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Triple-negative breast cancer (TNBC) accounts for approximately 15–20% of all breast cancer types, indicating a poor survival prognosis with a more aggressive biology of metastasis to the lung and a short response duration to available therapies. Ibulocydine (IB) is a novel (cyclin-dependent kinase) CDK7/9 inhibitor prodrug displaying potent anti-cancer effects against various cancer cell types. We performed in vitro and in vivo experiments to determine whether IB inhibits metastasis and eventually overcomes the poor drug response in TNBC. The result showed that IB inhibited the growth of TNBC cells by inducing caspase-mediated apoptosis and blocking metastasis by reducing MMP-9 expression in vitro. Concurrently, in vivo experiments using the metastasis model showed that IB inhibited metastasis of MDA-MB-231-Luc cells to the lung. Collectively, these results demonstrate that IB inhibited the growth of TNBC cells and blocked metastasis by regulating MMP-9 expression, suggesting a novel therapeutic agent for metastatic TNBC. [ABSTRACT FROM AUTHOR]

Purpose GC1118 is a novel antibody targeting epidermal growth factor receptor (EGFR) with enhanced blocking activity against both low- and high-affinity EGFR ligands. A phase 1b/2a study was conducted to determine a recommended phase 2 dose (RP2D) of GC1118 in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) (phase 1b) and to assess the safety and efficacy of GC1118 plus FOLFIRI as a second-line therapy for recurrent/metastatic colorectal cancer (CRC) (phase 2a). Materials and Methods Phase 1b was designed as a standard 3+3 dose-escalation study with a starting dose of GC1118 (3 mg/kg/wk) in combination with biweekly FOLFIRI (irinotecan 180 mg/m2; leucovorin 400 mg/m2; 5-fluorouracil 400 mg/m2 bolus and 2,400 mg/m2 infusion over 46 hours) in patients with solid tumors refractory to standard treatments. The subsequent phase 2a part was conducted with objective response rate (ORR) as a primary endpoint. Patients with KRAS/NRAS/BRAF wild-type, EGFR-positive, recurrent/metastatic CRC resistant to the first-line treatment were enrolled in the phase 2a study. Results RP2D of GC1118 was determined to be 3 mg/kg/wk in the phase 1b study (n=7). Common adverse drug reactions (ADRs) observed in the phase 2a study (n=24) were acneiform rash (95.8%), dry skin (66.7%), paronychia (58.3%), and stomatitis (50.0%). The most common ADR of = grade 3 was neutropenia (33.3%). ORR was 42.5% (95% confidence interval [CI], 23.5 to 62.0), and median progression-free survival was 6.7 months (95% CI, 4.0 to 8.0). Conclusion GC1118 administered weekly at 3 mg/kg in combination with FOLFIRI appears as an effective and safe treatment option in recurrent/metastatic CRC. [ABSTRACT FROM AUTHOR]

Carcinoembryonic antigen (CEA) is the most widely used tumor marker in metastatic colorectal cancer (mCRC). However, its potential as a predictive marker of progression in mCRC during systemic chemotherapy, particularly in patients receiving monoclonal antibodies as a combination therapy, has remained of interest. Herein, we investigated whether CEA changes could predict disease progression and clinical outcomes in patients with mCRC cotreated with systemic chemotherapy and/or biologic agents. A total of 1261 patients with mCRC undergoing a first-line systemic treatment were included in this retrospective study. We analyzed the optimal cut-off value for CEA changes to predict progression at the first response evaluation by the treatment arm (chemotherapy alone, chemotherapy plus anti-vascular endothelial growth factor (VEGF) monoclonal antibody [mAb], and chemotherapy plus anti-epidermal growth factor receptor [EGFR] mAb). These cut-off values were then used to predict overall survival (OS) and progression-free survival (PFS). When stratified by their treatment arm, 891 (70.6%), 266 (21.0%), and 104 (8.2%) of the study patients were included in the chemotherapy alone-, anti-VEGF mAb, and anti-EGFR mAb groups, respectively. The optimal CEA cut-off values were 16.5% and 38.9% increase in the whole cohort and anti-EGFR mAb group, respectively, and these values showed high sensitivity and specificity for predicting disease progression. The patients in the entire population and anti-EGFR mAb group with CEA changes below these cut-off values showed significantly better OS and PFS outcomes compared those whose changes were above cut-off values. Among the patients with mCRC treated with anti-VEGF mAb, no associations were found between OS or PFS outcomes and CEA changes. CEA is potentially a good surrogate marker for predicting disease progression and survival outcomes in patients with mCRC receiving first-line systemic chemotherapy alone or chemotherapy with anti-EGFR mAb, whereas it is less effective in those treated with anti-VEGF mAb. [ABSTRACT FROM AUTHOR]

We aimed to investigate the dynamic changes of gene expression profiles and immune microenvironment linked to resistance to cetuximab-based treatments in patients with metastatic colorectal cancer (mCRC). A total of 106 patients with RAS-wild type mCRC who were treated with cetuximab-based treatments were included as the study population. RNA-sequencing and multiplexed immunohistochemistry were performed using paired or unpaired pre-treatment and post-treatment tumor tissues. Differentially expressed gene analysis of paired pre-treatment and post-treatment tumor tissues that develop acquired resistance (AR) identified the AR signature. Gene ontology analysis of the AR signature indicated enrichment of immune-related pathway genes. Among the immune subsets whose abundance was estimated by CIBERSORT, M2 macrophages showed the most prominent positive correlation with the expression of the AR signature. Among the post-treatment samples, progressive disease (PD) tumors showed a significantly higher abundance of M2 macrophages compared to non-PD tumors. These findings were validated by multiplexed immunohistochemistry analysis: the density of CD68+CD206+ M2 macrophages significantly increased at the time of PD following cetuximab-based treatment, whereas it did not consistently change in the tumor pairs of non-PD. In conclusion, a dynamic increase of M2 macrophages is associated with disease progression during cetuximab-based treatment of mCRCs. Targeting M2 macrophages is a promising immunotherapeutic strategy in this clinical context. [ABSTRACT FROM AUTHOR]

Summary: Introduction The combination of an anti-angiogenic agent with cytotoxic chemotherapy is a standard treatment strategy for metastatic colorectal cancer. CKD-516 is an oral vascular disrupting agent that was preliminarily shown to be safe and efficacious as a monotherapy in refractory solid cancers. We evaluated the recommended phase 2 dose, safety, and preliminary efficacy of CKD-516 in combination with irinotecan in treatment-refractory metastatic colorectal cancer. Methods This phase 1 dose-escalation and dose-expansion study included patients with treatment-refractory metastatic colorectal cancer. CKD-516 tablets were administered for five consecutive days followed by two days off in combination with intravenous irinotecan (120 mg/m2) administered on day one of each treatment cycle every two weeks. A traditional 3 + 3 dose-escalation design was used. Results In total, 16 and 23 patients were enrolled in the dose-escalation and dose-expansion cohorts, respectively. The most common adverse events included diarrhea (79%), nausea (74%), vomiting (67%), and neutropenia (62%). No dose-limiting toxicity occurred, and the recommended phase 2 dose was determined at CKD-516/irinotecan doses of 11/120 mg/m2. No cases of cardiac ischemia, cardiac dysfunction, or thromboembolism were reported. Among the 34 patients with available tumor response assessments, one patient achieved partial response (3%) and 26 patients achieved stable disease (76%). The median progression-free survival and overall survival were 4.1 and 11.6 months, respectively. Conclusion This phase 1 study showed that the combination of oral CKD-516 and irinotecan is safe and tolerable in metastatic, treatment-refractory colorectal patients and showed favorable efficacy outcomes. Further studies to confirm these preliminary findings are warranted. Trial registration number NCT03076957 (Registered at March 10, 2017). [ABSTRACT FROM AUTHOR]

