Complications during neoadjuvant therapy and prognosis following surgery for esophageal cancer

Complications during neoadjuvant therapy and prognosis following surgery for esophageal cancer Summary Previous researchers have focused upon the influence of postoperative complications upon prognosis from esophagectomy, with very little attention paid to the potential negative effects of complications during neoadjuvant therapy. The hypothesis under investigation in this study was that the prognosis after esophageal cancer surgery is negatively influenced by complications causing hospital admission during neoadjuvant therapy. Patients receiving neoadjuvant therapy and surgery for esophageal cancer between 1987 and 2010 were identified from a population-based nationwide Swedish cohort study and followed up until 2016. The association between hematological and nonhematological complications during neoadjuvant therapy and risk of short- and long-term mortality following surgery was analyzed using a multivariable Cox proportional hazards model, providing hazard ratios (HRs) with 95% confidence intervals (CIs). The HRs were adjusted for appropriate confounding variables. Among 587 patients, complications during neoadjuvant therapy requiring emergency hospitalization affected 65 (12%) patients. Hematological complications were associated with an increased 90-day overall mortality (HR = 5.60; 95% CI 1.27–24.75), particularly in subgroups of patients of tumor stage 0–II, adenocarcinoma, and radical and nonradical resection margins, and rendered increased 5-year disease-specific mortality specifically for esophageal adenocarcinoma (HR = 3.22; 95% CI 1.00–10.40). Occurrence of nonhematological complications was followed by an increase in 5-year mortality (HR = 2.35; 95% CI 1.15–4.81) in poor prognostic groups (tumor stage III–IV). There was no increased 5-year mortality following hematological or nonhematological complications in other subgroups of patients. Complications during neoadjuvant therapy may adversely impact short and long-term mortality in subgroups of patients with esophageal cancer receiving esophagectomy. Patient selection, optimization of neoadjuvant therapy, and timing of surgical resection, remain important areas for future development in the management of esophageal cancer. INTRODUCTION Randomized clinical trials have demonstrated a limited, but consistent prognostic benefit to the utilization of neoadjuvant chemotherapy or combined chemoradiotherapy followed by surgery over surgery alone for locally advanced esophageal cancer.1–4 The results of these trials have been incorporated into national guidelines, with increased uptake of neoadjuvant therapy.5 Despite the prognostic benefits of neoadjuvant therapy, it does carry its own complication rate, especially in elderly or frailer patients.6 Therefore allocation to neoadjuvant therapy remains a balance between the risk of complications with failure of course completion and a potential prognostic benefit. In recent years, studies have indicated that postoperative complications, including anastomotic leak, may increase locoregional recurrence and reduce long-term survival following esophagectomy for cancer.7–9 However, the influence of neoadjuvant treatment toxicity upon short- and long-term mortality from upper gastrointestinal cancer surgery has only been evaluated to a limited extent. It has been suggested that neoadjuvant toxicity is associated with reduced rates of radical resection margin status (R0) and poorer short- and long-term mortality.10 The hypothesis under investigation in the present national study is that the prognosis after esophageal cancer surgery is negatively influenced by complications of neoadjuvant therapy. METHODS Study design Earlier versions of this population-based cohort study have been described in detail elsewhere.11–14 In brief, this Swedish nationwide cohort study included almost all patients with esophageal cancer treated surgically with curative intent between 1987 and 2010. Patients with esophageal cancer were identified from the Swedish Cancer Registry, a registry with 98% nationwide coverage of esophageal cancer.15 Esophageal cancer patients who underwent esophagectomy were identified from the Swedish Patient Registry, which has an excellent positive predictive value (99.6%) for esophageal cancer surgery.16 The Patient Registry also provided data pertaining to comorbidities.17 The comorbidities were classified according to the most recently updated and validated version of the Charlson comorbidity index, and the esophageal cancer diagnosis was not counted.18 The Swedish personal identity number, assigned to each Swedish resident at birth or immigration, was used to link individuals’ data between registries and to identify their medical records. Medical records containing operation notes and histopathology reports of the cohort members were retrieved from all Swedish hospitals where esophageal cancer surgery was performed. This clinical data collection was facilitated by a nationwide Swedish clinical network established in the mid-1990s.19 Data concerning operating hospital, names of the surgeons, neoadjuvant therapy, surgical therapy, pathological tumor stage, and histological tumor type were obtained from these individual patient records. The histopathological review has been demonstrated for its high accuracy of pathological stage, histological subtype, and lymph node harvest.12 Tumor stage was classified according to the TNM classification of the Union Internationale Contre le Cancer (UICC).20 Open transthoracic esophageal resection with intrathoracic anastomosis was the predominant surgical procedure (95%). For the purpose of this study, only patients in the cohort who had received neoadjuvant therapy and underwent surgery between 1987 and 2010 were eligible and the follow-up of mortality was up-dated to 31st May 2016. The Regional Ethical Review Board in Stockholm, Sweden approved the study. Exposures The study exposure was emergency hospital admission during neoadjuvant therapy, resulting from hematological or nonhematological complications. Hematological complications included leukopenia, neutropenia, thrombocytopenia, and anemia. Nonhematological complications included anorexia, constipation, diarrhea, esophageal perforation, esophagitis, nausea or vomiting, neuropathy, stomatitis, and thromboembolism. Data on these complications were retrieved from the Patient Registry. Any individual patient may have had more than one complication from neoadjuvant therapy, but only the primary diagnosis code was used to classify the admission as hematological or nonhematological complication. Outcomes The outcomes were all-cause 90-day and 5-year mortality as well as disease-specific 5-year mortality from the date of surgery. The Swedish Causes of Death Registry provided accurate data for date and causes of death. This Registry has 100% coverage. If the diagnosis esophageal cancer was listed as a cause of death, this mortality was defined as disease specific. Statistical analysis The occurrence of complications during neoadjuvant therapy was analyzed in relation to mortality using a multivariable Cox-proportional hazards model, providing hazard ratios (HRs) with 95% confidence intervals (CIs), adjusted for potential confounding factors. The confounders (with categorizations) in the model were age (continuous variable), sex (male or female) pathological tumor stage (0 or I, II, III or IV), Charlson comorbidity index (≤1 or >I), histological tumor type (adenocarcinoma or squamous cell carcinoma), cumulative surgeon volume of esophagectomies during study period (≤16 or >16), calendar period of surgery (1987–1994, 1995–2002, or 2003–2010), resection margin status (radical [R0] or nonradical [R1/2]) and reoperation within 30 days of surgery (yes or no). Subgroup analyses by tumor stage, histological subtype, and resection margin with regression for the confounders described above were also performed. Follow-up ended at the date of death or end of study period (31st May 2016), whichever occurred first. The statistical software SPSS 23.0 (Statistical Package for the Social Sciences software, SPSS Chicago (IL), USA) was used for the data management and statistical analysis. RESULTS Patients Within the entire study cohort of 1820 patients, 587 patients received neoadjuvant chemotherapy or chemoradiotherapy followed by open esophagectomy and were thus included in this study. Of these, 65 (12%) patients experienced hematological (n = 9) or nonhematological (n = 56) complications requiring emergency hospitalization. Of the hematological complications, eight patients were admitted with anemia, 1 with leukopenia, 1 with neutropenia, and 1 with thrombocytopenia. Of the nonhematological complications, 24 patients were admitted with nausea, 10 with esophagitis, 16 with a thromboembolic event, 7 with constipation, 5 with stomatitis, 1 with diarrhea and 1 with esophageal perforation (any individual patient may have had more than one complication from neoadjuvant therapy). Table 1 provides data regarding patient demographics. For the study cohort 90-day, 5-year all-cause and disease-specific mortality were 11% (65/587), 72% (421/587), and 65% (382/587). Table 1 Characteristics of esophageal cancer patients requiring and not requiring emergency hospital admission for complications during neoadjuvant therapy Overall No complications Complications Variable Number (%) number (%) number (%) Total 587 (100) 524 (100) 63 (100) Age (mean [95% CI]) 63 (63–64) 64 (64–64) 60 (57–63) Sex  Male 445 (76) 397 (76) 48 (76)  Female 142 (24) 127 (24) 15 (24) Charlson comorbidity score  ≤1 243 (41) 215 (41) 28 (44)  >1 344 (59) 309 (59) 35 (56) Tumor stage  0–I 210 (36) 182 (35) 28 (44)  II 249 (43) 225 (43) 24 (38)  III–IV 125 (21) 114 (22) 11 (17) Histology  Adenocarcinoma 197 (34) 165 (32) 32 (51)  Squamous cell 289 (66) 358 (68) 31 (49) Surgeon volume  ≤6 153 (27) 144 (29) 9 (15)  7–16 150 (27) 136 (27) 14 (23)  >16 263 (46) 225 (45) 38 (62) Resection  R0 456 (78) 406 (77) 50 (79)  R1/2 72 (12) 65 (12) 7 (11)  Missing 59 (10) 53 (10) 6 (10) Calendar period  1987–1994 200 (34) 190 (36) 10 (16)  1995–2002 181 (31) 171 (33) 10 (16)  2003–2010 206 (35) 163 (31) 43 (68) Overall No complications Complications Variable Number (%) number (%) number (%) Total 587 (100) 524 (100) 63 (100) Age (mean [95% CI]) 63 (63–64) 64 (64–64) 60 (57–63) Sex  Male 445 (76) 397 (76) 48 (76)  Female 142 (24) 127 (24) 15 (24) Charlson comorbidity score  ≤1 243 (41) 215 (41) 28 (44)  >1 344 (59) 309 (59) 35 (56) Tumor stage  0–I 210 (36) 182 (35) 28 (44)  II 249 (43) 225 (43) 24 (38)  III–IV 125 (21) 114 (22) 11 (17) Histology  Adenocarcinoma 197 (34) 165 (32) 32 (51)  Squamous cell 289 (66) 358 (68) 31 (49) Surgeon volume  ≤6 153 (27) 144 (29) 9 (15)  7–16 150 (27) 136 (27) 14 (23)  >16 263 (46) 225 (45) 38 (62) Resection  R0 456 (78) 406 (77) 50 (79)  R1/2 72 (12) 65 (12) 7 (11)  Missing 59 (10) 53 (10) 6 (10) Calendar period  1987–1994 200 (34) 190 (36) 10 (16)  1995–2002 181 (31) 171 (33) 10 (16)  2003–2010 206 (35) 163 (31) 43 (68) View Large Table 1 Characteristics of esophageal cancer patients requiring and not requiring emergency hospital admission for complications during neoadjuvant therapy Overall No complications Complications Variable Number (%) number (%) number (%) Total 587 (100) 524 (100) 63 (100) Age (mean [95% CI]) 63 (63–64) 64 (64–64) 60 (57–63) Sex  Male 445 (76) 397 (76) 48 (76)  Female 142 (24) 127 (24) 15 (24) Charlson comorbidity score  ≤1 243 (41) 215 (41) 28 (44)  >1 344 (59) 309 (59) 35 (56) Tumor stage  0–I 210 (36) 182 (35) 28 (44)  II 249 (43) 225 (43) 24 (38)  III–IV 125 (21) 114 (22) 11 (17) Histology  Adenocarcinoma 197 (34) 165 (32) 32 (51)  Squamous cell 289 (66) 358 (68) 31 (49) Surgeon volume  ≤6 153 (27) 144 (29) 9 (15)  7–16 150 (27) 136 (27) 14 (23)  >16 263 (46) 225 (45) 38 (62) Resection  R0 456 (78) 406 (77) 50 (79)  R1/2 72 (12) 65 (12) 7 (11)  Missing 59 (10) 53 (10) 6 (10) Calendar period  1987–1994 200 (34) 190 (36) 10 (16)  1995–2002 181 (31) 171 (33) 10 (16)  2003–2010 206 (35) 163 (31) 43 (68) Overall No complications Complications Variable Number (%) number (%) number (%) Total 587 (100) 524 (100) 63 (100) Age (mean [95% CI]) 63 (63–64) 64 (64–64) 60 (57–63) Sex  Male 445 (76) 397 (76) 48 (76)  Female 142 (24) 127 (24) 15 (24) Charlson comorbidity score  ≤1 243 (41) 215 (41) 28 (44)  >1 344 (59) 309 (59) 35 (56) Tumor stage  0–I 210 (36) 182 (35) 28 (44)  II 249 (43) 225 (43) 24 (38)  III–IV 125 (21) 114 (22) 11 (17) Histology  Adenocarcinoma 197 (34) 165 (32) 32 (51)  Squamous cell 289 (66) 358 (68) 31 (49) Surgeon volume  ≤6 153 (27) 144 (29) 9 (15)  7–16 150 (27) 136 (27) 14 (23)  >16 263 (46) 225 (45) 38 (62) Resection  R0 456 (78) 406 (77) 50 (79)  R1/2 72 (12) 65 (12) 7 (11)  Missing 59 (10) 53 (10) 6 (10) Calendar period  1987–1994 200 (34) 190 (36) 10 (16)  1995–2002 181 (31) 171 (33) 10 (16)  2003–2010 206 (35) 163 (31) 43 (68) View Large Patients that experienced complications during neoadjuvant therapy had a greater proportion tumor stage 0–I, adenocarcinoma, surgery performed by high volume surgeons, and in later study period (2003–2010). In regression analysis for confounders including age, sex, pathological tumor stage, Charlson comorbidity index, histological tumor type, cumulative surgeon volume of esophagectomies during study period, calendar period of surgery, resection margin status, and reoperation within 30 days of surgery, the only factor that influenced the risk of complications during neoadjuvant therapy was later calendar period (2003–2010) (OR = 4.74; 95% CI 1.92–11.73). Mortality following all (hematological or nonhematological) complications of neoadjuvant therapy The occurrence of any hematological or nonhematological complication requiring hospitalization during neoadjuvant therapy did not statistically significantly increase the 90-day all-cause, 5-year all-cause, or 5-year disease-specific mortality following esophagectomy when all patients were analyzed (Table 2). Subgroup analysis of patients with adenocarcinoma showed an increased in 5-year disease-specific mortality (HR = 1.78; 95% CI 1.01–3.16) with neoadjuvant complications. While subgroup analysis of patients with squamous cell carcinoma (HR = 0.48; 95% CI 0.27– 0.86) showed a reduction in 5-year disease-specific mortality with neoadjuvant complications (Table 2). Table 2 Hazard ratios (HRs) with 95% confidence intervals (CIs) of mortality after surgery for esophageal cancer following complications during neoadjuvant therapy 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality All patients HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.16 (0.40–3.37) 0.79 (0.54–1.15) 0.84 (0.56–1.27) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.00 (0.30–3.33) 0.65 (0.42–1.00) 0.70 (0.43–1.13) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 2.14 (0.25–17.97) 1.71 (0.84–3.49) 1.39 (0.66–2.95) Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.82 (0.10–6.54) 0.88 (0.52–1.49) 1.78 (1.01–3.16) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.34 (0.40–4.45) 0.64 (0.38–1.08) 0.48 (0.27–0.86) Clear resection margins (R0) HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.78 (0.18–3.33) 0.67 (0.44–1.04) 0.82 (0.50–1.33) Not clear resection margins (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.78 (0.22–14.68) 0.78 (0.31–1.99) 0.68 (0.26–1.73) 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality All patients HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.16 (0.40–3.37) 0.79 (0.54–1.15) 0.84 (0.56–1.27) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.00 (0.30–3.33) 0.65 (0.42–1.00) 0.70 (0.43–1.13) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 2.14 (0.25–17.97) 1.71 (0.84–3.49) 1.39 (0.66–2.95) Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.82 (0.10–6.54) 0.88 (0.52–1.49) 1.78 (1.01–3.16) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.34 (0.40–4.45) 0.64 (0.38–1.08) 0.48 (0.27–0.86) Clear resection margins (R0) HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.78 (0.18–3.33) 0.67 (0.44–1.04) 0.82 (0.50–1.33) Not clear resection margins (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.78 (0.22–14.68) 0.78 (0.31–1.99) 0.68 (0.26–1.73) *Adjusted for age, sex (male or female), tumor stage (0-I, II, or III-IV), Charlson comorbidity index (≤1 or >1), histological subtype (adenocarcinoma or squamous cell carcinoma), surgeon volume (≤16 or >16), calendar period (1987–1994, 1995–2002, or 2003–2010), resection margin (R0 or R1/2), and reoperation (yes or no). View Large Table 2 Hazard ratios (HRs) with 95% confidence intervals (CIs) of mortality after surgery for esophageal cancer following complications during neoadjuvant therapy 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality All patients HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.16 (0.40–3.37) 0.79 (0.54–1.15) 0.84 (0.56–1.27) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.00 (0.30–3.33) 0.65 (0.42–1.00) 0.70 (0.43–1.13) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 2.14 (0.25–17.97) 1.71 (0.84–3.49) 1.39 (0.66–2.95) Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.82 (0.10–6.54) 0.88 (0.52–1.49) 1.78 (1.01–3.16) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.34 (0.40–4.45) 0.64 (0.38–1.08) 0.48 (0.27–0.86) Clear resection margins (R0) HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.78 (0.18–3.33) 0.67 (0.44–1.04) 0.82 (0.50–1.33) Not clear resection margins (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.78 (0.22–14.68) 0.78 (0.31–1.99) 0.68 (0.26–1.73) 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality All patients HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.16 (0.40–3.37) 0.79 (0.54–1.15) 0.84 (0.56–1.27) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.00 (0.30–3.33) 0.65 (0.42–1.00) 0.70 (0.43–1.13) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 2.14 (0.25–17.97) 1.71 (0.84–3.49) 1.39 (0.66–2.95) Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.82 (0.10–6.54) 0.88 (0.52–1.49) 1.78 (1.01–3.16) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.34 (0.40–4.45) 0.64 (0.38–1.08) 0.48 (0.27–0.86) Clear resection margins (R0) HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.78 (0.18–3.33) 0.67 (0.44–1.04) 0.82 (0.50–1.33) Not clear resection margins (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.78 (0.22–14.68) 0.78 (0.31–1.99) 0.68 (0.26–1.73) *Adjusted for age, sex (male or female), tumor stage (0-I, II, or III-IV), Charlson comorbidity index (≤1 or >1), histological subtype (adenocarcinoma or squamous cell carcinoma), surgeon volume (≤16 or >16), calendar period (1987–1994, 1995–2002, or 2003–2010), resection margin (R0 or R1/2), and reoperation (yes or no). View Large Mortality following hematological complications of neoadjuvant therapy Analysis of all patients showed an increase in 90-day all-cause mortality associated with neoadjuvant hematological complications (HR = 5.60; 95% CI 1.27–24.75 (Table 3). This increased 90-day mortality was particularly evident in subgroups of patients with tumor stage 0–II (HR = 6.67; 95% CI 1.51–29.48), adenocarcinoma (HR = 8.39; 95% CI 1.02–69.13), R0 resection margin (HR = 5.66; 95% CI 1.28–24.98), and R1/2 resection margin (HR = 5.66; 95% CI 1.28–24.98). No increase in 5-year all-cause or disease-specific mortality was found following neoadjuvant hematological