Portfolio learning: a proposal for undergraduate cancer teaching

This paper describes a randomized study to evaluate a longitudinal approach to undergraduate education using cancer patients and cancer medicine as a model. Medical students were randomized to the study or control group. Those in the study were allocated to tutors (general practitioners or consultants) in groups of three. Each student was allocated three consenting patients with cancer to follow longitudinally. They compiled a portfolio to record events, interactions, relevant articles, etc. based around the patients' case histories. The students received tutorials to provide direction, discussion and support bimonthly during the course. Evaluation was by central review of the portfolios, appraisal in the clinical competence examination and hidden questions in the standard MCQ examinations. The aim was to provide the learner with a personal experience of cancer patients at all stages of the disease, an understanding of the natural history of cancer and an insight into the impact of the disease and its treatment on the patient and family. The study evaluates whether these aims were achieved to a greater extent in those students receiving the portfolio teaching compared with a control group receiving the standard curriculum teaching only

Developing a biomarker-stratified trial design in advanced colorectal cancer: the MRC FOCUS 3 feasibility study

It is likely that future trials for many solid tumours will be stratified by predictive/prognostic biomarkers in order to a) derive more homogeneous patient cohorts; b) "personalize" treatment interventions in relation to tumour (or host) phenotype; and c) improve the likelihood of discovering a beneficial effect, in at least a subset of patients with the disease. In some settings there are likely to be multiple relevant biomarkers and treatments to be tested. For logistical reasons it would be efficient to combine these into single trials. Moreover, the inclusion of overlapping or common treatment arms could serve to further validate the use of a given biomarker for selection and support retrospective testing of other biomarker selection algorithms that may arise during the course of a trial’s enrolment period. These requirements present significant challenges both for creating efficient designs and for making these comprehensible for prospective subjects. Methods: FOCUS 3 is a feasibility study designed to address these issues and test a novel design for examining the predictive role of biomarkers (KRAS/BRAF mutations and topo-1 expression) for 1st-line therapy of aCRC. It employs an unusual design in which the two biomarkers defined four possible cohorts. Specific treatment questions were relevant to each marker and, because each cohort was defined by 2 markers, there were 2 relevant experimental arms for each cohort, plus 1 common control arm for all cohorts (FOLFIRI). The study thus incorporates 5 treatment regimens, but only 3 possibilities for each patient, defined by marker phenotype. We will complete recruitment of 240 patients by April 2011. Paraffin blocks from 24 sites were obtained for central biomarker analysis and aim to feedback results within 10 working days. A 4 stage suite of patient information sheets (PIS) was designed to avoid patient overload and we are assessing patients’ comprehension in a qualitative study. Conclusion: Patient samples can be collected and analysed centrally within acceptable time constraints. Complex, stratified, multi arm designs can be made acceptable to patients through good PIS design, ensured by patient and carer input into their design

Developing a biomarker-stratified trial design in advanced colorectal cancer: the MRC FOCUS 3 feasibility study

It is likely that future trials for many solid tumours will be stratified by predictive/prognostic biomarkers in order to a) derive more homogeneous patient cohorts; b) "personalize" treatment interventions in relation to tumour (or host) phenotype; and c) improve the likelihood of discovering a beneficial effect, in at least a subset of patients with the disease. In some settings there are likely to be multiple relevant biomarkers and treatments to be tested. For logistical reasons it would be efficient to combine these into single trials. Moreover, the inclusion of overlapping or common treatment arms could serve to further validate the use of a given biomarker for selection and support retrospective testing of other biomarker selection algorithms that may arise during the course of a trial’s enrolment period. These requirements present significant challenges both for creating efficient designs and for making these comprehensible for prospective subjects. Methods: FOCUS 3 is a feasibility study designed to address these issues and test a novel design for examining the predictive role of biomarkers (KRAS/BRAF mutations and topo-1 expression) for 1st-line therapy of aCRC. It employs an unusual design in which the two biomarkers defined four possible cohorts. Specific treatment questions were relevant to each marker and, because each cohort was defined by 2 markers, there were 2 relevant experimental arms for each cohort, plus 1 common control arm for all cohorts (FOLFIRI). The study thus incorporates 5 treatment regimens, but only 3 possibilities for each patient, defined by marker phenotype. We will complete recruitment of 240 patients by April 2011. Paraffin blocks from 24 sites were obtained for central biomarker analysis and aim to feedback results within 10 working days. A 4 stage suite of patient information sheets (PIS) was designed to avoid patient overload and we are assessing patients’ comprehension in a qualitative study. Conclusion: Patient samples can be collected and analysed centrally within acceptable time constraints. Complex, stratified, multi arm designs can be made acceptable to patients through good PIS design, ensured by patient and carer input into their design

