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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.

Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients with KRAS wild-type tumours still do not respond. We studied the effect of other downstream mutations on the efficacy of cetuximab in, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre-KRAS selection era.1022 tumour DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from patients treated with cetuximab between 2001 and 2008 were gathered from 11 centres in seven European countries. 773 primary tumour samples had sufficient quality DNA and were included in mutation frequency analyses; mass spectrometry genotyping of tumour samples for KRAS, BRAF, NRAS, and PIK3CA was done centrally. We analysed objective response, progression-free survival (PFS), and overall survival in molecularly defined subgroups of the 649 chemotherapy-refractory patients treated with cetuximab plus chemotherapy.40.0% (299/747) of the tumours harboured a KRAS mutation, 14.5% (108/743) harboured a PIK3CA mutation (of which 68.5% [74/108] were located in exon 9 and 20.4% [22/108] in exon 20), 4.7% (36/761) harboured a BRAF mutation, and 2.6% (17/644) harboured an NRAS mutation. KRAS mutants did not derive benefit compared with wild types, with a response rate of 6.7% (17/253) versus 35.8% (126/352; odds ratio [OR] 0.13, 95% CI 0.07-0.22; p0.0001), a median PFS of 12 weeks versus 24 weeks (hazard ratio [HR] 1.98, 1.66-2.36; p0.0001), and a median overall survival of 32 weeks versus 50 weeks (1.75, 1.47-2.09; p0.0001). In KRAS wild types, carriers of BRAF and NRAS mutations had a significantly lower response rate than did BRAF and NRAS wild types, with a response rate of 8.3% (2/24) in carriers of BRAF mutations versus 38.0% in BRAF wild types (124/326; OR 0.15, 95% CI 0.02-0.51; p=0.0012); and 7.7% (1/13) in carriers of NRAS mutations versus 38.1% in NRAS wild types (110/289; OR 0.14, 0.007-0.70; p=0.013). PIK3CA exon 9 mutations had no effect, whereas exon 20 mutations were associated with a worse outcome compared with wild types, with a response rate of 0.0% (0/9) versus 36.8% (121/329; OR 0.00, 0.00-0.89; p=0.029), a median PFS of 11.5 weeks versus 24 weeks (HR 2.52, 1.33-4.78; p=0.013), and a median overall survival of 34 weeks versus 51 weeks (3.29, 1.60-6.74; p=0.0057). Multivariate analysis and conditional inference trees confirmed that, if KRAS is not mutated, assessing BRAF, NRAS, and PIK3CA exon 20 mutations (in that order) gives additional information about outcome. Objective response rates in our series were 24.4% in the unselected population, 36.3% in the KRAS wild-type selected population, and 41.2% in the KRAS, BRAF, NRAS, and PIK3CA exon 20 wild-type population.While confirming the negative effect of KRAS mutations on outcome after cetuximab, we show that BRAF, NRAS, and PIK3CA exon 20 mutations are significantly associated with a low response rate. Objective response rates could be improved by additional genotyping of BRAF, NRAS, and PIK3CA exon 20 mutations in a KRAS wild-type population.Belgian Federation against Cancer (Stichting tegen Kanker).

Background: Clinical trials in metastatic colorectal cancer (mCRC) have shown few patients with microsatellite instable high (MSI-H) tumors and BRAF mutations (mutBRAF). Recent data show that patients with MSI-H tumors benefit from immunotherapy and there are promising data of adding BRAF inhibitors to standard treatment in patients with mutBRAF. It is therefore important to know the frequency of these molecular changes and their importance for outcome in unselected populations of mCRC. Methods: A prospectively collected population-based cohort of 798 mCRC patients from three geographic areas in Scandinavia was studied. Gene analysis was available for 446 cases for BRAF and KRAS analysis, MSI analysis was done for mutBRAF only. Immunohistochemistry was performed for BRAF and MMR in 611 patients. Kaplan-Meier method, logistic regression and Cox proportional hazards models were used for statistical analyses. Results: Totally 8 % (46/589 patients) were MSI-H and 20 % (119/586 patients) were mutBRAF. MSI-H tumours harboured mutBRAF in 76 % of cases and 29 % of mutBRAF was MSI-H. MSI-H correlated to female sex, age >75 years, right-sided tumor, mutBRAF, lymph node metastasis and less often lung and liver metastasis. Patients with MSI-H received less often chemotherapy compared to MSS patients; 46 % vs. 64 % received 1st line, 13 % vs. 38 % received 2nd line and 2 % vs. 17 % received 3rd line chemotherapy, respectively. Patients with MSI-H had poorer prognosis, however only significant in BRAF wildtype (wtBRAF) patients, and the negative prognostic potential of mutBRAF was only valid in MSS tumors. Median overall survival (OS) was 4 months in MSI-H vs. 11 months in MSS tumors (p < 0.001). After multivariate analysis of OS in patients given 1st line chemotherapy MSI-H and mutBRAF was independent poor prognostic factors with HR 2.2 (95 % CI: 1.09, 4.60, p = 0.028) and HR 1.9 (95 % CI: 1.24, 2.97, P = 0.004) respectively. Median progression-free survival (PFS) during 1st line chemotherapy was 4 months for MSI-H vs. 8 months for MSS tumors (p = 0.087), and multivariate analysis of PFS showed HR 2.21 (95 % CI: 1.10, 4.44, p = 0.027). MSI-H and wtBRAF patients (n=10) had the worst prognosis with median OS of 1 month (p Conclusion: In unselected patients with mCRC, MSI-H and mutBRAF are more common than previously reported, and consequently more patients could benefit from immunotherapy and BRAF inhibitor treatments. Most MSI-H patients harbored mutBRAF (non-Lynch) in contrast to patients in recent mCRC immunotherapy trials, and further studies are needed to evaluate the effect of immunotherapy in this subgroup. Chemotherapy had minimal effect in MSI-H patients and fewer received 2-line palliative chemotherapy indicating that these patients could be considered for immunotherapy as 1st line treatment. Citation Format: Kristine Aasebø, Anca Dragomir, Magnus Sundström, Per Pfeiffer, Per-Henrik Edqvist, Geir Eide, Fredrik Ponten, Camilla Qvortrup, Bengt Glimelius, Halfdan Sørbye. Consequences of a high incidence of microsatellite instability (non-Lynch) and BRAF mutated tumors in a population based cohort of metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2610.