complications in the analyses of all patients. However, the subgroup of patients with adenocarcinoma were at an increased 5-year disease-specific mortality (HR = 3.22; 95% CI 1.00–10.40) (Table 3). Table 3 Hazard ratios (HRs) with 95% confidence intervals (CIs) of mortality after surgery for esophageal cancer following hematological complications during neoadjuvant therapy 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality All patients HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.60 (1.27–24.75) 1.32 (0.58–3.00) 1.69 (0.61–4.66) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 6.67 (1.51–29.48) 2.23 (0.98–5.07) 1.69 (0.61–4.64) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes – – – Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 8.39 (1.02–69.13) 2.33 (0.73–7.43) 3.22 (1.00–10.40) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 4.29 (0.56–33.05) 1.21 (0.38–3.80) 0.60 (0.08–4.36) Resection margin (R0) HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.66 (1.28–24.98) 1.59 (0.70–3.60) 1.55 (0.57–4.26) Resection margin (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.66 (1.28–24.98) 1.59 (0.70–3.60) 1.55 (0.57–4.26) 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality All patients HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.60 (1.27–24.75) 1.32 (0.58–3.00) 1.69 (0.61–4.66) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 6.67 (1.51–29.48) 2.23 (0.98–5.07) 1.69 (0.61–4.64) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes – – – Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 8.39 (1.02–69.13) 2.33 (0.73–7.43) 3.22 (1.00–10.40) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 4.29 (0.56–33.05) 1.21 (0.38–3.80) 0.60 (0.08–4.36) Resection margin (R0) HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.66 (1.28–24.98) 1.59 (0.70–3.60) 1.55 (0.57–4.26) Resection margin (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.66 (1.28–24.98) 1.59 (0.70–3.60) 1.55 (0.57–4.26) *Adjusted for age, sex (male or female), tumor stage (0–I, II, or III–IV), Charlson co-morbidity index (≤1 or >1), histological subtype (adenocarcinoma or squamous cell carcinoma), surgeon volume (≤16 or >16), calendar period (1987–1994, 1995–2002, or 2003–2010), resection margin (R0 or R1/2), and reoperation (yes or no). View Large Table 3 Hazard ratios (HRs) with 95% confidence intervals (CIs) of mortality after surgery for esophageal cancer following hematological complications during neoadjuvant therapy 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality All patients HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.60 (1.27–24.75) 1.32 (0.58–3.00) 1.69 (0.61–4.66) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 6.67 (1.51–29.48) 2.23 (0.98–5.07) 1.69 (0.61–4.64) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes – – – Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 8.39 (1.02–69.13) 2.33 (0.73–7.43) 3.22 (1.00–10.40) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 4.29 (0.56–33.05) 1.21 (0.38–3.80) 0.60 (0.08–4.36) Resection margin (R0) HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.66 (1.28–24.98) 1.59 (0.70–3.60) 1.55 (0.57–4.26) Resection margin (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.66 (1.28–24.98) 1.59 (0.70–3.60) 1.55 (0.57–4.26) 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality All patients HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.60 (1.27–24.75) 1.32 (0.58–3.00) 1.69 (0.61–4.66) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 6.67 (1.51–29.48) 2.23 (0.98–5.07) 1.69 (0.61–4.64) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes – – – Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 8.39 (1.02–69.13) 2.33 (0.73–7.43) 3.22 (1.00–10.40) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 4.29 (0.56–33.05) 1.21 (0.38–3.80) 0.60 (0.08–4.36) Resection margin (R0) HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.66 (1.28–24.98) 1.59 (0.70–3.60) 1.55 (0.57–4.26) Resection margin (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.66 (1.28–24.98) 1.59 (0.70–3.60) 1.55 (0.57–4.26) *Adjusted for age, sex (male or female), tumor stage (0–I, II, or III–IV), Charlson co-morbidity index (≤1 or >1), histological subtype (adenocarcinoma or squamous cell carcinoma), surgeon volume (≤16 or >16), calendar period (1987–1994, 1995–2002, or 2003–2010), resection margin (R0 or R1/2), and reoperation (yes or no). View Large Mortality following nonhematological complications of neoadjuvant therapy For all patients, nonhematological complications during neoadjuvant therapy did not significantly increase the 90-day all-cause, 5-year all-cause or 5-year disease-specific mortality following esophagectomy (Table 4). However, for patients with tumor stage III–IV neoadjuvant nonhematological complications increased the 5-year all-cause mortality (HR = 2.35; 95% CI 1.15–4.81). Neoadjuvant nonhematological complications were seen to reduce the 5-year all-cause mortality in subgroup analyses of patients with tumor stage 0–II (HR = 0.58; 95% CI 0.36–0.93) and decrease the 5-year disease-specific mortality in patients with squamous cell carcinoma (HR = 0.47; 95% CI 0.25–0.87) (Table 4). Table 4 Hazard ratios (HRs) with 95% confidence intervals (CIs) of mortality after surgery for esophageal cancer following nonhematological complications during neoadjuvant therapy 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality Variable HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.95 (0.29–3.17) 0.78 (0.52–1.16) 0.79 (0.51–1.22) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.72 (0.17–3.06) 0.58 (0.36–0.93) 0.62 (0.37–1.06) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 2.36 (0.28–19.85) 2.35 (1.15–4.81) 1.39 (0.66–2.95) Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes – 0.82 (0.47–1.42) 1.57 (0.85–2.88) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.49 (0.45–4.95) 0.62 (0.36–1.10) 0.47 (0.25–0.87) Resection margin (R0) HR (95% CI) HR (95% CI) HR (95% CI) Non-hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.44 (0.06–3.26) 0.62 (0.39–1.00) 0.75 (0.44–1.26) Resection margin (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.74 (0.21–14.36) 0.78 (0.31–1.99) 0.67 (0.26–1.73) 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality Variable HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.95 (0.29–3.17) 0.78 (0.52–1.16) 0.79 (0.51–1.22) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.72 (0.17–3.06) 0.58 (0.36–0.93) 0.62 (0.37–1.06) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 2.36 (0.28–19.85) 2.35 (1.15–4.81) 1.39 (0.66–2.95) Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes – 0.82 (0.47–1.42) 1.57 (0.85–2.88) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.49 (0.45–4.95) 0.62 (0.36–1.10) 0.47 (0.25–0.87) Resection margin (R0) HR (95% CI) HR (95% CI) HR (95% CI) Non-hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.44 (0.06–3.26) 0.62 (0.39–1.00) 0.75 (0.44–1.26) Resection margin (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.74 (0.21–14.36) 0.78 (0.31–1.99) 0.67 (0.26–1.73) *Adjusted for age, sex (male or female), tumor stage (0–I, II, or III–IV), Charlson comorbidity index (≤1 or >1), histological subtype (adenocarcinoma or squamous cell carcinoma), surgeon volume (≤16 or >16), calendar period (1987–1994, 1995–2002, or 2003–2010), resection margin (R0 or R1/2), and reoperation (yes or no). View Large Table 4 Hazard ratios (HRs) with 95% confidence intervals (CIs) of mortality after surgery for esophageal cancer following nonhematological complications during neoadjuvant therapy 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality Variable HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.95 (0.29–3.17) 0.78 (0.52–1.16) 0.79 (0.51–1.22) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.72 (0.17–3.06) 0.58 (0.36–0.93) 0.62 (0.37–1.06) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 2.36 (0.28–19.85) 2.35 (1.15–4.81) 1.39 (0.66–2.95) Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes – 0.82 (0.47–1.42) 1.57 (0.85–2.88) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.49 (0.45–4.95) 0.62 (0.36–1.10) 0.47 (0.25–0.87) Resection margin (R0) HR (95% CI) HR (95% CI) HR (95% CI) Non-hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.44 (0.06–3.26) 0.62 (0.39–1.00) 0.75 (0.44–1.26) Resection margin (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.74 (0.21–14.36) 0.78 (0.31–1.99) 0.67 (0.26–1.73) 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality Variable HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.95 (0.29–3.17) 0.78 (0.52–1.16) 0.79 (0.51–1.22) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.72 (0.17–3.06) 0.58 (0.36–0.93) 0.62 (0.37–1.06) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 2.36 (0.28–19.85) 2.35 (1.15–4.81) 1.39 (0.66–2.95) Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes – 0.82 (0.47–1.42) 1.57 (0.85–2.88) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.49 (0.45–4.95) 0.62 (0.36–1.10) 0.47 (0.25–0.87) Resection margin (R0) HR (95% CI) HR (95% CI) HR (95% CI) Non-hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.44 (0.06–3.26) 0.62 (0.39–1.00) 0.75 (0.44–1.26) Resection margin (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.74 (0.21–14.36) 0.78 (0.31–1.99) 0.67 (0.26–1.73) *Adjusted for age, sex (male or female), tumor stage (0–I, II, or III–IV), Charlson comorbidity index (≤1 or >1), histological subtype (adenocarcinoma or squamous cell carcinoma), surgeon volume (≤16 or >16), calendar period (1987–1994, 1995–2002, or 2003–2010), resection margin (R0 or R1/2), and reoperation (yes or no). View Large DISCUSSION This study suggests that hematological complications increase the 90-day mortality following