Background: Concomitant use of proton pump inhibitors (PPIs) with capecitabine was suggested to be associated with poor outcomes in gastrointestinal cancers. We analyzed the differential impact of PPI use on capecitabine and fluorouracil using the data set from the AXEPT trial, a phase III randomized trial that demonstrated the noninferiority of mXELIRI (modified XELIRI: capecitabine plus irinotecan) to FOLFIRI (leucovorin, fluorouracil, and irinotecan), either with or without bevacizumab in patients with metastatic colorectal cancer. Patients and Methods: Out of the per‐protocol set (n = 620), patients with information on concomitant medications (n = 482) were included in this post hoc analysis. PPI use was defined as concomitant exposure of capecitabine and the use of any PPI for 20% or more of the study period. The treatment‐by‐PPI‐use interaction was examined after adjusting for stratification factors. Results: Of the 482 patients, 49 (10.1%) used PPI. Among the PPI users, the mXELIRI group tended to have poorer overall survival compared with the FOLFIRI group. In contrast, among the nonusers, the overall survival of the mXELIRI group was significantly better than that of the FOLFIRI group. Similarly, a trend of worse progression‐free survival with mXELIRI compared with FOLFIRI was observed in PPI users but not in nonusers. Treatment‐by‐PPI‐use interaction was significant for overall survival and progression‐free survival. Conclusion: The significant interaction between PPI use and the type of fluoropyrimidine in terms of overall and progression‐free survival suggests that fluorouracil could be a more favorable option than capecitabine for patients with metastatic colorectal cancer using PPIs. Implications for Practice: This study showed a significant interaction between the use of proton pump inhibitors (PPIs) and the type of fluoropyrimidines. This interaction mainly comes from the positive impact of PPIs in the survival outcomes in the fluorouracil arm rather than a negative impact of PPIs in the capecitabine arm. The possible drug‐drug interaction shown in this study suggests that fluorouracil, rather than capecitabine, could be a more appropriate choice of fluoropyrimidine for patients who are taking PPIs in the treatment of metastatic colorectal cancer. This article analyzes the differential effect of proton pump inhibitor use on capecitabine and fluorouracil using the data set from the AXEPT trial, which demonstrated the noninferiority of modified capecitabine plus irinotecan with FOLFIRI, either with or without bevacizumab in patients with metastatic colorectal cancer. [ABSTRACT FROM AUTHOR]

There is an unmet medical need for later-line treatment options for patients with metastatic colorectal cancer (mCRC). Considering that, beyond progression, co-treatment with bevacizumab and cytotoxic chemotherapy showed less toxicity and a significant disease control rate, we aimed to evaluate the efficacy of capecitabine and bevacizumab. This single-center retrospective study included 157 patients between May 2011 and February 2018, who received bevacizumab plus capecitabine as later-line chemotherapy after progressing with irinotecan, oxaliplatin, and fluoropyrimidines. The study treatment consisted of bevacizumab 7.5 mg/kg on day 1 and capecitabine 1,250 mg/m2 orally (PO) twice daily on day 1 to 14, repeated every 3 weeks. The primary endpoint was progression-free survival (PFS). The median PFS was 4.6 months (95% confidence interval [CI] 3.9–5.3). The median overall survival (OS) was 9.7 months (95% CI 8.3–11.1). The overall response rate was 14% (22/157). Patients who had not received prior targeted agents showed better survival outcomes in the multivariable analysis of OS (hazard ratio [HR] = 0.59, 95% CI 0.43–0.82, P = 0.002) and PFS (HR = 0.61, 95% CI 0.43–0.85, P = 0.004). Bevacizumab plus capecitabine could be a considerably efficacious option for patients with mCRC refractory to prior standard treatments. [ABSTRACT FROM AUTHOR]

Antibodies against epidermal growth factor receptor (EGFR), panitumumab, a fully human monoclonal antibody, and cetuximab, a human/mouse chimeric monoclonal antibody, have shown clinical efficacy in metastatic colorectal cancer (mCRC). In the phase 3 noninferiority ASPECCT (ClinicalTrials.gov, NCT01001377) study, panitumumab was demonstrated to be noninferior to cetuximab and provided a similar overall survival benefit for patients with chemotherapy-refractory wild-type KRAS exon 2 mCRC. However, some patients eventually develop resistance to anti-EGFR therapy. EGFR p.S492R mutation was previously identified as conferring resistance to cetuximab, but not to panitumumab. This biomarker study analyzed plasma samples from ASPECCT collected at both baseline and posttreatment. No EGFR p.S492R mutations were identified at baseline; however, after treatment the EGFR p.S492R mutation was detected in 1% of patients treated with panitumumab versus 16% of those treated with cetuximab, supporting that, in a large population, this mutation is more likely to be induced by cetuximab than by panitumumab. There were, however, no significant differences in progression-free survival or overall survival between patients who were wild-type compared with those with the S492R mutation within the cetuximab arm or the overall population. These results may support targeting treatment to small patient subgroups based on the presence of emerging EGFR mutations and provide a molecular rationale for rechallenging with a different anti-EGFR agent in patients who develop resistance. Prospective studies are needed to evaluate the efficacy of panitumumab in the EGFR p.S492R mutant population. [ABSTRACT FROM AUTHOR]

Background: Epithelial-mesenchymal transition (EMT) is the most common cause of death in colorectal cancer (CRC). In this study, we investigated the functional roles of miRNA-17-5p in EMT of CRC cells.Methods: In order to determine if miRNA-17-5p regulated EMT, the precursors and inhibitors of miR-17-5p were transduced into four CRC cells. To evaluate the regulatory mechanism, we performed argonaute 2 (Ago2) immunoprecipitation (IP) and luciferase assay. In addition, we used an intra-splenic injection mouse model of BALB/c nude mice to investigate the metastatic potential of miRNA-17-5p in vivo.Results: The miRNA-17-5p expression was lower in primary CRC tissues with metastasis than in primary CRC tissues without metastasis in our RNA sequencing data of patient tissue. Real-time quantitative PCR revealed that miRNA-17-5p was inversely correlated with that of vimentin in five CRC cell lines. Over-expression of miRNA-17-5p decreased vimentin expression and inhibited cell migration and invasion in both LoVo and HT29 cells. However, inhibition of miRNA-17-5p showed the opposite effect. Ago2 IP and luciferase assay revealed that miRNA-17-5p directly bound to the 3'UTR of VIM mRNA. Furthermore, miRNA-17-5p inhibited the metastasis of CRC into liver in vivo.Conclusions: Our results demonstrated that miRNA-17-5p regulates vimentin expression, thereby regulating metastasis of CRC. [ABSTRACT FROM AUTHOR]

