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Quality of life data from randomized trials are lacking in older patients with metastatic colorectal cancer (mCRC). In the randomized NORDIC9-study, reduced-dose S1+oxaliplatin (SOx) showed superior efficacy compared to full-dose S1 monotherapy. We hypothesized that treatment with SOx does not result in inferior quality of life. Patients with mCRC aged ≥70 years and that were not a candidate for standard combination chemotherapy were included and randomly assigned to receive either S1 or SOx. The EORTC QLQ-C30 questionnaire was completed at baseline, after 9, and 18 weeks. The primary endpoint was global Quality of Life (QoL) at 9 weeks. For statistical analysis, a non-inferiority design was chosen applying linear mixed effects models for repeated measurements. The results were interpreted according to statistical significance and anchor-based, clinically relevant between-group minimally important differences (MID). A total of 160 patients aged (median (Interquartile range (IQR))) 78 years (76-81) were included. The QLQ-C30 questionnaire was completed by 150, 100, and 60 patients at baseline, at 9, and 18 weeks, respectively. The difference at 9 weeks in global QoL was 6.85 (95%CI-1.94; 15.65) and 7.37 (0.70; 14.05) in the physical functioning domain in favor of SOx exceeding the threshold for MID. At 18 weeks, the between-group MID in physical functioning was preserved. Dose-reduced combination chemotherapy may be recommended in vulnerable older patients with mCRC, rather than full-dose monotherapy.

Background MicroRNAs (miRs) are small non-coding RNAs. Circulating miRs in plasma are deregulated in patients with metastatic colorectal cancer (mCRC). The aim was to find prognostic circulating miRs for overall survival (OS) in patients with mCRC treated with chemotherapy and cetuximab. Methods A prospective biomarker study was conducted. A full plasma miR-panel was tested with TaqMan Human MicroRNA assay in 151 patients treated with 3rd line irinotecan and cetuximab (Discovery cohort, Biweekly study). Significant miRs were validated with Fluidigm arrays, in 95 patients, treated with 1st line chemotherapy and cetuximab (Validation cohort, NORDIC-7.5 study1). Cox regression analysis was conducted, and multivariate analyses performed with adjustment for sidedness, number of metastatic sites, RAS/BRAF mutation status, age and performance status. Consecutive samples after 3 months of treatment were available for 117 and 86 patients in the discovery and validation cohorts, respectively. Results Baseline high expression of miR-1247 in the discovery and validation cohorts, was significantly associated with short OS (hazard ratio [HR]) = 2.33, p = 0.0005) based on the multivariate analysis in the validation cohort. High miR-1290 expression after 3 months was prognostic for short progression free-survival (HR = 1.57, p = 0.0465) in both cohorts. In both cohorts, we found a statistically significant decrease in, miR-1290 (p = 0.0051), miR-200b (p = 0.036), and miR-375 (p = 0.00005), from baseline to 3 month-sample, in patients with partial/complete (n = 78) response compared to patients with progressive disease (n = 72). Conclusions High expression of miR-1247 was prognostic for short OS in the multivariate analysis in a discovery and validation cohort of patients treated with chemotherapy and cetuximab in both first and third line. A decrease in miR-1247 and miR-1290 during treatment was associated with favorable response. 1Pfeiffer et al, Clin Colorectal Cancer 2015. Legal entity responsible for the study Jakob Vasehus Scho. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background Cetuximab (cet) improves efficacy of first-line FOLFIRI in pts with RAS/RAFwt metastatic colorectal cancer (mCRC). Triplet chemotherapy improves efficacy further but with increased toxicity. Alternating FOLFIRI/FOLFOX is a different way to administer all 3 cytotoxic drugs. We report the updated results from Nordic 8, a multi-centre, randomised trial comparing cet with FOLFIRI (arm A) or with FOLFIRI alternating with FOLFOX (arm B). Methods In this investigator initiated randomised trial, 173 chemo-naive mCRC patients received cet with FOLFIRI or cet with FOLFIRI (2 cycles) alternating with FOLFOX until PD. Main inclusion criteria were PS 0 or 1, RASwt and ESMO group 1-3 (prior to April 2014 only ESMO group 1 when 36 patients had been included)). The primary endpoint was RR (increase from 60% to 75%) and secondary endpoints were PFS, OS and safety. All endpoints were evaluated by the local investigator. Results From May 2012 to May 2018, 173 patients were randomized. Median age was 64 years (25% were at least 70 years), female 34%, PS 0 61%, ESMO group 1/2/3 64%/23%/13%. Baseline characteristics were well-balanced between the two groups. Median duration of therapy was 6.2 months in both arms and patients received a median of 11 and 12 cycles, respectively, without any difference in dose-intensity. In arm A and B overall RR was 69% and 78% (p = 0.17), median PFS was 11.9 (arm A) and 11.8 months (arm B) (HR 1.10; p = 0.60), and median OS was 40.7 and 39.2 months (HR 1.05; p = 0.82), respectively. Most important grade ≥ 3 adverse events were neutropenia (15% vs 17%), rash (9% vs 15%), diarrhoea (7% vs 11%), fatigue (7% vs 7%), and febrile neutropenia (3% vs 1%); 20% in arm B experienced neuropathy grade 2 (no grade 3). Final and updated PFS and OS with sub-group analysis will be presented. Conclusions Cet every two weeks in combination with FOLFIRI or alternating FOLFIRI/FOLFOX is well tolerated with high RR and long OS. We recommend FOLFIRI + cet every 2 weeks in patients with RAS and BRAFwt mCRC. Clinical trial identification 2011-004188-65. Legal entity responsible for the study Nordic Biomodulation Group. Funding Merck. Disclosure C. Kersten: Research grant / Funding (institution), Licensing / Royalties, Relationship is unrelated to this study: Merck KGaA. All other authors have declared no conflicts of interest.

