Fluoropyrimidine type, patient age, tumour sidedness and mutation status as determinants of benefit in patients with metastatic colorectal cancer treated with EGFR monoclonal antibodies: individual patient data pooled analysis of randomised trials from the ARCAD database.

BACKGROUND: KRAS mutations in metastatic colorectal cancer (mCRC) are used as predictive biomarkers to select therapy with EGFR monoclonal antibodies (mAbs). Other factors may be significant determinants of benefit. METHODS: Individual patient data from randomised trials with a head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or best supportive care) in mCRC, across all lines of therapy, were pooled. Overall survival (OS) and progression-free survival (PFS) were compared between groups. Treatment effects within the predefined KRAS biomarker subsets were estimated by adjusted hazard ratio (HRadj) and 95% confidence interval (CI). EGFR mAb efficacy was measured within the KRAS wild-type subgroup according to BRAF and NRAS mutation status. In both KRAS wild-type and mutant subgroups, additional factors that could impact EGFR mAb efficacy were explored including the type of chemotherapy, line of therapy, age, sex, tumour sidedness and site of metastasis. RESULTS: 5675 patients from 8 studies were included, all with known mCRC KRAS mutation status. OS (HRadj 0.90, 95% CI 0.84-0.98, p = 0.01) and PFS benefit (HRadj 0.73, 95% CI 0.68-0.79, p < 0.001) from EGFR mAbs was observed in the KRAS wild-type group. PFS benefit was seen in patients treated with fluorouracil (HRadj 0.75, 95% CI 0.68-0.82) but not with capecitabine-containing regimens (HRadj 1.04, 95% CI 0.86-1.26) (pinteraction = 0.002). Sidedness also interacted with EGFR mAb efficacy, with survival benefit restricted to left-sided disease (pinteraction = 0.038). PFS benefits differed according to age, with benefits greater in those under 70 (pinteraction = 0.001). The survival benefit was not demonstrated in those patients with mutations found in the KRAS, NRAS or BRAF genes. The presence of liver metastases interacted with EGFR mAb efficacy in patients with KRAS mutant mCRC (pinteraction = 0.004). CONCLUSION: The benefit provided by EGFR mAbs in KRAS WT mCRC is associated with left-sided primary tumour location, younger patient age and absence of NRAS or BRAF mutations. Survival benefit is observed with fluorouracil but not capecitabine. Exploratory results support further research in KRAS mutant mCRC without liver metastases.

Registry-derived stage (RD-Stage) for capturing cancer stage at diagnosis for endometrial cancer.

BACKGROUND: Capture of cancer stage at diagnosis is important yet poorly reported by health services to population-based cancer registries. In this paper we describe current completeness of stage information for endometrial cancer available in Australian cancer registries; and develop and validate a set of rules to enable cancer registry medical coders to calculate stage using data available to them (registry-derived stage or 'RD-Stage'). METHODOLOGY: Rules for deriving RD-stage (Endometrial carcinoma) were developed using the American Joint Commission on Cancer (AJCC) TNM (tumour, nodes, metastasis) Staging System (8th Edition). An expert working group comprising cancer specialists responsible for delivering cancer care, epidemiologists and medical coders reviewed and endorsed the rules. Baseline completeness of data fields required to calculate RD-Stage, and calculation of the proportion of cases for whom an RD stage could be assigned, was assessed across each Australian jurisdiction. RD-Stage (Endometrial cancer) was calculated by Victorian Cancer Registry (VCR) medical coders and compared with clinical stage recorded by the patient's treating clinician and captured in the National Gynae-Oncology Registry (NGOR). RESULTS: The necessary data completeness level for calculating RD-Stage (Endometrial carcinoma) across various Australian jurisdictions varied from 0 to 89%. Three jurisdictions captured degree of spread of cancer, rendering RD-Stage unable to be calculated. RD-Stage (Endometrial carcinoma) could not be derived for 64/485 (13%) cases and was not captured for 44/485 (9%) cases in NGOR. At stage category level (I, II, III, IV), there was concordance between RD-Stage and NGOR captured stage in 393/410 (96%) of cases (95.8%, Kendall's coefficient = 0.95). CONCLUSION: A lack of consistency in data captured by, and data sources reporting to, population-based cancer registries meant that it was not possible to provide national endometrial carcinoma stage data at diagnosis. In a sample of Victorian cases, where surgical pathology was available, there was very good concordance between RD-Stage (Endometrial carcinoma) and clinician-recorded stage data available from NGOR. RD-Stage offers promise in capturing endometrial cancer stage at diagnosis for population epidemiological purposes when it is not provided by health services, but requires more extensive validation.