PURPOSE: ERBB2 amplification (human epidermal growth factor receptor 2 positivity [HER2+]) in metastatic colorectal cancer (mCRC) has important therapeutic implications that necessitate the need for accurate diagnostics. The study purpose was to establish and validate harmonized diagnostic criteria for HER2+ mCRC among 3 groups (GI-SCREEN-Japan, NCTN-SWOG-USA, and Korea). PATIENTS AND METHODS: We assessed HER2 status by immunohistochemistry (IHC), ERBB2/CEP17 ratio, gene copy number (GCN) by fluorescence in situ hybridization (FISH), and copy number variation (CNV) using two targeted next-generation sequencing (NGS) panels. Tumor samples from 475 and 16 patients with mCRC in exploratory and validation cohorts, respectively, were used for cross-validation of the NGS panels. RESULTS: Consensus diagnostic criteria among the 3 groups for HER2+ mCRC were established as follows: IHC 3+ or IHC 2+ and ERBB2/CEP17 ratio by FISH ≥ 2.0, tumor content > 10% for surgically resected specimens, and necessary tumor content not defined for biopsy specimens. The median GCN and CNV for HER2+ patients were 10.9 and 27.7 compared with 2.5 (P <.0001) and 3.5 (P <.0001), respectively, in HER2-negative patients. These findings were validated in a validation cohort (GCN, 16.2 v 2.4 [ P =.0002]; CNV, 42.5 v 2.0 [ P =.0003]). GCN correlated with CNV in both cohorts (exploratory, r = 0.90; validation, r = 0.97; P <.0001). CNV in cross-validation of the 2 NGS panels also showed a strong correlation (r = 0.98; P <.0001). CNV in patients who fulfilled the consensus criteria was > 4.0 in all, which demonstrates the accuracy of the IHC/FISH criteria and cross-validation of NGS panels. CONCLUSION: We have established and verified harmonized diagnostic criteria for HER2+ and demonstrated consistency between IHC/FISH and CNV determined by NGS in mCRC. [ABSTRACT FROM AUTHOR]

Summary: Lanreotide autogel is a long-acting somatostatin analogue with proven efficacy and safety in patients with well-differentiated (WD) gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) in a prior randomized phase III trial (CLARINET). However, the CLARINET study only enrolled patients with Ki-67 index <10%, and few patients of Asian ethnicity were included. We retrospectively analyzed the efficacy and safety of lanreotide in Korean patients with GEP-NETs in the daily practice setting. Between January 2015 and May 2018, 64 patients with metastatic WD GEP-NETs received lanreotide at Asan Medical Center, Seoul, Korea. Of them, 45 (70.3%) patients who received lanreotide as monotherapy were included in the current analysis. The most common primary tumor site was the pancreas (n = 22, 48.9%), followed by the rectum (10, 22.2%) and the small bowel (7, 15.6%). According to RECIST v1.1, a partial response was achieved in one patient (2.2%) and stable disease was achieved in 40 patients (88.9%). The median progression-free survival (PFS) was 16.4 months (95% confidence interval, 9.5–23.3 months). There were no differences in PFS according to the primary tumor site (p = 0.77). Hepatic tumor volume > 25% and prior systemic therapy were significantly associated with poorer PFS in the multivariate analysis. Lanreotide is well-tolerated and effective for Korean patients with GEP-NETs in the daily practice setting. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to evaluate the value of 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for early prediction of standard anatomic response and survival outcomes in patients with metastatic colorectal cancer (mCRC) receiving Regorafenib. Methods: Sixty-eight patients with mCRC refractory to standard cytotoxic chemotherapy were enrolled and received Regorafenib (160 mg/day on days 1–21, following a 7-day break). Standard anatomical response was evaluated every 8 weeks. Both scans were performed before and on day 21 of Regorafenib. Results: Of the 61 patients included in per-protocol analysis, complete response was not observed, but partial response was observed in 8.2% (n = 5), stable disease in 67.2% (n = 41), and progressive disease in 24.6% (n = 15). The objective response rate was 8.2% and disease control rate 75.4%. Five responders (8.2%) and 13 non-responders (21.3%) met the CT and 18F-FLT PET/CT criteria (maximum standardized uptake value decrease ≥ 10.6% for responders). Forty-three (70.5%) exhibited discordant responses on CT and 18F-FLT PET/CT (McNemar test, P < 0.001). At a median follow-up of 8.9 months, median progression-free survival (PFS) and median overall survival (OS) were 3.6 months (95% confidence interval [CI], 3.34–3.80 months) and 8.5 months (95% CI, 6.95–10.10 months), respectively. Comparison of PFS and OS according to 18F-FLT PET/CT response revealed slightly longer PFS (P = 0.015) in responders, but the correlation with OS was not significant. The PET Response Criteria in Solid Tumours (PERCIST) of 18F-FDG PET/CT revealed differences in PFS and OS between partial metabolic response (PMR) and non-PMR (P = 0.048 and P = 0.014, respectively), and between progressive metabolic disease (PMD) and non-PMD (P = 0.189 and P = 0.007, respectively). Conclusions: Survival outcome was significantly associated with PERCIST using 18F-FDG PET/CT but the change of 18F-FLT uptake was only slightly associated with PFS. 18F-FDG PET/CT can be used as imaging biomarker to predict clinical outcomes early in patients with mCRC receiving Regorafenib. [ABSTRACT FROM AUTHOR]

Background: Microsatellite-stable metastatic colorectal cancer is typically unresponsive to immunotherapy. This phase 3 study was designed to assess atezolizumab plus cobimetinib in metastatic colorectal cancer. Here, we report the comparison of atezolizumab plus cobimetinib or atezolizumab monotherapy versus regorafenib in the third-line setting.Methods: IMblaze 370 is a multicentre, open-label, phase 3, randomised, controlled trial, done at 73 academic medical centres and community oncology practices in 11 countries. Patients aged at least 18 years with unresectable locally advanced or metastatic colorectal cancer, baseline Eastern Cooperative Oncology Group performance status of 0-1, and disease progression on or intolerance to at least two previous systemic chemotherapy regimens were enrolled. We used permuted-block randomisation (block size four) to assign patients (2:1:1) via an interactive voice and web response system to atezolizumab (840 mg intravenously every 2 weeks) plus cobimetinib (60 mg orally once daily for days 1-21 of a 28-day cycle), atezolizumab monotherapy (1200 mg intravenously every 3 weeks), or regorafenib (160 mg orally once daily for days 1-21 of a 28-day cycle). Stratification factors were extended RAS status (wild-type vs mutant) and time since diagnosis of first metastasis (<18 months vs ≥18 months). Recruitment of patients with high microsatellite instability was capped at 5%. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. IMblaze370 is ongoing and is registered with ClinicalTrials.gov, number NCT02788279.Findings: Between July 27, 2016, and Jan 19, 2017, 363 patients were enrolled (183 patients in the atezolizumab plus cobimetinib group, 90 in the atezolizumab group, and 90 in the regorafenib group). At data cutoff (March 9, 2018), median follow-up was 7·3 months (IQR 3·7-13·6). Median overall survival was 8·87 months (95% CI 7·00-10·61) with atezolizumab plus cobimetinib, 7·10 months (6·05-10·05) with atezolizumab, and 8·51 months (6·41-10·71) with regorafenib; the hazard ratio was 1·00 (95% CI 0·73-1·38; p=0·99) for the combination versus regorafenib and 1·19 (0·83-1·71; p=0·34) for atezolizumab versus regorafenib. Grade 3-4 adverse events were reported in 109 (61%) of 179 patients in the atezolizumab plus cobimetinib group, 28 (31%) of 90 in the atezolizumab group, and 46 (58%) of 80 in the regorafenib group. The most common all-cause grade 3-4 adverse events in the combination group were diarrhoea (20 [11%] of 179), anaemia (ten [6%]), increased blood creatine phosphokinase (12 [7%]), and fatigue (eight [4%]). Serious adverse events were reported in 71 (40%) of 179 patients in the combination group, 15 (17%) of 90 in the atezolizumab group, and 18 (23%) of 80 in the regorafenib group. Two treatment-related deaths occurred in the combination group (sepsis) and one in the regorafenib group (intestinal perforation).Interpretation: IMblaze370 did not meet its primary endpoint of improved overall survival with atezolizumab plus cobimetinib or atezolizumab versus regorafenib. The safety of atezolizumab plus cobimetinib was consistent with those of the individual drugs. These results underscore the challenge of expanding the benefit of immunotherapy to patients whose tumours have lower baseline levels of immune inflammation, such as those with microsatellite-stable metastatic colorectal cancer.Funding: F Hoffmann-La Roche Ltd/Genentech Inc. [ABSTRACT FROM AUTHOR]