Results of continuous sunitinib, in combination with cetuximab and irinotecan every other week (SIC) for compassionate use in heavily pre-treated patients with mCRC are presented.Patients with mCRC resistant to oxaliplatin, irinotecan, 5-FU and cetuximab received SIC at two Danish oncologic departments. The regimen consisted of sunitinib given as a continuous-dosing in combination with cetuximab and irinotecan every other week (CetIri). The first six patients started with a daily oral dose of sunitinib of 12.5 mg. Subsequent patients started at a daily dose of 25 mg with the possibility to escalate to 37.5 mg.Twenty-nine patients received SIC. No patient had an objective response, but 13 patients had subjective relief and 42% had stable disease. The median time to progression was 3.2 months and median overall survival was 7.4 months. Fatigue and leukopenia were the most frequently reported severe adverse event (18% grade 3 and 18% grade 3/4, respectively).Sunitinib continuous-dosing with 25 mg/day can safely be combined with CetIri administered every other week.

e15587Background: Podocalyxin-like 1 (PODXL) is an anti-adhesive transmembrane protein associated with an aggressive tumor phenotype and poor prognosis in numerous malignancies, including colorecta...

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.

707 Background: Special AT-rich sequence binding protein 1 (SATB1) is a transcription factor involved in global gene regulation. SATB1 expression has been associated with poor prognosis in numerous cancer forms, including colorectal cancer (CRC). The value of SATB1 expression in metastatic CRC (mCRC) has, however, not yet been described. The aim was to evaluate the expression and prognostic significance of SATB1 in mCRC. Methods: SATB1 expression was analysed by immunohistochemistry in tissue microarrays with tumors from a prospective cohort with 454 mCRC patients from three Nordic countries. Cox regression proportional hazards models were applied to assess the impact of SATB1 expression on overall survival (OS); in the entire cohort, and in strata per chemotherapy and mutational status. Results: Among the 454 evaluable cases, 144 (32%) were positive and 310 (68%) were negative for SATB1 expression. Positive SATB1 expression was significantly more frequent in cases with lung metastases (41% vs 29%, p = 0.018), but did not correlate with other sites of distant metastasis. SATB1 expression (positive vs negative) was not prognostic in the entire cohort. The prognostic value of SATB1 did not differ between patients receiving palliative treatment (n = 281) and untreated patients (n = 178), and did not differ in relation to type of chemotherapy. In patients with BRAF wild type tumors, SATB1 expression was significantly associated with prolonged OS, whereas the opposite was seen in BRAF mutated tumors (hazard ratio = 0.77 vs 1.60, p for interaction = 0.005). SATB1 expression was significantly associated with prolonged OS in patients with KRAS mutated tumors (hazard ratio = 0.68), but not in KRAS wild type tumors, and there was no significant prognostic interaction between SATB1 expression and KRAS status. The prognostic value of SATB1 expression did not differ by tumor location. Conclusions: The prognostic value of SATB1 expression in mCRC appears to depend on the mutational status of the tumors, in particular BRAF. The potential value of SATB1 expression as a predictive biomarker for targeted therapies merits further investigation.

267 Background: Interleukin-6 (IL-6) and YKL-40 (CHI3L1) are produced by pancreatic cancer (PC) cells and macrophages and activate inflammation. The aim of this prospective-retrospective biomarker study was to determine the prognostic value of serum IL-6 and YKL-40 and systemic inflammatory response in patients with PC receiving palliative chemotherapy. Methods: 625 patients with PC (M/F: 283/342; age 4.92 pg/ml, for CA19-9 > 2183 U/ml and for YKL-40 > 95% age-corrected percentile. The main outcome was overall survival (OS) and hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were computed using Cox proportional hazards regression. Results: 598 (95.7%) patients died during follow-up. In univariate analysis elevated IL-6 (HR 1.93, 95% CI 1.63-2.28) and elevated YKL-40 (HR 1.74, 95% CI 1.47-2.05) were associated with short OS. Similar results were found if IL-6 and YKL-40 were included as continuous log2-transformed variables. Multivariable analysis showed that elevated IL-6 (HR 1.61, 95% CI 1.33-1.94), elevated YKL-40 (HR 1.36, 95% CI 1.13-1.64), elevated CA19-9 (HR 1.30, 95% CI 1.09-1.56), higher PS (1 vs. 0; HR 1.46, 95% CI 1.21-1.77 and PS 2 vs. 0; HR 2.73, 95% CI 2.08-3.58) and stage 4 vs. 3 (HR 1.79, 95% CI 1.44-2.24) were independently associated with a poor OS. In a subgroup of 386 patients with available laboratory data, higher C-reactive protein (HR 1.20, 95% CI 1.13-1.26), white blood cells (HR 1.41, 1.17-1.71) and absolute neutrophils count (HR 1.35, 95% CI 1.15-1.59) log2-transformed and adjusted for age, sex, PS, CA 19-9 and stage were associated with short OS. Conclusions: Serum IL-6, YKL-40 and CA19-9 along with CRP, WBC and ANC are independent prognostic biomarkers in patients with unresectable PC.

838 Background: Chemotherapy treatment of Colorectal Cancer, often include 5-Fluorouracil (5- FU). 5-FU inhibits the enzyme thymidylate synthase (TS), stopping the supply of thymidine for DNA synthesis. 5-FU is always combined with a folate, which enhances the 5-FU effect. Marketed folates such as LV/L-LV are prodrugs needing enzymatic conversion. Modufolin is the natural, biologically active form of the folates and is expected to be efficacious in a larger proportion of patients with less inter- and intra-individual variability Methods: ISO-CC-005 is a multi-center, phase I/II study in mCRC patients eligible for 5-FU/folate therapy alone or in combination with irinotecan or oxaliplatin ± bevacizumab. The study investigates safety and tolerability of Modufolin at 4 dose levels by analysing the number and severity of AEs, SAEs and DLTs. Efficacy is evaluated as ORR after four cycles of chemotherapy. Gene expression, deoxyuridine levels as an indirect marker of TS inhibition and time to death is also investigated. Three to six patients per cohort are included. All receives Modufolin twice every two weeks during at least four cycles of chemotherapy. Results: Today, 42 patients have been enrolled and 40 have initiated treatment. 13 are 1st line patients, 16 are in 2nd line, 10 are in 3rd line and 1 is in 5th treatment line. 19 SAEs have been reported in 12 patients, 3 of these were judged as at least possibly related to Modufolin. No SAE were judged as solely related to Modufolin. 31 patients have today been evaluated for efficacy. ORR 1st line patients (n=12) All 50% (6 PR, 6 SD) Patients with Modufolin dose ≥60 mg/m2 71% (5 PR, 2 SD) Patients with Modufolin dose ≥60 mg/m2 + oxaliplatin 100% (3 PR) Conclusions: The lack of need for metabolic activation makes Modufolin a better candidate than LV/L-LV for improved outcome of 5-FU-based chemotherapy regimens in mCRC. The ISO-CC-005 study evaluates Modufolin in combination with 5-FU, irinotecan, oxaliplatin ± bevacizumab in mCRC patients in 4 countries in Europe. The results, so far, for both safety and efficacy seems promising. Clinical trial information: NCT02244632.

