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A model of undergraduate education based on a one to one relationship between a student and a patient with cancer has become a core module within the University of Wales College of Medicine undergraduate curriculum. The project combines the powerful impact of a one to one interaction with an active investigative and reflective approach to issues triggered from that patient's cancer journey. The aim is to provide each medical student with an understanding of the impact of a malignant disease and its treatment on patients and their families through the experience of one patient with cancer. The benefits of the project cover the areas of attitudes, skills and knowledge. Students are assessed on their involvement with the patient, in tutorials and on their portfolio, in which they record all aspects of the project. Student evaluations indicate high levels of appreciation of the project, despite its potentially strong emotional content.

Radiotherapy contributes to the cure of 40% of patients diagnosed with cancer who survive 5 years or more, second only to surgery in its curative effectiveness [1]. Major technological developments are improving the accuracy of radiotherapy treatments, opening the door to a reduction in shortand long-term side-effects of treatment. The biological understanding of cancer is demonstrating the central role of issues fundamental to radiotherapy, notably the microenvironment and DNA repair, in the development of cancer and the response to treatment. The development of targeted agents able to selectively inhibit the cancer cell’s response to therapy offers the potential for further improvements in the synergy between radiotherapy and systemic treatments to enhance local tumour cure and reduce metastatic relapse. All these factors underlie the very significant opportunity that exists for radiotherapy and radiobiology-related research at the present time. The National Cancer Research Institute (NCRI) recognised the weakness of this research arena in the UK in 2002 [2], following at least two decades of impoverished funding based on the flawed belief that radiotherapy’s contribution would wane in the near future. The report resulted in a number of actions, the most substantial of which was the establishment of the Gray Institute of Radiation Oncology and Biology in Oxford under the direction of Professor Gillies McKenna, jointly funded by Cancer Research UK and the Medical Research Council. Those who attended their inaugural symposium in September 2008 will be aware that there is a new focus of excellence and critical mass in basic and translational radiotherapy-related research in the UK, with 17 independent research groups and an active fellowship programme established. However, it is recognised that it will be a decade before the effect of this development will have a major impact outside Oxford. The other actions initiated by the NCRI in 2003 were the establishment of the Royal College of Radiologists’ joint fellowship programme with the Medical Research Council and Cancer Research UK and ACORRN, the Academic Clinical Oncology and Radiobiology Research Network. In 2008, the NCRI undertook a rapid review of this field [3], which recognised that there are significant opportunities to be grasped. The advice of the National Radiotherapy Advisory Group has been accepted in full by the Department of Health and its implementation is now underway under the aegis of the Cancer Reform Strategy [4,5]

The aim of the study was to assess whether endoscopic ultrasound (EUS) could accurately measure the locoregional response to chemoradiotherapy in patients with carcinoma of the esophagus. Seventeen patients with esophageal carcinoma underwent EUS examination before and on completion of chemoradiotherapy. The EUS findings were correlated with the results of histologic examination of the esophagectomy specimen. The accuracy of EUS in these patients was compared with the accuracy of EUS in a control group of 17 patients treated by surgery alone. In 16 of 17 patients EUS-determined tumor (T) stage was unchanged following treatment and in one patient there was T-stage progression. No patient demonstrated downstaging of the primary tumor according to classical EUS criteria. In 10 of 17 patients a reduction in maximum tumor depth of >-2 mm was observed (range 2 to 18 mm). Histologic examination revealed that four patients with squamous cell carcinoma had experienced a complete pathologic response. These four patients had significantly lower posttreatment EUS tumor depths compared to patients without a complete response (5.0 vs. 9.0 mm; P

3504 Background: Resection of liver metastases from colorectal cancer with or without neoadjuvant chemotherapy is the standard of care. The EPOC study (Nordlinger et al, Lancet 2008) randomised patients between surgery and surgery with chemotherapy and demonstrated an improvement in 3 year progression free survival (PFS) of 7·3% (from 28·1% to 35·4%). As a rational extension to the EPOC study data, the New EPOC study evaluates the benefit of cetuximab, an EGF receptor antibody, in addition to standard chemotherapy in patients with operable liver metastases. Methods: 272 patients were randomised between February 2007 and November 2012 into the New EPOC study. Eligible patients were required to be k-RAS wild type, have operable liver metastases and to be sufficiently fit for chemotherapy and surgery. Patients with the primary tumour in situ, and those who required short course rectal radiation were eligible. Patients were randomised to receive a fluoropyrimidine and oxaliplatin plus or minus cetuximab for 12 weeks before, then 12 weeks following surgery. Patients who had been treated with adjuvant oxaliplatin could receive irinotecan and 5 – fluorouracil. Results: Following a recommendation from the Independent Data Monitoring Committee on 19/11/2012, the New EPOC study was stopped when the study met a protocol pre-defined futility analysis. With 45.3% (96/212) of the expected events observed, progression free survival was significantly worse in the cetuximab arm (14.8 vs 24.2 months, HR (95%CI) 1.50037 (1.000707 to 2.249517) p< 0.048). The result of a pre-planned analysis excluding the 23 patients treated with irinotecan based chemotherapy was similar (15.2 vs 24.2 months, HR 1.565546 (1.014967-2.414793) P

