Search

Most unresectable metastatic colon cancer remains incurable, with a median survival of less than 3 years. Molecularly targeted therapies have recently been developed; in particular, monoclonal antibodies against the epidermal growth factor receptor, which are efficacious in 40% to 60% of chemotherapy-resistant patients with wild-type KRAS. This study shows that cetuximab plus irinotecan, compared with cetuximab alone, increases the response rate and delays progression in irinotecan-resistant RAS wild-type colorectal cancer. Background(s): The Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation (ICECREAM) study assessed the efficacy of cetuximab monotherapy compared with cetuximab combined with chemotherapy for quadruple wild-type (KRAS, NRAS, BRAF, or P13KCA exon 20) metastatic colorectal cancer. Patients and Methods: Patients were enrolled in an open-label, multicenter, phase II trial and randomly assigned to cetuximab 400 mg/m2, then 250 mg/m2 cetuximab weekly, with or without irinotecan 180 mg/m2 every 2 weeks. The primary endpoint was 6-month progression-free survival; secondary endpoints were response rate, overall survival, toxicity, and quality of life. Result(s): From 2012 to 2016, 48 patients were recruited. Two were ineligible, and 2 were not evaluable for response. Characteristics were balanced, except gender (male, 62% vs. 72%) and primary sidedness (left, 95% vs. 68%). For cetuximab compared with cetuximab-irinotecan, progression-free survival was 14% versus 41% (hazard ratio, 0.39; 95% confidence interval, 0.20-0.78; P =.008); response rate was 10% (2 partial responses) versus 38% (1 complete, 8 partial); P =.04. Grade 3 to 4 toxicities were less with cetuximab monotherapy (23% vs. 50%); global and specific quality of life scores did not differ. Conclusion(s): In comparison with cetuximab alone, cetuximab plus irinotecan increases the response rate and delays progression in irinotecan-resistant RAS wild-type colorectal cancer. This echoes

Background: SIRFLOX, an international multi-centre open-label RCT in first-line pts with non-resectable, liver-only or liver-dominant mCRC, showed that compared to FOLFOX (+/- bev) chemotherapy alone [arm A] FOLFOX (+/- bev) plus SIRT using Y-90 resin microspheres [arm B] did not improve overall PFS (median 10.2 v 10.7 months arm A v B, HR: 0.93; 95% CI 0.77-1.12; p = 0.429). However, liver PFS by competing risk analysis was improved with the addition of SIRT (median 12.6 v 20.5 months in arm A v B, HR: 0.69; 95% CI 0.55-0.90; p = 0.002). The current analysis examines patterns of disease progression and potential impact on the primary study endpoint. Method(s): Site and pattern (intra/extra-hepatic) of first progression, and whether progression was due to growth of existing lesions or the appearance of new lesions, was judged by an independent reader blinded to study arm. Result(s): From Oct 2006 to Apr 2013, 530 pts were randomised (arm A, n = 263; arm B, n = 267); 212 (40%) had extra-hepatic metastases at study entry; 292 (55%) were stratified to receive bev. As of 31 Jan 2015, the total number of patients with disease progression in arm A v B were 178 and 166, respectively. The site of first progression was more frequently in the liver (+/- other sites) in arm A v B (92.1% v 72.3%; p < 0.001). Conversely, site of first progression was less frequent in the lung (+/- other sites) in arm A v B (19.1% v 42.8%; p < 0.001). A higher proportion of first progression occurred in the liver alone in arm A v B (77.0% v 52.4%; p < 0.001). Conversely, a lower proportion of first progression occurred only in non-liver sites, primarily lung, in arm A v B (7.9% v 47.7%; p < 0.001). Of patients with first progression in the liver, a higher proportion occurred in existing liver lesions (+/- extrahepatic sites) in arm A v B (72.5% v48.2%; p < 0.001). Conclusion(s): The addition of SIRT to FOLFOX chemotherapy alone (+/- bev) reduced the frequency at which first disease progression oc

Purpose: SIRFLOX was a randomized, multicenter trial designed to assess the efficacy and safety of adding selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres to standard fluorouracil, leucovorin, and oxaliplatin (FOLFOX)-based chemotherapy in patients with previously untreated metastatic colorectal cancer. Patients and Methods: Chemotherapy-naive patients with liver metastases plus or minus limited extrahepatic metastases were randomly assigned to receive either modified FOLFOX (mFOLFOX6; control) or mFOLFOX6 plus SIRT (SIRT) plus or minus bevacizumab. The primary end point was progression-free survival (PFS) at any site as assessed by independent centralized radiology review blinded to study arm. Result(s): Between October 2006 and April 2013, 530 patients were randomly assigned to treatment (control, 263; SIRT, 267).Median PFS at any site was 10.2 v 10.7months in control versus SIRT (hazard ratio, 0.93; 95% CI, 0.77 to 1.12; P = .43). Median PFS in the liver by competing risk analysis was 12.6 v 20.5 months in control versus SIRT (hazard ratio, 0.69; 95%CI, 0.55 to 0.90; P = .002). Objective response rates (ORRs) at any site were similar (68.1% v 76.4%in control v SIRT; P = .113). ORR in the liver was improved with the addition of SIRT (68.8%v 78.7% in control v SIRT; P = .042). Grade >= 3 adverse events, including recognized SIRT-related effects, were reported in 73.4% and 85.4% of patients in control versus SIRT. Conclusion(s): The addition of SIRT to FOLFOX-based first-line chemotherapy in patients with liver-dominant or liveronly metastatic colorectal cancer did not improve PFS at any site but significantly delayed disease progression in the liver. The safety profile was as expected and was consistent with previous studies.Copyright © 2016 by American Society of Clinical Oncology.