Patient-reported outcome (PRO) results from the AGITG DOCTOR trial: a randomised phase 2 trial of tailored neoadjuvant therapy for resectable oesophageal adenocarcinoma.

BACKGROUND: AGITG DOCTOR was a randomised phase 2 trial of pre-operative cisplatin, 5 fluorouracil (CF) followed by docetaxel (D) with or without radiotherapy (RT) based on poor early response to CF, detected via PET, for resectable oesophageal adenocarcinoma. This study describes PROs over 2 years. METHODS: Participants (N = 116) completed the EORTC QLQ-C30 and oesophageal module (QLQ-OES18) before chemotherapy (baseline), before surgery, six and 12 weeks post-surgery and three-monthly until 2 years. We plotted PROs over time and calculated the percentage of participants per treatment group whose post-surgery score was within 10 points (threshold for clinically relevant change) of their baseline score, for each PRO scale. We examined the relationship between Grade 3+ adverse events (AEs) and PROs. This analysis included four groups: CF responders, non-responders randomised to DCF, non-responders randomised to DCF + RT, and "others" who were not randomised. RESULTS: Global QOL was clinically similar between groups from 6 weeks post-surgery. All groups had poorer functional and higher symptom scores during active treatment and shortly after surgery, particularly the DCF and DCF + RT groups. DCF + RT reported a clinically significant difference (-13points) in mean overall health/QOL between baseline and pre-surgery. Similar proportions of patients across groups scored +/- 10 points of baseline scores within 2 years for most PRO domains. Instance of grade 3+ AEs were not related to PROs at baseline or 2 years. CONCLUSIONS: By 2 years, similar proportions of patients scored within 10 points of baseline for most PRO domains, with the exception of pain and insomnia for the DCF + RT group. Non-responders randomised to DCF or DCF + RT experienced additional short-term burden compared to CF responders, reflecting the longer duration of neoadjuvant treatment and additional toxicity. This should be weighed against clinical benefits reported in AGITG DOCTOR. This data will inform communication of the trajectory of treatment options for early CF non-responders. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry (ANZCTR), ACTRN12609000665235 . Registered 31 July 2009.

Final analysis of the randomized trial on imatinib as an adjuvant in localized gastrointestinal stromal tumors (GIST) from the EORTC Soft Tissue and Bone Sarcoma Group (STBSG), the Australasian Gastro-Intestinal Trials Group (AGITG), UNICANCER, French Sarcoma Group (FSG), Italian Sarcoma Group (ISG), and Spanish Group for Research on Sarcomas (GEIS)☆.

BACKGROUND: In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery in localized, high/intermediate-risk gastrointestinal stromal tumors (GIST) patients. Interim analysis results were published in 2015 upon recommendation from an independent data review committee. We report the final outcome of the study. PATIENTS AND METHODS: This was a randomized, open-label, multicenter phase III trial carried out at 112 hospitals in 12 countries. Patients were randomized to 2 years of imatinib, 400 mg daily, or no further therapy after surgery. The primary endpoint was imatinib failure-free survival (IFFS), while relapse-free survival (RFS), relapse-free interval (RFI), overall survival (OS) and toxicity were secondary endpoints. Adjusting for the interim analyses, results on IFFS were assessed on a 4.3% significance level; for the other endpoints, 5% was used. RESULTS: Nine hundred and eight patients were randomized between January 2005 and October 2008: 454 to imatinib and 454 to observation; 835 patients were eligible. With a median follow-up of 9.1 years, 5 (10)-year IFFS was 87% (75%) in the imatinib arm versus 83% (74%) in the control arm [hazard ratio (HR) = 0.87, 95.7% confidence interval (CI) (0.65; 1.15), P = 0.31]; RFS was 70% versus 63% at 5 years and 63% versus 61% at 10 years, [HR = 0.71, 95% CI (0.57; 0.89), P = 0.002]; OS was 93% versus 92% at 5 years and 80% versus 78% at 10 years [HR = 0.88, 95% CI (0.65; 1.21), P = 0.43]. Among 526 patients with high-risk GIST by local pathology, 10-year IFFS and RFS were 69% versus 61%, and 48% versus 43%, respectively. CONCLUSIONS: With 9.1 years of follow-up, a trend toward better long-term IFFS in imatinib-treated patients was observed in the high-risk subgroup. Although the difference was not statistically significant and the surrogacy value of such an endpoint is not validated, this may be seen as supporting the results reported by the Scandinavian/German trial, showing a sustained small but significant long-term OS benefit in high-risk GIST patients treated with 3 years of adjuvant imatinib.

