Extent of Lymphadenectomy and Long-term Survival in Esophageal Cancer.

OBJECTIVE: To examine the hypothesis that survival in esophageal cancer increases with more removed lymph nodes during esophagectomy up to a plateau, after which it levels out or even decreases with further lymphadenec-tomy. SUMMARY OF BACKGROUND DATA: There is uncertainty regarding the ideal extent of lymphadenectomy during esophagectomy to optimize long-term survival in esophageal cancer. METHODS: This population-based cohort study included almost every patient who underwent esophagectomy for esophageal cancer in Sweden or Finland in 2000-2016 with follow-up through 2019. Degree of lymphadenectomy, divided into deciles, was analyzed in relation to all-cause 5-year mortality. Multivariable Cox regression provided hazard ratios (HR) with 95% confidence intervals (95% CI) adjusted for all established prognostic factors. RESULTS: Among 2306 patients, the second (4-8 nodes), seventh (21-24 nodes) and eighth decile (25-30 nodes) of lymphadenectomy showed the lowest all-cause 5-year mortality compared to the first decile [hazard ratio (HR) = 0.77, 95% CI 0.61-0.97, HR = 0.76, 95% CI 0.59-0.99, and HR = 0.73, 95% CI 0.57-0.93, respectively]. In stratified analyses, the survival benefit was greatest in decile 7 for patients with pathological T-stage T3/T4 (HR = 0.56, 95% CI0.40-0.78), although it was statistically improved in all deciles except decile 10. For patients without neoadjuvant chemotherapy, survival was greatest in decile 7 (HR = 0.60, 95% CI 0.41-0.86), although survival was also statistically significantly improved in deciles 2, 6, and 8. CONCLUSION: Survival in esophageal cancer was not improved by extensive lymphadenectomy, but resection of a moderate number (20-30) of nodes was prognostically beneficial for patients with advanced T-stages (T3/T4) and those not receiving neoadjuvant therapy.

Aspirin or statin use in relation to survival after surgery for esophageal cancer: a population-based cohort study.

BACKGROUND: Adjuvant postoperative treatment with aspirin and statins may improve survival in several solid tumors. This study aimed to assess whether these medications improve the survival after curatively intended treatment (including esophagectomy) for esophageal cancer in an unselected setting. METHODS: This nationwide cohort study included nearly all patients who underwent esophagectomy for esophageal cancer in Sweden from 2006 to 2015, with complete follow-up throughout 2019. Risk of 5-year disease-specific mortality in users compared to non-users of aspirin and statins was analyzed using Cox regression, providing hazard ratios (HR) with 95% confidence intervals (CI). The HRs were adjusted for age, sex, education, calendar year, comorbidity, aspirin/statin use (mutual adjustment), tumor histology, pathological tumor stage, and neoadjuvant chemo(radio)therapy. RESULTS: The cohort included 838 patients who survived at least 1 year after esophagectomy for esophageal cancer. Of these, 165 (19.7%) used aspirin and 187 (22.3%) used statins during the first postoperative year. Neither aspirin use (HR 0.92, 95% CI 0.67-1.28) nor statin use (HR 0.88, 95% CI 0.64-1.23) were associated with any statistically significant decreased 5-year disease-specific mortality. Analyses stratified by subgroups of age, sex, tumor stage, and tumor histology did not reveal any associations between aspirin or statin use and 5-year disease-specific mortality. Three years of preoperative use of aspirin (HR 1.26, 95% CI 0.98-1.65) or statins (HR 0.99, 95% CI 0.67-1.45) did not decrease the 5-year disease-specific mortality. CONCLUSIONS: Use of aspirin or statins might not improve the 5-year survival in surgically treated esophageal cancer patients.

Long-term Survival in Esophageal Cancer After Minimally Invasive Esophagectomy Compared to Open Esophagectomy.

