**4. Combined modality therapy**

#### **4.1. Neoadjuvant chemotherapy**

The use of preoperative chemotherapy compared with surgical treatment has been assessed in randomized trials in order to obtain improved surgical outcomes. However, the results are highly disputed. The three meta-analyses built on these randomized trials showed no difference in survival when the endpoint was 1-year survival in six of these trials. On the contrary, in comparison with surgical treatment, 2-year survival rates were improved following preoperative chemotherapy (4.4%) when the endpoint was 2-year survival in seven randomized trials [53]. When the meta-analysis was restricted to four recently randomized trials based on cisplatin and 5-fluorouracil therapy, there was a 6.3% improvement in 2-year survival. Still, this increase did not occur in one meta-analysis where the endpoint was 2-year survival [54]. The impact of preoperative chemotherapy is still uncertain.

#### **4.2. Neoadjuvant chemoradiotherapy**

Used in Europe and America since the end of the 1980s, preoperative chemoradiotherapy determined survival rate improvement in patients with cancer of the esophagus. Despite being used on a small scale due to the advanced surgical procedures available in Japan, a randomized trial reported the efficiency of hyperthermochemoradiotherapy in esophageal cancer [55]. Five meta-analyses built on five to seven randomized trials assess the impact of surgery alone, on the one hand, with preoperative chemoradiotherapy used in combination with surgery, on the other hand. There were no improvements in survival rates following preoperative chemoradiotherapy when the endpoint was 1-year or 2-year survival. When the endpoint was 3-year survival, there was an increase in perioperative mortality within 90 days after surgery, contrasted by a decrease in local recurrence and an improvement in 3-year survival rates in analogy to surgery alone (Int J Hyperthermia 1992; 8:289–295). There was a 14% decrease in death risk following preoperative chemoradiotherapy when the endpoint was the hazard ratio of survival curves [56]. Several reports [57–59] of six randomized trials showed higher survival rates following preoperative chemoradiotherapy than after surgery alone. Another report focusing on esophageal adenocarcinoma reported much higher survival rates following preoperative chemoradiotherapy versus surgery alone [60].

A meta-analysis of randomized trials conducted in Europe and America reported no improvement in survival with postoperative chemotherapy following curative resection in patients with cancer of the esophagus. In contrast, a randomized trial conducted in Japan showed that postoperative chemotherapy determined a major improvement in disease-free survival. In conclusion, postoperative chemotherapy recommends itself as an efficient measure to prevent recurrence after surgery.

#### **4.3. Adjuvant radiotherapy**

have demonstrated that the three procedures have similar outcomes, even though there are differences in terms of perioperative complications [51]. Another drawback was the difficulty in differentiating between patients who underwent hybrid procedures, such as laparoscopy combined with minithoracotomy, and patients who were treated with total MIE. These limitations pave the way for the occurrence of unknown interactions and confounding variables. Currently, there are two different clinical trials comparing E to MIE patients, namely the French MIRO trial [52] and the British ROMIRO trail [53]. Still, the study that we conducted is the most extensive comparative effectiveness research of MIE assessing long-term survival. As a result, MIE determines poor improvement in perioperative outcomes, with no negative impact on survival rates.

The use of preoperative chemotherapy compared with surgical treatment has been assessed in randomized trials in order to obtain improved surgical outcomes. However, the results are highly disputed. The three meta-analyses built on these randomized trials showed no difference in survival when the endpoint was 1-year survival in six of these trials. On the contrary, in comparison with surgical treatment, 2-year survival rates were improved following preoperative chemotherapy (4.4%) when the endpoint was 2-year survival in seven randomized trials [53]. When the meta-analysis was restricted to four recently randomized trials based on cisplatin and 5-fluorouracil therapy, there was a 6.3% improvement in 2-year survival. Still, this increase did not occur in one meta-analysis where the endpoint was 2-year survival [54].

Used in Europe and America since the end of the 1980s, preoperative chemoradiotherapy determined survival rate improvement in patients with cancer of the esophagus. Despite being used on a small scale due to the advanced surgical procedures available in Japan, a randomized trial reported the efficiency of hyperthermochemoradiotherapy in esophageal cancer [55]. Five meta-analyses built on five to seven randomized trials assess the impact of surgery alone, on the one hand, with preoperative chemoradiotherapy used in combination with surgery, on the other hand. There were no improvements in survival rates following preoperative chemoradiotherapy when the endpoint was 1-year or 2-year survival. When the endpoint was 3-year survival, there was an increase in perioperative mortality within 90 days after surgery, contrasted by a decrease in local recurrence and an improvement in 3-year survival rates in analogy to surgery alone (Int J Hyperthermia 1992; 8:289–295). There was a 14% decrease in death risk following preoperative chemoradiotherapy when the endpoint was the hazard ratio of survival curves [56]. Several reports [57–59] of six randomized trials showed higher survival rates following preoperative chemoradiotherapy than after surgery alone. Another report focusing on esophageal adenocarcinoma reported much higher survival rates

**4. Combined modality therapy**

**4.2. Neoadjuvant chemoradiotherapy**

The impact of preoperative chemotherapy is still uncertain.

following preoperative chemoradiotherapy versus surgery alone [60].

**4.1. Neoadjuvant chemotherapy**

26 Esophageal Abnormalities

Four randomized trials assessing the differences between surgery alone and postoperative radiotherapy (45–65 Gy) reported no major improvements in survival. However, there was a decrease in local recurrence in the irradiated area following postoperative radiotherapy. No major improvements in survival were observed in a meta-analysis of these randomized trials. In conclusion, postoperative radiotherapy is not a conventional treatment option.

#### **4.4. Postoperative outcome**

The incidence of postoperative mortality was assessed in a considerable number of studies [61–65], fewer assessed in-hospital mortality, and 30-day mortality was determined in two studies [66]. Values were higher in patients who were treated with salvage esophagectomy after definitive chemoradiotherapy (23 patients—9.50%) than in patients who treated with planned esophagectomy after neoadjuvant chemoradiotherapy (29 patients—4.07%). Pooling of results validated the much higher incidence of postoperative mortality in the case of salvage esophagectomy (prevalence odds ratios (POR) = 3.02; 95% CI 1.64–5.58; *p* < 0.001).