Diagnosis and management of tropomyosin receptor kinase (TRK) fusion sarcomas: expert recommendations from the World Sarcoma Network.

Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.

Preoperative cisplatin, fluorouracil, and docetaxel with or without radiotherapy after poor early response to cisplatin and fluorouracil for resectable oesophageal adenocarcinoma (AGITG DOCTOR): results from a multicentre, randomised controlled phase II trial.

BACKGROUND: Patients with oesophageal/gastro-oesophageal junction adenocarcinoma (EAC) not showing early metabolic response (EMR) to chemotherapy have poorer survival and histological response rates <5%. We investigated whether tailoring neoadjuvant therapy can improve outcomes in these patients. PATIENTS AND METHODS: Patients with resectable EAC were enrolled and randomised into two single-arm, multicentre phase II trials. After induction cisplatin and 5-fluorouracil (CF), all were assessed by day 15 positron emission tomography (PET). Patients with an EMR [maximum standardised uptake values (SUVmax) ≥35% reduction from baseline to day 15 PET] received a second CF cycle then oesophagectomy. Non-responders were randomised 1 : 1 to two cycles of CF and docetaxel (DCF, n = 31) or DCF + 45 Gy radiotherapy (DCFRT, n = 35) then oesophagectomy. The primary end point was major histological response (<10% residual tumour) in the oesophagectomy specimen; secondary end points were overall survival (OS), progression-free survival (PFS), and locoregional recurrence (LR). RESULTS: Of 124 patients recruited, major histological response was achieved in 3/45 (7%) with EMR, 6/30 (20%) DCF, and 22/35 (63%) DCFRT patients. Grade 3/4 toxicities occurred in 12/45 (27%) EMR (CF), 13/31 (42%) DCF, and 25/35 (71%) DCFRT patients. No treatment-related deaths occurred. LR by 3 years was seen in 5/45 (11%) EMR, 10/31 (32%) DCF, and 4/35 (11%) DCFRT patients. PFS [95% confidence interval (CI)] at 36 months was 47% (31% to 61%) for EMR, 29% (15% to 45%) for DCF, and 46% (29% to 61%) for DCFRT patients. OS (95% CI) at 60 months was 53% (37% to 67%) for EMR, 31% (16% to 48%) for DCF, and 46% (29% to 61%) for DCFRT patients. CONCLUSIONS: EMR is associated with favourable OS, PFS, and low LR. For non-responders, the addition of docetaxel augmented histological response rates, but OS, PFS, and LR remained inferior compared with responders. DCFRT improved histological response and PFS/LR outcomes, matching the EMR group. Early PET/CT has the potential to tailor therapy for patients not showing an early response to chemotherapy. TRIAL REGISTRATION: ACTRN12609000665235.

Tools for predicting patient-reported outcomes in prostate cancer patients undergoing radical prostatectomy: a systematic review of prognostic accuracy and validity.

BACKGROUND: Radical prostatectomy is a common surgical procedure performed to treat prostate cancer. Patient-reported outcomes after surgery include urinary incontinence, erectile dysfunction, decreased quality of life and psychological effects. Predictive tools to assess the likelihood of an individual experiencing various patient-reported outcomes have been developed to aid decision-making when selecting treatment. METHODS: A systematic review was undertaken to identify all papers describing tools for the prediction of patient-reported outcome measures in men with prostate cancer treated with radical prostatectomy. To be eligible for inclusion, papers had to provide a summary measure of accuracy. PubMed and EMBASE were searched from July 2007. Title/abstract screening, and full-text review were undertaken by two reviewers, while data extraction and critical appraisal was performed by a single reviewer. RESULTS: The search strategy identified 3217 potential studies, of which 191 progressed to full-text review and 14 were included. From these studies, 27 tools in total were identified, of which 18 predicted urinary symptoms, six predicted erectile function and one predicted freedom from a group of three outcomes ('trifecta') (biochemical recurrence, incontinence and erectile dysfunction). On the basis of tool accuracy (>70%) and external validation, two tools predicting incontinence and two tools predicting erectile dysfunction are ready for implementation. CONCLUSIONS: A small number of tools for the prediction of patient-reported outcomes following radical prostatectomy have been developed. Four tools were found to have adequate accuracy and validation and are ready for implementation for the prediction of urinary incontinence and erectile dysfunction.

