Gastrointestinal Unit

Location: Royal Marsden

Section: NHS Clinical Research Programme

Head of Unit: Professor D Cunningham MD FRCP

Introduction

A strong commitment to research, combined with the delivery of high-quality clinical care, remains the guiding principle of the Gastrointestinal (GI) Cancers Unit. Approximately 1,000 new patients are seen annually; referred from other institutions within the UK, from abroad, and from local hospitals within the Cancer Network. In the case of the latter group, management options will have been already discussed in the weekly joint multidisciplinary team meetings. This comprises surgeons, radiologists, clinical and medical oncologists, histopathologists and gastroenterologists as well as clinical nurse specialists and research nurses from local hospitals and the Royal Marsden. Each group brings its own expertise and specialist knowledge ensuring that patients receive the best care available with minimum delay.

Relevance to the NHS Research and Development Programme

The GI Cancer Unit has a broad portfolio of clinical trials and a history of leading clinical research both nationally and internationally. The Unit undertakes a number of innovative ‘in-house’ clinical trials that are run locally or as small multicentre studies. These studies are often examining as yet untested hypothesis with the aim of informing clinical practice and aiding the design of future studies. Research areas include; therapeutic drugs, radiotherapy, multimodality therapy, imaging studies, supportive care measures and novel diagnostic techniques.  As Chair of the National Cancer Research Institute (NCRI) Upper GI Clinical Studies Group, Professor Cunningham plays an influential role in the design, planning and co-ordination of many important national and international studies. The Unit has played a pivotal role in a number of practice changing research projects.

Research Highlights

Oesophago-gastric Cancer

• The final results of the 1002 patient REAL2 study were published in the New England Journal of Medicine in January, 2008. The study clearly demonstrates that the oral tablet capecitabine, can be substituted for 5-flurouracil and oxaliplatin can be substituted for cisplatin in the ECF regimen (epirubicin, cisplatin and infused 5-fluorouracil) for the treatment of patients with advanced oesophago-gastric cancer. The EOX regimen (epirubicin, oxaliplatin and capecitabine) was associated with the longest survival. The results widen the treatment options available to patients with oesophago-gastric cancer and allow for more convenient less time consuming treatment options to be used. EOX has been adopted as a new standard of care for future clinical trials
• REAL3: This study, planned to open later this year, will follow on from the success of the REAL2 trial described above. 730 patients with previously untreated advanced oesophago-gastric cancer will be randomised to treatment with EOX chemotherapy (epirubicin, oxaliplatin and capecitabine) with or without the targeted agent, panitumumab. This will be amongst the first randomised Phase III studies to evaluate modern targeted therapies in this disease
• ST03: This is a 1000 patient randomized trial of peri-operative chemotherapy with or without the anti-angiogenic agent, bevacizumab. Run by the Medical Research Council Clinical Trials Unit and included in the UK NCRI trials portfolio, the GI cancers unit has had significant input into the design of this study protocol and Professor Cunningham is the trial’s Chief Investigator. ST03 opened to recruitment in 2007
• Translational research is a major focus and expanding area for the GI Unit in collaboration with The Institute of Cancer Research. The results of an ongoing project of microarray-based gene expression profiling in patients with operable oeosophago-gastric cancer were accepted for oral presentation at the 2007 Gastrointestinal Cancers Symposium, Orlando and 2007 ASCO annual meeting, Chicago by Dr Sheela Rao. Using this relatively new high-throughput technology, distinct gene expression profiles were identified for patients with good and poor prognoses and important molecular pathways involved in oeosphago-gastric cancers identified. Gene expression data identifying potential molecular mechanisms involved in toxicity related to the EGFR targeted agent, matuzumab, for patients with advanced oesophago-gastric cancer were presented at the 2008 Gastrointestinal Cancers Symposium, Orlando. This work has formed the platform for other lines of molecular investigation of this disease in the department and may ultimately help to deliver a more tailored treatment approach

