Ben Eyck

Esophageal cancer is a highly lethal disease with a poor prognosis. Roughly half of patients present with locally advanced disease without distant metastases and can be treated with curative intent. The current standard of care for these patients is neoadjuvant chemoradiotherapy (nCRT) or chemotherapy followed by esophagectomy. After first publication of the CROSS trial, most countries implemented this nCRT regimen as standard of care. In this thesis, new insights into the treatment of locally advanced esophageal cancer are discussed. In part I, the long-term results of the CROSS trial are described and the effect of this neoadjuvant regimen in specific groups is addressed. In part II, open, hybrid and totally minimally invasive Ivor Lewis esophagectomy are compared in terms of surgical morbidity, lasting symptoms and long-term quality of life. In part III, different diagnostic modalities for clinical response evaluations after nCRT are discussed and the feasibility of active surveillance is addressed.

Part I: Effects of neoadjuvant chemoradiotherapy
The optimal (neo)adjuvant treatment strategy in addition to surgery has been widely investigated. In chapter 2, an overview is provided of neoadjuvant and adjuvant regimens that have been studied in randomized controlled trials. Neoadjuvant radiotherapy, adjuvant radiotherapy, or adjuvant chemotherapy without any preoperative chemotherapy do not provide a clear survival benefit compared to surgery alone. Survival can be improved if neoadjuvant chemotherapy, perioperative chemotherapy or nCRT is given in addition to surgery. Squamous cell carcinoma is widely treated by nCRT. For adenocarcinoma, the optimal neoadjuvant strategy is still disputed and both perioperative chemotherapy and nCRT are being used. In chapter 3, the comparison of perioperative chemotherapy and nCRT is discussed in depth. To further increase the beneficial effect of neoadjuvant therapies, response evaluation has been investigated. Based on current literature, discontinuation of treatment guided by PET/CT or MRI early during the course of nCRT is not recommended. Response evaluations with a combination of different modalities may be used to postpone surgery in patients with a clinically complete response.

Since first publication of the CROSS trial in 2012, this nCRT regimen has become a standard of care in many parts of the world. In this randomized controlled trial, patients either received five weekly cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery, or surgery alone. Patients were included from 2004 through 2008. In chapter 4, the long term outcome of the CROSS trial is reported. An absolute ten-year overall survival benefit of 13% and a stable effect on overall survival up to ten year were observed for patients who were treated with nCRT followed by surgery, compared to surgery alone. The absolute survival benefit was larger for patients with squamous cell carcinoma (23%) than for patients with adenocarcinoma (10%). The long-term beneficial effect of CROSS was mainly achieved by a decrease in locoregional relapse, and not by a decrease in distant relapse. These results show that nCRT according to CROSS can still be regarded as a standard of care.

In addition to the greater effect on overall survival, the original CROSS trial reported a pathologically complete response (pCR) in the resection specimen in 49% of patients with squamous cell carcinoma, compared to 23% of patients with adenocarcinoma. Of all new esophageal cancer cases, 80% is concentrated in Asia, of whom 90% have squamous cell carcinoma. Several individual retrospective studies performed in Asia, however, have reported poorer response to CROSS compared to the original CROSS trial and other Western studies using the CROSS regimen.

In chapter 5, patients with esophageal squamous cell carcinoma who underwent nCRT according to the CROSS regimen in East Asian (Queen Mary Hospital in Hong Kong, Chang Gung Memorial Hospital in Taiwan, and Shanghai Chest Hospital) were directly compared with patients who were treated in the Netherlands (Dutch Upper GI Cancer Audit database). East Asian patients had more proximal tumors and had higher clinical T and N stage. After adjusting for these and other confounding factors, the pCR rate was still lower in the East Asian patients (28%) than in Dutch patients (44%). This difference in response was mainly observed in the primary tumor, not in the regional lymph nodes. While slight differences in treatment protocols could not be adjusted for, these results suggest that the response to the CROSS regimen is modulated by ethnic and/or genetic differences. Also, this suggests future trials should take into account ethnic and genetic differences and that novel regimens should be externally validated in different parts of the world.

In chapter 6, the relapse rate as well as the location and timing of relapse are assessed in patients with a pCR to nCRT according to the CROSS regimen. Patients who were included in the phase II and III CROSS trials as well as patients who were treated at the Erasmus MC after completion of the CROSS trials were identified. Of all patients with a pCR, 21% (25% with adenocarcinoma, 13% with squamous cell carcinoma) still relapsed, mostly within two years. Most patients had a relapse outside the initial radiation field, and none of the patients with squamous cell carcinoma relapsed within this field. These findings suggest that better systemic rather than intensifying neoadjuvant radiation or extending the surgical resection will lead to better survival.

Part II: Minimally invasive surgery
After neoadjuvant therapy, most patients undergo surgical resection of the esophagus. Several surgical approaches are applied, of which the two-phased Ivor Lewis esophagectomy is most commonly used. Historically, surgery was performed in an open fashion. At present, the majority of esophagectomies is performed in a minimally invasive fashion. The respective randomized TIME trial and MIRO trial have shown that both totally minimally invasive and hybrid minimally invasive esophagectomy (in which the abdominal phase is performed by laparoscopy but the thoracic phase by thoracotomy) decrease surgical morbidity compared to open esophagectomy.

In chapter 7, postoperative complications were compared between all three techniques using data from the international Esodata Study Group. Patients who underwent totally minimally invasive esophagectomy had a lower incidence of pneumonia and shorter hospital stay, but higher incidence of anastomotic leakage than patients who had hybrid or open esophagectomy. In chapter 8, lasting symptoms and long-term health-related quality of life are compared between the three techniques using data from the international LASER study. While chest pain was reported less after totally minimally invasive than after hybrid esophagectomy, this difference was not observed after totally minimally invasive versus open esophagectomy. Abdominal pain, fatigue and physical functioning as well as the impact of symptoms on taking medication, return to work, and performance status were comparable between the three techniques. It was therefore concluded from chapters 7 and 8 that there may not be a clear benefit in short-term and long-term outcomes for any of the three different surgical techniques.

Part III: Response evaluation and active surveillance
Non-surgical treatment was originally reserved for patients who are ineligible for surgery and who are treated with definitive (high-dose) chemoradiotherapy. Given the high pCR rates after nCRT and the substantial surgical morbidity and mortality after esophagectomy, organ-sparing strategies may also be attractive for those patients with a complete response to nCRT. In chapter 9, it is addressed how the organ-sparing approach emerged for patients with locally advanced esophageal cancer.

Patients with residual disease after nCRT should be accurately identified in order to safely postpone surgery in patients with a clinically complete response. In chapter 10, a systematic review and meta-analysis of current literature on the accuracy of PET-CT, endoscopic biopsies and endoscopic ultrasonography for detecting residual disease after nCRT is described. Individually, all these modalities yield insufficient accuracy to discriminate patients who should undergo surgery from patients in whom surgery may be postponed. Several studies investigating combinations of diagnostic modalities yielded better results. The Dutch preSANO trial showed that a combination of endoscopic tumor biopsies and endoscopic ultrasonography with fine-needle aspiration of suspected lymph nodes detected substantial residual disease (>10% tumor residue) with a sensitivity of 90%. The corresponding specificity for correctly identifying patients with