A need to simplify informed consent documents in cancer clinical trials. A position paper of the ARCAD Group.

Background: In respect of the principle of autonomy and the right of self-determination, obtaining an informed consent of potential participants before their inclusion in a study is a fundamental ethical obligation. The variations in national laws, regulations, and cultures contribute to complex informed consent documents for patients participating in clinical trials. Currently, only few ethics committees seem willing to address the complexity and the length of these documents and to request investigators and sponsors to revise them in a way to make them understandable for potential participants. The purpose of this work is to focus on the written information in the informed consent documentation for drug development clinical trials and suggests (i) to distinguish between necessary and not essential information, (ii) to define the optimal format allowing the best legibility of those documents. Methods: The Aide et Recherche en Cancérologie Digestive (ARCAD) Group, an international scientific committee involving oncologists from all over the world, addressed these issues and developed and uniformly accepted a simplified informed consent documentation for future clinical research. Results: A simplified form of informed consent with the leading part of 1200-1800 words containing all of the key information necessary to meet ethical and regulatory requirements and 'relevant supportive information appendix' of 2000-3000 words is provided. Conclusions: This position paper, on the basis of the ARCAD Group experts discussions, proposes our informed consent model and the rationale for its content.

Germline polymorphisms as biomarkers of tumor response in colorectal cancer patients treated with anti-EGFR monoclonal antibodies: a systematic review and meta-analysis.

Studies of germline polymorphisms as predictors of tumor response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody agents in metastatic colorectal cancer have reported inconsistent results. We performed a systematic review of studies from 1990 to September 2015, followed by random-effects meta-analyses for polymorphisms examined in at least three studies. Of 87 studies, 40 passed the criteria for systematic review and 23 for meta-analysis. The polymorphisms suitable for meta-analysis were CCND1 (rs17852153), COX2 (rs20417), EGF (rs4444903), EGFR (rs712829, rs11543848, 3'UTR CA repeat), FCGR2A (rs1801274), FCGR3A (rs396991), IL8 (rs4073), KRAS (rs61764370) and VEGFA (rs3025039). Meta-analysis yielded nominal significance (at α=0.05) for rs4444903 and rs11543848, but showed no significant results after multiple testing correction; this was unchanged by sensitivity analyses to address subgroups, funnel-plot asymmetries, and study quality. This highlights a tendency for lack of replication in the face of initial positive results, and possibly the unsuitability of relying on tumor response as a surrogate marker in this setting.

TACTIC: a multicentre, open-label, single-arm phase II trial of panitumumab, cisplatin, and gemcitabine in biliary tract cancer.

PURPOSE: The phase II TACTIC trial prospectively selected patients with KRAS wild-type advanced biliary tract cancer for first-line treatment with panitumumab and combination chemotherapy. METHODS: Of 78 patients screened, 85 % had KRAS wild-type tumours and 48 were enrolled. Participants received cisplatin 25 mg/m(2) and gemcitabine 1000 mg/m(2) on day 1 and day 8 of each 21-day cycle and panitumumab 9 mg/kg on day 1 of each cycle. Treatment was continued until disease progression, unacceptable toxicity, or request to discontinue. The primary endpoint was the clinical benefit rate (CBR) at 12 weeks (complete response, partial response, or stable disease). CBR of 70 % was considered to be of clinical interest. Secondary outcomes were progression-free survival, time to treatment failure, overall survival, CA19.9 response and safety. RESULTS: Thirty-four patients had a clinical benefit at 12 weeks, an actuarial rate of 80 % (95 % CI 65-89 %). 46 % had a complete or partial response. Median progression-free survival was 8.0 months (95 % CI 5.1-9.9) and median overall survival 11.9 months (95 % CI 7.4-15.8). Infection accounted for 27 % of the grade 3 or 4 toxicity, with rash (13 %), fatigue (13 %), and hypomagnesemia (10 %) among the more common grade 3 or 4 non-haematological toxicities. CONCLUSION: A marker-driven approach to patient selection was feasible in advanced biliary tract cancer in an Australian population. The combination of panitumumab, gemcitabine, and cisplatin in KRAS wild-type cancers was generally well tolerated and showed promising clinical efficacy. Further exploration of anti-EGFR therapy in a more selected population is warranted.