3509 Background: Inherited genetic factors may influence a patient’s response to, and side effects from, chemotherapy and biological therapies. Here, we sought to generate a comprehensive inherited pharmacogenetic profile for advanced colorectal cancer (aCRC). Methods: We analysed 260 potentially functional coding region and promoter variants in genes within the 5-FU, capecitabine, oxaliplatin, EGFR and DNA repair pathways in 2183 patients with aCRC treated with oxaliplatin-fluoropyrimidine chemotherapy ± cetuximab (from the MRC COIN and COIN-B trials). Primary outcomes assessed were 12-week response, skin rash (SR) (for those receiving cetuximab), dose-reduction or delay in treatment due to any toxicity and peripheral neuropathy (PN). Results: For variants with minor allele frequencies >20%, we had >85% power to detect an effect on response / toxicity with an OR of 1.3. In patients treated with chemotherapy + cetuximab, 5 and 4 coding region variants in the EGFR pathway were associated with response and SR, respectively. The most significant associations were with variants in members of phosphatidylinositol 3-kinase regulatory subunit. In patients treated with chemotherapy ± cetuximab, 8 coding region variants in the 5-FU, capecitabine, oxaliplatin or DNA repair pathways were associated with response, 8 with any toxicity and 5 with PN. The most significant associations for response were with variants in DNA repair genes and, for any toxicity, with common variants in DPYD. Conclusions: Our study highlights the difficulty in identifying inherited biomarkers for the treatment of aCRC - despite using samples from the largest reported randomised trial for aCRC, with considerable power to detect alleles of small effects, none of the associations remained significant after rigorous correction for multiple testing.

TPS3645 Background: Targeted therapies based on somatic gene mutations or activated pathways have inhibited progression of some cancers. However, although various targets are identifiable in CRC, KRAS mutation is currently the only validated predictive biomarker for selection of a targeted therapy. FOCUS4 is a rolling phase II-III trial for testing in a staged way both the utility of molecular stratification and the efficacy of novel agents in subpopulations of mCRC patients. It is also a trial of a new strategy for testing stratified approaches to therapy in any biologically complex tumour type using a Multi-Arm, Multi-Stage design. Methods: The study population consists of subjects with newly diagnosed inoperable mCRC. Subjects receive first-line chemotherapy for 16 weeks. During this time the tumour is tested for BRAF/PIK3CA/KRAS/NRAS mutations and PTEN loss. Subjects with responding or stable disease on CT, who would normally be candidates for a treatment break, are then randomised to four coherent biomarker-based subgroups: FOCUS4-A: BRAF mutant, FOCUS4-B: PIK3CA mutant or complete loss of PTEN on IHC, FOCUS4-C: KRAS or NRAS mutant, FOCUS4-D: All wild type (no mutations of BRAF, PIK3CA, KRAS or NRAS). For each subgroup, a relevant novel agent or combination is to be tested in an adaptive double-blind placebo controlled randomised trial design with multiple interim analyses for early termination if there is no strong evidence of worthwhile activity. There will also be a 5thsubgroup FOCUS4-N testing maintenance capecitabine for unclassifiable tumours or for patients whose marker defined cohort is temporarily suspended. The primary endpoint is progression free survival. Promising results in any biomarker defined cohort will then be tested for response in cohorts without the biomarker. Within the overall trial, biomarker developments can be accommodated with changes in the distribution of the cohorts or testing of new targeted agents. Enrolment will commence in May 2013. Upto 3400 patients will be registered over a 4-5 year period depending on which cohorts pass their staged interim analyses and proceed to later stages, including an overall survival endpoint. Clinical trial information: 2012-005111-12.

LBA146 Background: CRT with G or 5FU (F) is used to treat LAPC. No multicenter, randomized studies have compared G-CRT vs. F-CRT or the oral fluropyrimidine, Cap-CRT. In the UK, where chemotherapy is traditionally standard of care for LAPC, a trial was conducted to assess the safety, efficacy, and deliverability of G-CRT and Cap-CRT. Methods: Eligibility: histologically proven inoperable LAPC < 7 cm in diameter. Induction chemotherapy: 3 cycles of GEMCAP (G 1,000 mg/m2 days 1, 8, 15; Cap 830 mg/m2 days 1-21 q28 days). Patients with stable/responding disease, tumor diameter ≤ 6cm, and PS 0-1 were eligible for CRT randomisation where patients received a further cycle of GEMCAP followed by either Cap (830 mg/m2 bd weekdays only) or G (300 mg/m2 weekly) with radiation (50.4 Gy/28 fractions). Treatment volume = tumour plus enlarged nodes and margins of 2 cm sup-inf and 1.5 cm radially. Prospective RT quality assurance was mandated. Primary end-point was 9-month PFS (Fleming’s design). Funder: Cancer Research UK (CR UK 07/040). Results: Between July 2009 and October 2011, 114 patients from 28 UK centres were registered of whom 74 patients were randomised. Randomised patient characteristics: median age 64.6; 55.4% male; WHO PS (0:1) 41.9%:58.1%; median tumor diameter 4cm; site (head:body) 85.1%:14.9%. During CRT, more patients in the G arm experienced grade 3/4 haematological (18.4% vs 0%, p=0.007) and non-haematological (26.3% vs 11.1%, p=0.095) toxicity. Both C and G arms passed the primary endpoint with 9-month PFS of 62.9% (80% CIs: 50.6%-73.9%) and 51.4% (80% CIs: 39.4%-63.4%) respectively. OS was significantly superior in the Cap-CRT arm (median OS 15.2 vs 13.4 months, HR=0.50, log rank p=0.025). Conclusions: SCALOP is the largest RCT comparing radio-sensitizers in pancreatic cancer and demonstrates that both G-CRT and Cap-CRT can be delivered safely and effectively. Both regimens met the pre-specified PFS criteria. Compared to G-CRT, Cap-CRT demonstrated significantly better survival and toxicity and should form the template regimen for future trials investigating RT dose escalation and combination with novel radio-sensitizers. Clinical trial information: NCT01032057.