Background. Denosumab therapy is used to reduce skeletalrelated events in metastatic bone disease (MBD). There have been reports of atypical femoral fracture (AFF) in osteoporotic patients treated with denosumab but none in the context of higher dose and more frequent denosumab therapy for MBD. The goal of this study was to assess the incidence of AFF in MBD. Patients and Methods.We conducted a retrospective review of 253 patients who received a minimum of 12 doses of denosumab at 120 mg each for MBD. To identify patients with asymptomatic atypical stress reactions in the lateral subtrochanteric femur (which precede fractures), we reviewed the skeletal images of 66 patients who had received at least 21 doses of denosumab for AFF features. Results. These patients received a median of 17 doses, with a median treatment duration of 23 months. There was 1 case of undiagnosed clinical AFF detected after chart review and 2 cases of subclinical atypical femoral stress reaction observed on imaging review after 23 doses of denosumab over 33 months, 28 doses over 27 months, and 21 doses over 21 months, respectively. Scout computed tomography films showed diffuse cortical thickening of diaphysis with localized periosteal reaction of lateral femoral cortex. Bone scan and magnetic resonance imaging scan of 2 patients with stress reactions confirmed the diagnosis. Conclusion. The incidence of clinical AFF in this context is 0.4% (1/253; 95% confidence interval [CI] 0.1%-2.2%), and the incidence of atypical femoral stress reaction based on imaging review is 4.5% (3/66; 95% CI 1.6%-12.5%). Clinicians should be aware of the clinical prodrome (which may or may not be present) and antecedent imaging changes associated with AFF. [ABSTRACT FROM AUTHOR]

Purpose The primary analysis of the ASPECCT study demonstrated that panitumumab was non-inferior to cetuximab for overall survival (OS) in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (mCRC). Here, we report the final analysis results of ASPECCT. Patients and methods Patients with wild-type KRAS exon 2 mCRC who progressed on or were intolerant to irinotecan- or oxaliplatin-based chemotherapy were randomised to receive panitumumab 6 mg/kg once every 2 weeks or cetuximab (400 mg/m 2 ) followed by 250 mg/m 2 weekly. The primary end-point was OS assessed for non-inferiority. Patients were followed for survival for 24 months after the last patient was randomised and a final analysis was conducted. No formal hypothesis testing was done. Post hoc analyses of outcomes by prior bevacizumab exposure, worst-grade skin toxicity (0–1 versus 2–4) and worst-grade hypomagnesaemia (0 versus 1–4) were conducted. Results Nine hundred ninety-nine patients were randomised and received ≥1 treatment dose (panitumumab, n = 499; cetuximab, n = 500). Median OS was 10.2 months with panitumumab versus 9.9 months with cetuximab (hazard ratio = 0.94; 95% confidence interval = 0.82–1.07). Median progression-free survival was 4.2 months with panitumumab and 4.4 months with cetuximab (hazard ratio = 0.98; 95% confidence interval = 0.87–1.12). Longer OS was observed for patients with increased skin toxicity and with hypomagnesaemia in both arms. Furthermore, OS was longer for patients with prior bevacizumab exposure treated with panitumumab than with cetuximab. The observed safety profiles were consistent with previous studies. Conclusion Consistent with the primary analysis, the final analysis of ASPECCT showed panitumumab was non-inferior to cetuximab for OS for patients with chemotherapy-refractory, wild-type KRAS exon 2 mCRC. Trial registration: ClinicalTrials.gov , NCT01001377 . [ABSTRACT FROM AUTHOR]

Using our data set (GSE50760) previously established by RNA sequencing, the present study aimed to identify upregulated genes associated with colorectal cancer (CRC) liver metastasis (CLM) and verify their biological behavior. The potential roles of candidate genes in tumors were assessed using cell proliferation and invasion assays. Tissue samples were collected from 18 CRC patients with synchronous CLM and two CRC cell lines (SW480 and SW620) were used for transfection and cloning. The roles of the genes identified in CLM were verified using immunohistochemistry in 48 nude mice after intrasplenic transplantation of CRC cells. mRNA and protein expression was determined by quantitative real-time reverse transcription polymerase chain reaction and western blot, respectively. Nine genes were initially selected according to the relevance of their molecular function and biological process and, finally, ALDH1A1 and IGFBP1 were chosen based on differential mRNA expression and a positive correlation with protein expression. The overexpression of ALDH1A1 and IGFBP1 significantly and time-dependently decreased cell proliferation (p ≤ 0.001–0.003) and suppressed invasiveness by ≥3-fold over control cells (p < 0.001) in the SW480 cell line, whereas they had a slight effect on reducing SW620 cell proliferation. The protein expression levels of E-cadherin, N-cadherin, claudin-1, and vimentin were significantly higher in CLM than in primary tumor tissues (p < 0.05). However, the cadherin switch, namely, N-cadherin overexpression with reduced E-cadherin expression, was not observed in CLM tissues and transfected CRC cells. Irrespective of reduced proliferation and invasion found on in vitro cell assays, persistent overexpression of β-catenin, vimentin, and ZO-1 in IGFBP1-overexpressing SW480 cells possibly contributed to CLM development in mice implanted with IGFBP1-overexpressing SW480 cells (CLM occurrences: SW480/IGFBP1-transfected mice vs. SW480/vector- and SW480/ALDH1A1-transfected mice, 4/8 vs. 0/10, p = 0.023). In conclusion, ALDH1A1 and IGFBP1 are differentially overexpressed in CLM and may play a dual role, functioning as both tumor suppressors and metastasis promoters in CRC. [ABSTRACT FROM AUTHOR]

Background: Limited data describe the prognosis after stereotactic ablative radiotherapy for lung metastases arising from colorectal cancer. Thus, we evaluated treatment outcomes of stereotactic ablative radiotherapy for those patients.Methods: The study involved patients received stereotactic ablative radiotherapy for one to three lung metastases arising from colorectal cancer at a single institution. A total dose of 40-60 Gy (median, 48 Gy) in three or four fractions was prescribed.Results: A total of 79 metastatic lung lesions from 50 patients who underwent curative resection for their primary colorectal cancer or salvage treatment at a recurrent site were included. The one- and three-year local control rates were 88.7 % and 70.6 %, respectively. The three-year overall survival and progression-free survival rates were 64.0 % and 24.0 %, respectively. Patients with tumor volume ≤1.5 mL had a significantly better overall survival rate than those with tumor volume >1.5 mL (68.0 % vs. 60.0 % at three-year, p = 0.02). Local control was associated with a trend towards better survival (p = 0.06). No pulmonary complications greater than grade 2 were observed.Conclusion: Stereotactic ablative radiotherapy is a competitive treatment modality for the management of lung metastases arising from colorectal cancer. [ABSTRACT FROM AUTHOR]