Colorectal cancer (CRC) affects nearly 1.4 million new patients each year worldwide.1 The treatment algorithm for local or locally advanced colon and rectal cancer (RC), and also for patients with never-resectable metastases, is well established.2–4 However, the optimal strategy in patients with synchronous metastasis is more controversial and, especially in patients with RC, several modalities must be combined to achieve the most favorable outcome. Before the introduction of total mesorectal excision (TME) a local recurrence was frequently seen in 30–40% of patients with locally advanced RC.5 Neoadjuvant long-course chemo-radiation (LC-CRT) or short-course radiotherapy (SC-RT) followed by appropriate TME has reduced local recurrence (LR) rates to 5% or even less as shown not only in randomized trial with selected patients but also in population cohorts.6,7 However, the role and timing of neoadjuvant radiation is less well defined in patients presenting with synchronous metastasis. Randomized studies have focused on one treatment modality (e.g. preoperative LC-CRT or SC-RT in patients with resectable RC or chemotherapy in the setting of widespread nonresectable metastatic disease) but the sequence of different modalities (surgery, chemotherapy, and radiation) has not been studied in a randomized strategy trial. Based on lack of consensus regarding the optimal sequence of surgery, systemic therapy and radiotherapy for patients with stage 4 RC treated with curative intent, a ‘multidisciplinary session: synchronous liver metastases in RC: which treatment first?’ was organized by the European Society for Medical Oncology (ESMO) and presented during the ESMO 2017 conference in Madrid, Spain. Three distinct lectures focused on the radiation therapy perspective, the surgical oncology perspective, and the medical oncology perspective. The present paper is a summary of those three lectures with focus on a multidisciplinary approach and with an update on recent literature.

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.

IntroductionTotal mesorectal excision (TME) is the highly effective standard treatment for rectal cancer but is associated with significant morbidity and may be overtreatment for low-risk cancers. This study is designed to determine the feasibility of international recruitment in a study comparing organ-saving approaches versus standard TME surgery.Methods and analysisSTAR-TREC trial is a multicentre international randomised, three-arm parallel, phase II feasibility study in patients with biopsy-proven adenocarcinoma of the rectum. The trial is coordinated from Birmingham, UK with national hubs in Radboudumc (the Netherlands) and Odense University Hospital Svendborg UMC (Denmark). Patients with rectal cancer, staged by CT and MRI as ≤cT3b (up to 5 mm of extramural spread) N0 M0 can be included. Patients will be randomised to either standard TME surgery (control), organ-saving treatment using long-course concurrent chemoradiation or organ-saving treatment using short-course radiotherapy. For patients treated with an organ-saving strategy, clinical response to (chemo)radiotherapy determines the next treatment step. An active surveillance regime will be performed in the case of a complete clinical regression. In the case of incomplete clinical regression, patients will proceed to local excision using an optimised platform such as transanal endoscopic microsurgery or other transanal techniques (eg, transanal endoscopic operation or transanal minimally invasive surgery). The primary endpoint of this phase II study is to demonstrate sufficient international recruitment in order to sustain a phase III study incorporating pelvic failure as the primary endpoint. Success in phase II is defined as randomisation of at least four cases per month internationally in year 1, rising to at least six cases per month internationally during year 2.Ethics and disseminationThe medical ethical committees of all the participating countries have approved the study protocol. Results of the primary and secondary endpoints will be submitted for publication in peer-reviewed journals.Trial registration numberISRCTN14240288, 20 October 2016. NCT02945566; Pre-results, October 2016.

Udgivelsesdato: 2008-Aug-26 Epirubicin, cisplatin and continuous infusion of 5-FU is a widely used palliative regimen in patients with gastric cancer. If cisplatin is substituted by oxaliplatin and 5-FU by capecitabine this regimen can be administered in the outpatient setting. Dose-limiting toxicity of oxaliplatin is peripheral sensory neuropathy and it is recommended to give oxaliplatin as a 120 min infusion. However, in patients with colorectal cancer a 30 min infusion of oxaliplatin can safely be administered without increasing neurotoxicity, standard infusion time is 30 min at our departments. In our phase I study the recommended doses of EXE was established (Dupont et al, 2006). Patients with non-resectable gastric adenocarcinoma were eligible. Patients received EXE (epirubicin 50 mg m(-2) day 1; capecitabine 1000 mg m(-2) day(-1) continuously and oxaliplatin 130 mg m(-2) day 1) as outpatient therapy every third week for a maximum of 8 cycles. From June 2004 to September 2005, we enroled 54 patients. Median age was 60 years (31-74 years) Median number of courses was 6 (1-8). Response rate was 45%. Median PFS was 6.8 (5.2-7.9) months and median survival was 10.1 (7.9-11.1) months. Most important grade 3 toxicities were as follows: nausea, vomiting, and diarrhoea (6%). Neurotoxicity grade 2 was seen in 36.5%. We therefore conclude, that EXE every third week is a convenient regimen that easily can be administrated in the outpatient setting but the regimen needs further evaluation in a phase III study.British Journal of Cancer advance online publication, 26 August 2008; doi:10.1038/sj.bjc.6604569 www.bjcancer.com.

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.

Udgivelsesdato: 2008-null Background. Preoperative radiochemotherapy is a cornerstone in patients with non- resectable locally advanced rectal cancer (LARC). To improve outcome (number of R0 resections and survival) high-dose radiotherapy (RT) was combined with oral UFT/l-leucovorin to allow tumour regression before radical intended surgery. Methods. Pelvic RT was delivered with megavoltage photons using a 5 field technique. RT was CT-based, given 5 days a week through one posterior field and two lateral fields (48.6 Gy/27 fractions) to encompass the primary tumour and the regional lymph nodes. In addition, the tumour bed received a concurrent boost (5.4 Gy/27 fractions) and a final boost (6 Gy/3 fractions); thus GTV received 60 Gy/30 fractions. Concurrent with RT patients received a daily dose of oral UFT 300 mg/m(2) plus l-leucovorin 22.5 mg 5/7days (divided in three doses). Results. From September 2000 to November 2004, 52 patients (median age 60 years (32-83); median PS 0 (0-2)) with LARC (36 primary, 16 recurrent) were included in this phase II study. All but three patients received the planned 60 Gy, median duration of RT was 42 days (25-49). Toxicity was very modest; only four patients had a dose reduction of UFT. No hematological toxicity of clinical significance was seen. Non-hematological toxicity grade 1 (GI-toxicity, fatigue and/or dysuria) was frequently observed but only four patients experienced grade 3 toxicity (diarrhoea and/or nausea/vomiting). Forty patients (77%) were operated (30 R0, 5 R1, 5 R2) median 55 days (27-112) after completion of RT. Seven (13%) patients had a pathological complete response (pCR). Thirty-one patients (60%) died after median 25.4 months (1.6-45.2 months). Twenty-one patients (40%) are still alive June 2007. Conclusions. Preoperative high-dose RT and concomitant UFT produces major regression in most patients with non-resectable LARC and thus a good chance of cure.