LBA3 Background: SCOPE 1 is the largest multicentre trial of definitive chemo-radiotherapy (dCRT) in localised oesophageal cancer (LOC) in the UK and investigated adding cetuximab to standard cisplatin and fluoropyrimidine treatment. Methods: Patients in this phase II/III trial had LOC and been selected to receive dCRT and were randomised to receive cisplatin 60mg/m2 D1 and capecitabine 625mg/m2 daily D1-21 for 4 cycles, cycles 3 and 4 given concurrently with 50Gy in 25 fractions of RT with or without cetuximab 400mg/m2 D1 followed by 250mg/m2weekly. Recruitment continued from 02/2008 until analysis of the phase II endpoint (24 week failure free survival in the cetuximab arm, overall sample size 180: p1=0.60 and p2=0.75, α=0.05, β=0.9) in 01/2012. The phase II endpoint was not met and the IDMC recommended trial closure on the basis of futility. Results: 258 patients were recruited. Median age 67; morphology(%) SCC:ACA 73:27; tumour location(%) upper:middle:lower 11:45:44; stage(%) I:II:III 3:37:60; reason not for surgery(%) disease extent:patient choice:comorbidity 47:38:16. Patients who received cetuximab had: higher non-haematologic toxicity (78 vs 62.8%, p=0.004; primarily dermatological (22 vs 4%) and metabolic (24% vs 11%)); a lower rate of completion of standard therapy (capecitabine 69 vs 85%, p=0.002; cisplatin 77 vs 90%, p=0.005 and radiotherapy (75 vs 86%, p=0.027); reduced failure free survival at 24 weeks (66 vs 77%), median survival (22 vs 25 months, log rank p=0.043) and 2-yr survival (41 vs 56%). Conclusions: In SCOPE 1, disease control and survival in the standard dCRT arm is superior to any previous published multi-centre studies. The use of cetuximab was associated with greater toxicity, lower doses of dCRT and worse survival. Cetuximab cannot be recommended in combination with standard dCRT for unselected patients with oesophageal cancer. Strategies to build on these results should incorporate biomarker driven treatment and latest radiotherapy technologies to safely intensify treatment. This trial was sponsored by Velindre NHS Trust, conducted by Wales Cancer Trials Unit at Cardiff University and supported by CR-UK [grant number C20177/A7256]. Clinical trial information: 47718479.

32 Background: Previous data suggests the EGF ligands EREG/AREG may predict outcome of KRAS wt patients (pts) treated with cet in the chemo-refractory setting but this finding has not been previously reported from first line randomised trials. Methods: FFPE samples from primary tumours of pts in Arms A&B of the COIN trial of Ox fluoropyrimidine (Fp) +/- cet were analysed for EGFR IHC, KRAS/NRAS/BRAF mutation and EREG/AREG expression by RT-PCR. Ligand levels were assessed against baseline data, prognostic markers as uni/multivariate analyses and as predictive markers in wild type (wt) and mutant (mt) cohorts and separately by Fp backbone [capecitabine (CapOx) or 5FU (FOLFOX)]. Tests for interaction were performed with EREG/AREG continuous, using Flexible Parametric survival analysis. Results: 952/1630 (57%) of pts were evaluable for all parameters. High EREG/AREG levels were associated with KRAS wt (p

Introduction In stage II-III CRC the overall incidence of BRAF mt and dMMR is 8% and 10-20%, resp. The incidence of BRAF mt in sporadic dMMR is high (24%, Roth et al., JCO 2010), and BRAF mt, in contrast to dMMR, has a negative prognostic value. The incidence of dMMR and BRAF mt in mCRC is approx. 4% and 8%, resp. No data from large series of mCRC pts are available on the prognostic value of BRAF mt in combination with dMMR. Methods We performed a meta-analysis of 4 mCRC trials: CAIRO, CAIRO2, COIN and FOCUS. The primary outcome measure was the hazard ratio (HR) for progression free survival (PFS) and overall survival (OS) in relation to BRAF and MMR status. For the meta-analysis a cox regression analysis was performed on individual pt data. Results In total 3064 pts were analysed, of whom 151 (4.9%) exhibited dMMR, and 263 (8.6%) BRAF mt. A BRAF mt was observed in 211 (7.2%), and 52 (34.4%) of the pts with a proficient mismatch repair system (pMMR) and dMMR, resp. PFS was significantly worse for dMMR vs. pMMR pts (HR 1.22; 95% CI, 1.03-1.46), but not OS (HR 1.13; 95% CI, 0.94-1.36). PFS and OS were significantly worse for BRAF mt vs. BRAF wildtype (wt) pts (HR 1.28; 95% CI, 1.12-1.46 and HR 1.81; 95% CI, 1.57-2.09, resp.). Within the pMMR group, BRAF mt pts had a significantly worse PFS and OS compared to BRAF wt pts (HR 1.32; 95% CI 1.09-1.61, and HR 1.88; 95% CI 1.53-2.30, resp.). Within the dMMR group no significant differences were found for PFS and OS in BRAF mt pts vs. BRAF wt pts (HR 1.05; 95% CI 0.65-1.68, and HR 1.49; 95% CI 0.91-2.43, resp.). Within the BRAF mt group PFS and OS were not significantly different between pMMR and dMMR pts (HR 0.96; 95% CI 0.63-1.47, and HR 1.03; 95% CI 0.67-1.59, resp.). Within the BRAF wt group, PFS and OS were not significantly different for pMMR vs. dMMR pts (HR 1.32; 95% CI 0.99-1.75, and HR 1.22; 95% CI 0.90-1.65, resp.). Conclusion In this meta-analysis of mCRC pts we observed a higher incidence of BRAF mt in dMMR than reported for early-stage CRC pts. In mCRC pts, dMMR is associated with a worse PFS compared to pMMR. The prognostic role of BRAF mt in mCRC is restricted to pMMR pts. Our data confirm the worse prognostic value of BRAF mt vs BRAF wt. Disclosure All authors have declared no conflicts of interest.