Oxaliplatin and 5-FU/folinic acid (modified FOLFOX6) with or without aflibercept in first-line treatment of patients with metastatic colorectal cancer: the AFFIRM study.

BACKGROUND: The combination of aflibercept with FOLFIRI has been shown to significantly prolong overall survival in patients with metastatic colorectal cancer (mCRC) after progression on oxaliplatin-based therapy. This trial evaluated the addition of aflibercept to oxaliplatin-based first-line treatment of patients with mCRC. PATIENTS AND METHODS: Patients with mCRC were randomized to receive first-line therapy with mFOLFOX6 plus aflibercept (4 mg/kg) or mFOLFOX6 alone. The primary end point of this phase II study was the progression-free survival (PFS) rate at 12 months in each arm. The analysis of efficacy between the arms was a pre-planned secondary analysis. RESULTS: Of 236 randomized patients, 227 and 235 patients were evaluable for the primary efficacy analysis and safety, respectively. The probabilities of being progression-free at 12 months were 25.8% [95% confidence interval (CI) 17.2-34.4] for the aflibercept/mFOLFOX6 arm and 21.2% (95% CI 12.2-30.3) for the mFOLFOX6 arm. The median PFS was 8.48 months (95% CI 7.89-9.92) for the aflibercept/mFOLFOX6 arm and 8.77 months (95% CI 7.62-9.27) for the mFOLFOX6 arm; the hazard ratio of aflibercept/mFOLFOX6 versus mFOLFOX6 was 1.00 (95% CI 0.74-1.36). The response rates were 49.1% (95% CI 39.7-58.6) and 45.9% (95% CI 36.4-55.7) for patients treated with and without aflibercept, respectively. The most frequent treatment-emergent grade 3/4 adverse events (AEs) excluding laboratory abnormalities reported for aflibercept/mFOLFOX6 versus mFOLFOX6 were neuropathy (16.8% versus 17.2%) and diarrhea (13.4% versus 5.2%). Neutropenia grade 3/4 occurred in 36.1% versus 29.3%. The most common vascular endothelial growth factor inhibition class-effect grade 3/4 AEs for aflibercept/mFOLFOX6 versus mFOLFOX6 were hypertension (35.3% versus 1.7%), proteinuria (9.2% versus 0%), deep vein thrombosis (5.9% versus 0.9%) and pulmonary embolism (5.9% versus 5.2%). CONCLUSION: No difference in PFS rate was observed between treatment groups. Adding aflibercept to first-line mFOLFOX6 did not increase efficacy but was associated with higher toxicity. CLINICAL TRIAL NUMBER: NCT00851084, www.clinicaltrials.gov, EudraCT 2008-004178-41.

Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17.

BACKGROUND: Right- and left-sided colon cancers (RC, LC) differ with respect to biology, pathology and epidemiology. Previous data suggest a mortality difference between RC and LC. We examined if primary tumour side also predicts for outcome in chemotherapy refractory, metastatic colon cancer (MCC). We also compared RC versus LC as a predictor of efficacy of epidermal growth factor receptor (EGFR) inhibition with cetuximab. METHODS: Reanalyzing NCIC CO.17 trial (cetuximab versus best supportive care [BSC]), we coded the primary tumour side as RC (caecum to transverse colon) or LC (splenic flexure to rectosigmoid). The association between tumour side and baseline characteristics was assessed. Cox regression models determined factors affecting overall survival (OS) and progression free survival (PFS). RESULTS: Patients with RC (150/399) had more poorly differentiated, mutant KRAS, mutated PIK3CA and wild-type BRAF tumours, fewer liver and lung metastases, and shorter interval between diagnosis and study entry. Among BSC patients, tumour side was not prognostic for PFS (hazard ratios (HR) 1.07 [0.79-1.44], p = 0.67) or OS (HR 0.96 [0.70-1.31], p = 0.78). Among wild-type KRAS patients, those with LC had significantly improved PFS when treated with cetuximab compared to BSC (median 5.4 versus 1.8 months, HR 0.28 [0.18-0.45], p < 0.0001), whereas those with RC did not (median 1.9 versus 1.9 months, HR 0.73 [0.42-1.27], p = 0.26), [interaction p = 0.002]. CONCLUSION: In refractory MCC, tumour location within the colon is not prognostic, but is strongly predictive of PFS benefit from cetuximab therapy. Additional research is needed to understand the molecular differences between RC and LC and their interaction with EGFR inhibition.