Udgivelsesdato: 2007-May-28 In less than 10 years, the number and importance of non-surgical treatment modalities in patients with colorectal cancer (CRC) have increased dramatically, both in the adjuvant and the advanced settings. However, despite the improvement of cytotoxic therapy in CRC, many patients still develop progressive disease and unfortunately in patients with disease resistant to 5-fluorouracil/folinic acid, irinotecan and oxaliplatin, no effective cytotoxic therapy is known. The rapidly expanding knowledge in tumor biology has encouraged optimism for the possibility to find and target tumor-specific mechanisms and thereby increase both efficacy and tolerance. A great number of 'targeted drugs' are being tested in clinical trials and some of these new drugs, like bevacizumab, cetuximab and panitumumab, are available for routine use in health care. These new targeted drugs will expand the therapeutic arsenal in CRC to a great extent, but they will also add to the complexity of treatment of CRC. In this review, we summarize the current status of antibody therapy in patients with CRC

RAS and BRAF mutations impact treatment and prognosis of metastatic colorectal cancer patients (mCRC), but the knowledge is based on trial patients usually not representative for the general cancer population. Patient characteristics, treatment and efficacy according to KRAS, BRAF and MSI status were analyzed in a prospectively collected unselected population-based cohort of 798 non-resectable mCRC patients. The cohort contained many patients with poor performance status (39% PS 2-4) and elderly (37% age>75), groups usually not included in clinical trials. Patients without available tissue micro array (TMA) (42%) had worse prognostic factors and inferior survival (all patients; 7m vs 11m, chemotherapy-treated;12m vs 17m). The 92 patients (21%) with BRAF mutation had a poor prognosis regardless of microsatellite instability, but receipt of 1-2nd chemotherapy was similar to wildtype BRAF patients. Median survival in this cohort varied from 1 month in BRAF mutated patients not given chemotherapy to 26 months in wildtype KRAS/BRAF patients

The objective of the study was to investigate whether specific single nucleotide polymorphisms (SNPs) with influence on drug transport, biotransformation and repair mechanisms are associated with treatment outcome and toxicity in metastatic colorectal cancer (mCRC). We genotyped blood samples from 519 mCRC patients treated with first-line 5-fluorouracil and oxaliplatin cetuximab for 17 SNPs in 10 genes involved in membrane transport (ABCC1 and ABCC2), drug biotransformation (GSTP1 and AGXT) and DNA repair (ERCC1, ERCC2, XRCC1, XRCC3, XPG and MSH6). The AGXT-rs34116584 and the ERCC2-rs238406 polymorphisms were significantly associated with progression-free survival (P=0.002 and P=0.001, respectively). Associations between 18 toxicity variables and SNPs were identified, although none were significant after Bonferroni correction for multiple comparisons. The study identified SNPs of potential use as markers of clinical outcome in oxaliplatin-treated mCRC patients. If validated in other studies, they could improve the selection of therapy in mCRC.

Current standard treatments for metastatic colorectal cancer (CRC) are based on combination regimens with one of the two chemotherapeutic drugs, irinotecan or oxaliplatin. However, drug resistance frequently limits the clinical efficacy of these therapies. In order to gain new insights into mechanisms associated with chemoresistance, and departing from three distinct CRC cell models, we generated a panel of human colorectal cancer cell lines with acquired resistance to either oxaliplatin or irinotecan. We characterized the resistant cell line variants with regards to their drug resistance profile and transcriptome, and matched our results with datasets generated from relevant clinical material to derive putative resistance biomarkers. We found that the chemoresistant cell line variants had distinctive irinotecan- or oxaliplatin-specific resistance profiles, with non-reciprocal cross-resistance. Furthermore, we could identify several new, as well as some previously described, drug resistance-associated genes for each resistant cell line variant. Each chemoresistant cell line variant acquired a unique set of changes that may represent distinct functional subtypes of chemotherapy resistance. In addition, and given the potential implications for selection of subsequent treatment, we also performed an exploratory analysis, in relevant patient cohorts, of the predictive value of each of the specific genes identified in our cellular models. publisher: Elsevier articletitle: Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance journaltitle: Molecular Oncology articlelink: http://dx.doi.org/10.1016/j.molonc.2015.02.008 content_type: article copyright: Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. ispartof: Molecular Oncology vol:9 issue:6 pages:1169-85 ispartof: location:United States status: published

Background Circulating cell-free DNA (cfDNA) in plasma is a mixture of DNA from malignant and normal cells, and can be used as a liquid biopsy to detect and quantify tumour specific mutations e.g. KRAS . We investigated the clinical value of KRAS mutations when detected in plasma compared to tumour in patients from metastatic colorectal cancer (mCRC) prior to anti-epidermal growth factor receptor (anti-EGFR) therapy. Secondly, we investigated the concentration of total cfDNA in relation to clinical outcome. Patients and methods Patients were resistant to 5-FU, oxaliplatin and irinotecan and treated with 3rd line irinotecan (180mg/m 2 ) and cetuximab (500mg/m 2 ) q2w in a prospective phase II trial. The study was conducted prior to implementation of KRAS as selection criteria. Plasma was obtained from a pre-treatment EDTA blood-sample, and the total cfDNA, and KRAS mutations were quantified by an in-house qPCR method. Results are presented according to REMARK. Results One-hundred-and-forty patients were included. Thirty-four percent had detectable KRAS mutations in the tumour, compared to 23% in plasma. KRAS detection in archival tumour tissue showed no correlation to survival, whereas plasma KRAS status remained a strong predictive and prognostic factor in multivariate analysis (Hazard Ratio (HR)=2.98 (95% CI 1.53–5.80, p =0.001) and 2.84 (1.46–5.53, p =0.002), for OS and PFS, respectively). Combining the information of total cell free DNA levels and plasma KRAS mutation status, produced an additional prognostic effect. Conclusion The value of clinically relevant mutations could be improved by performing the analysis on circulation plasma DNA rather than archival tumour tissue.