In metastatic colorectal cancer (mCRC) trials, median survival has increased from 6 months to above 20 months during the previous decades. Uncertainty exists in how this survival improvement has translated to the general mCRC population.Survival data from patients with synchronous mCRC were collected from the Norwegian (1980-2008), Swedish (1996-2008) and Danish (2001-09) cancer registries.A total of 29 628 patients were identified. From 1980-1985 to 2006-2008, median survival increased from 5 to 10 months for Norwegian patients. Three-year survival increased from 7% to 21% and 5-year survival from 4% to 9%. For patients60 years, median survival was doubled to 16 months, 3-year survival increased fourfold up to 28% and 5-year survival threefold up to 14%. Similar improvements were seen in Sweden and Denmark. In all countries, the improved outcome was seen especially for younger patients and much less for patients75 years of age.An increase in median and long-term survival over time was found in unselected population-based registries of patients with synchronous mCRC. The improved outcome in survival was especially seen in younger patients, raising concerns over our ability to adapt available treatment options for elderly patients.

BACKGROUND: The aim was to evaluate the association between plasma tissue inhibitor of metalloproteinase-1 (TIMP-1) and serum carcinoembryonic antigen (CEA) levels and outcome in patients with metastatic colorectal cancer (mCRC) receiving XELOX (combination chemotherapy with capecitabine and oxaliplatin) as first-line treatment. PATIENTS AND METHODS: One hundred and twenty patients were included. Blood samples were collected before treatment and 3 weeks later before the next treatment cycle. Plasma TIMP-1 and serum CEA levels were correlated to treatment outcome. RESULTS: No significant associations between baseline TIMP-1 or CEA levels and best response to treatment or progression-free survival (PFS) could be demonstrated. In contrast, high baseline plasma TIMP-1 levels were associated with poor overall survival (OS), P = 0.008, hazard ratio (HR) = 1.80 [95% confidence interval (CI): 1.17-2.78]. Furthermore, increase in TIMP-1 levels from baseline to immediately before the second cycle of chemotherapy had a significant negative effect on survival (P = 0.03, HR = 1.30, 95% CI: 1.02-1.65) while a decrease in TIMP-1 was significantly associated with a higher objective response rate (P = 0.03). Conclusions: Both high baseline and subsequent increase in TIMP-1 levels were associated with shorter OS in patients with mCRC receiving XELOX as first-line treatment, whereas baseline TIMP-1 levels were not associated with response or PFS following XELOX treatment.