Realising opportunities for evidence-based cancer service delivery and research: linking cancer registry and administrative data in Australia.

The traditional roles of Australian cancer registries have been incidence, mortality and survival surveillance although increasingly, roles are being broadened to include data support for health-service management and evaluation. In some Australian jurisdictions, cancer stage and other prognostic data are being included in registry databases and this is being facilitated by an increase in structured pathology reporting by pathology and haematology laboratories. Data linkage facilities are being extended across the country at national and jurisdictional level, facilitating data linkage between registry data and data extracts from administrative databases that include treatment, screening and vaccination data, and self-reported data from large population cohorts. Well-established linkage protocols exist to protect privacy. The aim is to gain better data on patterns of care, service outcomes and related performance indicators for health-service management and population health and health-services research, at a time of increasing cost pressures. Barriers include wariness among some data custodians towards releasing data and the need for clearance for data release from large numbers of research ethics committees. Progress is being made though, and proof of concept is being established.

Phase II trial evaluating the feasibility of interdigitating folfox with chemoradiotherapy in locally advanced and metastatic rectal cancer.

BACKGROUND: Patients (pts) with metastatic rectal cancer and symptomatic primary, require local and systemic control. Chemotherapy used during chemoradiotherapy (CRT) is adequate for radiosensitisation, but suboptimal for systemic control. The aim of this phase II study was to assess tolerability, local/systemic benefits, of a novel regimen delivering interdigitating intensive chemotherapy with radical CRT. METHODS: Eligible pts had untreated synchronous symptomatic primary/metastatic rectal cancer. A total of 12 weeks of treatment with split-course pelvic CRT (total 50.4 Gy with concurrent oxaliplatin and 5-FU infusion) alternating with FOLFOX chemotherapy. All pts staged with CT, MRI and FDG-PET pre and post treatment. RESULTS: Twenty-six pts were treated. Rectal primary MRI stage: T3 81% and T4 15%. Liver metastases in 81%. Twenty-four pts (92%) completed the 12-week regimen. All patients received planned RT dose, and for both agents over 88% of patients achieved a relative dose intensity of >75%. Grade 3 toxicities: neutropenia 23%, diarrhoea 15%, and radiation skin reaction 12%. Grade 4 toxicity: neutropenia 15%. FDG-PET metabolic response rate for rectal primary 96%, and for metastatic disease 60%. CONCLUSIONS: Delivery of interdigitating chemotherapy with radical CRT was feasible to treat both primary and metastatic rectal cancer. High completion and response rates were encouraging.

Epiregulin gene expression as a biomarker of benefit from cetuximab in the treatment of advanced colorectal cancer.

BACKGROUND: Anti-EGFR antibody, cetuximab, improves overall survival (OS) in K-ras wild-type chemotherapy-refractory colorectal cancer. Epidermal growth factor receptor ligand epiregulin (EREG) gene expression may further predict cetuximab benefit. METHODS: Tumour samples from a phase III clinical trial of cetuximab plus best supportive care (BSC) vs BSC alone (CO.17) were analysed for EREG mRNA gene expression. Predictive effects of high vs low EREG on OS and progression-free survival (PFS) were examined for treatment-biomarker interaction. RESULTS: Both EREG and K-ras status were ascertained in 385 (193 cetuximab, 192 BSC) tumour samples. Within the high EREG and K-ras wild-type status ('co-biomarker')-positive group (n=139, 36%), median PFS was 5.4 vs 1.9 months (hazard ratio (HR) 0.31; P<0.0001), and median OS was 9.8 vs 5.1 months (HR 0.43; P<0.001) for cetuximab vs BSC, respectively. In the rest (n=246, 64%), PFS (HR 0.82; P=0.12) and OS (HR 0.90; P=0.45) were not significantly different. Test for treatment interaction showed a larger cetuximab effect on OS (HR 0.52; P=0.007) and PFS (HR 0.49; P=0.001) in the co-biomarker-positive group. CONCLUSION: In pre-treated K-ras wild-type status colorectal cancer, patients with high EREG gene expression appear to benefit more from cetuximab therapy compared with low expression. Epiregulin as a selective biomarker requires further evaluation.

A phase I trial of imatinib in combination with mFOLFOX6-bevacizumab in patients with advanced colorectal cancer.