3516 Background: Previous data suggest the EGF ligands EREG/AREG may predict outcome of KRAS wt patients (pts) in the chemo-refractory setting but has not been previously reported from first line randomised trials. Methods: FFPE samples from primary tumors of pts in Arms A&B of the COIN trial of Ox fluoropyrimidine (Fp) +/- cet were analysed for EGFR IHC, KRAS/NRAS/BRAF mutation and EREG/AREG expression by RT-PCR. Ligand levels were assessed against baseline data, prognostic markers as uni/multivariate analyses and as predictive markers in wild type (wt) and mutant (mt) cohorts and separately by Fp backbone [capecitabine (CapOx) or 5FU (FOLFOX)]. Tests for interaction were performed with EREG/AREG continuous, using Flexible Parametric survival analysis. Optimal cutoffs for predictive effects were defined using point at which 95% CI first excluded zero. Results: 952/1630 (57%) of pts were evaluable for all parameters. EREG/AREG were highly correlated Pearson’s rho (ρ) = 0.74; p

3574 Background: Infusional 5-FU/FA + oxaliplatin is a widely used schedule in the first-line treatment of mCRC. In the randomized phase II OPUS study, the addition of cetuximab to one such regimen (FOLFOX4) significantly improved response and progression-free survival (PFS) in patients (pts) with KRAS wild-type (wt) mCRC. However, in the randomized phase III COIN study, a benefit for the addition of cetuximab to first-line fluoropyrimidine (administered as either infusional 5-FU or capecitabine) + oxaliplatin was not confirmed in pts with KRAS wt tumors. Methods: A pooled study-based analysis of treatment outcome in pts with KRAS wt tumors from the OPUS study and COIN subgroup who received infusional 5-FU/FA + oxaliplatin (as the OxMdG regimen) was carried out using a random effects model. Outcome in the pooled analysis was considered in the context of other randomized studies investigating first-line chemotherapy regimens +/- cetuximab in pts with mCRC. Results: The pooled KRAS wt population included 179 pts from the OPUS study and 244 from the OxMdG subgroup of the COIN study. A benefit for the addition of cetuximab to infusional 5-FU/FA was suggested for response (odds ratio 1.87, 95% CI 1.07–3.28) and PFS (hazard ratio, HR 0.69, 95% CI 0.52–0.92) but overall survival (OS) did not show a statistically significant improvement (HR 0.90, 95% CI 0.73–1.11). These response and PFS data are similar to those of the KRAS wt population of the CRYSTAL study investigating infusional 5-FU/FA and irinotecan +/- cetuximab (response: odds ratio 2.07, 95% CI 1.52–2.83; PFS: HR 0.70, 95% CI 0.56–0.87) whereas the improvement in OS was statistically significant in that study (HR 0.80, 95% CI 0.67–0.95). Similar efficacy of FOLFOX + cetuximab and FOLFIRI + cetuximab in the first-line treatment of mCRC was also suggested by data from the randomized phase II CORE 1.2.001 and CELIM studies. Overall, the safety profile of infusional 5-FU/FA and oxaliplatin + cetuximab was found to be acceptable and manageable. Conclusions: The pooled analysis supports the use of cetuximab combined with infusional 5-FU/FA and oxaliplatin in the first-line treatment of KRAS wt mCRC.

2522 Background: IMA910 is a novel multi-peptide cancer vaccine consisting of 10 HLA class I and 3class II tumor-associated peptides (TUMAPs), which were selected based on natural presentation on colorectal tumors by the XPRESIDENT antigen discovery platform. Methods: 92 HLA-A*02+ advanced colorectal cancer (aCRC) patients (pts) with stable or responding disease after 12 weeks of first-line oxaliplatin-based therapy were enrolled in this phase I/II trial. After pre-treatment with cyclophosphamide (300 mg/m2), patients were immunized intradermally with IMA910 plus the immune modulator GM-CSF without (cohort 1; n=66) or with (cohort 2; n=26) topically applied imiquimod, another immune modulator acting via toll-like receptor 7 on antigen presenting cells. T-cell responses to individual IMA910 peptides were analyzed by HLA multimer and intracellular cytokine staining (ICS) assays. Results: IMA910 elicited immune responses towards multiple class I (43%) and class II TUMAPs (65%). 34% of pts responded to multiple class I and class II TUMAPs. Pts that received imiquimod were more often multi-peptide class I responders in the ICS assay (p=0.016) and showed an approx. 2x higher frequency of T-cell response (p=0.12). Responses to multiple class I and class II TUMAPs were associated with higher disease control rate at all time points (all p