Background: Liver metastases are the dominant site of disease in mCRC and the dominant cause of death. The SIRFLOX study was designed to assess the efficacy and safety of combining FOLFOX chemotherapy (+/- bevacizumab) with SIRT using yttrium-90 (Y-90) resin microspheres as first-line treatment of patients with liver metastases from mCRC. Method(s): SIRFLOX was an international, multi-centre, open-label, RCT in chemotherapy-naive patients with non-resectable, liver-only or liver-dominant (liver plus lung and/or lymph node metastases) mCRC. Arm A: mFOLFOX6 (+/- bevacizumab, at investigator discretion) was compared to arm B: mFOLFOX6 + SIRT (SIR-Spheres; Sirtex) administered once with cycle 1 (+/- bevacizumab, at investigator discretion) until disease progression. The primary endpoint was Progression-Free Survival (PFS) using RECIST v1.0 by independent central imaging review in the intention-to-treat (ITT) cohort. PFS in the liver, as defined by Cumulative Incidence of Liver Progression (Liver CIP), was assessed by Competing Risk analysis. Stratification variables included presence of extra-hepatic metastases (liver-only vs. liver-dominant), degree of liver involvement (<=25% vs. >25%), and ITT with bevacizumab (with vs. no bevacizumab). Result(s): From October 2006 to April 2013, 530 patients were randomised (arm A, n = 263; arm B, n = 267); 212 (40%) had extra-hepatic metastases; 292 (55%) were stratified to receive bevacizumab. Median follow-up was 36.1 months. The median overall PFS was 10.2 vs. 10.7 months in arms Avs. B, respectively (hazard ratio [HR]: 0.93; 95% CI 0.77-1.12; p = 0.429) by Kaplan-Meier analysis. The median Liver PFS was 12.6 vs. 20.5 months in arm Avs. B (HR: 0.69; 95% CI 0.55-0.90; p = 0.002). Median Liver PFS was 12.4 vs. 21.1 months in arm Avs. B (HR: 0.64; 95% CI 0.48-0.86; p = 0.003) for patients with liver-only metastases, and 12.6 vs. 16.7 months (HR: 0.77, 95% CI 0.54-1.09; p = 0.147) for those with liver and extra-hepatic metastases. M

Background: The SIRFLOX study assessed the efficacy and safety of combining FOLFOX chemotherapy (+/- bev) with SIRT as first-line treatment of patients with CRC liver metastases. Planned sub-analyses analyses included +/- extra-hepatic metastases, +/- bev and site of first progression. Method(s): SIRFLOX was an international, multi-centre, open-label, RCT in chemotherapy-naive patients with non-resectable, liver-only or liverdominant mCRC. Arm A: mFOLFOX6 +/- bev vs. arm B: mFOLFOX6 +/- bev +SIRT using yttrium-90 resin microspheres (SIR-Spheres; Sirtex) administered once with cycle 1. The primary endpoint was overall PFS using RECIST v1.0. Stratification variables included +/- extra-hepatic metastases, and +/- bev. Liver PFS was assessed by Competing Risk analysis. First progression was judged by independent reader blinded to study arm. Result(s): 530 patients were randomised (A, n = 263; B, n = 267), 212 (40%) had EHD; 292 (55%) received bev. Median follow-up was 36.1 months. Median overall PFS was 10.2 vs. 10.7 months in A vs. B, respectively (p = 0.428). Median liver PFS was 12.6 vs. 20.5 months in A vs. B (p = 0.002). Median Liver PFS was 12.4 vs. 21.1 months in A vs. B (p = 0.003) for patients with liver-only metastases, and 12.6 vs. 16.7 months (p = 0.147) for those with liver and extra-hepatic metastases. Median Liver PFS was 10.6 vs. 18.9 months in A vs. B (p = 0.028) for patients with ITT -bev, and 12.7 vs. 21.0 months (p = 0.018) for those with ITT +bev. The site of first progression was more frequently the liver (+/- other sites) in A [164/ 178, 92.1%] vs. B [120/166, 72.3%] (p < 0.001). All-causality grade >=3 adverse events occurred in 73.3% vs. 85.4% (NS) of patients in A vs. B. Conclusion(s): In first-line treatment of patients with non-resectable CRC liver metastases, adding SIRT to FOLFOX-based chemotherapy failed to improve overall PFS. The addition of SIRT significantly extended median liver PFS and reduced the frequency that first disease progres