PURPOSE: Platelet-derived growth factor receptor (PDGFR) inhibition by reducing tumoral interstitial fluid pressure might increase the efficacy of chemotherapy. Imatinib inhibits PDGFR kinase activity at therapeutically relevant doses. This phase I study aimed to assess the maximal tolerated dose (MTD) of imatinib in combination with mFOLFOX6-bevacizumab in patients with advanced colorectal cancer and to identify pharmacokinetic (PK) interactions and toxicities. METHODS: Eligible patients had measurable disease and adequate organ function. On day-14, patients commenced imatinib daily plus bevacizumab (5 mg/kg/2 weekly). Two weeks later (day 1), patients were also treated with full dose mFOLFOX6-bevacizumab for 12 cycles. Blood samples were taken for PK. DLTs defined in the first 6 weeks. Standard dose escalation of imatinib, with 3 patient cohorts: planned dose levels (DL): DL1; 400 mg, DL2; 600 mg, DL3; 800 mg daily. RESULTS: Ten patients enrolled. DL1 3 patients, DL2 7 patients. DLTs observed in 3 of 6 patients in DL2: febrile neutropenia (2); Grade 3 infection and Grade 4 neutropenia (1). Neutropenia was most frequent AEs: Grade 3/4 in >60 % of patients overall. In DL2 pts, imatinib clearance was reduced post-chemotherapy (P < 0.05). Oxaliplatin and 5FU PK unchanged by imatinib. CONCLUSIONS: MTD was imatinib 400 mg plus full dose mFOLFOX-bevacizumab. Dose escalation of imatinib limited by neutropenia. Further study is warranted as imatinib can be delivered at levels that inhibit PDGFR.

Association of hypomagnesemia with inferior survival in a phase III, randomized study of cetuximab plus best supportive care versus best supportive care alone: NCIC CTG/AGITG CO.17.

BACKGROUND: Cetuximab-induced hypomagnesemia has been associated with improved clinical outcomes in advanced colorectal cancer (CRC). We explored this relationship from a randomized clinical trial of cetuximab plus best supportive care (BSC) versus BSC alone in patients with pretreated advanced CRC. PATIENTS AND METHODS: Day 28 hypomagnesemia grade (0 versus ≥1) and percent reduction (<20% versus ≥20%) of Mg from baseline was correlated with outcome. RESULTS: The median percentage Mg reduction at day 28 was 10% (-42.4% to 63.0%) for cetuximab (N = 260) versus 0% (-21.1% to 25%) for BSC (N = 251) [P < 0.0001]. Grade ≥1 hypomagnesemia and ≥20% reduction from baseline at day 28 were associated with worse overall survival (OS) [hazard ratio, HR 1.61 (95% CI 1.12-2.33), P = 0.01 and 2.08 (95% CI 1.32-3.29), P = 0.002, respectively] in multivariate analysis including grade of rash (0-1 versus 2+). Dyspnea (grade ≥3) was more common in patients with ≥20% versus < 20% Mg reduction (68% versus 45%; P = 0.02) and grade 3/4 anorexia were higher in patients with grade ≥1 hypomagnesemia (81% versus 63%; P = 0.02). CONCLUSIONS: In contrast to prior reports, cetuximab-induced hypomagnesemia was associated with poor OS, even after adjustment for grade of rash.

The role of biological agents in the resection of colorectal liver metastases.

Surgically resecting liver metastases from colorectal cancer (CLMs) offers the only potentially curative option. Chemotherapy-induced downsizing of CLMs increases the proportion of patients with resectable metastases. Several recent studies have reported that adding a biological agent such as cetuximab, panitumumab or bevacizumab to chemotherapy could further increase response and resectability rates. This overview discusses the reported resection rates for biological agents combined with chemotherapy and the difficulties of cross-trial comparisons, the pre-, peri- and postoperative roles of biological agents, particularly with regards to comparisons of surgical complications, and ongoing clinical trials in which the resectability of CLMs is a predefined end point. Currently, targeted therapies combined with chemotherapy probably increase the resection rate of CLMs, although this has been shown in only one phase III randomised study and it is difficult to draw definitive conclusions about the relative efficacy and safety of the different available biological agents in terms of converting unresectable CLMs to resectable lesions. Available data for each of them are discussed. More data from phase III trials are expected to confirm the utility of the different biological agents in converting patients with unresectable CLMs to a resectable status.