Purpose: A UGT1A1 genotype-directed dose escalation of irinotecan (CPT-11) was performed in patients with metastatic colorectal cancer receiving first-line FOLFIRI chemotherapy. Methods: Patients were genotyped for UGT1A1 and stratified according to the number of defective alleles (DA; *28 and *6). The irinotecan dose was escalated with a fixed dose of 5-fluorouracil and leucovorin in a standard 3 + 3 design. Results: In 43 enrolled patients, the maximum tolerated dose (MTD) was 300 mg/m2 for the 1 DA group, while the MTD was not reached for the 0 DA group with 1 dose-limiting toxicity (DLT) at 330 mg/m2 and for the 2 DA group with 0 DLT at 150 mg/m2. Because of the risk of being exposed to unsafe doses, the trial was terminated before the MTD was reached in the 0 DA and 2 DA groups. The recommended doses were 300 (0 DA), 270 (1 DA) and 150 (0 DA) mg/m2. The 2 DA group displayed 27% lower SN-38 exposure levels relative to the 0 and 1 DA groups (95% CI, 0.47-1.15). Conclusions: The MTD of irinotecan differed according to the UGT1A1 genotype, and higher doses of irinotecan are feasible with sLV5FU2 compared to the present regulatory approved doses. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Purpose: To identify the indication and prognostic significance of lateral lymph node (LLN) excision in locally advanced rectal cancer patients underwent preoperative chemoradiotherapy. Methods: Included were 67 consecutive patients with suspicious LLN metastasis who underwent chemoradiotherapy and surgery including selective LLN excision (82 excisions). The excisions were grouped according to the presence of LLN metastasis and compared in terms of the clinicopathological findings and oncological results. The correlation between the largest short-axis diameter of LLN measured by imaging and metastasis rates was explored. Results: LLN metastases were identified in 32 excisions (40.0 %). The calculated short-axis LLN diameter predicting metastasis was 11.7 mm (before chemoradiotherapy) and 11.4 mm (before surgery). LLN metastasis was observed more frequently in the low rectum ( p = 0.031) and associated with higher CEA levels ( p = 0.048). The 3-year overall survival rates for patients with and without LLN metastasis were 60.3 % and 90.3 % ( p = 0.048), while the 3-year disease-free survival rates were 31.4 % and 70.5 % ( p = 0.009). The hazard ratio of LLN metastasis for recurrence was 2.938 (95 % CI = 1.258–6.863). Conclusions: LLN metastasis in rectal cancer patients underwent chemoradiotherapy was a distinct poor prognostic factor. Selective LLN excision based on imaging studies may have a role for such patients. [ABSTRACT FROM AUTHOR]

Background: Doses and schedules of the combination of S-1 and cisplatin for the treatment of advanced gastric cancer (AGC) have not been standardized. We therefore evaluated the efficacy and feasibility of a 3-week schedule of S-1 and cisplatin in patients with AGC, as well as assessing factors prognostic of patient outcomes. Methods: A total of 159 patients with AGC were treated with S-1 (40 mg/m 2 bid on days 1–14) and cisplatin (60 mg/m 2 IV on day 1) between January 2004 and December 2008. Results: Median follow-up duration was 20.0 months (range, 11.4–48.5 months), during which time 129 patients (81.1%) died. Patients received a median 6 cycles of chemotherapy (range, 1–19 cycles). Among the 59 patients with measurable disease, 1 achieved a complete response (1.7%) and 24 (40.7%) had partial responses, giving an overall response rate of 42.4% (95% CI, 23.0–61.8%). The median progression-free survival (PFS) was 5.8 months (95% CI, 4.8–6.9 months), and the median overall survival (OS) was 11.3 months (95% CI, 9.6–13.0 months). Multivariate analysis showed that initial metastasis, bone metastasis, and liver metastasis were independent prognostic factors for reduced PFS, whereas poor performance status, initial metastasis, and bone metastasis were prognostic for reduced OS. Application of a previous prognostic model showed that observed PFS and OS survival curves for patients in various risk groups differed significantly ( P < 0.001 each). Conclusions: A 3-week regimen of S-1 plus cisplatin was active and well tolerated as first-line treatment in patients with AGC. Disease status and bone metastasis were the most important prognostic factors. [ABSTRACT FROM AUTHOR]

Objectives: We investigated the efficacy and safety of the combination of irinotecan (CPT-11) and S-1 (IRIS regimen) as a first-line treatment in patients with metastatic colorectal cancer. We also evaluated the association between UGT1A1 and CYP2A6 polymorphisms and clinical phenotypes. Methods: The patients received CPT-11 (225 mg/m2) on day 1 and S-1 (80 mg/m2) on days 1-14 every 3 weeks. The association of the UGT1A1 (*6 and *28) and CYP2A6(*4, *7, *9, and *10) polymorphisms with toxicities and efficacy were analyzed. Results: Thirty patients were treated. The overall response rate was 66.7% (95% CI 48.7-84.6). The median time to progression was 7.6 months (95% CI 5.8-9.5). The most common grade 3/4 hematologic and non-hematologic toxicity were neutropenia (53.4%) and diarrhea (16.7%), respectively. The allele frequencies of UGT1A1*6 and *28 were 15.5 and 10.3%, respectively. The frequencies of CYP2A6*4, *7, *9, and *10 were 15.5, 8.6, 29.3, and 3.5%, respectively. Stratification of patients according to the number of UGT1A1*28 and *6 alleles showed a significant correlation between the number of defective alleles and the incidence of grade 3/4 neutropenia. Conclusions: Our results indicate that IRIS is a promising first-line regimen in patients with metastatic colorectal cancer. Severe neutropenia may be associated with interindividual variations in UGT1A1 polymorphisms. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Temsirolimus is a standard of care in patients with metastatic renal cell carcinoma (mRCC) with poor risk factors. The role of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) remains poorly defined in this setting. Methods: Records of our center were examined to identify patients with mRCC and 3 or more poor prognosis factors, as determined in the Advanced Renal Cell Carcinoma (ARCC) trial, who had been treated with VEGFR TKIs. Their baseline characteristics, radiologic response, adverse events, and survival status were assessed. Results: The 88 patients who met our inclusion criteria had a median age of 56 years (range 17-83 years). We observed clear cell histology in 71 (81%) patients, and 52 (59%) underwent prior nephrectomy. Seventy-six patients (86%) were treated with sunitinib and 10 (11%) with sorafenib. Of 85 patients with measurable lesions, 19 (22%) showed objective response, with disease control achieved in 49 (56%). At a median follow-up of 29.6 months, the median time to progression was 5.0 months (95% CI, 3.5-6.5 months) and the median overall survival (OS) was 9.3 months (95% CI, 7.1-11.5 months). Neutrophil count (>ULN), bone metastasis, and lymph node metastasis were independent prognostic factors for OS, whereas prior nephrectomy was not. Conclusions: VEGFR TKIs, especially sunitinib, are active and tolerated by mRCC patients with poor risk features. [ABSTRACT FROM AUTHOR]