Background:Cetuximab can reverse chemotherapy resistance in colorectal cancer. This study evaluated the efficacy and safety of the combination of docetaxel and cetuximab as a second-line treatment in docetaxel-refractory oesophagogastric cancer. Method(s):Patients received docetaxel 30 mg m-2 on days 1 and 8, every 3 weeks and cetuximab 400 mg m-2 on day 1, then 250 mg m-2 weekly. Biomarker mutation analysis was performed. Result(s):A total of 38 patients were enrolled. Response rates were PR 6% (95% CI 2-19%), s.d. 43% (95% CI 28-59%). Main grade 3/4 toxicities were febrile neutropenia, anorexia, nausea, diarrhoea, stomatitis, and acneiform rash. Median progression-free and overall survival were 2.1 and 5.4 months, respectively. A landmark analysis showed a trend to improved survival times with increased grade of acneiform rash. No KRAS, BRAF or PIK3CA mutations were observed. Conclusion(s):Cetuximab and docetaxel achieve modest responses rates, but maintain comparable survival times to other salvage regimens with low rates of toxicity. © 2013 Cancer Research UK.

Background: The CO.17 trial demonstrated that the addition of cetuximab monotherapy (C) to best supportive care (BSC) improves OS and progression-free survival (PFS) in patients (pts) with ACRC. We compared tumour measurement as a continuous variable and visualized by waterfall plot vs. categorized as response based on RECIST as potential early predictors of OS benefit. Method(s): Of the 572 randomized, 216 pts on C and 142 on BSC had tumor assessment at baseline and 8 weeks and are included in this analysis. Response at 8 weeks was assessed using standard RECIST criteria and categorised as partial response, stable disease or progressive disease. Continuous tumour size measurement was also assessed using waterfall plot, The absolute difference in logarithm transformed sum of the longest tumor diameters (LSLD) between 8 weeks and baseline were calculated for the entire group and the KRAS wild-type (WT) and mutant (MUT) subgroups and correlated with OS in a multivariate analysis including difference in LSLD, RECIST response and other prognostic factors as covariates. Result(s): The increase of tumor size (cm) from baseline of pts treated by C was significantly smaller than those that received BSC (mean difference in LSLD 0.02 vs. 0.23; p < 0.0001), and this remained significant after adjusting for baseline prognostic factors (p<0.0001). In a multivariate analysis of pts treated by C, difference in LSLD was significantly associated with OS (HR 14.84, per ln(cm) of increase, 95% CI 4.31 to 51.08; p<0.0001), whilst RECIST defined response was not. Results were similar for WT pts: HR 14.30 per ln(cm) of increase in LSLD, 95% CI 1.32 to 96.5; p=0.03. For MUT pts, neither change in LSLD nor RECIST response was associated with OS. Conclusion(s): Change of tumor size at 8 weeks following commencement of C using a waterfall plot analysis was a better predictor of OS than standard RECIST categories. This may be a better early signal of treatment efficacy for molecular targeted

Purpose: To determine whether adding bevacizumab, with or without mitomycin, to capecitabine monotherapy improves progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC) in an open-label, three-arm randomized trial. Patients and Methods: Overall, 471 patients in Australia, New Zealand, and the United Kingdom with previously untreated, unresectable mCRC were randomly assigned to the following: capecitabine; capecitabine plus bevacizumab (CB); or capecitabine, bevacizumab, and mitomycin (CBM). We compared CB with capecitabine and CBM with capecitabine for progression-free survival (PFS). Secondary end points included overall survival (OS), toxicity, response rate (RR), and quality of life (QOL). Result(s): Median PFS was 5.7 months for capecitabine, 8.5 months for CB, and 8.4 months for CBM (capecitabine v CB: hazard ratio [HR], 0.63; 95% CI, 0.50 to 0.79; P < .001; C v CBM: HR, 0.59; 95% CI, 0.47 to 0.75; P < .001). After a median follow-up of 31 months, median OS was 18.9 months for capecitabine and was 16.4 months for CBM; these data were not significantly different. Toxicity rates were acceptable, and all treatment regimens well tolerated. Bevacizumab toxicities were similar to those in previous studies. Measures of overall QOL were similar in all groups. Conclusion(s): Adding bevacizumab to capecitabine, with or without mitomycin, significantly improves PFS without major additional toxicity or impairment of QOL. Copyright © 2010 by American Society of Clinical Oncology.