surgery for esophageal cancer (in particular for patients with tumor stage 0–II, adenocarcinoma, and R0 resection margin) and the 5-year disease-specific mortality in patients with adenocarcinoma. Nonhematological complications increased the 5-year mortality only in patients with tumor stage III–IV. In subgroup analyses of good prognostic groups (stage 0–II and R0 resection margins) and squamous cell carcinoma, nonhematological complications were rather seen to reduce the 5-year mortality. The population-based design with virtually complete inclusion of all eligible patients in Sweden is a significant strength of the study, along with the complete follow-up of all patients for at least 5 years, and the adjustment for relevant confounding factors. There are also limitations associated with observational studies such as this. However, the cohort utilized for this study has high accuracy in the correct identification of patients undergoing esophagectomy for cancer. The relevant data were collected from extensive review of medical records and nationwide registries, which made it possible to have accurate and detailed information on exposures, outcomes, and covariates. However, data pertaining to the exact neoadjuvant treatment and its completion as well as severity and treatment of neoadjuvant complications or other types of toxicity are missing. Furthermore WHO performance status was not collected within this dataset, which is more commonly used by oncologists during the physiological assessment of patients. The limited number of patients that received neoadjuvant therapy and experiencing complications severe enough to motivate hospitalization indicates a low power to demonstrate survival differences associated with neoadjuvant complications. As only 63 patients developed complications requiring hospitalization during neoadjuvant therapy, unfortunately we were unable to calculate hazard ratios for the effect of hematological and nonhematological complications in some subset analyses. However, the strengths of some associations improved the statistical precision. Previously a retrospective comparative study demonstrated that high-grade toxicity during neoadjuvant treatment was associated with increased postoperative morbidity and worse oncological outcomes in upper gastrointestinal cancers.10 Those findings parallel the findings for hematological complications observed in this study. The general increase in 90-day mortality observed with hematological complications may be the result of the associated inherent reduction in physiological reserve to cope with surgical stress and surgically related complications. Stage subgroup analysis showed that this effect was maximized in stage 0–II disease, which may reflect more aggressive neoadjuvant therapy regimes causing downstaging of the tumor with the consequence of greater hematological complications to the patient. However these findings must be interpreted with caution given the wide confidence intervals of the risk estimates. Subgroup analysis of adenocarcinoma showed an increase in 5-year disease-specific mortality associated with hematological complications. This may be the result of a cancer-immunological mediated phenomenon paralleling findings observed with infectious surgical complications.7–9 Alternatively, the most commonly represented hematological complication was anemia, and thus this increase in disease-specific mortality may be the result of blood transfusion to treat anemia, which previously has been suggested to increase cancer recurrence and mortality in esophageal cancer.21,22 The most commonly observed nonhematological complications were nausea, thromboembolic events and esophagitis, none of which are likely to modulate response to surgery or from cancer. However, an unexpected, but yet potentially interesting finding of the study was a reduction in 5-year mortality in good prognostic groups (stage 0–II and R0 resection margin) associated with nonhematological complications. Simultaneously, such complications were followed by an increase in 5-year mortality in poor prognostic groups (stage III–IV). Given the nature of these nonhematological complications, it may be suggested that they are a function of aggressive neoadjuvant therapy and good local tumor response in the good prognostic groups thus showing a reduction in 5-year mortality. However in advanced tumor stage groups, they may indicate disease progression and poor prognosis, given the increase in 5-year mortality in this subgroup. A survival benefit of neoadjuvant chemotherapy or chemoradiotherapy over a surgery alone approach for advanced esophageal cancer has been established in large randomized controlled trials.1–4 However, given the patient selection criteria employed in these trials and the modest effects seen, the applicability of the intensive neoadjuvant treatment regimens to all patients with esophageal cancer remains questionable. Further this study demonstrated the only factor that influenced the risk of complications during neoadjuvant therapy was later calendar period (2003–2010) (OR = 4.74; 95% CI 1.92–11.73). This maybe in part a reflection of the extension of the indications for neoadjuvant therapy in clinical practice to patient populations not included in previous positive randomized trials. The results of this study demonstrate the short- and long-term consequences of complications during neoadjuvant therapy. Approaches to reducing these neoadjuvant complications may include improved patient selection for intensive treatment pathway, pretreatment prehabilitation to optimize patient's physiological status prior to therapy, optimizing the timing of surgery, or producing less toxic neoadjuvant regimens that maintain prognostic benefits. A good example of this is the CROSS regimen, which combines a relatively low-level toxicity chemotherapy (paclitaxel and carboplatin) with concurrent radiotherapy (41.4Gy),1,2 and showed a high rate of completion of therapy (91%), which might be a way of maximizing the prognostic benefits of neoadjuvant chemoradiotherapy. In conclusion, this population-based and nationwide cohort study suggests that hematological complications during neoadjuvant therapy may, independent of other prognostic factors, adversely impact short and long-term mortality in subgroups of patients receiving esophagectomy for cancer. The mechanisms of these associations require further focused investigation. Patient selection and optimization for neoadjuvant therapy, along-with development of less toxic regimes, remain important areas for future development in the management of esophageal cancer. Notes Conflicts of interest and Disclosure: None. Funding source: The study was funded by the Swedish Research Council (839-2008-7496), the Swedish Cancer Society (CAN 2015/460). Sheraz R. Markar is supported by the National Institute of Health Research (NIHR-CTF-2015-04-09). Jesper Lagergren is supported by the Karolinska Institutet Distinguished Professor Award (Dnr: D-02418/2010). Specific author contributions: Study conception & design: Sheraz R. Markar, Jesper Lagergren; Data interpretation: Sheraz R. Markar; Manuscript writing: Sheraz R. Markar; Statistical design and analysis: Asif Johar; Study conception and manuscript reviewing: Nick Maisey; Study conception and manuscript reviewing: Pernilla Lagergren; Manuscript reviewing: Jesper Lagergren. References 1 Van Hagen P , Hulshof M C , van Lanschot J J et al. Preoperative chemoradiotherapy for esophageal or junctional cancer . N Engl J Med 2012 ; 366 : 2074 – 84 . Google Scholar CrossRef Search ADS PubMed 2 Ychou M , Boige V , Pignon J P et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicentre phase III trial . J Clin Oncol 2011 ; 29 : 1715 – 21 . Google Scholar CrossRef Search ADS PubMed 3 Cunningham D , Allum W H , Stenning S P et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer . N Engl J Med 2006 ; 355 : 11 – 20 . Google Scholar CrossRef Search ADS PubMed 4 Allum W H , Stenning S P , Bancewicz J et al. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer . J Clin Oncol 2009 ; 27 : 5062 – 7 . Google Scholar CrossRef Search ADS PubMed 5 National Oesophago-Gastric Cancer Annual report 2013 . http://www.augis.org/pdf/audits/2013_AUGIS_O_G_audit.pdf [Accessed 1 July 2017] . 6 Mak R H , Mamon H J , Ryan D P et al. Toxicity and outcomes after chemoradiation for esophageal cancer in patients age 75 or older . Dis Esophagus 2010 ; 23 : 316 – 23 . 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Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma . N Engl J Med 1999 ; 340 : 825 – 31 . Google Scholar CrossRef Search ADS PubMed 20 Sobin L H , Gospodarowicz M K , Wittekind C . UICC TNM Classification of Malignant Tumors , 6th edn . Hoboken, NJ, USA : Wiley Blackwell ; 2009 . 21 Swisher S G , Holmes E C , Hunt K K et al. Perioperative blood transfusions and decreased long-term survival in esophageal cancer . J Thorac Cardiovasc Surg 1996 ; 112 : 341 – 8 . Google Scholar CrossRef Search ADS PubMed 22 Tachibana M , Tabara H , Kotoh T et al. Prognostic significance of perioperative blood transfusions in resectable thoracic esophageal cancer . Am J Gastroenterol 1999 ; 94 : 757 – 65 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diseases of the Esophagus Oxford University Press

Complications during neoadjuvant therapy and prognosis following surgery for esophageal cancer

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The International Society for Diseases of the Esophagus
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© The Author(s) 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.
ISSN
1120-8694
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1442-2050
D.O.I.