Background: Reliable biomarkers in patients (pts) with pancreatic cancer (PC) are highly warranted. The aim of this prospective-retrospective biomarker study was to investigate the clinical value of cell-free DNA (cfDNA) in pts with PC.Methods: A total of 377 consecutive pts with histologically confirmed PC and 94 healthy controls were included. Total cfDNA levels were determined by a direct fluorescent assay in EDTA plasma samples obtained before operation (stage I and II) or start of palliative chemotherapy (stage III and IV). Serum CA19-9 (IMMULITE 2000, Siemens), hyaluronic acid (HA) (ELISA, R\amp;D), interleukin-6 (IL-6) (ELISA, R\amp;D) and YKL-40 (ELISA, Quidel) were measured. The main outcome was association of cfDNA with overall survival (OS) for pts with PC. Hazard ratios (HRs) and 95\% confidence intervals (CIs) were estimated by Cox proportional hazards regression.

Background: Most patients (pts) with mCRC are older than 70 years, but they are underrepresented in clinical trials. NORDIC9 evaluated efficacy of palliative treatment strategies based on S-1, which has previously demonstrated less toxicity but similar efficacy as 5FU, and here we present initial results.Methods: Older mCRC pts (≥70 years) who were not candidates for full-dose combination therapy, were randomized to full-dose monotherapy (Arm A: S-1 30 mg/m2 po bid d 1-14 q3w, followed by irinotecan upon progression) or reduced (80\ combination therapy (Arm B: S-1 20 mg/m2 po bid d 1-14 + oxaliplatin 100 mg/m2 iv d 1 q3w, followed by S-1 + irinotecan q3w). Addition of bevacizumab (7.5 mg/kg iv d 1) before randomization was optional. Geriatric screening tools (G-8, VES-13, handgrip strength, Timed-Up-and-Go), Charlson Comorbidity Index and quality of life were evaluated at baseline. Blood samples and tumor tissue were prospectively collected. Primary endpoint was PFS. Secondary endpoints were response rate, survival and correlations between screening tools, efficacy and safety.

BACKGROUND: Preclinically, protein kinase C and AKT activation can be inhibited by enzastaurin and reduce tumor growth of colorectal cancer cells. In asymptomatic patients with metastatic colorectal cancer (mCRC), enzastaurin activity was evaluated by measuring the 6-month progression-free survival (PFS) rate in a window study design. PATIENTS AND METHODS: Chemonaive patients with asymptomatic mCRC who did not require immediate chemotherapy-induced tumor reduction received a 400-mg thrice daily loading dose of enzastaurin on day 1 of cycle 1, followed by 500 mg once daily for the remaining 28-day cycles. Progression was assessed on the basis of radiographic imaging, rise in carcinoembryonic antigen or lactate dehydrogenase (LDH) levels or by appearance of clinical symptoms. RESULTS: Twenty-eight patients received daily enzastaurin. The 6-month PFS rate was 28% [95% confidence interval (CI) 13%-45%] and median PFS was 1.9 months (95% CI 1.8-4.5 months). Twelve (43%) patients had stable disease with a median duration of 6.1 months. The survival rate at 20 months was 77% (95% CI 47%-92%). No grade 4 toxicity was reported and grade 3 toxic effects were observed in three patients with one patient showing probable drug-related elevation of liver transaminases. CONCLUSION: The window design in asymptomatic patients with mCRC can be safely applied to assess the activity and safety of novel cytostatic agents like enzastaurin.

Udgivelsesdato: 2009-Jul-21 BACKGROUND: Chronotherapy is one of the several approaches to increase efficacy and reduce toxicity of chemotherapy. In a phase II study in the second-line in patients with metastatic colorectal cancer (mCRC), we found that chronomodulated XELOX (XELOX(30Chron)) was a well-tolerated regimen with potentially reduced toxicity. PATIENTS AND METHODS: One hundred and forty-one patients with unresectable mCRC were enrolled in a randomized study comparing standard XELOX (XELOX(30)), arm A, and XELOX(30Chron), arm B-both with short-time infusion of oxaliplatin-with the primary aim of reducing overall toxicity. RESULTS: Overall toxicity grade 2-4 was 90% versus 85%, P = 0.47 and grade 3-4 was 31% versus 37%, P = 0.6 in arm A and B, respectively. We found no significant differences in median overall survival (17.6 versus 15.5 months; P = 0.068) and median progression-free survival (8.9 versus 8.8 months; P = 0.7). The incidence of grade 3 neuropathy was 16% in arm A and 19% in arm B (P = 0.7) after a cumulative dose of oxaliplatin of 1000 mg/m(2). CONCLUSION: XELOX(30Chron) does not reduce toxicity or improve efficacy. A 30-min infusion of oxaliplatin is safe and does not increase the severity of chronic neuropathy.