OBJECTIVE: To examine 5-year survival in esophageal cancer after MIE compared to OE. SUMMARY BACKGROUND DATA: MIE is becoming an increasingly common approach in the surgical treatment of esophageal cancer. A recent meta-analysis suggested 18% lower 5-year all-cause mortality after MIE compared to OE, but the quality of the included studies was limited. METHODS: Population-based cohort study including almost all patients who underwent elective esophagectomy for esophageal cancer in Sweden or Finland in 2010 to 2016, with follow-up until end of 2019. Cox regression was used to provide hazard ratios (HRs) with 95% confidence intervals (CIs) of all-cause 5-year mortality (main outcome) after MIE (hybrid or total) versus OE. Adjustments were made for age, sex, comorbidity, pathological tumor stage, histological tumor type, neoadjuvant chemo(radio)therapy, country, and annual hospital volume of esophagectomy. RESULTS: Among all 1264 patients, 470 (37.2%) underwent MIE and 794 (62.8%) underwent OE. MIE was associated with an 18% decreased risk of all-cause 5-year mortality, compared to OE [adjusted HR 0.82, 95% CI 0.67- 1.00 ( P = 0.048)]. The HR of all-cause 5-year mortality was seemingly lower after total MIE compared to OE (adjusted HR 0.77, 95% CI 0.60-0.98) than after hybrid MIE compared to OE (adjusted HR 0.87, 95% CI 0.68-1.11). CONCLUSIONS: This bi-national study indicates that MIE is associated with a higher 5-year survival than OE in patients with esophageal cancer, and that the survival benefit is greater after total MIE than hybrid MIE.

Presentation, Treatment, and Prognosis of Esophageal Carcinoma in a Nationwide Comparison of Sweden and the Netherlands.

OBJECTIVE: This population-based study aimed to compare presentation, treatment allocation and survival of potentially curable esophageal cancer patients between Sweden and the Netherlands. SUMMARY OF BACKGROUND DATA: Identification of inter-country differences in treatment allocation and survival may be used for targeted esophageal cancer care improvement. METHODS: Nationwide datasets were acquired from a Swedish cohort study and the Netherlands Cancer Registry. Patients with potentially curable (cT1-T4a/Tx, cN0/+, cM0/x) esophageal adenocarcinoma or squamous cell carcinoma (SCC) diagnosed in 2011-2015 were included. Multivariable logistic regression provided odds ratios (OR) for treatment allocation, and multivariable Cox model provided hazard ratios (HR) for overall survival, all with 95% confidence intervals (CI), adjusted for age, sex, year, tumor sub-location and stage. RESULTS: Among 1980 Swedish and 7829 Dutch esophageal cancer patients, Swedish patients were older (71 vs 69 years, P <0.001) and had higher cT-stage (cT3: 49% vs 46%, P <0.001). After adjustment for confounders, Swedish patients were less frequently allocated to curative treatment (adenocarcinoma: OR=0.31, 95%CI 0.26-0.36; SCC: OR=0.28, 95%CI 0.22-0.36). Overall survival was lower in Swedish patients (adenocarcinoma: HR=1.36, 95%CI 1.27-1.46; SCC: HR=1.38, 95%CI 1.24-1.53), also when allocated to curative treatment (adenocarcinoma: HR=1.12, 95%CI 1.01-1.24; SCC: HR=1.34, 95%CI 1.14-1.59). CONCLUSION: Swedish patients with potentially curable esophageal cancer were less frequently allocated to curative treatment, and showed lower survival compared to Dutch patients. The less pronounced inter-country survival difference after curative treatment suggests that the overall survival difference could at least partly be due to relative undertreatment of Swedish patients. Shared curative treatment thresholds across Europe may help improve survival of esophageal cancer patients.

Prognosis after surgery for gastric adenocarcinoma in the Swedish Gastric Cancer Surgery Study (SWEGASS).