BACKGROUND: Recent clinical trials have demonstrated the benefit and feasibility of perioperative chemotherapy for treatment of gastroesophageal adenocarcinoma (GEA). Despite convincing results, patients entering such trials usually represent only a fraction of those who are candidates for treatment. Confirmation of trial-reported effects and tolerability in unselected cohorts is therefore required. The aims of this study were to confirm the safety and efficacy of perioperative chemotherapy for resectable GEA and to delineate risks of treatment failure.METHODS: We conducted a national retrospective cohort analysis of patients admitted for perioperative chemotherapy for resectable GEA. Regimens were epirubicin and capecitabine combined with oxaliplatin or cisplatin.RESULTS: The intention-to-treat analysis included 271 patients. Eighty-seven percent of patients completed preoperative chemotherapy, and 63 % received radical resection. Age >70 years (odds ratio 2.58) and hypoalbuminemia (odds ratio 4.10) were independent predictors of not undergoing scheduled surgery (P = 0.033). Grade 3 or higher febrile neutropenia, fatigue, and diarrhea were common in the oxaliplatin group (n = 128), but hypomagnesaemia and tinnitus/hearing loss were more common in the cisplatin group (n = 135). The median overall survival was 26.4 months, and the 1- and 2-year survival rates were 76 and 53 %, respectively. Performance status >0 (hazard ratio 1.64) and elevated serum lactate dehydrogenase (hazard ratio 3.03) were independent predictors of poor prognosis (P ≤ 0.05).CONCLUSIONS: Perioperative chemotherapy is feasible and well tolerated in patients with good performance status and low incidence of comorbidities.

Over the past decade, the effi cacy of modern chemotherapy, with or without targeted therapy, has been markedly improved. Systemic therapy generates substantial tumour regression in around 50 % of patients with metastatic colorectal cancer, median progression-free survival is prolonged to around 9 months, median overall survival approaches 2 years and the chance for resection is increased. The optimal strategy must be decided on by a multidisciplinary team.

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.

OBJECTIVE: To evaluate treatment outcome in a large population-based cohort of patients with anal cancer treated according to Nordic guidelines.MATERIAL: Clinical data were collected on 1266 patients with anal squamous cell carcinoma diagnosed from 2000 to 2007 in Sweden, Norway and Denmark. 886 of the patients received radiotherapy 54-64Gy with or without chemotherapy (5-fluorouracil plus cisplatin or mitomycin) according to different protocols, stratified by tumor stage.RESULTS: High age, male gender, large primary tumor, lymph node metastases, distant metastases, poor performance status, and non-inclusion into a protocol were all independent factors associated with worse outcome. Among patients treated according to any of the protocols, the 3-year recurrence-free survival ranged from 63% to 76%, with locoregional recurrences in 17% and distant metastases in 11% of patients. The highest rate of inguinal recurrence (11%) was seen in patients with small primary tumors, treated without inguinal irradiation.CONCLUSIONS: Good treatment efficacy was obtained with Nordic, widely implemented, guidelines for treatment of anal cancer. Inguinal prophylactic irradiation should be recommended also for small primary tumors.

Circulating forms of the urokinase plasminogen activator receptor (uPAR) are associated with prognosis in patients with colorectal cancer. Preclinical studies have shown that uPAR can influence the state of phosphorylation and signalling activity of the epidermal growth factor receptor (EGFR) in a ligand-independent manner. The purpose of the study was to evaluate whether plasma soluble intact and cleaved uPAR(I-III)+(II-III) levels could identify a subpopulation of patients with metastatic colorectal cancer (mCRC) where treatment with cetuximab would have a beneficial effect. Plasma samples were available from 453 patients treated in the NORDIC VII study. Patients were randomized between FLOX and FLOX + cetuximab. The levels of uPAR(I-III)+(II-III) were determined by time-resolved fluorescence immunoassay. We demonstrated that higher baseline plasma uPAR(I-III)+(II-III) levels were significantly associated with shorter progression-free survival (PFS) (HR = 1.30, 1.14-1.48, p = 0.0001) and overall survival (OS) (HR = 1.75, 1.52-2.02, p 0.0001). Multivariate Cox analysis showed that plasma uPAR(I-III)+(II-III) was an independent biomarker of short OS (HR = 1.45, 1.20-1.75, p = 0.0001). There were no significant interactions between plasma uPAR(I-III)+(II-III) levels, KRAS mutational status and treatment either PFS (p = 0.43) or OS (p = 0.095). However, further explorative analyses indicated that patients with low levels of circulating suPAR and a KRAS wild-type tumor have improved effect from treatment with FLOX + cetuximab as compared to patients with KRAS wild-type and high levels of suPAR. These results thus support the preclinical findings and should be further tested in an independent clinical data set.

From having been a 'single-drug not very interesting cancer type' from a medical treatment perspective, treatment of colorectal cancer (CRC) has during the past five years become a more complex issue of the appropriate use of several cytotoxic drugs sometimes integrated with advanced metastatic surgery with curative intent. The new drugs have provided significant benefit to the patients, so far mostly in the metastatic setting but also in adjuvant treatment. The significant progress in molecular and tumour biology has produced a great number of new 'targeted' drugs that are now in various stages of clinical development. Two of these drugs, the monoclonal antibodies bevacizumab (Avastin) and cetuximab (Erbitux), directed against VEGF and EGFR, respectively, have recently been approved within the EU for use in metastatic CRC. This Nordic Expert Consensus Report summarizes the current status of chemotherapy in metastatic CRC, overviews the clinical status of targeted drugs in CRC and, finally, provides guidelines for the routine clinical use of bevacizumab and cetuximab based on the most recently available clinical data.

The main objectives of this phase II study were to determine efficacy and safety of the combination of UFT with Leucovorin and mitomycin C in patients with metastatic colorectal cancer. Ninety-seven patients were treated with UFT (91 patients 300 mg/m2, 6 patients 250 mg/m2) + Leucovorin 90 mg days 1-28 q 5 weeks. During the first 4 cycles the patients also received mitomycin C 7 mg/m2 on day 1. At the end of 4 courses patients with benefit from the treatment could receive further courses of UFT and Leucovorin alone. Two patients had a complete response (2%), 20 (21%) had a partial response, 40 (41%) had no change, 19 (20%) had progression, and 16 (17%) were not evaluable for response. The overall response rate by intention to treat was 22/97 (23%). Median time to progression was 5 months and median survival 13 months. Severe (grade 3-4) toxicities included: anorexia 3%, nausea 6%, vomiting 7%, diarrhoea 7%, and fatigue 9%. Febrile neutropenia, renal failure, and thrombocytopenia were seen in 1% of the patients, respectively. The combination of UFT with Leucovorin and mitomycin C shows similar clinical activity with regard to overall response rate (23%) and survival (13 months) to other frontline 5-fluorouracil-based therapies in metastatic colorectal cancer patients. The results indicate that mitomycin C did not increase either efficacy or toxicity. Therefore, phase III trials with this regimen cannot be recommended.

