for progression-free survival in patients with oesophageal squamous cell carcinoma (6·3 months vs 5·8 months; 0·65 [0·54-0·78]; p<0·0001), PD-L1 CPS of 10 or more (7·5 months vs 5·5 months; 0·51 [0·41-0·65]; p<0·0001), and in all randomised patients (6·3 months vs 5·8 months; 0·65 [0·55-0·76]; p<0·0001). Treatment-related adverse events of grade 3 or higher occurred in 266 (72%) patients in the pembrolizumab plus chemotherapy group versus 250 (68%) in the placebo plus chemotherapy group.
INTERPRETATION: Compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy improved overall survival in patients with previously untreated, advanced oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients regardless of histology, and had a manageable safety profile in the total as-treated population.
FUNDING: Merck Sharp & Dohme.
Copyright © 2021 Elsevier Ltd. All rights reserved.
Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Ostoich SA, Kim HR, Ueno M, Mansoor W, Yang WC, Liu T, Bridgewater J, Makino T, Xynos I, Liu X, Lei M, Kondo K, Patel A, Gricar J, Chau I, Kitagawa Y; CheckMate 648 Trial Investigators.
Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma.
N Engl J Med. 2022 Feb 3;386(5):449-462. doi: 10.1056/NEJMoa2111380.
Abstract/Text
BACKGROUND: First-line chemotherapy for advanced esophageal squamous-cell carcinoma results in poor outcomes. The monoclonal antibody nivolumab has shown an overall survival benefit over chemotherapy in previously treated patients with advanced esophageal squamous-cell carcinoma.
METHODS: In this open-label, phase 3 trial, we randomly assigned adults with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamous-cell carcinoma in a 1:1:1 ratio to receive nivolumab plus chemotherapy, nivolumab plus the monoclonal antibody ipilimumab, or chemotherapy. The primary end points were overall survival and progression-free survival, as determined by blinded independent central review. Hierarchical testing was performed first in patients with tumor-cell programmed death ligand 1 (PD-L1) expression of 1% or greater and then in the overall population (all randomly assigned patients).
RESULTS: A total of 970 patients underwent randomization. At a 13-month minimum follow-up, overall survival was significantly longer with nivolumab plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (median, 15.4 vs. 9.1 months; hazard ratio, 0.54; 99.5% confidence interval [CI], 0.37 to 0.80; P<0.001) and in the overall population (median, 13.2 vs. 10.7 months; hazard ratio, 0.74; 99.1% CI, 0.58 to 0.96; P = 0.002). Overall survival was also significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (median, 13.7 vs. 9.1 months; hazard ratio, 0.64; 98.6% CI, 0.46 to 0.90; P = 0.001) and in the overall population (median, 12.7 vs. 10.7 months; hazard ratio, 0.78; 98.2% CI, 0.62 to 0.98; P = 0.01). Among patients with tumor-cell PD-L1 expression of 1% or greater, a significant progression-free survival benefit was also seen with nivolumab plus chemotherapy over chemotherapy alone (hazard ratio for disease progression or death, 0.65; 98.5% CI, 0.46 to 0.92; P = 0.002) but not with nivolumab plus ipilimumab as compared with chemotherapy. The incidence of treatment-related adverse events of grade 3 or 4 was 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, and 36% with chemotherapy alone.
CONCLUSIONS: Both first-line treatment with nivolumab plus chemotherapy and first-line treatment with nivolumab plus ipilimumab resulted in significantly longer overall survival than chemotherapy alone in patients with advanced esophageal squamous-cell carcinoma, with no new safety signals identified. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 648 ClinicalTrials.gov number, NCT03143153.).
Copyright © 2022 Massachusetts Medical Society.
Shenfine J, McNamee P, Steen N, Bond J, Griffin SM.
A randomized controlled clinical trial of palliative therapies for patients with inoperable esophageal cancer.
Am J Gastroenterol. 2009 Jul;104(7):1674-85. doi: 10.1038/ajg.2009.155. Epub 2009 May 12.
Abstract/Text
OBJECTIVES: A dramatic rise in incidence, an aging population, and expensive palliative treatments have led to an escalating burden on clinicians managing inoperable esophageal cancer with only limited evidence of effectiveness. This study compares the clinical effectiveness and cost-effectiveness of self-expanding metal stents (SEMSs) with other palliative therapies to aid clinicians in making an evidence-based treatment choice.
METHODS: We conducted a prospective, multicenter, randomized, controlled, clinical trial with 215 patients followed until death or study closure. The primary outcome measures were dysphagia, quality of life (QL) 6 weeks following treatment, and total cost of treatment. Secondary outcome measures included treatment-associated morbidity, mortality, survival, and cost-effectiveness. An intention-to-treat analysis was carried out.