Udgivelsesdato: 2008-Jun BACKGROUND: Oxaliplatin in combination with capecitabine prolongs survival in patients with metastatic colorectal cancer (mCRC). Chronomodulation might reduce toxicity and improve efficacy. PATIENTS AND METHODS: A phase II study examining chronomodulated XELOX(30) (XELOX(30chron)): oxaliplatin: 130 mg/m(2) on day 1, as a 30-min infusion between 1 and 3 p.m. Capecitabine: total daily dose of 2000 mg/m(2), 20% of the dose between 7 and 9 a.m. and 80% of the dose between 6 and 8 p.m. in patients with mCRC resistant to irinotecan. Seventy-one patients were enrolled. Response rate was 18%; median progression-free survival 5.1 months and median overall survival (OS) 10.2 months. Platelet count and performance status were significantly correlated to OS in multivariate analyses. Neurotoxicity grade 2 and 3 was seen in 25% and 2% of patients, respectively, other grade 3 toxic effects were as follows: nausea 6%, vomiting 3%, diarrhoea 12% (3% experienced grade 4) and palmoplantart erytem 9%. CONCLUSION: XELOX(30chron) is a convenient second-line regimen with efficacy and safety profile similar to other oxaliplatin schedules. To further investigate chronomodulated XELOX, we have started a Nordic randomised phase II study comparing XELOX(30) and XELOX(30chron) as first-line therapy in patients with mCRC.

Udgivelsesdato: 2008-May BACKGROUND: To compare irinotecan with the Nordic 5-fluorouracil (5-FU) and folinic acid (FA) bolus schedule [irinotecan 180 mg/m(2) on day 1, 5-FU 500 mg/m(2) and FA 60 mg/m(2) on day 1 and 2 (FLIRI)] or the Lv5FU2 schedule [irinotecan 180 mg/m(2) on day 1, FA 200 mg/m(2), 5-FU bolus 400 mg/m(2) and infused 5-FU 600 mg/m(2) on day 1 and 2 (Lv5FU2-IRI)] due to uncertainties about how to administrate 5-FU with irinotecan. PATIENTS AND METHODS: Patients (n = 567) with metastatic colorectal cancer were randomly assigned to receive FLIRI or Lv5FU2-IRI. Primary end point was progression-free survival (PFS). RESULTS: Patient characteristics were well balanced. PFS did not differ between groups (median 9 months, P = 0.22). Overall survival (OS) was also similar (median 19 months, P = 0.9). Fewer objective responses were seen in the FLIRI group (35% versus 49%, P = 0.001) but the metastatic resection rate did not differ (4% versus 6%, P = 0.3). Grade 3/4 neutropenia (11% versus 5%, P = 0.01) and grade 2 alopecia (18% versus 9%, P = 0.002) were more common in the FLIRI group. The 60-day mortality was 2.4% versus 2.1%. CONCLUSIONS: Irinotecan with the bolus Nordic schedule (FLIRI) is a convenient treatment with PFS and OS comparable to irinotecan with the Lv5FU2 schedule. Neutropenia and alopecia are more prevalent, but both regimens are equally well tolerated.

The efficacy of oxaliplatin combined with capecitabine (XELOX) as second-line therapy in patients with advanced colorectal cancer (ACRC) resistant to irinotecan is not well established. Oxaliplatin induces acute, cold-induced neuropathy in most patients. The incidence is claimed to be infusion rate-dependent and therefore a 2-h infusion is recommended.For practical and economic reasons, but also for patient's convenience, we performed a phase II study to examine XELOX30 (capecitabine 1000 mg/m2 orally twice daily on days 1-14 and oxaliplatin 130 mg/m2 as a 30 min infusion on day 1) in patients with ACRC resistant to irinotecan. In addition the pharmacokinetics of oxaliplatin was studied.From November 2002 to September 2003, 70 patients with ACRC were treated with XELOX30. Median age was 62 (range 33-74 years) years and median performance status was 1 (range 0-2). The median number of courses was four (range 1-12) and median cumulative dose of oxaliplatin was 530 (range 125-1560) mg/m2. The response rate was 17% (95% CI 10-23), median time to progression (TTP) was 5.4 months (95% CI 4.6-6.4) and median survival 9.5 months (95% CI 8.5-11.2). White blood cell count (WBC) and performance status were significantly correlated to TTP. Neurotoxicity was moderate: grade 1 56%, grade 2 17% and grade 3 6%. Other grade 3 toxicities were nausea/vomiting 9%, diarrhoea 14% and PPE 8%. The maximum blood concentration and total body clearance of oxaliplatin was higher than previously reported in studies examining 2-h infusions, but the volume of distribution and terminal half-life was in close agreement with previous results.XELOX30 is a very convenient second-line regimen in ACRC with an activity and safety profile similar to other oxaliplatin schedules.

NORDIC9 : A randomized phase II trial exploring treatment of older patients with metastatic colorectal cancer (mCRC) by comparing full dose monotherapy (S-1 followed by irinotecan) with reduced combination regimen (S-1/oxaliplatin followed by S-1/irinotecan)

e15725Background: Locally advanced pancreatic cancer (LAPC) is often a mix of borderline and never-resectable tumors. Multimodality treatment might downstage these tumors to allow a potential radic...

Aim: Regional and hospital payers increasingly require analyses assessing the cost-benefit profile of new drugs. This analysis evaluates the cost profile in Nordic countries of nano albumin-bound paclitaxel (nab-paclitaxel [nab-P]) in pancreatic cancer vs other drugs per gained month in OS and PFS in high-unmet need solid tumour indications. Methods: Trial data on solid tumour therapies (comparator, treatment duration, PFS, OS) was retrieved from the European Medicine Agency (EMA) website. Total drug costs were calculated from ex-manufacturer prices without local discounts, using minimization of wastage and costs, and multiplying each drug cost by its maximum number of cycles or until disease progression, according to posology indications. Costs per month of OS and PFS achieved (dividing total drug costs by OS and PFS months, respectively) were evaluated for a selection of drugs: (1) trials for first-line metastatic cancer or noncurable treatment intention patients; (2) approved by EMA after 2000; (3) indicated in high-unmet need tumours (defined as OS for trial comparator ≤ 12 mo). Results: Results for the OS analysis are shown on the table: In all countries, a good correlation between costs per OS month and relative benefit vs trial comparator was observed. Similar correlation was found for the PFS analysis. Conclusions: The most recently approved drug, nab-P in pancreatic cancer, showed a similar cost per OS or PFS month ratio compared with other drugs for high-unmet need solid tumours. Drug Indication (year of EMA approval) Relative OS Gain vs Trial Comparator Total Drug Cost per OS Month (e) Norway Denmark Finland Sweden nab-P Pancreas (2014) 27% 1407 1697 2003 2280 Pemetrexed Mesothelioma (2004) 30% 1875 1886 1991 2064 Bevacizumab Lung (2007) 19% 1810 1531 1620 1722 Cetuximab Head and neck (2004) 36% 3036 2865 2828 2972 Trastuzumab Stomach (2009) 24% 1743 1008 1786 1945 Erlotinib Pancreas (2006) 7% 1119 870 1209 950 Tegafur/gimeracil/ oteracil (Teysuno S-1) Stomach (2011) 9% 264 236 185 249 Temsirolimus Kidney (2007) 49% 1736 1315 1411 1539 Vemurafenib Melanoma (2012) 40% 5864 4700 4814 4,919 Ipilimumab Melanoma (2011) 67% 8741 6725 6964 7248 Disclosure: P. Osterlund: No financial disclosures, panelist on the Metastatic pancreatic cancer webcast for Celgene in April 2014; P. Pfeiffer: No financial disclosures, chairman on the Metastatic pancreatic cancer webcast for Celgene in April 2014; R. Smaaland: Rune Smaaland has no financial disclosures. He has been in the scientific panel on the Metastatic pancreatic cancer webcast for Celgene in April 2014; F. Rodrigues: Employment or leadership position and stock ownership, Celgene; G. Furneri: No financial disclosures, panelist on the Metastatic pancreatic cancer webcast for Celgene in April 2014; Consulting fees from Celgene.