Background: High expression of the RNA-binding motif protein 3 (RBM3) has been shown to correlate, with prolonged survival in several malignant diseases and with the benefit of platinum-based chemotherapy in ovarian cancer. The aim of this study was to evaluate RBM3 in metastatic colorectal cancer (mCRC) as a prognostic factor for overall survival and in relation to benefit of first-line chemotherapy. Methods: Immunohistochemical staining was conducted and evaluated in tumours from 455 mCRC patients. Kaplan-Meier analysis and Cox regression proportional hazards models were used to access the impact of RBM3 expression on overall survival (OS) and progression-free survival (PFS). Results: High RBM3 expression, both nuclear and cytoplasmic, was an independent prognostic factor for prolonged OS (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.50–0.90 and HR 0.66, 95% CI 0.48–0.91, respectively). PFS was significantly longer in patients with high RBM3 expression who had received first-line oxaliplatin based treatment, compared to those who had received irinotecan based treatment, both regarding nuclear and cytoplasmic expression (p-value 0.020 and 0.022 respectively). Conclusion: High RBM3 expression is an independent predictor of prolonged survival in mCRC patients, in particular in patients treated with first-line oxaliplatin based chemotherapy.

10032 Background: More than half of the patients (pts) diagnosed with mCRC are older, but they are underrepresented in clinical trials. Data about the best treatment strategy in pts who are not candidates for standard full-dose combination therapy is scanty. Here we present a preplanned safety analysis in the NORDIC 9 trial. Methods: NORDIC 9 explores treatment of older mCRC pts (≥70 years) who are not candidates for full-dose combination therapy. Pts receive full dose monotherapy (Arm A: S-1 30 mg/m2 po bid day 1-14 q3w, followed by irinotecan upon progression or reduced dose (80%) combination therapy (Arm B: S-1 20 mg/m2 po bid day 1-14 + oxaliplatin 100 mg/m2 iv day 1 q3w, followed by reduced dose S-1 + irinotecan q3w). Bevacizumab (7.5 mg/kg iv day 1) may be added at the discretion of the treating clinician. Geriatric screening tools (eg G-8 and VES-13) and quality-of-life are evaluated at baseline. Blood samples and tumor tissue are prospectively collected. Primary endpoint is PFS. Secondary endpoints are correlations between the geriatric screening and safety but also efficacy. Results: The safety analysis was performed when 50 pts had received 3 cycles. 12 pts received bevacizumab. Median age was 79 (range 70-88) years, 26 pts were male, performance status was 0 (43%), 1 (38%) or 2 (19%). Five (10%) pts discontinued therapy after only 1 cycle due to toxicity (n = 2) or PD/clinical deterioration (n = 3); 45 pts (90%) continued therapy beyond 3 cycles. Pts receiving only 1 cycle had numerically a worse G-8 and VES-13 score. Grade 3-4 non-hematological toxicity was fatigue (6%), diarrhea (10%), nausea (4%) and vomiting (6%), and was experienced by 10 pts, 6 of them received ≥3 cycles of treatment. There was no hand-foot-syndrome, cardiac or hematological grade 3-4 toxicity. Dose intensity for S-1 was 0.98 (0.7-1.0) (arm A) and 0.93 (0.6-1.0) (Arm B), respectively, and for oxaliplatin 0.99 (0.4-1.0). Conclusions: The safety committee recommends to continue the trial without dose adjustments according to the original design. February 2017, 118 of planned 150 pts had been included. Clinical trial information: EudraCT no 2014-000394-39.

e15131 Background: CEA is regarded as the marker of choice for monitoring patients with colorectal cancer (CRC), but the value of using CA19-9 is insufficient. The prognostic value of serum CA19-9 in combination with CEA was evaluated in patients with metastatic CRC (mCRC) before first (1) and third line therapy (3LT). Methods: From April 2004 to May 2015, pretreatment serum samples were collected from 160 and 255 patients with mCRC before 1LT and 3LT, respectively. Median age was 64 [range 33-87] and male/female ratio 243(59%)/172(41%). Serum CA19-9 was determined by routine chemiluminescent immunometric assay (normal range 0-37 KU/l). Progression-free survival (PFS) and overall (OS) crude, adjusted hazard ratios (HR) and corresponding 95% confidence intervals (CIs) were estimated using Cox regression analysis. CA19-9 and CEA were included as log2-transformed continuous variables and adjustment included mutually between CA19-9 and CEA in addition to primary tumor location, sex and age. Results: In 3LT median pretreatment CEA levels were higher than in 1LT (59 µg/l [IQR 14-288] vs. 23[6-153] P < 0.01) while CA19-9 values were similar (112 KU/l [23-626] vs. 98[19-390]). In patients treated with 3LT univariate analysis showed that high levels of CA19-9 and CEA were associated with short PFS (CA19-9: HR = 1.06, 95% CI 1.02-1.10, P < 0.01; CEA: HR = 1.05, 1.00-1.09, P = 0.04). In 1LT neither CA19-9 nor CEA were significantly associated with PFS. In a multivariate analysis, none of the biomarkers were significantly associated with PFS. In patients treated with 3LT univariate analysis showed that high levels of CA 19-9 and CEA were associated with short OS (CA19-9: HR = 1.11, 1.07-1.16, P < 0.01; CEA: HR = 1.1, 1.06-1.16, P < 0.01). In patients treated with 1LT high levels of CA-19-9 but not CEA was significantly associated with a shorter OS (HR = 1.07, 1.00-1.14, P = 0.04). In 3LT multivariate analyses showed that high levels of CA19-9 and CEA were the only factors associated with a shorter OS (CA19-9: HR = 1.08, 1.03-1.13, P < 0.01; CEA: HR = 1.07, 1.01-1.14, P < 0.01), while there was no significant association to OS in 1LT. Conclusions: Serum CA19-9 may be a valuable prognostic biomarker in combination with CEA in mCRC patients receiving third line therapy.

