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Background Large studies comparing totally minimally invasive oesophagectomy (TMIE) with laparoscopically assisted (hybrid) oesophagectomy are lacking. Although randomized trials have compared TMIE invasive with open oesophagectomy, daily clinical practice does not always resemble the results reported in such trials. The aim of the present study was to compare complications after totally minimally invasive, hybrid and open Ivor Lewis oesophagectomy in patients with oesophageal cancer. Methods The study was performed using data from the International Esodata Study Group registered between February 2015 and December 2019. The primary outcome was pneumonia, and secondary outcomes included the incidence and severity of anastomotic leakage, (major) complications, duration of hospital stay, escalation of care, and 90-day mortality. Data were analysed using multivariable multilevel models. Results Some 8640 patients were included between 2015 and 2019. Patients undergoing TMIE had a lower incidence of pneumonia than those having hybrid (10.9 versus 16.3 per cent; odds ratio (OR) 0.56, 95 per cent c.i. 0.40 to 0.80) or open (10.9 versus 17.4 per cent; OR 0.60, 0.42 to 0.84) oesophagectomy, and had a shorter hospital stay (median 10 (i.q.r. 8–16) days versus 14 (11–19) days (P = 0.041) and 11 (9–16) days (P = 0.027) respectively). The rate of anastomotic leakage was higher after TMIE than hybrid (15.1 versus 10.7 per cent; OR 1.47, 1.01 to 2.13) or open (15.1 versus 7.3 per cent; OR 1.73, 1.26 to 2.38) procedures. Conclusion Compared with hybrid and open Ivor Lewis oesophagectomy, TMIE resulted in a lower pneumonia rate, a shorter duration of hospital stay, but higher anastomotic leakage rates. Therefore, no clear advantage was seen for either TMIE, hybrid or open Ivor Lewis oesophagectomy when performed in daily clinical practice.

I: Clinical factors: age and co-morbidityIn chapter 1-3 of this thesis the use of definitive chemoradiotherapy (dCRT) as a lessaggressive alternative treatment approach in elderly patients and in patients with severe comorbidities was studied. We showed that the use of nCRT plus surgery in operable patients with a potentially curative resectable esophageal adenocarcinoma (EAC) was associated with a better overall survival (OS) irrespective of age, number and type of co-morbidities. The administration of dCRT was preferably given in patients with esophageal squamous cell carcinoma (ESCC) with at least 2 co-morbidities or >75 years old. There was no difference in OS in patients who underwentdCRT compared to patients with nCRT plus surgery. These findings suggest a similar longtermsurvival after both treatment modalities in elderly patients with ESCC. In patients with EAC, nCRT plus surgery resulted in a better survival than dCRT, including patients with diabetes mellitus, hypertension or cardiovascular disease, as has been shown by others.II: Pathological factors: circumferential resection margin and extramural venous invasionThe prognostic value of the circumferential margin (CRM) after neoadjuvantchemoradiotherapy (nCRT) is not well defined yet. As described in chapter 4, nCRTaffected the CRM cutoff values. After nCRT, the CRM-R0 as defined according to theCollege of American Pathologists (CAP; >0 mm) was only prognostic for 2-year localrecurrence-free survival (LRFS). However, in the surgery-alone group, it was also prognosticfor the 2-year disease-free survival (DFS). CRM assessment depends on accurate histologicalexamination of residual tumor, which might be related to tumor heterogeneity. Current TNM classifications recognize lymphovascular invasion (LVI) as a prognostic factor in EC. It is important to report the type of vascular invasion (VI). Pathologists stress on the presence of extramural venous invasion (EMVI), i.e. tumor cells in the vasculature of vessels beyond the muscularis propria, as an independent predictor of poor prognosis in colorectal cancer (CRC). In chapter 5 and 6, we described the presence of EMVI in approximately 25% of patients with a at least pT3 tumor after surgery alone, and in 21.6% after nCRT. EMVI was common in tumors withadvanced T- and N-stage and also in tumors with perineural tumor growth and with LVI.III: Treatment-related factors: salvage surgeryIn chapter 7 we showed that even though the amplitude of breathing seemed relatively constant, offsets of the diaphragm positions, and consequently tumor positions, were large. This might result in geographical misses of tumor or dose deviations in terms of hot or cold spots in dose distribution. The magnitude of and variation in breathing amplitude and offset position can be determined more specific on 4DCT scan. The mean diaphragm expiration and inspiration delineations offset of the diaphragm that we observed were in the same order of magnitude as found in other studies with 4 D-CT scan.In chapter 8 we have evaluated the site of residual disease related to tumor target volumes at pathologic examination. In radical resected (R0) specimens, 19.8% had a pCR and 14% nearly no response (TRG 4-5). Residual tumor was limited to the esophagus (ypT+N0) in 57.8% and commonly in the adventitia (43.1%), while 7.3% was in the mucosa (ypT1a), 16.5% in the submucosa (ypT1b) and 6.4% only in lymph nodes (ypT0N+). In TRG 2-5 R0 specimens, macroscopic residue was in- and outside the gross tumor volume (GTV) in 33.3% and 8.9%, while microscopic residue in- and outside the clinical target volume (CTV) margin only in 58.9% and 1.1%, respectively. Residual nodal disease was observed proximally in two and distally to the CTV in 5 patients. Disease Free Survival (DFS) decreased if macroscopic tumor was outside the GTV (9 vs. 27 months; p=0.009) and in ypT2-4aN+.In chapter 9 we have shown that salvage surgery is a feasible and may be potentially curative in patients with locoregional regrowth EC after dCRT and nCRT.Besides a R0 resection, the presence of early and small tumor remnants (cT>2/N0) is the most favorable prognostic factor in patients after dCRT. This stresses the importance of better locoregional control through improved chemoradiation strategies in dCRT and adequate staging with accurate imaging methods to ensure a complete tumor resection.