10.1093/dote/dox151
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Abstract

Summary Previous researchers have focused upon the influence of postoperative complications upon prognosis from esophagectomy, with very little attention paid to the potential negative effects of complications during neoadjuvant therapy. The hypothesis under investigation in this study was that the prognosis after esophageal cancer surgery is negatively influenced by complications causing hospital admission during neoadjuvant therapy. Patients receiving neoadjuvant therapy and surgery for esophageal cancer between 1987 and 2010 were identified from a population-based nationwide Swedish cohort study and followed up until 2016. The association between hematological and nonhematological complications during neoadjuvant therapy and risk of short- and long-term mortality following surgery was analyzed using a multivariable Cox proportional hazards model, providing hazard ratios (HRs) with 95% confidence intervals (CIs). The HRs were adjusted for appropriate confounding variables. Among 587 patients, complications during neoadjuvant therapy requiring emergency hospitalization affected 65 (12%) patients. Hematological complications were associated with an increased 90-day overall mortality (HR = 5.60; 95% CI 1.27–24.75), particularly in subgroups of patients of tumor stage 0–II, adenocarcinoma, and radical and nonradical resection margins, and rendered increased 5-year disease-specific mortality specifically for esophageal adenocarcinoma (HR = 3.22; 95% CI 1.00–10.40). Occurrence of nonhematological complications was followed by an increase in 5-year mortality (HR = 2.35; 95% CI 1.15–4.81) in poor prognostic groups (tumor stage III–IV). There was no increased 5-year mortality following hematological or nonhematological complications in other subgroups of patients. Complications during neoadjuvant therapy may adversely impact short and long-term mortality in subgroups of patients with esophageal cancer receiving esophagectomy. Patient selection, optimization of neoadjuvant therapy, and timing of surgical resection, remain important areas for future development in the management of esophageal cancer. INTRODUCTION Randomized clinical trials have demonstrated a limited, but consistent prognostic benefit to the utilization of neoadjuvant chemotherapy or combined chemoradiotherapy followed by surgery over surgery alone for locally advanced esophageal cancer.1–4 The results of these trials have been incorporated into national guidelines, with increased uptake of neoadjuvant therapy.5 Despite the prognostic benefits of neoadjuvant therapy, it does carry its own complication rate, especially in elderly or frailer patients.6 Therefore allocation to neoadjuvant therapy remains a balance between the risk of complications with failure of course completion and a potential prognostic benefit. In recent years, studies have indicated that postoperative complications, including anastomotic leak, may increase locoregional recurrence and reduce long-term survival following esophagectomy for cancer.7–9 However, the influence of neoadjuvant treatment toxicity upon short- and long-term mortality from upper gastrointestinal cancer surgery has only been evaluated to a limited extent. It has been suggested that neoadjuvant toxicity is associated with reduced rates of radical resection margin status (R0) and poorer short- and long-term mortality.10 The hypothesis under investigation in the present national study is that the prognosis after esophageal cancer surgery is negatively influenced by complications of neoadjuvant therapy. METHODS Study design Earlier versions of this population-based cohort study have been described in detail elsewhere.11–14 In brief, this Swedish nationwide cohort study included almost all patients with esophageal cancer treated surgically with curative intent between 1987 and 2010. Patients with esophageal cancer were identified from the Swedish Cancer Registry, a registry with 98% nationwide coverage of esophageal cancer.15 Esophageal cancer patients who underwent esophagectomy were identified from the Swedish Patient Registry, which has an excellent positive predictive value (99.6%) for esophageal cancer surgery.16 The Patient Registry also provided data pertaining to comorbidities.17 The comorbidities were classified according to the most recently updated and validated version of the Charlson comorbidity index, and the esophageal cancer diagnosis was not counted.18 The Swedish personal identity number, assigned to each Swedish resident at birth or immigration, was used to link individuals’ data between registries and to identify their medical records. Medical records containing operation notes and histopathology reports of the cohort members were retrieved from all Swedish hospitals where esophageal cancer surgery was performed. This clinical data collection was facilitated by a nationwide Swedish clinical network established in the mid-1990s.19 Data concerning operating hospital, names of the surgeons, neoadjuvant therapy, surgical therapy, pathological tumor stage, and histological tumor type were obtained from these individual patient records. The histopathological review has been demonstrated for its high accuracy of pathological stage, histological subtype, and lymph node harvest.12 Tumor stage was classified according to the TNM classification of the Union Internationale Contre le Cancer (UICC).20 Open transthoracic esophageal resection with intrathoracic anastomosis was the predominant surgical procedure (95%). For the purpose of this study, only patients in the cohort who had received neoadjuvant therapy and underwent surgery between 1987 and 2010 were eligible and the follow-up of mortality was up-dated to 31st May 2016. The Regional Ethical Review Board in Stockholm, Sweden approved the study. Exposures The study exposure was emergency hospital admission during neoadjuvant therapy, resulting from hematological or nonhematological complications. Hematological complications included leukopenia, neutropenia, thrombocytopenia, and anemia. Nonhematological complications included anorexia, constipation, diarrhea, esophageal perforation, esophagitis, nausea or vomiting, neuropathy, stomatitis, and thromboembolism. Data on these complications were retrieved from the Patient Registry. Any individual patient may have had more than one complication from neoadjuvant therapy, but only the primary diagnosis code was used to classify the admission as hematological or nonhematological complication. Outcomes The outcomes were all-cause 90-day and 5-year mortality as well as disease-specific 5-year mortality from the date of surgery. The Swedish Causes of Death Registry provided accurate data for date and causes of death. This Registry has 100% coverage. If the diagnosis esophageal cancer was listed as a cause of death, this mortality was defined as disease specific. Statistical analysis The occurrence of complications during neoadjuvant therapy was analyzed in relation to mortality using a multivariable Cox-proportional hazards model, providing hazard ratios (HRs) with 95% confidence intervals (CIs), adjusted for potential confounding factors. The confounders (with categorizations) in the model were age (continuous variable), sex (male or female) pathological tumor stage (0 or I, II, III or IV), Charlson comorbidity index (≤1 or >I), histological tumor type (adenocarcinoma or squamous cell carcinoma), cumulative surgeon volume of esophagectomies during study period (≤16 or >16), calendar period of surgery (1987–1994, 1995–2002, or 2003–2010), resection margin status (radical [R0] or nonradical [R1/2]) and reoperation within 30 days of surgery (yes or no). Subgroup analyses by tumor stage, histological subtype, and resection margin with regression for the confounders described above were also performed. Follow-up ended at the date of death or end of study period (31st May 2016), whichever occurred first. The statistical software SPSS 23.0 (Statistical Package for the Social Sciences software, SPSS Chicago (IL), USA) was used for the data management and statistical analysis. RESULTS Patients Within the entire study cohort of 1820 patients, 587 patients received neoadjuvant chemotherapy or chemoradiotherapy followed by open esophagectomy and were thus included in this study. Of these, 65 (12%) patients experienced hematological (n = 9) or nonhematological (n = 56) complications requiring emergency hospitalization. Of the hematological complications, eight patients were admitted with anemia, 1 with leukopenia, 1 with neutropenia, and 1 with thrombocytopenia. Of the nonhematological complications, 24 patients were admitted with nausea, 10 with esophagitis, 16 with a thromboembolic event, 7 with constipation, 5 with stomatitis, 1 with diarrhea and 1 with esophageal perforation (any individual patient may have had more than one complication from neoadjuvant therapy). Table 1 provides data regarding patient demographics. For the study cohort 90-day, 5-year all-cause and disease-specific mortality were 11% (65/587), 72% (421/587), and 65% (382/587). Table 1 Characteristics of esophageal cancer patients requiring and not requiring emergency hospital admission for complications during neoadjuvant therapy Overall No complications Complications Variable Number (%) number (%) number (%) Total 587 (100) 524 (100) 63 (100) Age (mean [95% CI]) 63 (63–64) 64 (64–64) 60 (57–63) Sex  Male 445 (76) 397 (76) 48 (76)  Female 142 (24) 127 (24) 15 (24) Charlson comorbidity score  ≤1 243 (41) 215 (41) 28 (44)  >1 344 (59) 309 (59) 35 (56) Tumor stage  0–I 210 (36) 182 (35) 28 (44)  II 249 (43) 225 (43) 24 (38)  III–IV 125 (21) 114 (22) 11 (17) Histology  Adenocarcinoma 197 (34) 165 (32) 32 (51)  Squamous cell 289 (66) 358 (68) 31 (49) Surgeon volume  ≤6 153 (27) 144 (29) 9 (15)  7–16 150 (27) 136 (27) 14 (23)  >16 263 (46) 225 (45) 38 (62) Resection  R0 456 (78) 406 (77) 50 (79)  R1/2 72 (12) 65 (12) 7 (11)  Missing 59 (10) 53 (10) 6 (10) Calendar period  1987–1994 200 (34) 190 (36) 10 (16)  1995–2002 181 (31) 171 (33) 10 (16)  2003–2010 206 (35) 163 (31) 43 (68) Overall No complications Complications Variable Number (%) number (%) number (%) Total 587 (100) 524 (100) 63 (100) Age (mean [95% CI]) 63 (63–64) 64 (64–64) 60 (57–63) Sex  Male 445 (76) 397 (76) 48 (76)  Female 142 (24) 127 (24) 15 (24) Charlson comorbidity score  ≤1 243 (41) 215 (41) 28 (44)  >1 344 (59) 309 (59) 35 (56) Tumor stage  0–I 210 (36) 182 (35) 28 (44)  II 249 (43) 225 (43) 24 (38)  III–IV 125 (21) 114 (22) 11 (17) Histology  Adenocarcinoma 197 (34) 165 (32) 32 (51)  Squamous cell 289 (66) 358 (68) 31 (49) Surgeon volume  ≤6 153 (27) 144 (29) 9 (15)  7–16 150 (27) 136 (27) 14 (23)  >16 263 (46) 225 (45) 38 (62) Resection  R0 456 (78) 406 (77) 50 (79)  R1/2 72 (12) 65 (12) 7 (11)  Missing 59 (10) 53 (10) 6 (10) Calendar period  1987–1994 200 (34) 190 (36) 10 (16)  1995–2002 181 (31) 171 (33) 10 (16)  2003–2010 206 (35) 163 (31) 43 (68) View Large Table 1 Characteristics of esophageal cancer patients requiring and not requiring emergency hospital admission for complications during neoadjuvant therapy Overall No complications Complications Variable Number (%) number (%) number (%) Total 587 (100) 524 (100) 63 (100) Age (mean [95% CI]) 63 (63–64) 64 (64–64) 60 (57–63) Sex  Male 445 (76) 397 (76) 48 (76)  Female 142 (24) 127 (24) 15 (24) Charlson comorbidity score  ≤1 243 (41) 215 (41) 28 (44)  >1 344 (59) 309 (59) 35 (56) Tumor stage  0–I 210 (36) 182 (35) 28 (44)  II 249 (43) 225 (43) 24 (38)  III–IV 125 (21) 114 (22) 11 (17) Histology  Adenocarcinoma 197 (34) 165 (32) 32 (51)  Squamous cell 289 (66) 358 (68) 31 (49) Surgeon volume  ≤6 153 (27) 144 (29) 9 (15)  7–16 150 (27) 136 (27) 14 (23)  >16 263 (46) 225 (45) 38 (62) Resection  R0 456 (78) 406 (77) 50 (79)  R1/2 72 (12) 65 (12) 7 (11)  Missing 59 (10) 53 (10) 6 (10) Calendar period  1987–1994 200 (34) 190 (36) 10 (16)  1995–2002 181 (31) 171 (33) 10 (16)  2003–2010 206 (35) 163 (31) 43 (68) Overall No complications Complications Variable Number (%) number (%) number (%) Total 587 (100) 524 (100) 63 (100) Age (mean [95% CI]) 63 (63–64) 64 (64–64) 60 (57–63) Sex  Male 445 (76) 397 (76) 48 (76)  Female 142 (24) 127 (24) 15 (24) Charlson comorbidity score  ≤1 243 (41) 215 (41) 28 (44)  >1 344 (59) 309 (59) 35 (56) Tumor stage  0–I 210 (36) 182 (35) 28 (44)  II 249 (43) 225 (43) 24 (38)  III–IV 125 (21) 114 (22) 11 (17) Histology  Adenocarcinoma 197 (34) 165 (32) 32 (51)  Squamous cell 289 (66) 358 (68) 31 (49) Surgeon volume  ≤6 153 (27) 144 (29) 9 (15)  7–16 150 (27) 136 (27) 14 (23)  >16 263 (46) 225 (45) 38 (62) Resection  R0 456 (78) 406 (77) 50 (79)  R1/2 72 (12) 65 (12) 7 (11)  Missing 59 (10) 53 (10) 6 (10) Calendar period  1987–1994 200 (34) 190 (36) 10 (16)  1995–2002 181 (31) 171 (33) 10 (16)  2003–2010 206 (35) 163 (31) 43 (68) View Large Patients that experienced complications during neoadjuvant therapy had a greater proportion tumor stage 0–I, adenocarcinoma, surgery performed by high volume surgeons, and in later study period (2003–2010). In regression analysis for confounders including age, sex, pathological tumor stage, Charlson comorbidity index, histological tumor type, cumulative surgeon volume of esophagectomies during study period, calendar period of surgery, resection margin status, and reoperation within 30 days of surgery, the only factor that influenced the risk of complications during neoadjuvant therapy was later calendar period (2003–2010) (OR = 4.74; 95% CI 1.92–11.73). Mortality following all (hematological or nonhematological) complications of neoadjuvant therapy The occurrence of any hematological or nonhematological complication requiring hospitalization during neoadjuvant therapy did not statistically significantly increase the 90-day all-cause, 5-year all-cause, or 5-year disease-specific mortality following esophagectomy when all patients were analyzed (Table 2). Subgroup analysis of patients with adenocarcinoma showed an increased in 5-year disease-specific mortality (HR = 1.78; 95% CI 1.01–3.16) with neoadjuvant complications. While subgroup analysis of patients with squamous cell carcinoma (HR = 0.48; 95% CI 0.27– 0.86) showed a reduction in 5-year disease-specific mortality with neoadjuvant complications (Table 2). Table 2 Hazard ratios (HRs) with 95% confidence intervals (CIs) of mortality after surgery for esophageal cancer following complications during neoadjuvant therapy 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality All patients HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.16 (0.40–3.37) 0.79 (0.54–1.15) 0.84 (0.56–1.27) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.00 (0.30–3.33) 0.65 (0.42–1.00) 0.70 (0.43–1.13) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 2.14 (0.25–17.97) 1.71 (0.84–3.49) 1.39 (0.66–2.95) Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.82 (0.10–6.54) 0.88 (0.52–1.49) 1.78 (1.01–3.16) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.34 (0.40–4.45) 0.64 (0.38–1.08) 0.48 (0.27–0.86) Clear resection margins (R0) HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.78 (0.18–3.33) 0.67 (0.44–1.04) 0.82 (0.50–1.33) Not clear resection margins (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.78 (0.22–14.68) 0.78 (0.31–1.99) 0.68 (0.26–1.73) 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality All patients HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.16 (0.40–3.37) 0.79 (0.54–1.15) 0.84 (0.56–1.27) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.00 (0.30–3.33) 0.65 (0.42–1.00) 0.70 (0.43–1.13) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 2.14 (0.25–17.97) 1.71 (0.84–3.49) 1.39 (0.66–2.95) Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.82 (0.10–6.54) 0.88 (0.52–1.49) 1.78 (1.01–3.16) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.34 (0.40–4.45) 0.64 (0.38–1.08) 0.48 (0.27–0.86) Clear resection margins (R0) HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.78 (0.18–3.33) 0.67 (0.44–1.04) 0.82 (0.50–1.33) Not clear resection margins (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.78 (0.22–14.68) 0.78 (0.31–1.99) 0.68 (0.26–1.73) *Adjusted for age, sex (male or female), tumor stage (0-I, II, or III-IV), Charlson comorbidity index (≤1 or >1), histological subtype (adenocarcinoma or squamous cell carcinoma), surgeon volume (≤16 or >16), calendar period (1987–1994, 1995–2002, or 2003–2010), resection margin (R0 or R1/2), and reoperation (yes or no). View Large Table 2 Hazard ratios (HRs) with 95% confidence intervals (CIs) of mortality after surgery for esophageal cancer following complications during neoadjuvant therapy 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality All patients HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.16 (0.40–3.37) 0.79 (0.54–1.15) 0.84 (0.56–1.27) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.00 (0.30–3.33) 0.65 (0.42–1.00) 0.70 (0.43–1.13) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 2.14 (0.25–17.97) 1.71 (0.84–3.49) 1.39 (0.66–2.95) Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.82 (0.10–6.54) 0.88 (0.52–1.49) 1.78 (1.01–3.16) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.34 (0.40–4.45) 0.64 (0.38–1.08) 0.48 (0.27–0.86) Clear resection margins (R0) HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.78 (0.18–3.33) 0.67 (0.44–1.04) 0.82 (0.50–1.33) Not clear resection margins (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.78 (0.22–14.68) 0.78 (0.31–1.99) 0.68 (0.26–1.73) 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality All patients HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.16 (0.40–3.37) 0.79 (0.54–1.15) 0.84 (0.56–1.27) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.00 (0.30–3.33) 0.65 (0.42–1.00) 0.70 (0.43–1.13) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 2.14 (0.25–17.97) 1.71 (0.84–3.49) 1.39 (0.66–2.95) Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.82 (0.10–6.54) 0.88 (0.52–1.49) 1.78 (1.01–3.16) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.34 (0.40–4.45) 0.64 (0.38–1.08) 0.48 (0.27–0.86) Clear resection margins (R0) HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.78 (0.18–3.33) 0.67 (0.44–1.04) 0.82 (0.50–1.33) Not clear resection margins (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.78 (0.22–14.68) 0.78 (0.31–1.99) 0.68 (0.26–1.73) *Adjusted for age, sex (male or female), tumor stage (0-I, II, or III-IV), Charlson comorbidity index (≤1 or >1), histological subtype (adenocarcinoma or squamous cell carcinoma), surgeon volume (≤16 or >16), calendar period (1987–1994, 1995–2002, or 2003–2010), resection margin (R0 or R1/2), and reoperation (yes or no). View Large Mortality following hematological complications of neoadjuvant therapy Analysis of all patients showed an increase in 90-day all-cause mortality associated with neoadjuvant hematological complications (HR = 5.60; 95% CI 1.27–24.75 (Table 3). This increased 90-day mortality was particularly evident in subgroups of patients with tumor stage 0–II (HR = 6.67; 95% CI 1.51–29.48), adenocarcinoma (HR = 8.39; 95% CI 1.02–69.13), R0 resection margin (HR = 5.66; 95% CI 1.28–24.98), and R1/2 resection margin (HR = 5.66; 95% CI 1.28–24.98). No increase in 5-year all-cause or disease-specific mortality was found following neoadjuvant hematological complications in the analyses of all patients. However, the subgroup of patients with adenocarcinoma were at an increased 5-year disease-specific mortality (HR = 3.22; 95% CI 1.00–10.40) (Table 3). Table 3 Hazard ratios (HRs) with 95% confidence intervals (CIs) of mortality after surgery for esophageal cancer following hematological complications during neoadjuvant therapy 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality All patients HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.60 (1.27–24.75) 1.32 (0.58–3.00) 1.69 (0.61–4.66) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 6.67 (1.51–29.48) 2.23 (0.98–5.07) 1.69 (0.61–4.64) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes – – – Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 8.39 (1.02–69.13) 2.33 (0.73–7.43) 3.22 (1.00–10.40) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 4.29 (0.56–33.05) 1.21 (0.38–3.80) 0.60 (0.08–4.36) Resection margin (R0) HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.66 (1.28–24.98) 1.59 (0.70–3.60) 1.55 (0.57–4.26) Resection margin (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.66 (1.28–24.98) 1.59 (0.70–3.60) 1.55 (0.57–4.26) 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality All patients HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.60 (1.27–24.75) 1.32 (0.58–3.00) 1.69 (0.61–4.66) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 6.67 (1.51–29.48) 2.23 (0.98–5.07) 1.69 (0.61–4.64) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes – – – Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 8.39 (1.02–69.13) 2.33 (0.73–7.43) 3.22 (1.00–10.40) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 4.29 (0.56–33.05) 1.21 (0.38–3.80) 0.60 (0.08–4.36) Resection margin (R0) HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.66 (1.28–24.98) 1.59 (0.70–3.60) 1.55 (0.57–4.26) Resection margin (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.66 (1.28–24.98) 1.59 (0.70–3.60) 1.55 (0.57–4.26) *Adjusted for age, sex (male or female), tumor stage (0–I, II, or III–IV), Charlson co-morbidity index (≤1 or >1), histological subtype (adenocarcinoma or squamous cell carcinoma), surgeon volume (≤16 or >16), calendar period (1987–1994, 1995–2002, or 2003–2010), resection margin (R0 or R1/2), and reoperation (yes or no). View Large Table 3 Hazard ratios (HRs) with 95% confidence intervals (CIs) of mortality after surgery for esophageal cancer following hematological complications during neoadjuvant therapy 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality All patients HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.60 (1.27–24.75) 1.32 (0.58–3.00) 1.69 (0.61–4.66) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 6.67 (1.51–29.48) 2.23 (0.98–5.07) 1.69 (0.61–4.64) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes – – – Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 8.39 (1.02–69.13) 2.33 (0.73–7.43) 3.22 (1.00–10.40) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 4.29 (0.56–33.05) 1.21 (0.38–3.80) 0.60 (0.08–4.36) Resection margin (R0) HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.66 (1.28–24.98) 1.59 (0.70–3.60) 1.55 (0.57–4.26) Resection margin (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.66 (1.28–24.98) 1.59 (0.70–3.60) 1.55 (0.57–4.26) 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality All patients HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.60 (1.27–24.75) 1.32 (0.58–3.00) 1.69 (0.61–4.66) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 6.67 (1.51–29.48) 2.23 (0.98–5.07) 1.69 (0.61–4.64) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes – – – Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 8.39 (1.02–69.13) 2.33 (0.73–7.43) 3.22 (1.00–10.40) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 4.29 (0.56–33.05) 1.21 (0.38–3.80) 0.60 (0.08–4.36) Resection margin (R0) HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.66 (1.28–24.98) 1.59 (0.70–3.60) 1.55 (0.57–4.26) Resection margin (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 5.66 (1.28–24.98) 1.59 (0.70–3.60) 1.55 (0.57–4.26) *Adjusted for age, sex (male or female), tumor stage (0–I, II, or III–IV), Charlson co-morbidity index (≤1 or >1), histological subtype (adenocarcinoma or squamous cell carcinoma), surgeon volume (≤16 or >16), calendar period (1987–1994, 1995–2002, or 2003–2010), resection margin (R0 or R1/2), and reoperation (yes or no). View Large Mortality following nonhematological complications of neoadjuvant therapy For all patients, nonhematological complications during neoadjuvant therapy did not significantly increase the 90-day all-cause, 5-year all-cause or 5-year disease-specific mortality following esophagectomy (Table 4). However, for patients with tumor stage III–IV neoadjuvant nonhematological complications increased the 5-year all-cause mortality (HR = 2.35; 95% CI 1.15–4.81). Neoadjuvant nonhematological complications were seen to reduce the 5-year all-cause mortality in subgroup analyses of patients with tumor stage 0–II (HR = 0.58; 95% CI 0.36–0.93) and decrease the 5-year disease-specific mortality in patients with squamous cell carcinoma (HR = 0.47; 95% CI 0.25–0.87) (Table 4). Table 4 Hazard ratios (HRs) with 95% confidence intervals (CIs) of mortality after surgery for esophageal cancer following nonhematological complications during neoadjuvant therapy 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality Variable HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.95 (0.29–3.17) 0.78 (0.52–1.16) 0.79 (0.51–1.22) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.72 (0.17–3.06) 0.58 (0.36–0.93) 0.62 (0.37–1.06) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 2.36 (0.28–19.85) 2.35 (1.15–4.81) 1.39 (0.66–2.95) Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes – 0.82 (0.47–1.42) 1.57 (0.85–2.88) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.49 (0.45–4.95) 0.62 (0.36–1.10) 0.47 (0.25–0.87) Resection margin (R0) HR (95% CI) HR (95% CI) HR (95% CI) Non-hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.44 (0.06–3.26) 0.62 (0.39–1.00) 0.75 (0.44–1.26) Resection margin (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.74 (0.21–14.36) 0.78 (0.31–1.99) 0.67 (0.26–1.73) 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality Variable HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.95 (0.29–3.17) 0.78 (0.52–1.16) 0.79 (0.51–1.22) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.72 (0.17–3.06) 0.58 (0.36–0.93) 0.62 (0.37–1.06) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 2.36 (0.28–19.85) 2.35 (1.15–4.81) 1.39 (0.66–2.95) Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes – 0.82 (0.47–1.42) 1.57 (0.85–2.88) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.49 (0.45–4.95) 0.62 (0.36–1.10) 0.47 (0.25–0.87) Resection margin (R0) HR (95% CI) HR (95% CI) HR (95% CI) Non-hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.44 (0.06–3.26) 0.62 (0.39–1.00) 0.75 (0.44–1.26) Resection margin (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.74 (0.21–14.36) 0.78 (0.31–1.99) 0.67 (0.26–1.73) *Adjusted for age, sex (male or female), tumor stage (0–I, II, or III–IV), Charlson comorbidity index (≤1 or >1), histological subtype (adenocarcinoma or squamous cell carcinoma), surgeon volume (≤16 or >16), calendar period (1987–1994, 1995–2002, or 2003–2010), resection margin (R0 or R1/2), and reoperation (yes or no). View Large Table 4 Hazard ratios (HRs) with 95% confidence intervals (CIs) of mortality after surgery for esophageal cancer following nonhematological complications during neoadjuvant therapy 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality Variable HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.95 (0.29–3.17) 0.78 (0.52–1.16) 0.79 (0.51–1.22) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.72 (0.17–3.06) 0.58 (0.36–0.93) 0.62 (0.37–1.06) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 2.36 (0.28–19.85) 2.35 (1.15–4.81) 1.39 (0.66–2.95) Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes – 0.82 (0.47–1.42) 1.57 (0.85–2.88) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.49 (0.45–4.95) 0.62 (0.36–1.10) 0.47 (0.25–0.87) Resection margin (R0) HR (95% CI) HR (95% CI) HR (95% CI) Non-hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.44 (0.06–3.26) 0.62 (0.39–1.00) 0.75 (0.44–1.26) Resection margin (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.74 (0.21–14.36) 0.78 (0.31–1.99) 0.67 (0.26–1.73) 90-day all-cause 5-year all-cause 5-year disease-specific mortality mortality mortality Variable HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.95 (0.29–3.17) 0.78 (0.52–1.16) 0.79 (0.51–1.22) Stage 0–II HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.72 (0.17–3.06) 0.58 (0.36–0.93) 0.62 (0.37–1.06) Stage III–IV HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 2.36 (0.28–19.85) 2.35 (1.15–4.81) 1.39 (0.66–2.95) Adenocarcinoma HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes – 0.82 (0.47–1.42) 1.57 (0.85–2.88) Squamous cell carcinoma HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.49 (0.45–4.95) 0.62 (0.36–1.10) 0.47 (0.25–0.87) Resection margin (R0) HR (95% CI) HR (95% CI) HR (95% CI) Non-hematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 0.44 (0.06–3.26) 0.62 (0.39–1.00) 0.75 (0.44–1.26) Resection margin (R1/2) HR (95% CI) HR (95% CI) HR (95% CI) Nonhematological complications  No 1 (reference) 1 (reference) 1 (reference)  Yes 1.74 (0.21–14.36) 0.78 (0.31–1.99) 0.67 (0.26–1.73) *Adjusted for age, sex (male or female), tumor stage (0–I, II, or III–IV), Charlson comorbidity index (≤1 or >1), histological subtype (adenocarcinoma or squamous cell carcinoma), surgeon volume (≤16 or >16), calendar period (1987–1994, 1995–2002, or 2003–2010), resection margin (R0 or R1/2), and reoperation (yes or no). View Large DISCUSSION This study suggests that hematological complications increase the 90-day mortality following surgery for esophageal cancer (in particular for patients with tumor stage 0–II, adenocarcinoma, and R0 resection margin) and the 5-year disease-specific mortality in patients with adenocarcinoma. Nonhematological complications increased the 5-year mortality only in patients with tumor stage III–IV. In subgroup analyses of good prognostic groups (stage 0–II and R0 resection margins) and squamous cell carcinoma, nonhematological complications were rather