536^ Background: COIN-B is a trial of intermittent chemotherapy (ICT) plus intermittent cetuximab (C) vs ICT plus continuous C in the first-line treatment of aCRC. It complements the COIN trial by investigating how C might safely and effectively be added to an ICT strategy. Methods: Patients (pts) had measurable aCRC; no prior CT for metastases; WHO PS 0-2 and good organ function. Randomisation was: Arm D - continuous OxFU + weekly C for 12 wks then a planned break from all therapy; Arm E - OxFU + weekly C for 12 wks then weekly C. Upon RECIST progression on either arm, OxFU (or FU) plus C was restarted and continued until progression on maximal tolerated therapy. Prospective KRAS testing was introduced in May 2008. Primary outcome measure is Failure-Free Survival (FFS) at 10 months (mo) in KRAS-wt pts who had not progressed, died or failed the treatment strategy within 3 mo of randomisation. The trial was powered to differentiate between a desired 10-mo FFS rate of 50% and a minimum of 35%, in 136 pts (168 allowing for drop-outs). Secondary outcome measures included safety, overall survival (OS) and toxicity. Results: 169 KRAS-wt pts were randomised 07/07 to 06/10, 77 arm D / 92 arm E. Median age 64 years (IQR 55-70); 92% PS 0-1. In Arms D and E respectively, 65 (84%) and 67 (73%) pts were eligible for the primary analysis; 10-mo FFS rates were 48% vs 54% (one-sided 95% confidence limit 37% and 43% respectively). Median FFS was 12.0 vs 13.7 mo respectively (IQR 6.1-20.3 and 8.6-23.2). Median OS was 20.1 vs 18.4 mo. First CFI length was 3.7 mo vs 5.1 mo (IQR 2.5-6.2 and 2.5-8.9). In pre-planned exploratory analysis, median time to progression/death after chemo break was 3.1 mo (IQR 2.1-8.1) in Arm D and 6.0 mo (IQR 2.9-10.9) in Arm E. Toxicity was similar and only 1 arm D pt had G 3 hypersensitivity following C reintroduction. Analyses by BRAF & NRAS (tested retrospectively) will be presented. Conclusions: C was safely incorporated in 2 ICT strategies. Continuous C as maintenance was associated with a longer CFI and longer time to progression/death. This encouraging strategy of incorporating biological maintenance therapy needs validation in phase III trials.

e14117 Background: The epidermal growth factor receptor (EGFR) is the target of antibody therapeutics, with cetuximab approved for use in metastatic colorectal carcinoma (mCRC) among other indications. While KRAS mutation is a negative predictor of cetuximab response, patients with wtKRAS may show low response rates through a number of resistance mechanisms. Co-expression of receptor tyrosine kinases, such as IGF1R or cMet, can confer resistance by providing alternative ways to activate tumor growth pathways. Additionally, current diagnostic assays cannot quantitate receptor or pathway activation in tissue. Characterization of these various resistance mechanisms are critical to maximizing response rates to EGFR targeted therapies. Methods: In order to address these issues, we used mass spectrometry to develop a multiplexed SRM (selective reaction monitoring) assay to measure levels of multiple protein targets on FFPE tumor tissue. These assays are based on the Liquid Tissue-SRM technology platform. This a...

3523 Background: Phase III trials show inconsistent effects when anti-EGFR drugs are added to cytotoxic therapy in aCRC. Benefits, when present, are confined to patients (pts) determined retrospect...

3566 Background: Phase I/II data showed that ciclosporin (Cs) profoundly reduces the hepatobiliary clearance of irinotecan (Ir), and suggested that 40% standard dose Ir with concurrent Cs (IrCs) ma...

TPS161 Background: Plasma endothelin-1 levels are elevated in CRC patients and are prognostic for worse outcome. Endothelin-A receptor (ETAR) expression is increased in CRC samples compared with no...

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.

3525 Background: Figitumumab (F; CP-751,871) is a fully human monoclonal antibody (mAb) that inhibits IGF-IR. This phase II trial examined the efficacy and safety of F in patients (pts) with refrac...

