Efficacy and Safety Study of the Combined Modality Therapy in Adenocarcinoma of the Esophago-gastric Junction

• Pathological response to treatment [ Time Frame: 6-12 weeks after chemoradiotherapy ]
  Pathological response to treatment assessed as a tumor regresion grade in histopahological assessment of the surgical specimen
  
  

• Clinical response to treatment [ Time Frame: 5 weeks after chemoradiotherapy ]
  Clinical response to treatment based on the modified RECIST criteria measured by CT
  
  
• The curative resection (R0) rate [ Time Frame: 6-12 weeks after chemoradiotherapy ]
  The curative resection (R0) rate defined by the assessment of proximal, distal and circumferential margins
  
  
• chemoradiotherapy related toxicity [ Time Frame: 6-12 weeks after chemoradiotherapy ]
  The rate and intensity of chemo- and chemoradiotherapy related toxicity
  
  
• postoperative complications rate [ Time Frame: 30 days after surgical resection ]
  The rate and intensity of postoperative morbidity and mortality
  
  
• Overall and cancer free survival [ Time Frame: 5 years from onset of the chemoradiotherapy ]
  Overall and cancer free survival
  
  
• Quality of life changes [ Time Frame: 5 years after the onset of cheemoradiotherapy ]
  Quality of life changes
  
  
• The rate of chemo- and chemoradiotherapy dose reduction [ Time Frame: 11 weeks during chemo- and chemoradiotherapy ]
  The rate of dose reduction due to chemotherapy or radiotherapy related toxicity
  
  

Adenocarcinoma of the esophago-gastric junction (AEG) represents an aggressive disease with poor prognosis. Surgery is the traditional mainstay of treatment for patients presenting with locally advanced disease, defined as transmural invasion with or without lymph node involvement. Surgical approach may differ, but the principal is to achieve wide mural clearance, negative margins, and perform an adequate lymphadenectomy. Although surgery is the primary modality that can cure patients, the majority of patients reveal recurrence leading to death within 2 years after resection. The incidence of locoregional relapse in most series and in phase II and phase III trials ranges from 25% to 60%, and 20-30% of these patients have no evidence of distant metastases. Median survival with surgery alone for localized disease remains poor, and ranges from 13 to 19 months with 5-year survival rates at best approximately 40%. To improve a long-term outcome in patients with esophageal and gastric cancers a combined modality therapy concept has been investigating for many years. The experience in a combined modality therapy for adenocarcinoma of the esophago-gastric junction have been extrapolated from studies on esophageal or gastric cancer, where the investigated population involved in part patients with AEG.

The most eminent drawback of majority commonly cited randomized trials is heterogenicity of cancer patients population. Most of them overlap between esophageal adenocarcinoma and squamous cell carcinoma or between adenocarcinoma of the esophagus, esophagogastric junction and the stomach. When the investigators reviewed the composition of the most prominent 10 studies population including 3171 patients with easophageal and gastric cancer the investigators identified 911 (28.7%) patients with AEG. The remaining pooled population involved 1173 (36.9%) patients with adenocarcinoma of the esophagus, 598 (18.9%) patients with squamous cell carcinoma of the esophagus and 775 (24.4%) patients with adenocarcinoma of the stomach. Only 1 randomized controlled trial concerned exclusively patients with AEG. In this study preoperative chemoradiotherapy resulted in a 16% increase of 3-year survival. Although its superiority was not proven (p=0.07), these data provide evidence that preoperative chemoradiotherapy may improve survival and should be further investigated. Interestingly, the survival benefit was evident although the postoperative mortality was more than doubled (10.2% versus 3.8%) by adding chemotherapy. Although this study did not meet its accrual goals and could not provide statistical significance, the improvement in both local cancer free and overall survival suggest that preoperative chemoradiotherapy appears most valuable modality treatment to cure patients with localized AEG. As it is more than evident that major response to preoperative treatment is an important prognostic factor future trials should aim to optimize preoperative treatment by combining all treatment modalities.

All above mentioned discrepancies regarding the optimal treatment for AEG brought the investigators to an idea to design a study testing safety and efficacy of three-phase combined modality therapy accommodating induction taxane-based triple chemotherapy followed by concurrent chemoradiotherapy with 45Gy as a total dose of irradiation and subsequent surgical resection in homogenous population of patients with clearly defined AEG. Taking into account the results from recent phase II and III trials the proposed combined modality regimen suggests substantial response to the neoadjuvant therapy and promising highly effective loco-regional cancer clearance with moderate and acceptable tolerance despite a complex and extensive treatment.