seen to reduce the 5-year mortality. The population-based design with virtually complete inclusion of all eligible patients in Sweden is a significant strength of the study, along with the complete follow-up of all patients for at least 5 years, and the adjustment for relevant confounding factors. There are also limitations associated with observational studies such as this. However, the cohort utilized for this study has high accuracy in the correct identification of patients undergoing esophagectomy for cancer. The relevant data were collected from extensive review of medical records and nationwide registries, which made it possible to have accurate and detailed information on exposures, outcomes, and covariates. However, data pertaining to the exact neoadjuvant treatment and its completion as well as severity and treatment of neoadjuvant complications or other types of toxicity are missing. Furthermore WHO performance status was not collected within this dataset, which is more commonly used by oncologists during the physiological assessment of patients. The limited number of patients that received neoadjuvant therapy and experiencing complications severe enough to motivate hospitalization indicates a low power to demonstrate survival differences associated with neoadjuvant complications. As only 63 patients developed complications requiring hospitalization during neoadjuvant therapy, unfortunately we were unable to calculate hazard ratios for the effect of hematological and nonhematological complications in some subset analyses. However, the strengths of some associations improved the statistical precision. Previously a retrospective comparative study demonstrated that high-grade toxicity during neoadjuvant treatment was associated with increased postoperative morbidity and worse oncological outcomes in upper gastrointestinal cancers.10 Those findings parallel the findings for hematological complications observed in this study. The general increase in 90-day mortality observed with hematological complications may be the result of the associated inherent reduction in physiological reserve to cope with surgical stress and surgically related complications. Stage subgroup analysis showed that this effect was maximized in stage 0–II disease, which may reflect more aggressive neoadjuvant therapy regimes causing downstaging of the tumor with the consequence of greater hematological complications to the patient. However these findings must be interpreted with caution given the wide confidence intervals of the risk estimates. Subgroup analysis of adenocarcinoma showed an increase in 5-year disease-specific mortality associated with hematological complications. This may be the result of a cancer-immunological mediated phenomenon paralleling findings observed with infectious surgical complications.7–9 Alternatively, the most commonly represented hematological complication was anemia, and thus this increase in disease-specific mortality may be the result of blood transfusion to treat anemia, which previously has been suggested to increase cancer recurrence and mortality in esophageal cancer.21,22 The most commonly observed nonhematological complications were nausea, thromboembolic events and esophagitis, none of which are likely to modulate response to surgery or from cancer. However, an unexpected, but yet potentially interesting finding of the study was a reduction in 5-year mortality in good prognostic groups (stage 0–II and R0 resection margin) associated with nonhematological complications. Simultaneously, such complications were followed by an increase in 5-year mortality in poor prognostic groups (stage III–IV). Given the nature of these nonhematological complications, it may be suggested that they are a function of aggressive neoadjuvant therapy and good local tumor response in the good prognostic groups thus showing a reduction in 5-year mortality. However in advanced tumor stage groups, they may indicate disease progression and poor prognosis, given the increase in 5-year mortality in this subgroup. A survival benefit of neoadjuvant chemotherapy or chemoradiotherapy over a surgery alone approach for advanced esophageal cancer has been established in large randomized controlled trials.1–4 However, given the patient selection criteria employed in these trials and the modest effects seen, the applicability of the intensive neoadjuvant treatment regimens to all patients with esophageal cancer remains questionable. Further this study demonstrated the only factor that influenced the risk of complications during neoadjuvant therapy was later calendar period (2003–2010) (OR = 4.74; 95% CI 1.92–11.73). This maybe in part a reflection of the extension of the indications for neoadjuvant therapy in clinical practice to patient populations not included in previous positive randomized trials. The results of this study demonstrate the short- and long-term consequences of complications during neoadjuvant therapy. Approaches to reducing these neoadjuvant complications may include improved patient selection for intensive treatment pathway, pretreatment prehabilitation to optimize patient's physiological status prior to therapy, optimizing the timing of surgery, or producing less toxic neoadjuvant regimens that maintain prognostic benefits. A good example of this is the CROSS regimen, which combines a relatively low-level toxicity chemotherapy (paclitaxel and carboplatin) with concurrent radiotherapy (41.4Gy),1,2 and showed a high rate of completion of therapy (91%), which might be a way of maximizing the prognostic benefits of neoadjuvant chemoradiotherapy. In conclusion, this population-based and nationwide cohort study suggests that hematological complications during neoadjuvant therapy may, independent of other prognostic factors, adversely impact short and long-term mortality in subgroups of patients receiving esophagectomy for cancer. The mechanisms of these associations require further focused investigation. Patient selection and optimization for neoadjuvant therapy, along-with development of less toxic regimes, remain important areas for future development in the management of esophageal cancer. Notes Conflicts of interest and Disclosure: None. Funding source: The study was funded by the Swedish Research Council (839-2008-7496), the Swedish Cancer Society (CAN 2015/460). Sheraz R. Markar is supported by the National Institute of Health Research (NIHR-CTF-2015-04-09). Jesper Lagergren is supported by the Karolinska Institutet Distinguished Professor Award (Dnr: D-02418/2010). Specific author contributions: Study conception & design: Sheraz R. Markar, Jesper Lagergren; Data interpretation: Sheraz R. Markar; Manuscript writing: Sheraz R. Markar; Statistical design and analysis: Asif Johar; Study conception and manuscript reviewing: Nick Maisey; Study conception and manuscript reviewing: Pernilla Lagergren; Manuscript reviewing: Jesper Lagergren. References 1 Van Hagen P , Hulshof M C , van Lanschot J J et al. Preoperative chemoradiotherapy for esophageal or junctional cancer . N Engl J Med 2012 ; 366 : 2074 – 84 . Google Scholar CrossRef Search ADS PubMed 2 Ychou M , Boige V , Pignon J P et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicentre phase III trial . J Clin Oncol 2011 ; 29 : 1715 – 21 . Google Scholar CrossRef Search ADS PubMed 3 Cunningham D , Allum W H , Stenning S P et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer . N Engl J Med 2006 ; 355 : 11 – 20 . Google Scholar CrossRef Search ADS PubMed 4 Allum W H , Stenning S P , Bancewicz J et al. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer . J Clin Oncol 2009 ; 27 : 5062 – 7 . Google Scholar CrossRef Search ADS PubMed 5 National Oesophago-Gastric Cancer Annual report 2013 . http://www.augis.org/pdf/audits/2013_AUGIS_O_G_audit.pdf [Accessed 1 July 2017] . 6 Mak R H , Mamon H J , Ryan D P et al. Toxicity and outcomes after chemoradiation for esophageal cancer in patients age 75 or older . Dis Esophagus 2010 ; 23 : 316 – 23 . 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Disparities in the classification of esophageal and cardia adenocarcinomas and their influence on reported incidence rates . Ann Surg 2006 ; 243 : 479 – 85 . Google Scholar CrossRef Search ADS PubMed 16 Lagergren K , Derogar M . Validation of oesophageal cancer surgery data in the Swedish Patient Registry . Acta Oncol 2012 ; 51 : 65 – 8 . Google Scholar CrossRef Search ADS PubMed 17 Ludvigsson J F , Andersson E , Ekbom A et al. External review and validation of the Swedish national inpatient register . BMC Public Health 2011 ; 11 : 450 . Google Scholar CrossRef Search ADS PubMed 18 Armitage J N , vander Meulen J H . Royal College of Surgeons Comorbidity Consensus Group Identifying comorbidity in surgical patients using administrative data with the Royal College of Surgeons Charlson Score . Br J Surg 2010 ; 97 : 772 – 81 . Google Scholar CrossRef Search ADS PubMed 19 Lagergren J , Bergstrom R , Lindgren A et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma . N Engl J Med 1999 ; 340 : 825 – 31 . Google Scholar CrossRef Search ADS PubMed 20 Sobin L H , Gospodarowicz M K , Wittekind C . UICC TNM Classification of Malignant Tumors , 6th edn . Hoboken, NJ, USA : Wiley Blackwell ; 2009 . 21 Swisher S G , Holmes E C , Hunt K K et al. Perioperative blood transfusions and decreased long-term survival in esophageal cancer . J Thorac Cardiovasc Surg 1996 ; 112 : 341 – 8 . Google Scholar CrossRef Search ADS PubMed 22 Tachibana M , Tabara H , Kotoh T et al. Prognostic significance of perioperative blood transfusions in resectable thoracic esophageal cancer . Am J Gastroenterol 1999 ; 94 : 757 – 65 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. 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Diseases of the EsophagusOxford University Press

Published: Dec 22, 2017

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