Clinical trials in upper gastro-intestinal and gastric cancer

Together both oesophageal and stomach cancer cause approximately 13,000 deaths each year in the UK. At the time of diagnosis, if the cancer appears confined to the stomach or oesophagus then surgery is performed aiming to remove all the tumour. Unfortunately the chance of being alive 5 years after such an operation is in the region of 20-30%. Therefore an urgent need to improve outcomes in this disease is required.|The potential advantages of combining chemotherapy (drug treatment) with surgery are (i) chemotherapy before the operation may cause the tumour to shrink making it easier for the surgeon to remove it. (ii) chemotherapy after the operation may kill any cancer cells (micrometastases) that have not been removed at surgery (iii) chemotherapy may kill cancer cells that have spread away from the stomach or oesophagus but are too small to be detected with current imaging scans.|In oesophageal cancer we have performed a randomised trial of 802 patients (OEO2 Trial). Patients received either surgery alone or 2 cycles of chemotherapy before surgery. Overall survival was significantly increased in the patients allocated chemotherapy. Following on from this we are now conducting a trial to see if 4 cycles of a newer chemotherapy regimen before surgery will improve survival rates even further.|In stomach cancer we performed a randomised trial of 503 patients (MAGIC Trial). Patients received either surgery or 3 cycles of chemotherapy before and after their operation. Overall survival was significantly increased in the patients in the chemotherapy group. Following on from this we are undertaking a trial assessing the effect of adding a new treatment that affects the blood supply of tumours, and therefore their growth, to the chemotherapy treatment that is given before and after surgery. We are hopeful that this will improve survival rates even further.

Oesophagogastric cancers cause approximately 13,000 deaths per year in the UK, or 6% of all cancer deaths. The outlook is poor, with only 20 to 30% of patients who undergo potentially curative surgery alive 2 years later. There is therefore a great need to improve outcomes. |In patients with operable oesophageal cancer, OE02 compared surgical resection with or without two pre-operative cycles of cisplatin and fluorouracil (CF). 802 patients were randomised, making this the largest randomised trial ever conducted in this disease. The results, originally reported in 2002 (Lancet 2002, 359: 1727-1733) and updated in 2008 (J. Clin. Oncol) show that with pre-operative chemotherapy survival is prolonged and is now standard treatment in the UK. The trial attracted great interest internationally, not least because a similar, but substantially smaller American trial showed no advantage with chemotherapy. Both trials contributed to an individual patient data meta-analysis of all relevant trials and this confirmed a significant survival benefit to pre-operative chemotherapy.|Building on the success of OEO2 we are currently undertaking a randomised trial (OEO5) where patients either receive 2 cycles of CF chemotherapy followed by surgery or 4 cycles of ECX chemotherapy followed by surgery. The trial is on target to complete accrual of 842 patients in early 2011.|In patients with operable gastric cancer, the ST02 randomised trial, or MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial, compared surgical resection with or without peri-operative chemotherapy using a regimen of epirubicin and cisplatin with 5-fluorouracil by continuous infusion (3 cycles pre-operatively and 3 post-operatively.) 503 patients were randomised, and peri-operative chemotherapy was shown to significantly improve survival (HR for death 0.75 95%CI 0.6-0.93 p=0.009) with 5 year survival rates increased from 23% to 36% (N Engl J Med. 2006 Jul 6; 355(1):11-20).|Again building on this success ST03 is a phase II/III trial randomised trial where patients are randomized to 3 pre- and 3 post-operative cycles of ECX and surgery with or without bevacizumab, a monoclonal antibody against the vascular endothelial growth factor receptor. It is intended that this will be an international trial recruiting in the region of 1000 patients. Phase II recruitment is complete. |For all of these trials additional translational studies will be performed on tissue samples with the aim of identifying prognostic and predictive factors that identify patients likely to respond to these treatments.