A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3): a model for randomised controlled trials in the era of personalised medicine?

BACKGROUND: Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies. PATIENTS AND METHODS: Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload. RESULTS: A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival. CONCLUSIONS: Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.

Oxaliplatin/capecitabine vs oxaliplatin/infusional 5-FU in advanced colorectal cancer: the MRC COIN trial.

BACKGROUND: COIN compared first-line continuous chemotherapy with the same chemotherapy given intermittently or with cetuximab in advanced colorectal cancer (aCRC). METHODS: Choice between oxaliplatin/capecitabine (OxCap) and oxaliplatin/leucovorin (LV)/infusional 5-FU (OxFU) was by physician and patient choice and switching regimen was allowed. We compared OxCap with OxFU and OxCap+cetuximab with OxFU+cetuximab retrospectively in patients and examined efficacy, toxicity profiles and the effect of mild renal impairment. RESULTS: In total, 64% of 2397 patients received OxCap(± cetuximab). Overall survival, progression free survival and overall response rate were similar between OxCap and OxFU but rate of radical surgeries was higher for OxFU. Progression free survival was longer for OxFU+cetuximab compared with OxCap+cetuximab but other efficacy measures were similar. Oxaliplatin/LV/infusional 5-FU (± cetuximab) was associated with more mucositis and infection whereas OxCap(± cetuximab) caused more gastrointestinal toxicities and palmar-plantar erythema. In total, 118 patients switched regimen, mainly due to toxicity; only 16% came off their second regimen due to intolerance. Patients with creatinine clearance (CrCl) 50-80 ml min(-1) on OxCap(± cetuximab) or OxFU+cetuximab had more dose modifications than those with better renal function. CONCLUSIONS: Overall, OxFU and OxCap are equally effective in treating aCRC. However, the toxicity profiles differ and switching from one regimen to the other for poor tolerance is a reasonable option. Patients with CrCl 50-80 ml min(-1) on both regimens require close toxicity monitoring.

Measurement of activity in anthropomorphic organ phantoms.

This paper describes two nondestructive measurement techniques for determining the radioactivity in a homogeneous organ phantom with an acceptable error and the capability of being traceable to the National Institute of Standards and Technology. These two techniques are based on a method developed by Robley D. Evans in 1937 for measuring the amount of radium deposited in a living person. There are two significant improvements in the new techniques: 1) the radially-dependent error is eliminated, and 2) the effect of self absorption in the unknown body is measured and taken into account. The first assay method is a single-source technique involving four measurements and requiring only one standard source, the second one is a double-source technique involving six measurements and requiring two unequal standard sources. Three pairs of lung phantoms radiolabeled with 241Am, 137Cs, and 154Eu were measured with both the single- and double-source techniques. The results imply that the self-attenuation of photons within the organ phantom cannot be neglected, especially at low energies. Finally, potential applications (other than the calibration of bioassay phantoms of the single- and double-source techniques) and their limitations are discussed.

Optical lifetime measurements using a positive ion van de graaff accelerator.

A system for direct observation of excited state optical mean lives using the delayed coincidence counting technique is described. The system uses a pulsed proton beam for excitation, a high speed time-to-amplitude converter and an on-line digital computer for data reduction. Mean lives longer than 1 nsec can be measured. Preliminary measurements on the 3(1)p, 4(3)S, and 4(1)D levels of helium and several vibrational bands of N(2) are presented to illustrate the capabilities of the system.