COGENT (COlorectal cancer GENeTics) revisited

Many colorectal cancers (CRCs) develop in genetically susceptible individuals most of whom are not carriers of germ line mismatch repair or APC gene mutations and much of the heritable risk of CRC appears to be attributable to the co-inheritance of multiple low-risk variants. The accumulated experience to date in identifying this class of susceptibility allele has highlighted the need to conduct statistically and methodologically rigorous studies and the need for the multi-centre collaboration. This has been the motivation for establishing the COGENT (COlorectal cancer GENeTics) consortium which now includes over 20 research groups in Europe, Australia, the Americas, China and Japan actively working on CRC genetics. Here, we review the rationale for identifying low-penetrance variants for CRC and the current and future challenges for COGENT

Impact of gemcitabine (Gem)-or capecitabine (Cape)-based chemoradiation (CRT) on health-relatedquality of life (HRQL) in patients with locally advanced pancreatic cancer (LAPC): Outcomes from the randomized phase II SCALOP trial [Abstract]

Background: HRQL in pancreatic CRT trials have not been widely reported. In SCALOP, registered patients (n=114) received Gem and Cape induction chemotherapy (4 cycles) and non-progressing patients (n=74) were randomized to conformal RT (50.4Gy/28 fractions/5.5 weeks) in combination with Gem (300mg/m2 weekly) or Cape (830mg/m2 bd on days of RT). SCALOP demonstrated superior overall survival (15.2 mo vs 13.4 mo, HR 0.39, p=0.012) and lower Grade 3/4 hematological toxicity (18% v 0%, p=0.008) in the Cape-CRT arm (Mukherjee, Lancet Oncol, Apr 2013). The SCALOP trial was funded by Cancer Research UK (CR UK 07/040). Methods: HRQL was assessed with EORTC QLQ-C30 (generic domains) and EORTC PAN26 (pancreas specific) at Week 0 (pre-treatment), Week17 (pre-CRT), Week23 (post-CRT) and follow-up (Weeks 26, 39). The difference in change in function and symptom scores between trial arms from pre-CRT baseline (week 17) to later time-points were analysed using Wilcoxon rank sum tests. Results: HRQL form completion was 93%, 82%, 65%, 68% and 58% respectively across the time-points. Compared to pre-CRT baseline (week 17), at the end of CRT (week 23), patients on Cape-CRT arm experienced significantly better HRQL outcomes in terms of cognitive functioning (p=0.04), fatigue (p=0.05), bloating (p=0.04) and dry mouth (p=0.03). The differences were no longer significant at week 26 or 39 apart from cognitive function scores (p=0.01) and dry mouth (p<0.01), which remained significant at week 39. Conclusions: The better HRQL in the Cape-CRT arm complements the outcome from the main trial and further supports the use of Cape rather than Gem as concomitant chemotherapy with radiation in LAPC. Clinical trial information: NCT01032057

Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: a multicentre randomised trial.

BACKGROUND: Policies of UK clinicians regarding the duration of chemotherapy for patients with advanced colorectal cancer are not consistent. We aimed to compare effectiveness of continuous and intermittent chemotherapy in such patients. METHODS: Patients who responded or had stable disease after receiving 12 weeks of the regimens described by de Gramont and Lokich, or raltitrexed chemotherapy, were randomised to either intermittent (a break in chemotherapy, re-starting on the same drug on progression), or continuous chemotherapy until progression. FINDINGS: 354 patients (178 intermittent, 176 continuous) were enrolled from 42 UK centres. At randomisation, 41% of participants had part or complete response; 59% were stable. Only 66 (37%) patients allocated to intermittent treatment restarted as planned, after a median of 130 days. Median time on treatment after restarting was 84 days. Patients in the continuous group remained on treatment for a median of a further 92 days. Similar proportions of patients in both groups received second-line therapy. Patients on intermittent chemotherapy had significantly fewer toxic effects and serious adverse events than those in the continuous group. There was no clear evidence of a difference in overall survival (hazard ratio 0.87 favouring intermittent, 95% CI 0.69-1.09, p=0.23). INTERPRETATION: Our findings provided no clear evidence of a benefit in continuing therapy indefinitely until disease progression. They showed that it is safe to stop chemotherapy after 12 weeks and re-start the same treatment on progression in patients with chemosensitive advanced colorectal cancer