e15060 Background: The prognostic value of serum IL-6, YKL-40 and CEA before first (1) and third line therapy (3LT) in metastatic colorectal cancer (mCRC) is lacking and was evaluated in this study. Methods: From 2004 to 2015 serum samples were collected from 160 and 255 patients with mCRC before 1LT and 3LT, respectively. Median age was 64 years (range 33-87) and male/female ratio 243(59%)/172(41%). Serum IL-6 (R&D, UK) and YKL-40 (Quidel, USA) were determined by ELISA. Progression-free (PFS) and overall survival (OS), crude and adjusted hazard ratios (HR) and corresponding 95% confidence intervals (CI) were estimated with Cox regression analysis. CEA, IL-6 and YKL-40 were included as log2-transformed continuous variables with mutual adjustment between CEA, IL-6 and YKL-40, primary tumor location, sex and age. Results: In 3LT IL-6, YKL-40 and CEA levels were higher (P < 0.001) than in 1LT (IL-6: 9.5 pg/ml [IQR4.2-18.5] vs. 4.6 [2.5-10.5]; YKL-40: 140 ng/ml [77-272] vs. 101 [62-172]; and CEA: 59 ug/l [14-288] vs. 23[5.8-153]). In 3LT univariate analysis showed that increased levels of IL-6, YKL-40 and CEA were associated with shorter PFS (IL-6: HR = 1.19, 95% CI 1.07-1.31, P < 0.01; YKL-40: HR = 1.13, 1.04-1.24, P = 0.01; CEA: HR = 1.05, 1.00-1.09, P = 0.04). In 1LT only high IL-6 was associated with shorter PFS (HR = 1.09, 1.01-1.17, P = 0.03). In a multivariate analysis only high IL-6 was significantly associated with shorter PFS in 3LT (HR = 1.15, 1.03-1.29, P < 0.01) and none of the biomarkers in 1LT. In 3LT univariate analysis showed that increased levels of all 3 biomarkers were associated with a shorter OS (IL-6: HR = 1.36, 1.23-1.51, P < 0.01; YKL-40: HR = 1.21, 1.10-1.33, P < 0.01; CEA: HR = 1.11, 1.06-1.16, P < 0.01). In 1LT high levels of IL-6 (HR = 1.17, 1.08-1.27, P < 0.01) and YKL-40 (HR = 1.18, 1.00-1.38, P = 0.05), but not CEA, were associated with short OS. In 3LT the multivariate analysis showed that both higher IL-6 (HR = 1.34, 1.20-1.50, P < 0.01) and CEA (HR = 1.09, 1.03-1.14, P < 0.01), but not YKL-40 were significantly associated with a shorter OS. In 1LT only higher IL-6 was associated with a shorter OS (HR = 1.19, 1.08-1.31, P < 0.01) Conclusions: Serum IL-6 and YKL-40 may be useful prognostic biomarkers in combination with CEA in patients with mCRC

Objective: This study investigated early nursing interventions with the purpose to minimize cetuximab-induced acneiform eruption. The most important side-effect of cetuximab is dermatologic toxicity, up to 90%. Dose-reduction or interruption of cetuximab reduces severity of dermatologic toxicity, probably at the cost of reduced efficacy of the cancer therapy. Thus, prevention or effective supportive care during treatment is important. The study evaluated if patient education could ensure compliance of cancer treatment and effect of oral tetracycline on acneiform eruption, with the purpose to minimize severity of dermatologic toxicity and reduce the use of tetracycline.Methods: The design was a single group prospective interventional study. Gastro-intestinal (GI) cancer patients treated with cetuximab between April 2009 and June 2011 were educated to start treatment with tetracycline 500 mg twice daily when acneiform eruption occurred. Patient’s dermatologic toxicity were graded (by CTCAE) and registered by nurses.Results: Sixty-three patients were evaluable. Patients started tetracycline when acneiform eruption occurred. It reduced severity but not incidence of acneiform eruption, 10% of the patients never developed acneiform eruption and therefore never received tetracycline.Conclusions: Patient-education by a trained oncology nurse in the handling of cetuximab induced acneiform eruption is manageable and effective and ensures a high number of patients carrying through treatment with a full dose of cetuximab.

Recent modalities and strategies have increased the complexity of treatment choice in patients with colorectal cancer (CRC), and therefore all cases should be assessed at a multidisciplinary conference. Adjuvant chemotherapy for 6 months increases the chance of cure by absolutely 5 % in stage II and 10–15 % in stage III. Targeted therapy is not recommended in the adjuvant setting. Treatment options in patients with non- resectable CRC are based on the extent of disease (resectable/potential resectable/non-resectable) and symptoms. Surgery fi rst or chemotherapy fi rst in patients with synchronous metastasis is one of several yet unsolved questions which should be discussed at a MDT in each case taking into account patients symptoms and performance.

OBJECTIVE:: The primary objective was to compare overall survival (OS) in patients with colorectal cancer (CRC) with nonresectable liver-only metastases treated by liver transplantation or chemotherapy.BACKGROUND:: CRC is the third most common cancer worldwide. About 50% of patients will develop metastatic disease primarily to the liver and the lung. The majority of patients with liver metastases receive palliative chemotherapy, with a median OS of trial patients of about 2 years, and less than 10% are alive at 5 years.METHODS:: Patients with nonresectable liver-only CRC metastases underwent liver transplantation in the SECA study (n = 21). Disease-free survival (DFS) and OS of patients included in the SECA study were compared with progression-free survival (PFS) and OS in a similar cohort of CRC patients with liver-only disease included in a first-line chemotherapy study, the NORDIC VII study (n = 47). PFS/DFS and OS were estimated by the Kaplan-Meier method.RESULTS:: DFS/PFS in both groups were 8 to 10 months. However, a dramatic difference in OS was observed. The 5-year OS rate was 56% in patients undergoing liver transplantation compared with 9% in patients starting first-line chemotherapy. The reason for the large difference in OS despite similar DFS/PFS is likely different metastatic patterns at relapse/progression. Relapse in the liver transplantation group was often detected as small, slowly growing lung metastases, whereas progression of nonresectable liver metastases was observed in the chemotherapy group.CONCLUSIONS:: Compared with chemotherapy, liver transplantation resulted in a marked increased OS in CRC patients with nonresectable liver-only metastases.

Background and purpose Chemotherapy-induced peripheral neuropathy negatively affects the quality of life for many patients treated with oxaliplatin or docetaxel for gastrointestinal cancer or breast cancer. Symptoms can persist long after treatment and often include neuropathic pain. Our objective was to characterize the neuropathies with regard to symptoms, neurological signs and objective evidence of damage to the structure and function of the peripheral nerves. Furthermore, the diagnostic values of skin biopsy, quantitative sensory testing (QST) and nerve conduction studies (NCS) were compared. Methods Patients complaining of neuropathy symptoms at least 3 months after completion of treatment with oxaliplatin (n = 20) or docetaxel (n = 20) were recruited from the Department of Oncology or using hospital records. Neuropathy scores were determined along with the intraepidermal nerve fibre density in skin biopsies from the proximal and distal parts of the leg, QST and NCS. Results Clinically only sensory functions were affected. In general, neuropathy scores were higher in the oxaliplatin-treated group. Both sensory and motor fibres were affected in the NCS, showing predominantly signs of axonal damage. Mechanical detection threshold was most often affected in the QST. NCS, QTS and skin biopsy were abnormal in 11, 13 and 17 and 7, 11 and 15 of the oxaliplatin-treated patients and docetaxel-treated patients, respectively. Conclusions Chemotherapy-induced peripheral neuropathy after oxaliplatin or docetaxel treatment is a clinically sensory, axonal neuropathy affecting only small nerve fibres in some patients. NCS are often normal, whereas QST and skin biopsy have a higher diagnostic sensitivity.