Aim: Small fractions of cell-free DNA (cfDNA) can be quantified from blood samples, is a mixture of DNA from malignant and normal cells, and can be used as a liquid biopsy to detect and quantify tumor specific hotspot mutations such as KRAS. We investigated the total cfDNA and the tumor specific circulating DNA with KRAS mutations in plasma from patients with metastatic colorectal cancer (mCRC) treated with third line cetuximab and irinotecan. Methods: Patients with histopathologically verified mCRC and adequate PS and organ function were included. All patients were resistant to 5-FU, oxaliplatin and irinotecan and treated with 3rd line irinotecan (180 mg/m2) and cetuximab (500 mg/m2) every second week in a prospective phase II study until disease progression or unacceptable toxicity. Plasma was obtained from a pre-treatment EDTA blood-sample, and the total cfDNA and plasma mutations were quantified by an in-house qPCR method. Quantitative levels of cfDNA were analyzed in relation to clinical data, and to tumor volume as estimated from pretreatment PET-CT. Results: Ninety-five patients were included. There was a significantly higher PFS and OS in patients with low levels of cfDNA, and decreasing median survival with increasing number of alleles. The OS in patients with total cfDNA in the lowest quartile was 17,0 months (95% CI 12.7 -19,8 months ) and 12,1 months (9.6–13,4 ), 9,2 months (6,9 -14,0) and 6,9 months (4,3–8,6) in the higher, respectively (p = 0.0001). The HR for patients with cfDNA levels above the 75% quartile indicated a strong detrimental effect on survival in this group of patients. The rate of tumor KRAS mutation (Exon 2) in this cohort was 34%, and a total of 30 patients had detectable plasma KRAS mutations. The levels of total cfDNA and tumor KRAS mutational alleles in the plasma were strongly correlated (spearman rank 0.88, p = 0.0001). Studies investigating the correlation of both total cfDNA and number of mutated alleles to tumor volume as estimated from PET-CT scans are on-going. Conclusions: The present study confirms a strong prognostic value of circulating DNA, and correlation between tumor and plasma KRAS. The results of relation to tumor volume will be presented at the meeting. Disclosure: All authors have declared no conflicts of interest.

Aim: Cetuximab produce a range of commonly occurring side effects like cutaneous folliculitis. The physical and psychosocial discomfort might lead to interruption of treatment, dose modification or poor compliance. It is therefore important to effectively reduce these side effects as much as possible. Vitamin K3 (menadione) has preclinically shown to be a potential activator of the Epidermal Growth Factor Receptor (EGFR) by phosphorylating the receptor. The present study investigated the effect of a vitamin K3 lotion on cetuximab induced folliculitis. Methods: From May 2010 to May 2012 30 patients (pts) was included in a double-blinded randomised placebo controlled phase II trial. Pts receiving biweekly cetuximab 500 mg/m2 in combination with chemotherapy for metastatic cancer were included. Treatment with vitamin K3 lasted up to two months and was followed up 14 days after end of treatment. On each patient two areas (truncus or face) of 10x10 cm was selected. Each area was applied with either placebo or vitamin K3 lotion twice daily. Folliculitis was monitored by clinical photos every second week, registered according to CTCAE 4.0 and assessed by the patient. Systemic tetracycline but not topical prednisolone was allowed. Ten pts volunteered to have skin biopsies taken before and after one month of treatment from each treatment area. Biopsies were stained for p27, EGFR and p-EGFR. Results: Mean number of inflamed follicles was 4.9 (placebo) vs. 5.1 (K3) at baseline (p = 0.9), increasing to 11.1 (placebo) vs. 14.1 (K3) at two weeks (p = 0.5), and declining to 8.9 (placebo) vs. 7.3 (K3) at 4 weeks (p = 0.7). In fact, at any time point during the study there was no significant difference between placebo and vitamin K3 areas within 18 evaluable pts. No severe toxicity was observed. For skin biopsies, no difference in staining pattern or intensity of proliferation marker p27, EGFR or p-EGFR expression was observed. Furthermore, no subjective difference in skin toxicity between placebo and vitamin K3 areas was reported. Conclusions: We found no clinical objective or subjective benefit and no histologic difference after 4 weeks application of vitamin K3 or placebo lotion. Our results do not support the use of topical vitamin K3 for cetuximab-induced folliculitis. Disclosure: All authors have declared no conflicts of interest.

Long-term follow-up of chemonaive patients with asymptomatic metastatic colorectal cancer treated with enzastaurin in a window of opportunity phase II study

Age dependent increase in median and long-term survival in 29 628 metastatic colorectal cancer (mcrc) scandinavian patients during the past two decades