Pancreatic Cancer

• TARGET: This trial is exploring the novel use of a four drug combination for the treatment of advanced pancreatic cancer. Patients receive gemcitabine/capecitabine combination chemotherapy plus two biological targeted agents, erlotinib (a small molecule tyrosine kinase receptor against EGFR) and bevacizumab. Combining targeted agents together has shown promise in other tumour types. The initial part of this study has been successfully completed at the Royal Marsden and these results were presented at the 2008 Gastrointestinal Cancers Symposium. We aim to open to a select number of other UK centres in the second part of the study and have applied for NCRN adoption
• There is currently no standard treatment for patients with pancreatic cancer that has progressed during or after treatment with a gemcitabine-based chemotherapy regimen. The Unit is evaluating a novel strategy that may be of use in the treatment of this patient population. In this trial, the biological drug imatinib is added to the combination of gemcitabine and oxaliplatin in an attempt to improve the effect of chemotherapy by targeting platelet derived growth factor receptors. There is evidence that this may reduce the pressure inside tumours and potentially enhance delivery of the chemotherapy to the cancer cells
• Patients with locally advanced pancreatic cancer can often benefit from receiving radiotherapy to the tumour. In other tumour types the combination of EGFR targeted antibody therapy and radiotherapy has been shown to be beneficial. The PERU trial will evaluate the benefit from the addition of the EGFR targeted agent, cetuximab, to chemoradiation in the treatment of patients with locally advanced pancreatic cancer that have responded to induction chemotherapy. The study is planned to open during 2008

Colorectal Cancer

• EXPERT-C: This is an international multicentre trial evaluating the addition of the anti-epidermal growth factor receptor antibody (EGFR), cetuximab (Erbitux) to a treatment strategy of combination chemotherapy followed by chemoradiation which was developed in the preceding EXPERT trial. This treatment will be given before total mesorectal excision (TME) surgery in patients with rectal cancer who are identified using magnetic resonance imaging (MRI) as having cancers which have a high risk of coming back if they were treated with optimal surgery alone
• BOXER: Previous reports have shown that patients with advanced colorectal cancer, in whom the spread of their cancer is limited to the liver-only can be treated with chemotherapy prior to surgery. Patients who have a successful resection may have a better survival if they have also been treated with chemotherapy. In BOXER, these patients will be treated with standard chemotherapy plus bevacizumab to see if this combination may improve their likelihood of having successful surgery and their outcome. Already open to recruitment in RMH, this trial is planned to open to other UK centres in 2008
• The Unit was the lead centre in an international phase I study combining conventional chemotherapy with the novel multi-targeted VEGF receptor tyrosine kinase inhibitor, sunitinib. This drug has already shown important anti-tumour activity in renal cell cancer and gastrointestinal stromal tumours (GIST) and early pre-clinical evidence suggests a benefit in the management of colorectal cancer. Preliminary results were presented at the January 2007 Gastrointestinal Cancers Symposium and indicate the safe dosage for combination treatment with the FOLFIRI regimen
• CINATRA: Despite good activity of taxanes in breast and other cancers, the previous experience with taxanes in colorectal cancer has been very disappointing. This could be related to the genetic mechanisms of tumour development. The CINATRA study tests the novel taxane, patupilone, in patients with metastatic colorectal cancer who have previously received all standard chemotherapy, and compares the outcomes of the patients with and without the genetic changes thought to confer sensitivity to taxanes
• The GI Cancer unit is the lead clinical site involved in a study evaluating a novel Insulin-like growth factor receptor (IGFR) antibody therapy. It is hoped that this novel therapy will be beneficial in the treatment of patients who are failing to response to traditional chemotherapy

Future Aims

Considerable Global and National research efforts are currently focussed on the development of targeted anti-cancer therapies and their integration with the conventional cytotoxic therapies. Targeted agents that are able to exploit the molecular dysregulation commonly seen in malignant disease can provide either alternatives or adjuncts to existing therapies with potentially more favourable side effect profiles. The GI Unit has taken the lead in designing and running informative trials in an attempt to improve on current standards of care. Furthermore, through collaboration with The Institute of Cancer Research and other research organisations, we aim to develop improved methods for assessing a patient’s disease and also their response to therapy. The development of prognostic and predictive markers is an important field of research that would potentially allow for the delivery of individualised treatment strategies. These research efforts continue to place the Unit at the forefront of international research and will continue to evolve as the therapeutic landscape of gastrointestinal malignancies expands over the next few years.