Improving the prognosis for patients with cancer from the exocrine pancreas (PC) represents a challenge for health-care systems in the Western world. Vague and non-specific symptoms combined with rapid deterioration of the patients' condition often make diagnosis difficult. Multimodality therapy with a combination of surgery followed by adjuvant chemotherapy has improved the long-term survival of patients. Recent data suggest improved efficacy of aggressive chemotherapy. Multidisciplinary team management and research are essential in order to further improve the outcome of patients with PC.

INTRODUCTION: MicroRNAs (miRNAs) have important regulatory functions in cellular processes and have shown promising potential as prognostic markers for disease outcome in patients with cancer. The aim of the present study was to find miRNA expression profiles in whole blood that were prognostic for overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated with cetuximab and irinotecan.METHODS: From 138 patients with mCRC in 3rd line therapy with cetuximab and irinotecan in a prospective phase II study, 738 pretreatment miRNAs were isolated and profiled from whole blood using the TaqMan MicroRNA Array v2.0. Mutation status of KRAS, BRAF, and PI3KCA was known.RESULTS: After Bonferroni adjustment, 6 miRNAs: (miR-345, miR-143, miR-34a*, miR-628-5p, miR-886-3p and miR-324-3p), were found associated with short OS. miR-345 was the strongest prognostic miRNA, significant in the full cohort and in the non-KRAS mutant population. miR-345, as a continuous variable in the full cohort, resulted in a hazard ratio (HR) of 2.38 per IQR (CI 95%: 1.8-3.1, P-value = 2.86e-07, Bonferroni adjusted, univariable analysis) and a HR = 1.75 per IQR (CI 95%: 1.24-2.48, P-Wald = 1.45e-03) in the multivariable analysis adjusted for gender, age, KRAS, PI3KCA and performance status. miR-345 was prognostic in progression-free survival (PFS) with a HR = 1.63 per IQR (CI 95%: 1.25-2.114, P-Wald = 2.92e-4) in the multivariable analysis. In addition, high miR-345 expression was associated with lack of response to treatment with cetuximab and irinotecan.CONCLUSION: We identified miR-345 in whole blood as a potential biomarker for clinical outcome. MiR-345 was a single prognostic biomarker for both OS and PFS in all patients and also in the non-KRAS mutant population.

108 Background: Trastuzumab (T) improves efficacy of doublet chemotherapy (TOGA trial) in HER2 positive patients with advanced gastro-esophageal (GE) cancer but safety and efficacy with triple chemotherapy is presently unknown. We initiated a dose-finding trial to establish a safe 4 drug combination of docetaxel (D), short-time infusion of oxaliplatin (O), continuously capecitabine (C) and trastuzumab (T). Methods: This phase I, dose-finding trial was approved by the local etic committee. All pts had histologically confirmed GE adenocarcinoma. Therapy was given day 1 with escalating doses of D (42mg/m2 to 51 mg/m2 as a 60 minutes infusion), O (100 mg/m2 as a 30 minutes infusion) and C (1,250 mg/m2/day continuously). DOC was repeated every 3 weeks for a maximum of 6 courses. T was given as a loading dose (8 mg/kg) followed by 6 mg/kg every 3 weeks until PD or unacceptable toxicity. Toxicity was evaluated according to NCIC-CTC 3.0. DLT was evaluated after the first course and defined as non-haematological toxicity grade ≥ 3, neutropenia grade 4 more than 7 days or febrile neutropenia. Response was evaluated by the investigator according to RECIST 1.0 every 9th weeks. Data was updated September 1, 2013. Results: From May 2010 to October 2012 we included 11 pts. Median age was 62years (range 32-73), 5/11 pts had PS 0, all pts had metastatic disease. Neutropenia grade 3-4 was observed in two pts, one had febrile neutropenia grade 3 after four courses. Two pts had grade 3 vomiting, fatigue, or nausea, respectively and one patient had diarrhoea grade 3. Only one pt developed a DLT (grade 3 vomiting, nausea and fatigue). Dose-intensity, after six courses, in all 11 pts was: D = 89%, O= 88% C = 81% and T = 100%. Median number of DOC was 6; all pts continued T to a median of 12 courses and one pt is presently receiving T. Partial response was obtained in 9 pts (81%). Progression free survival was 8.8 months and overall survival was 16.5 months. Five pts are presently alive. Conclusions: DOC-T in HER2 positive GE pts is safe and easily administered in an out-patient setting. The recommended doses for further evaluation are: D 51 mg/m2, O 100 mg/m2, C 1,250 mg/m2. Efficacy is very promising and deserves evaluation in larger trials. Clinical trial information: NCT01295086.

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...

Background There is an unmet need for predictive markers for the antiangiogenic agent bevacizumab in metastatic colorectal cancer (mCRC). We aimed to assess whether the location of the primary tumor is associated with bevacizumab effectiveness when combined with capecitabine and oxaliplatin (CAPEOX) in the first-line treatment of patients with mCRC. Patients and methods A cohort of 667 consecutive patients with mCRC from the general community treated from 2006 to 2011 with CAPEOX and bevacizumab as standard first-line therapy was compared with a cohort of 213 patients treated with CAPEOX from 2003 to 2006, before bevacizumab was approved. Main outcome measures were progression-free survival (PFS) and overall survival (OS). Differences in outcome were tested using Kaplan–Meier curves and log-rank tests, and multivariate analyses were carried out using Cox Proportional Hazards models. Results Patients treated with CAPEOX and bevacizumab with primary tumors originating in the sigmoid colon and rectum had a significantly better outcome than patients with primary tumors originating from the cecum to the descending colon, both for PFS (median PFS 9.3 versus 7.2 months; hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.56–0.82) and for OS (median OS 23.5 versus 13.0 months; HR 0.47, 95% CI 0.38–0.57). This difference was confirmed in multivariate analyses after adjustment for other potentially prognostic factors. For patients treated with CAPEOX, there was no association between primary tumor location and outcome, neither in unadjusted nor adjusted analyses. Conclusions The addition of bevacizumab to CAPEOX in first-line treatment of patients with mCRC may primarily benefit patients with primary tumors originating in the rectum and sigmoid colon. This hypothesis needs to be validated in data from completed randomized trials. ClinicalTrials.gov identification number NCT00212615.