RESULTS: There was a significant difference in mean dysphagia grade between treatment arms 6 weeks following treatment (P=0.046), with worse swallowing reported by rigid stent-treated patients (mean dysphagia score difference=-0.49; 95% confidence interval (CI) -0.10 to -0.89, P=0.014). Global QL scores were lower at both 1 and 6 weeks following treatment for patients treated by SEMSs (mean difference QL index week 1=-0.66; 95% CI: -0.02 to -1.30, P=0.04; mean difference QL index week 6=-1.01; 95% CI -0.30 to -1.72, P=0.006). These findings were associated with higher post-procedure pain scores in the SEMS patient group (mean difference of the European Organisation for Research and Treatment of Cancer QLQ C-30 pain symptom score at week 1=11.13; 95% CI: 2.89-19.4; P=0.01). Although mean EQ-5D QL values differed between the treatments (P<0.001), this difference dissipated following generation of quality-adjusted life year values. Total costs varied between treatment arms but these findings canceled out when SEMSs were compared with non-SEMS therapies (95% CI -845.15-1,332.62). These results were robust to sensitivity analysis. There were no differences in the in-hospital mortality or early complication rates, but late complications were more frequent after rigid stenting (risk ratio=2.47; 95% CI 1.88-3.04). There was a survival advantage for non-stent-treated patients (log-rank statistic=4.21, P=0.04).
CONCLUSIONS: The treatment choice for patients with inoperable esophageal cancer should be between a SEMS or a non-stent treatment after consideration has been given to both patient and tumor characteristics and clinician and patient preferences.
Conio M, Repici A, Battaglia G, De Pretis G, Ghezzo L, Bittinger M, Messmann H, Demarquay JF, Blanchi S, Togni M, Conigliaro R, Filiberti R.
A randomized prospective comparison of self-expandable plastic stents and partially covered self-expandable metal stents in the palliation of malignant esophageal dysphagia.
Am J Gastroenterol. 2007 Dec;102(12):2667-77. doi: 10.1111/j.1572-0241.2007.01565.x.
Abstract/Text
OBJECTIVES: Self-expanding metal stents (SEMS) provide effective palliation in patients with malignant dysphagia, although severe complications and mortality may result. We performed a prospective controlled trial to compare a new self-expanding polyester mesh stent (Polyflex) with SEMS (Ultraflex).
METHODS: One hundred one patients with unresectable esophageal carcinoma were randomized to placement of a Polyflex (N=47) or a partially covered Ultraflex (N=54) stent. Patients with esophagogastric junction (EGJ) malignancy were excluded.
RESULTS: Placement was successful in 46 (98%) patients with the Polyflex and 54 (100%) patients with the Ultraflex stent. In one patient, the Polyflex stent could not be placed. After 1 wk, dysphagia was improved by at least 1 grade in 100% of the Polyflex group and in 94% of the Ultraflex group. Major complications were observed in 48% of the Polyflex group and 33% of the Ultraflex group. Intraprocedural perforation occurred in 1 Polyflex and 1 Ultraflex patient. Two Polyflex patients had postprocedural hemorrhage. Twenty (44%) patients with a Polyflex stent and 18 (33%) with an Ultraflex stent had recurrent dysphagia because of tumor overgrowth, stent migration, hyperplastic granulomatous reaction, or food bolus impaction. Multivariate analysis showed a significantly higher complication rate with Polyflex than with Ultraflex stents (odds ratio 2.3, 95% CI 1.2-4.4). However, median survival was 134 days with Polyflex and 122 days with Ultraflex stents (P=NS).
CONCLUSIONS: No difference was seen in palliation of dysphagia between the two stents. Significantly more complications, especially late stent migration, were observed in the Polyflex group.
Verschuur EM, Repici A, Kuipers EJ, Steyerberg EW, Siersema PD.
New design esophageal stents for the palliation of dysphagia from esophageal or gastric cardia cancer: a randomized trial.
Am J Gastroenterol. 2008 Feb;103(2):304-12. doi: 10.1111/j.1572-0241.2007.01542.x. Epub 2007 Sep 25.
Abstract/Text
BACKGROUND & AIM: Stents are often used for the palliation of inoperable esophageal or gastric cardia cancer. One of the drawbacks of the currently used stents is the high percentage of recurrent dysphagia due to stent migration and tissue growth. New stents have been designed to overcome this unwanted sequela of stent placement. In the present study, we investigated whether results of stent placement could be improved with newer stent designs.
METHODS: Between June 2004 and May 2006, 125 patients with dysphagia from inoperable carcinoma of the esophagus or gastric cardia were randomized to placement of an Ultraflex stent (N = 42), Polyflex stent (N = 41), or Niti-S stent (N = 42). Patients were followed by scheduled telephone calls at 14 days after treatment, and then monthly for 6 months or until death. Technical and functional outcome, complications, recurrent dysphagia, and survival were analyzed with, chi(2) tests, Kaplan-Meier curves, and log-rank tests.
RESULTS: Stent placement was technically successful in all patients with an Ultraflex stent, in 34/41 (83%) patients with a Polyflex stent, and in 40/42 (95%) patients treated with a Niti-S stent (P= 0.008). Dysphagia score improved from a median of 3 (liquids only) to 1 (ability to eat some solid food) in all patients. There were no differences in complications among the three stent types. Recurrent dysphagia, caused by tissue in- or overgrowth, migration, or food obstruction, was significantly different between patients with an Ultraflex stent and patients with a Polyflex stent or Niti-S stent (22 [52%]vs 15 [37%]vs 13 [31%], P= 0.03). Stent migration occurred more frequently with Polyflex stents, whereas tissue in- or overgrowth was more frequently seen with Ultraflex stents, and to a lesser degree, Niti-S stents. No differences were found in survival (median survival: Ultraflex stent 132 days vs Polyflex stent 102 days vs Niti-S stent 159 days) among the three stent types.