BACKGROUND: Most studies examining prognostic factors after gastrectomy come from selected patients and non-Western populations. This nationwide population-based cohort study aims to identify prognostic factors after surgery for gastric adenocarcinoma in an unselected Western cohort. METHODS: This study included 98% of patients who underwent gastrectomy for gastric adenocarcinoma in Sweden in 2006-2015, with follow-up through 2019. Data were collected from medical records and national registries. Exposures were sex, age, education, comorbidity, tumor sub-localization, tumor stage, calendar period, and pre-operative chemotherapy. Outcomes were 3-year all-cause and disease-specific mortality. Cox regression produced hazard ratios (HRs) with 95% confidence intervals (95% CIs), adjusted for the other study exposures. RESULTS: Among all 2154 patients, 3-year all-cause mortality was 53.3%. Factors influencing 3-year all-cause mortality after multivariable adjustment were tumor stage (stage IV vs. stage 0-I: HR 8.72, 95% CI 6.77-11.24), comorbidity (Charlson comorbidity score ≥2 vs. 0: HR 1.63, 95% CI 1.39-1.90), age (>75 vs. <65 years: HR 1.48, 95% CI 1.24-1.78), and calendar period (2006-2010 vs. 2011-2015: HR 0.83, 95% CI 0.73-0.95). No independent prognostic influence was found for sex (women vs. men: HR 1.01, 95% CI 0.85-1.09), pre-operative chemotherapy (yes vs. no: HR 0.92, 95% CI 0.78-1.08), tumor sub-localization (non-cardia vs. cardia: HR 1.01, 95% CI 0.83-1.22), or education (≥13 vs. ≤9 years: HR 0.89, 95% CI 0.74-1.07). The results were similar for 3-year disease-specific mortality. CONCLUSION: Survival after gastrectomy for gastric adenocarcinoma needs further improvement. Tumor stage, comorbidity, age, and calendar period were independently prognostic, while sex, pre-operative chemotherapy, tumor sub-localization, and education were not.

Long-term Survival in Esophageal Cancer After Minimally Invasive Compared to Open Esophagectomy: A Systematic Review and Meta-analysis.

OBJECTIVE: Evaluate the existing literature comparing long-term survival after minimally invasive esophagectomy (MIE) and open esophagectomy (OE), and conduct a meta-analysis based on relevant studies. BACKGROUND: It is unknown whether the choice between MIE and OE influences the long-term survival in esophageal cancer. METHODS: A systematic electronic search for articles was performed in Medline, Embase, Web of Science, and Cochrane Library for studies comparing long-term survival after MIE and OE. Additionally, an extensive hand-search was conducted. The I test and χ test were used to test for statistical heterogeneity. Publication bias and small-study effects were assessed using Egger test. A random-effects meta-analysis was performed for all-cause 5-year (main outcome) and 3-year mortality, and disease-specific 5-year and 3-year mortality. Meta-regression was performed for the 5-year mortality outcomes with adjustment for the covariates age, physical status, tumor stage, and neoadjuvant or adjuvant therapy. The results were presented as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: The review identified 55 relevant studies. Among all 14,592 patients, 7358 (50.4%) underwent MIE and 7234 (49.6%) underwent OE. The statistical heterogeneity was limited [I = 12%, 95% confidence interval (CI) 0%-41%, and χ = 0.26] and the funnel plot was symmetrical both according to visual and statistical testing (Egger test = 0.32). Pooled analysis revealed 18% lower 5-year all-cause mortality after MIE compared with OE (HR 0.82, 95% CI 0.76-0.88). The meta-regression indicated no confounding. CONCLUSIONS: The long-term survival after MIE compares well with OE and may even be better. Thus, MIE can be recommended as a standard surgical approach for esophageal cancer.

Surgeon Volume and Surgeon Age in Relation to Proficiency Gain Curves for Prognosis Following Surgery for Esophageal Cancer.

BACKGROUND: Surgery proficiency gain curves must be shortened to reduce patient harm during esophagectomy learning. OBJECTIVE: This study aimed to test whether surgeon volume and surgeon age influenced the length of period of surgical proficiency gain. METHODS: This population-based cohort study included 1384 patients with esophageal cancer who underwent esophagectomy by any of the 36 highest-volume surgeons in Sweden between 1987 and 2010, with follow-up until 2016. Annual surgeon volume was dichotomized by the median values into 'higher-volume surgeons' (≥ 4 cases per year) and 'lower-volume surgeons' (< 4 cases per year), and surgeon age at the start of practicing esophagectomies into 'younger surgeons' (aged < 45 years) and 'older surgeons' (aged ≥ 45 years). Proficiency gain curves were constructed using risk-adjusted cumulative sum analysis for 1- to 5-year mortality (main outcome) and secondary outcomes (presented below). The results were adjusted for all established prognostic factors. RESULTS: For 1- to 5-year mortality, the change point was at 14 cases among 'higher-volume surgeons', while 'lower-volume surgeons' had a later change point at 31 cases. The corresponding change points were at 13 cases among 'younger surgeons' and at 48 cases among 'older surgeons'. Similar patterns of differences in the proficiency gain curves were seen for the secondary outcomes of 30-day mortality and resection margin status (tumor involvement). CONCLUSION: Higher-volume- and younger surgeons seem to have a substantially shorter period of proficiency gain for long-term mortality and other outcomes following surgery for esophageal cancer. This indicates a value of intensified training of younger surgeons for these complex operations.

