Multimodality treatment of oesophageal cancer : effects and side effects

Abstract: Background: Oesophageal cancer is highly fatal and treatment with curative intent is beset with many side effects. Treatment options are (1) chemoradiotherapy, (2) chemotherapy with or without the addition of radiotherapy followed by surgery or (3) surgery alone. The aims of this thesis are to evaluate outcome and side effects from neoadjuvant treatment followed by surgery and from definitive chemoradiotherapy in combination with cetuximab. Patients and methods: NeoRes I is a prospective, randomised, multicentre trial reported in Papers I and II. Patients with resectable oesophageal cancer were randomly allocated to receive three 21-days cycles of cisplatin and fluorouracil with or without the addition of radiotherapy to 40 Gy followed by oesophageal resection. In Paper III the effects on cardiac exercise test and on pulmonary function after neoadjuvant treatment and 1-2 years after surgery were investigated in a cohort of 97 patients included in the NeoRes I trial. LERFOX-C is a prospective, non-randomised, multicentre trial reported in Paper IV. Eligible patients had localized oesophageal cancer not suitable for surgery. Treatment consisted of radiotherapy to 50 Gy concurrent with weekly cetuximab and three 21-days cycles of oxaliplatin and fluorouracil. Results: In papers I and II, 181 patients were included. All three chemotherapy cycles were delivered to 73% of the patients allocated to chemoradiotherapy and to 86% of those allocated to chemotherapy. 87% of those allocated to chemoradiotherapy received at least 30 Gy. 87% in the chemoradiotherapy group and 86% in the chemotherapy group underwent tumour resection. Tumour response was better among those allocated to chemoradiotherapy with fewer metastatic lymph nodes at resection, a higher rate of radical resection and a higher rate of complete histopathological response (28% versus 9%), but 5-year overall survival was similar (42% versus 40%). In Paper III we found a slight decrease in vital capacity and forced expiratory volume in 1 second after neoadjuvant treatment, and a more profound decrease 1-2 years after surgery. Maximum exercise capacity decreased after neoadjuvant treatment and persisted and 1-2 years after surgery. We did not find any significant differences between the treatment groups. In Paper IV, 51 patients were eligible for survival analysis and 46 were eligible for toxicity and recurrence analysis. Full radiotherapy dose was delivered to 80%, 75% received all three cycles of chemotherapy and 73% received four or more doses of cetuximab. Within six months from the end of treatment, six patients died from complications from fistulas between the oesophagus and aorta or airways. The estimated loco-regional progression-free survival at one year was 47%. Overall survival at three years was 29%. Conclusions: The addition of radiotherapy to neoadjuvant chemotherapy increases tumour response in patients with localized, resectable oesophageal cancer without affecting patterns of recurrence or survival. Multimodality treatment causes short-term and long-lasting impairment in pulmonary function and exercise capacity. Oxaliplatin and fluorouracil given concurrent with radiotherapy and cetuximab is well tolerated and has a curative potential in the treatment of localized oesophageal cancer. However, results from recent phase III trials do not support the addition of cetuximab and cannot be recommended as standard of care.