359 Background: KRAS mutation has been shown to be a more effective (though negative) biomarker for selection of patients for EGFR targeted therapy in aCRC. However, positive EGFR immunohistochemistry (IHC) remains a license requirement and was an inclusion criterion in most trials to date. The MRC COIN trial recruited 2445 pts into 3 arms of oxaliplatin + fluoropyrimidine +/- cetuximab without prior EGFR assessment. This trial provides a unique opportunity to definitively examine the role of EGFR IHC as prognostic and predictive marker and potentially the evidence required to remove this assessment from the license for this drug. Methods: Formalin-fixed paraffin embedded (FFPE) tissue was stained retrospectively for EGFR using Dako kit in a national reference lab. Results were assessed by 3 reviewers (BJ, SS, RA) using digital imaging software in a blinded fashion, then by BJ/SS providing consensus for discrepancies. EGFR scoring was assessed as a prognostic variable in association with selected patient, tumor and biochemical data. Cut off points examined for +ve vs -ve tumours, in terms of total tumour cells demonstrating membrane staining, were: 0% vs >0%; Results: EGFR IHC was adequately assessed for 1621 pts (66% of randomised), 22% were negative (0%) and 78% positive (>0%), balanced across arms. EGFR was not prognostic for PFS within KRAS wt pts at the standardized cut off point 0% vs >0% HR=1.11 95% CI 0.91-1.36 p=0.31 but was at Conclusions: Extensive assessment of samples from this trial suggest a role for EGFR IHC as a prognostic marker in KRAS wt aCRC but refute the predictive value embedded within the licence for cetuximab used in combination with chemo in first-line therapy. [Table: see text]

3502 Background: In COIN one randomization was between continuous oxaliplatin (Ox) and fluoropyrimidine (Fp) CT and the same CT plus cetuximab (C). The choice of Fp, capecitabine (Cap) or infusional 5-fluouroracil plus leucovorin (FU), was decided prior to randomization. The primary outcome was overall survival (OS) in KRAS wild-type (wt) pts. Further analysis of NRAS, BRAF, MSI and EGFR status has been performed. Methods: Pts had measurable, inoperable aCRC; no prior CT for metastases; WHO PS 0-2 and good organ function. Patients were randomized between (A) continuous OxFp (OxFU q2w or OxCap q3w) and (B) OxFp + weekly C. Results: 1,630 pts were accrued between 03/05 and 05/08 from the UK and Ireland. Pt characteristics: median age 63; 92% had PS 0-1; 66% received OxCap and 34% received OxFU. Tumor samples from 1,316 (81%) pts were available for KRAS analysis. 729 (55%) were KRAS wt. 102 (8%) had BRAF and 50 (4%) had NRAS mutations. 4% had MSI. In the primary analysis cohort there was no evidence of a dif...

e14001 Background: Recently reported RCTs of 1st and 2nd line treatment with anti-EGFR-targeted MAbs in patients with aCRC have shown conflicting results. Methods: We conducted a systematic review ...

TPS222 Background: Around 7,400 patients are diagnosed with pancreatic cancer in the UK each year and mortality from the disease parallels its incidence, indicating that an effective treatment is r...

1085 Background: The IV bisphosphonate zoledronate is widely used in the UK to treat metastatic bone disease from breast cancer. Oral bisphosphonates may have advantages over IV but this has not be...

3525 Background: Intervals off CT may be a welcome respite for pts. The COIN trial compared intermittent and continuous CT strategies. Methods: Pts had measurable, inoperable aCRC; no prior CT for ...

4122 Background: A recent systematic review, based largely on non-randomised, retrospective studies, suggested that K-ras mutations may identify patients who do not benefit from cetuximab and panitumumab. In support of this hypothesis, four RCTs have shown a lack of benefit or detriment of EGFR-targeted therapy in patients with K-ras mutations. In this systematic review, we aim to provide a comprehensive and unbiased synthesis of the effects of these MAbs, by K-ras status, in both chemotherapy (CT) responsive and CT-refractory ACRC patients. Methods: A systematic review and meta-analysis of all relevant RCTs is ongoing. Progression-free survival (PFS) is the primary outcome, with survival and response as secondary outcomes. We have conducted systematic searches of a number of trial sources. Data on trial and patient characteristics, and outcome have been extracted from trial reports or presentations, for all patients and for K-ras wild-type and mutant cohorts. Where possible, trial results were pooled in a stratified-by- trial meta-analysis. For unpublished RCTs, or those published with insufficient information, we are seeking further data. Results: Searches identified 15 eligible RCTs in CT-responsive patients, 12 using cetuximab and 3 panitumumab. Three of these trials included bevacizumab in both arms. PFS has only been reported for 6 RCTs, so further data are needed to ensure an unbiased analysis. Only two RCTs were identified in CT-refractory patients. Together, these showed an improvement in PFS with anti-EGFR MAb (HR=0.61, 95% CI 0.49–0.76, p [Table: see text]

15021 Background: The benefit of adding radiotherapy to chemotherapy (CT) in patients with locally advanced non-metastatic pancreatic cancer (LANPC) is uncertain with chemoradiation (CRT) being the treatment of choice in the USA and CT alone more common in the UK. To establish the outcome of LANPC treated with CT alone we undertook a review of outcomes of all patients with LANPC referred to a single UK Cancer Network (South East Wales, population 1.5 million) over a 4 year period. Methods: Case notes, radiology and histology reports of patients with LANPC referred to Velindre Cancer Centre between 1.1.2002 and 31.12.2005 were reviewed. Patient and tumour characteristics, treatment type and duration, response to treatment and overall survival were collected. The primary end-point of the study was overall survival. Log-rank was used to compare survival between groups, and Cox regression analysis model was used to evaluate whether age, sex, tumour site and treatment response correlated with overall survival. Results: 357 patients were identified with pancreatic cancer. 116/357 (32.5%) patients had LANPC of which 74/116 (64%) were fit for active treatment. Treatment included primary gemcitabine based CT (n= 68) and CRT (n=6). For patients receiving primary CT median duration of treatment was 3.2 months. The median survival of all patients with LANPC was 7.7 months (95% CI 6.7–8.7). Survival for patients receiving primary CT, CRT and no treatment were 10 (8.5–11.3) months, 10.3 (0–20.7) months and 4.6 (3.8–5.4) months respectively. Survival of 4 patients who received neoadjuvant CT prior to CRT was 12.9 (6.8–19) months. 32 patients (47%) progressed on CT. OS of patients with non-progressive disease was significantly better than those who progressed (12.1 v 6.7 months, p=0.039). Conclusions: In this UK Network, only a small proportion of patients are eligible for active treatment. The outcome of patients treated with CT alone is comparable to published series of CRT. There is an urgent need for a randomised trial to define the additional role of CRT over and above Gemcitabine-based chemotherapy and such trials should include a neo-adjuvant ‘chemotherapy-only’ phase to select out patients most likely to benefit from multi-modality treatment. No significant financial relationships to disclose.