Background and Aim: The aim of the present study was to evaluate associations between mismatch repair (MMR) status and clinicopathological characteristics and prognosis using immunohistochemistry (IHC) and microsatellite instability (MSI) analyses in a prospective cohort of a large number of accumulated samples. Methods: Tumor tissue samples obtained during curative surgery ( n = 2028) were analyzed using both MLH1/MSH2 IHC and MSI assays. Clinicopathological parameters and survival outcomes were compared according to IHC and MSI results. The median follow-up period was 43 months (range: 1-85 months). Results: IHC identified 207 tumor samples (10.2%) with a loss of either MLH1 or MSH2 expression. The MSI analysis identified 203 tumor samples (10%) with high-frequency MSI (MSI-H). Patients with MMR defects were younger, and had tumors characterized by right-colon predilection; large-size, infrequent lymph node metastasis; poorly-differentiated or mucinous histology, and synchronous adenomas ( P < 0.001-0.008). Patients with MSI-H status had higher 4-year disease-free survival rates than patients with microsatellite stable status (90.8% vs 80.6%, P = 0.001). A multivariate analysis showed that MSI-H status was a good prognostic factor for recurrence (hazard ratio: 0.48, 95% confidence interval: 0.30-0.83, P = 0.007). Conclusions: Patients with MMR defects had distinct clinicopathological characteristics, including a lower risk of recurrence. IHC and MSI analyses provided complementary information regarding specific clinicopathological parameters and prognosis. [ABSTRACT FROM AUTHOR]

The combination of gemcitabine with protracted 5-fluorouracil(5-FU) in the treatment of metastatic pancreatic cancer has shown activity with tolerable toxicity. The administration of UFT may simulate the effects of a protracted infusion of 5-FU. Patients with previously untreated metastatic or unresectable measurable pancreatic adenocarcinoma received gemcitabine (800 mg/m2 i.v., administered as an 80-min infusion on days 1, 8 and 15), UFT (200 mg/m2/day, on days 1 to 21), and oral leucovorin (90 mg/day, on days 1 to 21). Thirty patients were enrolled in this study. Five patients had partial responses, with an overall response rate of 17% (5/30), using the intent-to-treat principle (95% confidence interval (CI), 3–30%). Nine out of 25 (36%) patients experienced clinical benefit responses (95% CI; 17–55%). The median time to progression was 3.0 months, and the median overall survival was 7.2 months. The principal adverse event was neutropenia. The combination of gemcitabine, UFT, plus oral leucovorin shows significant antitumor activity and a beneficial clinical effect with an acceptable level of toxicity. [ABSTRACT FROM AUTHOR]

Background: Pembrolizumab has shown improved progression-free survival versus chemotherapy in patients with newly diagnosed microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. However, the treatment's effect on overall survival in this cohort of patients was unknown. Here, we present the final overall survival analysis of the KEYNOTE-177 study.Methods: This randomised, open-label, phase 3 study was done in 193 academic medical centres and hospitals in 23 countries. We recruited patients aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. Patients were randomly assigned (1:1) in blocks of four using an interactive voice response system or integrated web response system to intravenous pembrolizumab 200 mg every 3 weeks or to the investigator's choice of intravenous mFOLFOX6 (oxaliplatin 85 mg/m2 on day 1, leucovorin 400 mg/m2 on day 1, and fluorouracil 400 mg/m2 bolus on day 1 followed by a continuous infusion of 1200 mg/m2 per day for 2 days on days 1-2) or intravenous FOLFIRI (irinotecan 180 mg/m2 on day 1, leucovorin 400 mg/m2 on day 1, and fluorouracil 400 mg/m2 bolus on day 1 followed by a continuous infusion of 1200 mg/m2 per day for 2 days on days 1-2), every 2 weeks with or without intravenous bevacizumab 5 mg/kg every 2 weeks or intravenous weekly cetuximab (first dose 400 mg/m2, then 250 mg/m2 for every subsequent dose). Patients receiving chemotherapy could cross over to pembrolizumab for up to 35 treatment cycles after progression. The co-primary endpoints were overall survival and progression-free survival in the intention-to-treat population. KEYNOTE-177 is registered at ClinicalTrials.gov, NCT02563002, and is no longer enrolling patients.Findings: Between Feb 11, 2016, and Feb 19, 2018, 852 patients were screened, of whom 307 (36%) were randomly assigned to pembrolizumab (n=153) or chemotherapy (n=154). 93 (60%) patients crossed over from chemotherapy to anti-PD-1 or anti-PD-L1 therapy (56 patients to on-study pembrolizumab and 37 patients to off-study therapy). At final analysis (median follow-up of 44·5 months [IQR 39·7-49·8]), median overall survival was not reached (NR; 95% CI 49·2-NR) with pembrolizumab vs 36·7 months (27·6-NR) with chemotherapy (hazard ratio [HR] 0·74; 95% CI 0·53-1·03; p=0·036). Superiority of pembrolizumab versus chemotherapy for overall survival was not demonstrated because the prespecified α of 0·025 needed for statistical significance was not achieved. At this updated analysis, median progression-free survival was 16·5 months (95% CI 5·4-38·1) with pembrolizumab versus 8·2 months (6·1-10·2) with chemotherapy (HR 0·59, 95% CI 0·45-0·79). Treatment-related adverse events of grade 3 or worse occurred in 33 (22%) of 153 patients in the pembrolizumab group versus 95 (66%) of 143 patients in the chemotherapy group. Common adverse events of grade 3 or worse that were attributed to pembrolizumab were increased alanine aminotransferase, colitis, diarrhoea, and fatigue in three (2%) patients each, and those attributed to chemotherapy were decreased neutrophil count (in 24 [17%] patients), neutropenia (22 [15%]), diarrhoea (14 [10%]), and fatigue (13 [9%]). Serious adverse events attributed to study treatment occurred in 25 (16%) patients in the pembrolizumab group and in 41 (29%) patients in the chemotherapy group. No deaths attributed to pembrolizumab occurred; one death due to intestinal perforation was attributed to chemotherapy.Interpretation: In this updated analysis, although pembrolizumab continued to show durable antitumour activity and fewer treatment-related adverse events compared with chemotherapy, there was no significant difference in overall survival between the two treatment groups. These findings support pembrolizumab as an efficacious first-line therapy in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer.Funding: MSD. [ABSTRACT FROM AUTHOR]

• Cetuximab resistance in colorectal cancer comes with emergent genetic alterations. • Clonal expansion of PCBP1 variant occurred with progression after cetuximab. • Post-cetuximab tumor sample with resistance was enriched with TGF-beta pathway. Recurrent gene mutations and copy number alterations in cancer patients are presumably associated with resistance to targeted therapy. In the present study, we assessed the gene mutations and copy number alterations that recurrently occurred in cetuximab-treated patients with metastatic colorectal cancer (mCRC). Targeted next-generation sequencing was performed in the tumor samples obtained pre- and postcetuximab treatment to assess the variations that occurred during cetuximab treatment. Moreover, we identified the emergent gene mutations (CDK6, EPHA3, ERCC2, MYC, PCMTD1, PIK3CA, PRIM2, RICTOR, and ZNRF3) and copy number alterations (ARAF, BCL2, BRCA2, EGFR, MYC, and SMAD4) that were recurrently observed only in postprogression samples and not in pretreatment or posttreatment samples from patients revealing clinical response. Furthermore, to identify the feasible candidate variations implicated in treatment resistance, we examined the variants with clonal expansion during treatment and discovered PCBP1 as a variant associated with posttreatment progression. Various recurrent mutations were enriched in the TGF-beta signaling pathway. Collectively, we identified recurrent variations in mCRC samples exhibiting post-cetuximab progression. Additionally, future studies are required to evaluate the therapeutic potential of these variations. [ABSTRACT FROM AUTHOR]