CONCLUSIONS: All three stents are safe and offer adequate palliation of dysphagia from esophageal or gastric cardia cancer. Nonetheless, Polyflex stents seem the least preferable in this patient group, as placement of this device is technically demanding and associated with a high rate of stent migrations.
Yakoub D, Fahmy R, Athanasiou T, Alijani A, Rao C, Darzi A, Hanna GB.
Evidence-based choice of esophageal stent for the palliative management of malignant dysphagia.
World J Surg. 2008 Sep;32(9):1996-2009. doi: 10.1007/s00268-008-9654-1.
Abstract/Text
BACKGROUND: The type of stent used for the management of patients with malignant dysphagia is chosen according to subjective physician's preference. There is no recent study available to provide updated evidence on early outcomes related to the use of different types of stents.
METHODS: A literature search was performed using Embase, MEDLINE, Cochrane Library, and Google Scholar databases for comparative studies assessing different types of stents. The primary end point was stent-related mortality; secondary end points included: stent-related morbidity, successful palliation of dysphagia, and 30-day mortality. A random-effects model was used and heterogeneity was assessed.
RESULTS: Twelve studies that included 911 patients compared metallic (46.54%) and plastic stents (53.45%), and eight studies that included 564 patients compared covered (43.26%) and uncovered metal stents (56.73%). Meta-analysis of randomized, controlled trials showed that metallic stents were associated with significantly reduced stent-related mortality (1.7% vs. 11.1% for the plastic group, odds ratio (OR), 0.2; 95% confidence interval (CI), 0.06-0.74; P = 0.02), morbidity in the form of reduced esophageal perforation (1.4% vs. 9.4% for plastic stent, OR, 0.27; 95% CI, 0.08-0.89; P = 0.03), and stent migration, yet increased rate of tumor in-growth (13% vs. 1.6% for plastic stents, OR, 4.84; 95% CI, 0.99-23.76; P = 0.05). Covered metallic stents had significantly less tumor in-growth than the uncovered and an increased migration rate. There was no significant difference between metallic and plastic stents in terms of any other stent-related morbidity and 30-day mortality.
CONCLUSION: Self-expanding metallic stents are superior to plastic stents in terms of stent insertion-related mortality, morbidity, and quality of palliation. The uncovered variety is disadvantaged by high rate of tumor in-growth; adequately designed randomized, controlled trials need to examine outcomes and cost-effectiveness of covered versus uncovered metallic stents.
Nishimura Y, Nagata K, Katano S, Hirota S, Nakamura K, Higuchi F, Soejima T, Sai H; Japanese Society for Esophageal Diseases.
Severe complications in advanced esophageal cancer treated with radiotherapy after intubation of esophageal stents: a questionnaire survey of the Japanese Society for Esophageal Diseases.
Int J Radiat Oncol Biol Phys. 2003 Aug 1;56(5):1327-32. doi: 10.1016/s0360-3016(03)00198-6.
Abstract/Text
PURPOSE: A questionnaire survey was performed to evaluate the complications and prognosis of esophageal cancer treated with esophageal intubation before or during radiotherapy.
METHODS AND MATERIALS: Clinical data were accumulated on a total of 47 patients treated at 17 institutions in Japan. Five patients had Stage II, 30 Stage III, and 11 Stage IV, and the stage was unknown in 1 patient. Covered expandable metallic stents were inserted in 30 patients, uncovered expandable metallic stents in 13, plastic or silicon prosthesis in 3, and an unknown type in 1 patient. Esophageal stenting was performed before the start of RT for 23 patients and during the course of RT for 24 patients. The reasons for the stenting were severe stricture in 32 patients (Group 1) and esophageal fistula in 15 patients (Group 2).
RESULTS: The most frequent toxicity was formation or worsening of esophageal fistulas in 13 patients (28%), followed by massive hematemesis or GI bleeding in 10 patients (21%). In total, 24 patients (51%), including 10 patients with possible treatment-related deaths (Grade 5), had nonhematologic toxicities of Grade 3-5. The interval from the start of RT to the nonhematologic toxicity ranged from 16 to 312 days (median 78). The incidence of toxicities was higher for Group 1 (59%) than for Group 2 (33%), although the difference was not statistically significant. The median survival time for those with Stage II-III and Stage IV was 5 and 3.5 months, respectively.
CONCLUSIONS: Patients with esophageal intubation before or during RT have a high risk of life-threatening complications, especially for those with severe esophageal stricture. Because long survival is expected for a substantial proportion of patients with locally advanced esophageal cancer after chemoradiotherapy, palliative intubation should be delayed until radiotherapy or chemoradiotherapy appears to have failed.