4071 Background: Irinotecan containing first line therapy has been shown to improve efficacy in first line therapy. Pooled analyses demonstrated that elderly patients benefit in a similar way as younger patients if 5-FU or 5-FU/oxaliplatin is administered as palliative or adjuvant treatment within clinical trials (Sargent, NEJM 2001, Folprecht, Ann Oncol 2004, Goldberg JCO 2006). Methods: We present an updated metaanalysis using source data of randomized trials (Saltz 2000, Douillard 2000, Köhne 2005 [EORTC 40986] and Seymour 2005 [FOCUS]) and compared the efficacy and toxicity in older (=70 years) and younger (= 3 toxicity in the general population, but there were no significant differences regarding toxicity between older and younger patients ( table 1 ). Conclusion: Patients over 70 yrs who are selected for inclusion in phase III trials derive similar benefits from irinotecan-containing chemotherapy, and with similar risks of toxicity, compared with younger patients. [Table: see text] [Table: see text]

9030 Background: Elderly/frail patients, though commonly treated, are under-represented in clinical trials. Evidence is needed to guide choices of drugs and doses in this population. Methods: FOCUS2 is a multicenter, 2x2 factorial randomized trial for patients with unpretreated metastatic colorectal cancer judged unfit for full-dose combination chemotherapy. After comprehensive health assessment (CHA), randomization was to: (A) simplified LV5FU2 infusional fluorouracil/leucovorin (FU); (B) OxFU; (C) Cap; or (D) OxCap. In each case, starting doses were 80% standard, with an option to escalate to full-dose at 6 weeks (wk). The factorial questions were: (A+B v C+D) - does replacing FU with Cap improve quality of life (QL)? (primary endpoint: improved global QL at 12 wk [QLQ-C30]); and (A+C v B+D) - how much does Ox improve efficacy in this population? (primary endpoint: progression-free survival (PFS). Results: 460 patients were randomized, 22% < 70 yrs; 35% 70–75 yrs; 43% > 75 yrs. 22% were performance status (PS) 0; 49% PS1; 29% PS2. Primary comparisons: (see table ): global QL did not favor Cap over FU. Comparison of PFS favored the addition of oxaliplatin but did not reach significance (HR 0.87, 95% CI 0.71–1.06, p=0.16). Secondary comparisons: Compared with FU, Cap did not affect RR, PFS or 60-day mortality, but it increased the risk of gr =3 toxicity. Oxaliplatin significantly improved RECIST response (RR) by wk 12, did not increase gr =3 toxicity or 60-day mortality, but reduced the chance of improved QL at 12 wk. Conclusion: In this frail elderly population, substituting Cap for FU did not improve overall QL or efficacy, and significantly increased toxicity. Addition of Ox gave significantly higher anticancer activity without increasing toxicity, but at the cost of some reduction in QL at 12 wk. Planned analyses include correlating baseline CHA with treatment outcome. [Table: see text] [Table: see text]

3576 Background: The aim of this study is to determine maximum tolerated dose (MTD) and recommended scheduled dose of irinotecan on days 1–5 and 29–33, in combination with LV 20mg/m2 and 5-FU 350mg...

3737 Background: The improved safety profile of the oral fluoropyrimidine X (Xeloda) versus bolus 5-FU/LV has been demonstrated in over 3000 pts in 3 large randomized trials in 1st line metastatic and adjuvant colon cancer (Twelves EJC 2002, Scheithauer Ann Oncol 2003). In addition, the safety advantage over 5-FU/LV in the adjuvant setting was maintained in older pts (≥65 years) and also in terms of less early severe toxicity with X. The median age of pts at diagnosis of colon cancer is increasing in developed countries. Therefore we examined whether there is enough evidence to support the safe use of X in an elderly population, i.e. pts 70 years and older. Methods: We performed retrospective analyses on the safety database of the X-ACT adjuvant colon cancer trial, which compared X (993 pts) to 5-FU/LV Mayo Clinic Regimen (974 pts) in Dukes' C colon cancer pts. Adverse events (AEs) in the two arms were analyzed by age

The amino acid, l-glutamine is the major energy substrate of the intestinal epithelium. Dietary supplementation reduces GI toxicity after RT and CT in animal models. The maximal insult to the gut occurs during high dose conditioning therapy and in this study glycyl-l-glutamine (GLG) supplementation is commenced one day before high dose therapy starts. In vitro testing showed minimal shifts in chemo or radiosensitivity with glutamine supplementation. This double blind randomised trial compares 50 g/day GLG iv supplementation versus an isonitrogenous mixture of aminoacids. Serum glutamine concs were doubled from a mean of 398 at baseline to 812 μmolar at end of infusion. GLG (19) Placebo (12) Median days to 0.5 neutrophils 14 16 Median days to 50 platelets 18 21 Median hospital stay post graft 19 (12–44) 22 (14–48) Mucositis score (nurse) 3.1 7.5 These results suggest a beneficial effect of GLG supplementation on gastrointestinal toxicity and haematological recovery with reduction in hospital stay and warrant further study.