Background: In the KEYNOTE-177 study, pembrolizumab monotherapy provided statistically significant and clinically meaningful improvements in progression-free survival versus chemotherapy as first-line treatment in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. To further support the efficacy and safety findings of the KEYNOTE-177 study, results of the health-related quality of life (HRQOL) analyses are reported here.Methods: KEYNOTE-177 is an open-label, randomised, phase 3 trial being done at 192 cancer centres in 23 countries, in patients aged 18 years and older with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had not received previous systemic therapy for metastatic disease. Eligible patients were randomly assigned (1:1) centrally by use of interactive voice response or integrated web response technology to receive pembrolizumab 200 mg intravenously every 3 weeks or investigator's choice chemotherapy (mFOLFOX6 [leucovorin, fluorouracil, and oxaliplatin] or FOLFIRI [leucovorin, fluorouracil, and irinotecan] intravenously every 2 weeks with or without intravenous bevacizumab or cetuximab). Patients and investigators were not masked to treatment assignment. The primary endpoints were progression-free survival (previously reported) and overall survival (data to be reported at the time of the final analysis). HRQOL outcomes were evaluated as prespecified exploratory endpoints. The analysis population comprised all randomly assigned patients who received at least one dose of study treatment and completed at least one HRQOL assessment. HRQOL outcomes were mean change from baseline to prespecified week 18 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EORTC Quality of Life Questionnaire-Colorectal 29 (EORTC QLQ-CR29) scale and item scores, and in the EuroQoL 5 Dimensions 3 Levels (EQ-5D-3L) visual analogue scale and health utility scores; the proportion of patients with improved, stable, or deteriorated scores from baseline to prespecified week 18 in EORTC QLQ-C30 scales and items; and time to deterioration in EORTC QLQ-C30 global health status/quality of life (GHS/QOL), physical functioning, social functioning, and fatigue scores and EORTC QLQ-CR29 urinary incontinence scores. The threshold for a small and clinically meaningful mean difference in EORTC QLQ-C30 score was 5-8 points. This study is registered with ClinicalTrials.gov, NCT02563002 and is ongoing; recruitment is closed.Findings: Between Feb 11, 2016, and Feb 19, 2018, 307 patients were enrolled and randomly assigned to receive pembrolizumab (n=153) or chemotherapy (n=154). The HRQOL analysis population comprised 294 patients (152 receiving pembrolizumab and 142 receiving chemotherapy). As of Feb 19, 2020, median time from randomisation to data cutoff was 32·4 months (IQR 27·7-37·8). Least squares mean (LSM) change from baseline to prespecified week 18 showed a clinically meaningful improvement in EORTC QLQ-C30 GHS/QOL scores with pembrolizumab versus chemotherapy (between-group LSM difference 8·96 [95% CI 4·24-13·69]; two-sided nominal p=0·0002). Median time to deterioration was longer with pembrolizumab versus chemotherapy for GHS/QOL (hazard ratio 0·61 [95% CI 0·38-0·98]; one-sided nominal p=0·019), physical functioning (0·50 [95% CI 0·32-0·81]; one-sided nominal p=0·0016), social functioning (0·53 [95% CI 0·32-0·87]; one-sided nominal p=0·0050), and fatigue scores (0·48 [95% CI 0·33-0·69]; one-sided nominal p<0·0001).Interpretation: Pembrolizumab monotherapy led to clinically meaningful improvements in HRQOL compared with chemotherapy in patients with previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. These data, along with the previously reported clinical benefits, support pembrolizumab as a first-line treatment option for this population.Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether local excision (LE) outcomes were comparable to total mesorectal excision (TME) outcomes in node-positive (cN+) rectal cancer patients who were good responders.Methods and Materials: This retrospective study included clinical T2-3 and cN+ low rectal cancer patient who received preoperative chemoradiotherapy (PCRT) followed by TME or LE. Clinical stage T1 or T4 tumors, upper-to-middle rectal tumors (>7 cm from anal verge), and synchronous distant metastases were excluded. Lymph nodes ≥5 mm in size were defined as tumor-positive, and patients with metastatic lymph nodes >20 mm in size were excluded. Preoperative chemoradiotherapy comprised radiation (50-50.4 Gy/25-28 fractions over 5 weeks) with 2 cycles of 5-fluorouracil or oral capecitabine. Propensity scores were computed from tumor and patient variables and used for 1-to-1 matched analysis. Local recurrence-free survival, disease-free survival, and overall survival were compared between the 2 matched groups.Results: Between January 2007 and December 2013, 563 and 55 patients underwent TME and LE, respectively. The median follow-up period was 54 months. In propensity score-matched analysis, 48 patients were included in each group. No statistical differences were observed in 3-year local recurrence-free survival (97.9% vs 97.9%, P = .994), 3-year disease-free survival (91.5% vs 91.4%, P = .968), or 3-year OS (93.7% vs 97.9%, P = .809) between the TME and LE groups.Conclusions: In clinical N+ rectal cancer patients, oncologic outcomes of PCRT followed by LE were comparable to those of TME; this finding might be applicable only to those patients with good response in the primary tumor and small lymph node metastases. [ABSTRACT FROM AUTHOR]

Background The RAISE phase III clinical trial demonstrated that ramucirumab + (folinic acid plus 5-fluorouracil plus irinotecan) FOLFIRI significantly improved overall survival (OS) versus placebo + FOLFIRI for second-line metastatic colorectal carcinoma (mCRC) patients failing bevacizumab- and oxaliplatin-based chemotherapy (hazard ratio [HR] = 0.84, 95% CI = 0.73–0.98, P = 0.022). Post hoc analyses of RAISE patient data examined the association of carcinoembryonic antigen (CEA) subgroups with efficacy parameters. Methods CEA subgroups (≤10 versus >10 ng/ml) were based on 2X upper limit of normal (ULN) (5 ng/ml). The Kaplan–Meier method estimated the median OS and the progression-free survival (PFS). Log-rank test compared the survival distributions within the subgroups. Hazard ratio (HR) (95% confidence interval [CI]) and treatment-by-subgroup interaction p-values were calculated by Cox proportional hazards model. Results Ramucirumab treatment prolonged survival for the CEA ≤10 subgroup (HR = 0.68; 95% CI = 0.50–0.92; P = 0.013) and CEA >10 subgroup (HR = 0.90; 95% CI = 0.76–1.07; P = 0.233). However, the ramucirumab OS benefit over placebo was greater for the CEA ≤10 subgroup than for the CEA >10 subgroup (median OS: 3.6 versus 0.8 months greater, respectively). The interaction P-value between CEA level and treatment effect on OS was 0.088. This trend was observed across randomisation strata and to a lesser extent for PFS (P = 0.594). Conclusions Although patients in both high- and low-CEA subgroups derive OS and PFS benefits from ramucirumab treatment, the low baseline CEA level may identify a subgroup of patients with mCRC who obtain greater benefit from ramucirumab. [ABSTRACT FROM AUTHOR]

Summary Background Angiogenesis is an important therapeutic target in colorectal carcinoma. Ramucirumab is a human IgG-1 monoclonal antibody that targets the extracellular domain of VEGF receptor 2. We assessed the efficacy and safety of ramucirumab versus placebo in combination with second-line FOLFIRI (leucovorin, fluorouracil, and irinotecan) for metastatic colorectal cancer in patients with disease progression during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Methods Between Dec 14, 2010, and Aug 23, 2013, we enrolled patients into the multicentre, randomised, double-blind, phase 3 RAISE trial. Eligible patients had disease progression during or within 6 months of the last dose of first-line therapy. Patients were randomised (1:1) via a centralised, interactive voice-response system to receive 8 mg/kg intravenous ramucirumab plus FOLFIRI or matching placebo plus FOLFIRI every 2 weeks until disease progression, unacceptable toxic effects, or death. Randomisation was stratified by region, KRAS mutation status, and time to disease progression after starting first-line treatment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT01183780 .ld Findings We enrolled 1072 patients (536 in each group). Median overall survival was 13·3 months (95% CI 12·4–14·5) for patients in the ramucirumab group versus 11·7 months (10·8–12·7) for the placebo group (hazard ratio 0·844 95% CI 0·730–0·976; log-rank p=0·0219). Survival benefit was consistent across subgroups of patients who received ramucirumab plus FOLFIRI. Grade 3 or worse adverse events seen in more than 5% of patients were neutropenia (203 [38%] of 529 patients in the ramucirumab group vs 123 [23%] of 528 in the placebo group, with febrile neutropenia incidence of 18 [3%] vs 13 [2%]), hypertension (59 [11%] vs 15 [3%]), diarrhoea (57 [11%] vs 51 [10%]), and fatigue (61 [12%] vs 41 [8%]). Interpretation Ramucirumab plus FOLFIRI significantly improved overall survival compared with placebo plus FOLFIRI as second-line treatment for patients with metastatic colorectal carcinoma. No unexpected adverse events were identified and toxic effects were manageable. Funding Eli Lilly. [ABSTRACT FROM AUTHOR]