All-cause and cancer-specific mortality in GORD in a population-based cohort study (the HUNT study).

OBJECTIVE: Gastro-oesophageal reflux is a public health concern which could have associated oesophageal complications, including adenocarcinoma, and possibly also head-and-neck and lung cancers. The aim of this study was to test the hypothesis that reflux increases all-cause and cancer-specific mortalities in an unselected cohort. DESIGN: The Nord-Trøndelag health study (HUNT), a Norwegian population-based cohort study, was used to identify individuals with and without reflux in 1995-1997 and 2006-2008, with follow-up until 2014. All-cause mortality and cancer-specific mortality were assessed from the Norwegian Cause of Death Registry and Cancer Registry. Multivariable Cox regression was used to calculate HRs with 95% CIs for mortality with adjustments for potential confounders. RESULTS: We included 4758 participants with severe reflux symptoms and 51 381 participants without reflux symptoms, contributing 60 323 and 747 239 person-years at risk, respectively. Severe reflux was not associated with all-cause mortality, overall cancer-specific mortality or mortality in cancer of the head-and-neck or lung. However, for men with severe reflux a sixfold increase in oesophageal adenocarcinoma-specific mortality was found (HR 6.09, 95% CI 2.33 to 15.93) and the mortality rate was 0.27 per 1000 person-years. For women, the corresponding mortality was not significantly increased (HR 3.68, 95% CI 0.88 to 15.27) and the mortality rate was 0.05 per 1000 person-years. CONCLUSIONS: Individuals with severe reflux symptoms do not seem to have increased all-cause mortality or overall cancer-specific mortality. Although the absolute risk is small, individuals with severe reflux symptoms have a clearly increased oesophageal adenocarcinoma-specific mortality.

Treatment and outcome among patients with laryngeal squamous cell carcinoma in Stockholm-A population-based study.

Objective: Survival of patients with advanced laryngeal squamous cell carcinoma (LSCC) remains poor and management protocols warrant further development. We thus investigated treatment and outcome-related factors for LSCC in Stockholm, Sweden. Methods: In a retrospective setting, 520 patients with LSCC diagnosed during 2000-2014, were included. Data on stage, treatment, and outcome were correlated with recurrence-free and overall survival (RFS and OS, respectively). Results: Five-year OS for all patients was 65%. Five-year RFS for T1a, T1b, T2, T3, and T4 glottic LSCC was 90%, 91%, 77%, 47%, and 80%, respectively. The corresponding figures for T1, T2, T3, and T4 supraglottic LSCC were 64%, 66%, 64%, and 86%. Conclusion: Patients with a T3 glottic LSCC had unexpectedly poor survival, especially when compared with patients with a T4 tumor. Patients with T4 disease were primarily treated with laryngectomy and postoperative radiotherapy (RT)/chemoradiotherapy (CRT), while most patients with T3 LSCC were treated with RT/CRT.

Prediction of conditional survival in esophageal cancer in a population-based cohort study.

BACKGROUND: The authors aimed to produce a prediction model for survival at any given date after surgery for esophageal cancer (conditional survival), which has not been done previously. MATERIALS AND METHODS: Using joint density functions, the authors developed and validated a prediction model for all-cause and disease-specific mortality after surgery with esophagectomy, for esophageal cancer, conditional on postsurgery survival time. The model performance was assessed by the area under the receiver operating characteristic curve (AUC) and risk calibration, with internal cross-validation. The derivation cohort was a nationwide Swedish population-based cohort of 1027 patients treated in 1987-2010, with follow-up throughout 2016. This validation cohort was another Swedish population-based cohort of 558 patients treated in 2011-2013, with follow-up throughout 2018. RESULTS: The model predictors were age, sex, education, tumor histology, chemo(radio)therapy, tumor stage, resection margin status, and reoperation. The medians of AUC after internal cross-validation in the derivation cohort were 0.74 (95% CI: 0.69-0.78) for 3-year all-cause mortality, 0.76 (95% CI: 0.72-0.79) for 5-year all-cause mortality, 0.74 (95% CI: 0.70-0.78) for 3-year disease-specific mortality, and 0.75 (95% CI: 0.72-0.79) for 5-year disease-specific mortality. The corresponding AUC values in the validation cohort ranged from 0.71 to 0.73. The model showed good agreement between observed and predicted risks. Complete results for conditional survival any given date between 1 and 5 years of surgery are available from an interactive web-tool: https://sites.google.com/view/pcsec/home . CONCLUSION: This novel prediction model provided accurate estimates of conditional survival any time after esophageal cancer surgery. The web-tool may help guide postoperative treatment and follow-up.