The hydrophilic 2-nitroimidazole radiosensitizer etanidazole is currently undergoing clinical evaluation. Although considerably less neurotoxic than misonidazole because of its rapid renal clearance and partial exclusion from the nervous system, total dose is limited by peripheral neuropathy. Monitoring plasma etanidazole concentration in patients to determine the area under the curve (AUC0-infinity) has been proposed as a method of predicting patients at risk, and of providing a quantitative basis for dose reduction in such patients. Successful application of this policy requires accurate assessment of AUC0-infinity. We have analyzed plasma data for 18 patients receiving 2 g/m2 etanidazole to determine the errors introduced in the estimation of AUC0-infinity caused by omitting selected time points from the analysis. A 'baseline' AUC0-infinity value was calculated by integration of the rate equation for the 2-compartment model using data points at 0, 15, and 30 min and 1, 2, 4, 8, 12, and 24 hr after the end of infusion. The mean +/- SD area for AUC0-infinity was 502 +/- 152 micrograms ml-1 h (2.35 +/- 0.71 mM.h). Omitting the zero or the 24 hr time point, the average errors were quite small (2.5% in both cases), but errors of up to 16.4 and 7.3%, respectively, were seen for individual patients. Leaving out both the 8 hr and 12 hr points at the same time gave a similar low average error of 2.9%, with a highest error of 7.3%. Omitting all data points after 4 hr, the mean error was 24.7% and 15 of 18 patients had errors in excess of 10%. In addition, failure to correct for infusion time results in an underestimation of AUC0-infinity averaging 4.5% (range 1.9-8.7%). The choice of sampling times for toxicological monitoring will depend upon the accuracy with which the AUC0-infinity must be known. Including all data points between 0 and 24 hr will minimize errors. Considering the general similarity in the errors introduced by omitting the 8 hr and 12 hr points together compared to those seen with exclusion of the single 24 hr point, the choice between these truncated sampling options would be expected to lie in the relative inconvenience caused to patients and medical staff for the particular dose schedule used. The short sampling schedule (0-4 hr) should not be used.

The presence of cancer antigen CA125 has been assessed immunohistologically in formalin-fixed tumor tissue and immunoradiometrically in serum from 41 women with residual epithelial ovarian carcinoma after diagnostic laparotomy. CA125 was detected in tumor tissue from the majority of patients (34/41), including those with normal serum levels (15/18). The major determinant of serum CA125 concentration appears to be the size of the residual tumor. The results suggest that in the majority of patients with small residual tumor masses and normal postoperative serum antigen levels, progressive disease may well be associated with increasing serum CA125 levels.

Flavone acetic acid (FAA), 8.6 gm-2 has been administered by 6h intravenous infusion to 19 patients with advanced colorectal carcinoma and 15 patients with advanced malignant melanoma. The drug associated toxicity was generally mild and as predicted from the phase I study. No responses were seen in either disease.

188 Background: Unplanned subgroup analyses from several studies have suggested primary tumor sidedness (PTS) as a potential prognostic and predictive parameter in metastatic colorectal cancer (mCRC). We aimed to investigate the prognostic and predictive impact of PTS on outcomes. Methods: PTS data of 7,828 mCRC patients (pts) from 10 first-line randomized trials in the ARCAD database were pooled. PTS was defined as right-sided (RS) or left-sided (LS) if tumor arose from the cecum to the hepatic flexure or from the splenic flexure to the rectum, respectively; transverse colon cancers were not included. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for age, sex, performance status (PS), prior radiation/chemo, and stratified by treatment arm. Predictive value was tested by interaction term between PTS and treatment (anti-EGFR plus chemotherapy vs. chemotherapy alone). Results: Compared to RS pts (2407, 31%), LS pts (5421, 69%) had better OS (median: 21.6 v 16.8 mos; HRadj: 0.73, 95% CI 0.69-0.78, P < .001) and PFS (median 8.4 v 7.2 mos; HRadj: 0.81, 95% CI 0.76-0.86, P < .001). Results were consistent among subgroups defined by age, sex, PS, metastatic sites and chemo backbone (irinotecan- and oxaliplatin-based). Interaction between PTS and KRAS mutation was significant (Pinteraction< .001): LS is associated with better prognosis only among KRAS wild-type (wt) (HRadj: OS 0.62, 95% CI, 0.55-0.70; PFS 0.71, 95% CI 0.63-0.80), but not among KRAS mutated pts. Among KRAS wt pts, survival benefit from anti-EGFR was observed for LS, but not for RS (table). Conclusions: The prognostic value of PTS is restricted to the KRAS wt population. PTS is predictive of anti-EGFR efficacy, with a significant improvement of survival for LS mCRC pts. These results suggest treatment stratification in mCRC studies by both PTS and KRAS status. [Table: see text]