Summary: Background: Capecitabine plus oxaliplatin (CapeOX) is one of the reference doublet cytotoxic chemotherapy treatments for patients with metastatic colorectal cancer. We aimed to compare the efficacy and safety of CapeOX with that of S-1 plus oxaliplatin (SOX), a promising alternative treatment for patients with metastatic colorectal cancer. Methods: In this open-label, multicentre, randomised phase 3 trial, we randomly assigned patients (1:1) from 11 institutions in South Korea to receive either CapeOX (capecitabine 1000 mg/m2 twice daily on days 1–14 and oxaliplatin 130 mg/m2 on day 1) or SOX (S-1 40 mg/m2 twice daily on days 1–14 and oxaliplatin 130 mg/m2 on day 1). Treatment was repeated every 3 weeks and continued for as many as nine cycles of oxaliplatin-containing chemotherapy, except in instances of disease progression, unacceptable toxicity, or a patient''s refusal. Maintenance chemotherapy with S-1 or capecitabine was allowed after discontinuation of oxaliplatin. Randomisation was done with a computer-generated sequence (stratified by primary sites, previous adjuvant or neoadjuvant treatment, and the presence of measurable lesions). The primary endpoint was to show non-inferiority of SOX relative to CapeOX in terms of progression-free survival (PFS). The primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00677443. Findings: Between May 14, 2008, and Sept 23, 2009, we randomly assigned 168 patients to receive SOX and 172 to receive CapeOX. Median PFS was 8·5 months (95% CI 7·6–9·3) in the SOX group and 6·7 months (6·2–7·1) in the CapeOX group (hazard ratio, 0·79 [95% CI 0·60–1·04]; pnon-inferiority<0·0001, plog-rank=0·09). The upper limit of the CI was below the predefined margin of 1·43, showing the non-inferiority of SOX to CapeOX. We recorded a higher incidence of grade 3–4 neutropenia (49 [29%] vs 24 [15%]), thrombocytopenia (37 [22%] vs 11 [7%]), and diarrhoea (16 [10%] vs seven [4%]) in the SOX group than in the CapeOX group. The frequency of any grade of hand-foot syndrome was greater in the CapeOX group than it was in the SOX group (51 [31%] vs 23 [14%]). Interpretation: The SOX regimen could be an alternative first-line doublet chemotherapy strategy for patients with metastatic colorectal cancer. Further investigation is needed to explore its potential when used together with other targeted agents or as adjuvant chemotherapy. Funding: Korea Healthcare Technology Research and Development Project, Ministry of Health and Welfare, South Korea. [Copyright &y& Elsevier]

Abstract: Background: The incidence and prognostic impact of venous thromboembolism (VTE) in patients with advanced gastric cancer (AGC) have not been determined. We therefore investigated the incidence of VTE and the clinical characteristics associated with VTE in AGC patients treated with systemic chemotherapy. Patients/Methods: We retrospectively evaluated the incidence of VTE in 3095 patients diagnosed with inoperable AGC in the Department of Oncology at the Asan Medical Center. Results: We found that the 1-year cumulative incidence of VTE was 3.5% and incidence rate was 1.88 events/100 person-years (95% confidence interval, 1.54–2.28 events/100 person-years). Overall survival (OS) was poorer in patients concurrently diagnosed with AGC and VTE than in patients with VTE detected after AGC diagnosis (median OS, 4.5months versus 10.7months; HR, 2.171; 95%CI, 1.2–3.93; P =0.009). Multivariate analysis identified female sex, primary tumour site on the upper portion of stomach (cardia/fundus versus body/antrum), two or more metastatic sites, lung metastasis and increased baseline CA19-9 level as independent risk factors for VTE. OS rates were significantly lower in patients with than without VTE (1-year OS, 40% versus 45.3%; 2-year OS, 10.5% versus 19.3%; HR, 1.23; 95% CI, 1.0–1.52; P =0.048). Multivariate analysis, however, showed that VTE was not a statistically significant factor affecting survival (P =0.82). Conclusions: The incidence rate of VTE was lower in Korean than in Caucasian patients with AGC. VTE was not an independent prognostic factor, although patients with VTE detected at the time of AGC diagnosis had markedly poorer prognosis. [Copyright &y& Elsevier]

Background Irinotecan have been well known to correlate between UGT1A1 polymorphisms (UGT1A1) and adverse events. Modified XELIRI (irinotecan 200 mg/m2 on day 1, capecitabine 1600 mg/m2 on days 1 to14 every 3 weeks) has shown non inferiority of overall survival compared with FOLFIRI based on "Asian XELIRI ProjecT" (AXEPT) as second line chemotherapy for patients with mCRC. In this preplanned analysis of the AXEPT trial, we evaluated the relationship between UGT1A1 and the efficacy and safety of irinotecan-based chemotherapy. Methods Patients were randomized FOLFIRI ± bevacizumab (BV) or modified XELIRI ± BV based on UGT1A1 results (wild type, heterozygosity, and homozygosity). With regard to irinotecan dosage in both treatment arms, the reduced dosage (150mg/m2) were administered in case of homozygosity. Assessed endpoints were overall survival (OS), progression free survival (PFS), overall response rate (ORR), relative dose intensity (RDI) and safety. Result UGT1A1 was available for all 650 randomized patients (wild type, 309 (47.5%) heterozygosity, 291 (44.8%) and homozygosity, 50 (7.7%)). Median OS was of patients with a wild/hetero/homo was 14.3, 18.3 and 9.1 months in FOLFIRI arm and 18.1, 16.3 and 13.0 months in mXELIRI arm, respectively. Median PFS of patients with a wild/hetero/homo was 6.8, 8.8 and 4.8 months in FOLFIRI arm and was 8.3, 8.7 and 6.5 months in mXELIRI arm, respectively. Grade 3, 4 toxicities of special interests (wild/hetero/homo) were neutropenia (35.9%/50.4%/45.8% in FOLFIRI arm and 17.0%/15.7%/21.7% in mXELIRI arm), febrile neutropenia (5.9%/2.3%/4.2% in FOLFIRI arm and 1.4%/4.3%/8.7% in XELIRI arm), and diarrhea (1.3%/6.0%/0% in FOLFIRI arm and 4.8%/10.7%/0% in mXELIRI arm). Conclusions mXELIRI±BV was showed the good efficacy and well tolerated in patients with all UGT1A1 polymorphisms. mXELIRI+BV could be an alternative to FOLFIRI as a standard second line backbone treatment for mCRC. [ABSTRACT FROM AUTHOR]