Mortality in gastro-oesophageal reflux disease in a population-based nationwide cohort study of Swedish twins.

OBJECTIVES: The public health disorder gastro-oesophageal reflux disease (GORD) is linked with several comorbidities, including oesophageal adenocarcinoma (OAC), but whether life expectancy is reduced by GORD is uncertain. This study assessed all-cause and cancer-specific mortality in GORD after controlling for confounding by heredity and other factors. DESIGN: Population-based cohort study from 1998 to 2015. SETTING: Swedish nationwide study. PARTICIPANTS: Twins (n=40 961) born in 1958 or earlier in Sweden. EXPOSURE: GORD symptoms reported in structured computer-assisted telephone interviews. OUTCOMES: The primary outcome was all-cause mortality and the secondary outcome was cancer-specific mortality among twins with GORD and twins without GORD. HRs and 95% CIs were analysed using parametric survival models, both in individual twin analyses and co-twin pair analyses, with adjustment for body mass index, smoking, education and comorbidity. RESULTS: Among 40 961 individual twins, 5812 (14.2%) had GORD at baseline and 8062 (19.7%) died during follow-up of up to 16 years. The risks of all-cause mortality (HR=1.00, 95% CI: 0.94-1.07) and cancer-specific mortality (HR=0.99, 95% CI: 0.89-1.10) were not increased in individual twins with GORD compared with individual twins without GORD. Similarly, there were no differences in mortality outcomes in within-pair analyses. The OAC-specific mortality rate was 0.45 (95% CI: 0.32-0.66) per 1000 person-years in individual twins with GORD and 0.22 (95% CI: 0.18-0.27) per 1000 person-years without GORD, rendering an adjusted HR of 2.01 (95% CI: 1.35-2.98). CONCLUSIONS: GORD did not increase all-cause or cancer-specific mortality when taking heredity and other confounders into account. The increased relative risk of mortality in OAC was low in absolute numbers.

Annual hospital volume of surgery for gastrointestinal cancer in relation to prognosis.

BACKGROUND: Studies examining hospital volume for surgery for various gastrointestinal (GI) cancer types have shown conflicting results regarding the influence on long-term prognosis. The aim of this study was to examine annual hospital volume in relation to long-term survival after elective surgery for all GI cancers (esophagus, stomach, liver, pancreas, bile ducts, small bowel, colon, and rectum). METHODS: Population-based cohort study including all 45,908 patients who underwent elective surgery for GI cancers in Sweden in 2005-2013. Follow-up was until 2016 for disease-specific 5-year mortality (main outcome) and 2018 for all-cause 5-year mortality (secondary outcome). Hospitals were divided into quartiles for each GI cancer according to a 4-year average annual volume of the year of surgery and three years earlier. Multivariable Cox regression provided hazard ratios (HRs) with 95% confidence intervals (CIs), adjusted for relevant confounders. RESULTS: Higher hospital volume was associated with a survival benefit in the large group of patients (n = 26,688) who underwent colon cancer resection, with HR 0.89 (95% CI 0.84-0.96) for disease-specific 5-year mortality comparing the highest with the lowest quartile. Higher hospital volume improved 5-year mortality in sub-groups of patients who underwent surgery for cancer of the esophagus, pancreas, and rectum. No such improvements were found for cancer of the stomach, liver, bile ducts, or small bowel. CONCLUSION: Long-term survival was improved at higher volume hospitals for some GI cancers (colon, esophagus, pancreas, rectum), but not for others (stomach, liver, bile ducts, small bowel).