Title: Clinical trials in colorectal cancer
Funder: Medical Research Council

Abstract: Colorectal cancer is the second most common site of cancer, with around 1 million cases diagnosed each year worldwide, accounting for about 9% of all new cancer cases. In the UK around 35,000 people are diagnosed with the disease, and 16,000 patients die each year (CR-UK Cancer Stats 2003). Most patients die of advanced disease.||The colorectal team continues to run a series of large multicentre randomised trials, mainly aimed at optimising the treatment of patients with advanced disease. The team also manage follow-up of a trial in rectal cancer which completed accrual in 2005.||FOCUS (CR08) commenced in May 2000 and recruited 2,135 patients by December 2003. The trial was a 5-arm randomised trial comparing the use of irinotecan and oxaliplatin in combination with 5FU either given as first-line treatment or held in reserve as second-line treatment after the failure of 5FU alone. The control arm was the UK standard treatment of 5FU followed on progression by single-agent irinotecan. All four of the research arms gave longer overall survival than the control arm. Most of the differences did not reach the predetermined 1% significance level for superiority, the comparison between the first-line combination of Irinotecan and 5FU and the control arm was the most promising (HR 0.84 (0.73-0.96; p=0.01)). The main results from the trial were published in the Lancet in 2007 (Seymour et al., Lancet 2007; 370:143-152.).||Furthermore, all patients in FOCUS were asked at the time of randomisation for consent to retrieve surplus stored pathology material for molecular study. Thus FOCUS provided an excellent resource for studying the relationship between molecular variables and treatment effect. Preliminary results were presented at the American Society of Clinical Oncology (ASCO) annual meetings in 2004 and 2006. Several papers on this work have been published, while another was recently submitted for publication. This tumour tissue resource has been further expanded in the sequence of trials that followed and represents an increasingly valuable asset for biomarker and translational research.||FOCUS2 (CR09) opened in January 2004 and closed in July 2006 following the recruitment of 459 patients. FOCUS2 was designed to assess lower-dose treatment for patients with advanced colorectal cancer who were ineligible or unsuitable for trials of full-dose combination chemotherapy because of poor general health status, advanced age or both. Patients were randomised in a 2x2 fashion to receive one of the four following chemotherapy treatment plans:||1st-line: 5FU/FA (MdG) 1st-line: capecitabine (Cap)|2nd-line: Oxaliplatin(Ox)MdG 2nd-line: OxMdG|1st-line: OxMdG 1st-line: OxCap||Chemotherapy was started at 80% of standard dose with the option of increasing to 100% at 6 weeks if well-tolerated. The principal outcome measures were progression free survival for the addition of oxaliplatin (Ox) comparison and quality of life for the MdG/Capecitabine (Cap) comparison. Preliminary results have been presented in the form of a poster presentation at ASCO 2007 and the National Cancer Research Institute (NCRI) meeting in 2007. An oral presentation was given at the European CanCer Organisation (ECCO) meeting in 2007. Ox containing regimens showed a slightly longer progression free survival (PFS) however, these differences did not reach the pre-defined significance level of 5%. The addition of Ox did show an improvement in patients reported quality of life (QL) at 12 weeks (62% vs. 49%, p=0.04). There was no impact on the overall survival (OS) despite the significantly improved response rates (15% vs. 41%, p<0.001). There was some evidence that the addition of oxaliplatin reduced the ability to dose increase at the 6 week time point despite there being no difference in the grade 33 toxicity rates. The substitution of MdG with Cap had no effect on PFS, OS or the QL at 12 weeks, however there was a statistically significant increase in overall grade 33 toxicity (2


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS