Search

Introduction: Recommended treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (NACRT) followed by surgery and total mesorectal excision (TME). The role of adjuvant chemotherapy (ACT) in this regimen is still debated. Assessment of Dworak’s tumor regression grade (TRG) after NACRT could potentially select patients who might benefit from ACT.Materials and methods: Data for patients who underwent NACRT and TME for LARC between 2007 and 2014 were retrieved from the Bordet Institute database. Overall survival (OS) and disease-free survival (DFS) were calculated for the whole population, according to whether or not they received ACT, and according to TRG.Results: We included 74 patients (38 males) with a median age of 62.7 years (33-84 years). AJCC stage cIIIb disease was the most frequent (73%). Pathologic complete response (pCR) was achieved in 13 patients (17.6%). ACT was administered to 42 patients (56.8%). Five-year OS and DFS of patients who received ACT or not were 92 and 84.5% (p = ns), and 79.9 and 84.8% (p = ns), respectively. OS was related to TRG (cut-off value of 3) (p = 0.001). ACT administration was not correlated with improved outcomes in any TRG groups.Conclusion: TRG is a prognostic factor for both OS and DFS but does not appear to have a significant benefit for the selection of patients with LARC treated with NACRT who might benefit from the administration of ACT. Prospective randomized trials with larger populations are needed to identify factors that predict which patients may benefit from the administration of ACT. [ABSTRACT FROM AUTHOR]

Celyad recently initiated several clinical trials with the CYAD-01 product, a natural killer group 2D (NKG2D)-based chimeric antigen receptor (CAR), in both solid and hematologic tumor types. This review discusses the unique properties of CYAD-01, expecting to provide a new paradigm to fight against solid tumors. [ABSTRACT FROM AUTHOR]

Introduction: The introduction of targeted drugs has had a significant impact on the approach to assessing tumour response. These drugs often induce a rapid cytostatic effect associated with a less pronounced and slower tumoural volume reduction, thereby impairing the correlation between the absence of tumour shrinkage and the patient's unlikelihood of benefit. The aim of the study was to assess the predictive value of early metabolic response (mR) evaluation after one cycle, and its interlesional heterogeneity to a later metabolic and morphological response assessment performed after three cycles in metastatic colorectal cancer (mCRC) patients treated with combined sorafenib and capecitabine. Methods: This substudy was performed within the framework of a wider prospective multicenter study on the predictive value of early FDG PET-CT response assessment (SoMore study). A lesion-based response analysis was performed, including all measurable lesions identified on the baseline PET. On a per-patient basis, a descriptive 4-class response categorization was applied based upon the presence and proportion of non-responding lesions. For dichotomic response comparison, all patients with at least one resistant lesion were classified as non-responding. Results: On baseline FDG PET-CT, 124 measurable 'target' lesions were identified in 38 patients. Early mR assessments showed 18 patients (47 %) without treatment resistant lesions and 12 patients (32 %) with interlesional response heterogeneity. The NPV and PPV of early mR were 85 % (35/41) and 84 % (70/83), respectively, on a per-lesion basis and 95 % (19/20) and 72 % (13/18), respectively, on a dichotomized per-patient basis. Conclusions: Early mR assessment performed after one cycle of sorafenib-capecitabine in mCRC is highly predictive of non-response at a standard response assessment time. The high NPV (95 %) of early mR could be useful as the basis for early treatment discontinuation or adaptation to spare patients from exposure to non-effective drugs. [ABSTRACT FROM AUTHOR]

Background: This single-arm phase II study investigated the EGFR monoclonal antibody necitumumab plus modified FOLFOX6 (mFOLFOX6) in first-line treatment of locally advanced or metastatic colorectal cancer (mCRC).Methods: Patients received 800-mg intravenous necitumumab (day 1; 2-week cycles), followed by oxaliplatin 85 mg m(-2), folinic acid 400 mg m(-2), and 5-fluorouracil (400 mg m(-2) bolus then 2400 mg m(-2) over 46 h). Radiographic evaluation was performed every 8 weeks until progression. Primary endpoint was objective response rate.Results: Forty-four patients were enrolled and treated. Objective response rate was 63.6% (95% confidence interval 47.8-77.6); complete response was observed in four patients; median duration of response was 10.0 months (7.0-16.0). Median overall survival (OS) and progression-free survival (PFS) were 22.5 (11.0-30.0) and 10.0 months (7.0-12.0), respectively. Clinical outcome was better in patients with KRAS exon 2 wild type (median OS 30.0 months (23.0-NA); median PFS 12.0 (8.0-20.0)), compared with KRAS exon 2 mutant tumours (median OS 7.0 months (5.0-37.0); median PFS 7.0 (4.0-18.0)). The most common grade ⩾3 adverse events were neutropenia (29.5%), asthenia (27.3%), and rash (20.5%).Conclusion: First-line necitumumab+mFOLFOX6 was active with manageable toxicity in locally advanced or mCRC; additional evaluation of the impact of tumour RAS mutation status is warranted. [ABSTRACT FROM AUTHOR]

Background: Tumoral heterogeneity is a major determinant of resistance in solid tumors. FDG-PET/CT can identify early during chemotherapy non-responsive lesions within the whole body tumor load. This prospective multicentric proof-of-concept study explores intra-individual metabolic response (mR) heterogeneity as a treatment efficacy biomarker in chemorefractory metastatic colorectal cancer (mCRC). Methods: Standardized FDG-PET/CT was performed at baseline and after the first cycle of combined sorafenib (600mg/day for 21 days, then 800mg/day) and capecitabine (1700 mg/m²/day administered D1-14 every 21 days). MR assessment was categorized according to the proportion of metabolically non-responding (non-mR) lesions (stable FDG uptake with SUVmax decrease <15%) among all measurable lesions. Results: Ninety-two patients were included. The median overall survival (OS) and progression-free survival (PFS) were 8.2 months (95% CI: 6.8–10.5) and 4.2 months (95% CI: 3.4–4.8) respectively. In the 79 assessable patients, early PET-CT showed no metabolically refractory lesion in 47%, a heterogeneous mR with at least one non-mR lesion in 32%, and a consistent non-mR or early disease progression in 21%. On exploratory analysis, patients without any non-mR lesion showed a significantly longer PFS (HR 0.34; 95% CI: 0.21–0.56, P-value <0.001) and OS (HR 0.58; 95% CI: 0.36–0.92, P-value 0.02) compared to the other patients. The proportion of non-mR lesions within the tumor load did not impact PFS/OS. Conclusion: The presence of at least one metabolically refractory lesion is associated with a poorer outcome in advanced mCRC patients treated with combined sorafenib-capecitabine. Early detection of treatment-induced mR heterogeneity may represent an important predictive efficacy biomarker in mCRC. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Background: Surgery is a curative treatment for patients with locally advanced colon cancer, but recurrences are frequent for those with stage III disease. FOLFOX adjuvant chemotherapy has been shown to improve recurrence-free survival and overall survival by more than 20% and is nowadays considered a standard of care. However, the vast majority of patients will not benefit from receiving cytotoxic drugs because they have either already been cured by surgery or because their tumor cells are resistant to the chemotherapy, for which predictive factors are still not available. Identifying which patients are unlikely to respond to adjuvant chemotherapy from among those who are eligible for such treatment would be a major step towards treatment personalization. It would spare such patients from unnecessary toxicities and would improve the allocation of societal healthcare resources. Methods/design: PePiTA is a prospective, multicenter, non-randomised trial built on the hypothesis that preoperative chemosensitivity testing using FDG-PET/CT before and after one course of FOLFOX can identify the patients who are unlikely to benefit from 6 months of adjuvant FOLFOX treatment for stage III colon cancer. The study's primary objective is to examine the ability of PET/CT-assessed tumor FDG uptake after one course of preoperative chemotherapy to predict the outcome of adjuvant therapy, as measured by 3-year disease-free survival. Secondary objectives are to examine the predictive value of changes in PET/CT-assessed tumor FDG uptake on overall survival, to define the best cut-off value of FDG uptake for predicting treatment outcome, and to analyse the cost-effectiveness of such preoperative chemo-sensitivity testing. At study planning, exploratory translational research objectives were 1) to assess the predictive value of circulating tumor cells for disease-free survival, 2) to examine the predictive value of single nucleotide polymorphisms for disease-free survival with respect to genes related either to toxicity or to drug targets, 3) to assess genomic rearrangements associated with response or resistance to FOLFOX treatment, 4) to identify an immunologic signature associated with metabolic tumor response to FOLFOX therapy and, finally, 5) to create a bank of frozen tumor samples for future studies Discussion: PePiTA is the first study to use the primitive tumor chemosensitivity assessed by metabolic imaging as a guidance for adjuvant therapy in colon cancer. It could pave the way for tailoring the treatment and avoiding useless toxicities for the patients and inadequate expenses for the society. It could also give an interesting insight into tumoral heterogeneity, resistance to chemotherapy, genetic predisposants to oxaliplatin toxicity and immune response to cancer. [ABSTRACT FROM AUTHOR]

Background The study purpose was to assess the predictive value of 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG)–positron emission tomography (PET)/computerized tomography (CT) metabolic response after a single course of chemotherapy in patients with metastatic colorectal cancer (mCRC). Patients and methods FDG–PET/CT scans were carried out at baseline and on day 14 in 41 patients with unresectable mCRC treated with a biweekly regimen of chemotherapy. Metabolic nonresponse was defined by <15% decrease in FDG uptake in the dominant proportion of the patient's lesions or if a lesion was found metabolically progressive. The PET-based response was correlated with radiological response (primary end point) and patient's outcome (secondary end points). Results RECIST response rate in metabolically responding patients was 43% (10 of 23) compared with 0% (0 of 17) in nonresponding patients (P = 0.002). The metabolic assessment's predictive performance for RECIST response was sensitivity 100% [95% confidence interval (CI) 69% to 100%], specificity 57% (95% CI 37% to 75%), positive predictive value 43% (95% CI 23% to 66%), and negative predictive value 100% (95% CI 80% to 100%). Comparing metabolically responding versus nonresponding patients, the hazard ratio (HR) was 0.28 (95% CI 0.10–0.76) for overall survival and 0.57 (95% CI 0.27–1.21) for progression-free survival. Conclusion The metabolic response measured by FDG–PET/CT after a single course of chemotherapy in mCRC is able to identify patients who will not benefit from the treatment. [ABSTRACT FROM PUBLISHER]

Abstract: Aim: The safety, pharmacokinetics and efficacy of sorafenib plus docetaxel in patients with advanced refractory cancer were investigated in a Phase I, dose-escalation trial. Methods: Twenty-seven patients in four Cohorts received docetaxel on Day 1 (Cohorts 1 and 4: 75mg/m2; Cohorts 2 and 3: 100mg/m2) plus sorafenib on Days 2–19 (Cohorts 1 and 2: 200mg twice-daily (bid); Cohorts 3 and 4: 400mg bid) in 21-day cycles. Results: Most common adverse events (AEs) (Grade 3–5) included neutropenia (89%), leucopaenia (81%), hand–foot skin reaction (30%) and fatigue (30%). The most common drug-related AEs leading to dose reduction/interruption or permanent discontinuation were dermatologic (41%), gastrointestinal (26%) and constitutional (22%). Coadministration of sorafenib altered the pharmacokinetics of docetaxel. On average, docetaxel area under the concentration–time curve (AUC)0–24 increased by 5% (Cohort 1), 54% (Cohort 2), 36% (Cohort 3) and 80% (Cohort 4) with docetaxel plus sorafenib, while C max increased by 16–32%, independent of sorafenib/docetaxel doses. Three of 25 evaluable patients (11%) had partial responses; 14 (52%) had stable disease. Conclusion: Dose-limiting dermatologic AEs were more common than expected for either therapy alone. A starting dose of docetaxel 75mg/m2 plus sorafenib 400mg bid (with dose reductions for dermatological toxicities) is proposed for Phase II. [Copyright &y& Elsevier]

BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor (VEGFR) inhibitor that targets tumour cell proliferation and tumour angiogenesis. This Phase I study was undertaken to determine the safety profile, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and tumour response profile of oral BAY 43-9006 in patients with advanced, refractory solid tumours. BAY 43-9006 was administered daily for repeated cycles of 21 days on/7 days off. A total of 44 patients were enrolled at doses from 50 to 800?mg b.i.d. Pharmacokinetic profiles of BAY 43-9006 in plasma were determined during the first treatment cycle. The most frequently reported adverse events over multiple cycles were gastrointestinal (75%), dermatologic (71%), constitutional (68%), pain (64%), or hepatic (61%) related. A MTD of 400?mg b.i.d. BAY 43-9006 was defined. BAY 43-9006 was absorbed rapidly; steady-state conditions were reached within 7 days. BAY 43-9006 exposure increased nonproportionally with increasing dose. In all, 32 patients were evaluated for tumour response: 15 patients showed tumour progression, 16 patients experienced stable disease (>6 months in eight patients), and one patient with renal cell carcinoma achieved a partial response. BAY 43-9006 given for 21 days with 7 days off treatment was safe, well tolerated, and showed antitumour activity.British Journal of Cancer (2005) 92, 1855-1861. doi:10.1038/sj.bjc.6602584 www.bjcancer.com Published online 3 May 2005 [ABSTRACT FROM AUTHOR]

Simple Summary: There is an increased interest for the investigation of immunotherapy and immune-related biomarkers in rectal cancer. We retrospectively analysed the expression of the programmed death-ligand 1 (PD-L1) in diagnostic biopsies and resection samples from a cohort of 83 rectal cancer patients. Using three different methods for the analysis of PD-L1, we found that the expression of this biomarker was lower in resection samples than in diagnostic biopsies. Also, we observed that higher levels of PD-L1 in resection specimens were associated with better survival outcomes. The results of our study contribute to the knowledge of PD-L1 expression in rectal cancer, having the potential to inform the design of future immunotherapy trials in this setting. Immune checkpoint inhibitors and immune-related biomarkers are increasingly investigated in rectal cancer (RC). We retrospectively analysed PD-L1 expression in diagnostic biopsy and resection samples from RC patients treated at our centre between 2000 and 2020. PD-L1 immunostaining (22C3 clone) was evaluated according to tumour proportion (TPS), immune cell (ICS), and the combined positive score (CPS). Eighty-three patients were included. At diagnosis, PD-L1 expression ≥1%/≥5% was observed in 15.4%/0%, 80.7%/37.4%, and 69.2%/25.6% of patients based on TPS, ICS, and CPS, respectively. At surgery, the respective figures were 4.6%/1.5%, 60.2%/32.5%, and 50.7%/26.2%. Using the 1% cut-off and regardless of the scoring system, PD-L1 was less expressed in surgery than biopsy samples (p ≤ 0.04). In paired specimens, PD-L1-ICS reduction was especially observed following neoadjuvant long-course (chemo)radiotherapy (p = 0.03). PD-L1-ICS of ≥5% in surgical samples (HR: 0.17; p = 0.02), and a biopsy-to-surgery increase in PD-L1-ICS (HR: 0.19; p = 0.04) was predictive for longer disease-free survival, while the PD-L1-ICS of either ≥1% (HR 0.28; p = 0.04) or ≥5% (HR 0.19; p = 0.03) in surgical samples and the biopsy-to-surgery increase in PD-L1-ICS (HR: 0.20; p = 0.04) were associated with better overall survival. Our study suggests that PD-L1 expression in RC is largely reflective of immune cell infiltration, and its presence/increase in surgical samples predicts better outcomes. [ABSTRACT FROM AUTHOR]

Highlights: What are the main findings? This multicenter retrospective study, encompassing two hospital sites for training and leveraging data from forty-seven different hospitals for testing, aimed to develop machine learning models utilising both clinical and radiomics features (individually and in combination) extracted from pre-treatment CT scans. The objective was to predict PFS and OS in patients with PDAC. Among the various models developed, the model based on the combination of clinical and CT-derived tumour radiomics features demonstrated superior performance for OS with a C-index of 0.72 in the testing dataset. Conversely, the model based solely on clinical features excelled in predicting PFS, achieving a C-index of 0.70 in the testing dataset. What is the implication of the main finding? The analysis further highlighted the high relevance of clinical features both for OS and PFS outcomes in patients with PDAC. Purpose. This multicenter retrospective study aims to identify reliable clinical and radiomic features to build machine learning models that predict progression-free survival (PFS) and overall survival (OS) in pancreatic ductal adenocarcinoma (PDAC) patients. Methods. Between 2010 and 2020 pre-treatment contrast-enhanced CT scans of 287 pathology-confirmed PDAC patients from two sites of the Hopital Universitaire de Bruxelles (HUB) and from 47 hospitals within the HUB network were retrospectively analysed. Demographic, clinical, and survival data were also collected. Gross tumour volume (GTV) and non-tumoral pancreas (RPV) were semi-manually segmented and radiomics features were extracted. Patients from two HUB sites comprised the training dataset, while those from the remaining 47 hospitals of the HUB network constituted the testing dataset. A three-step method was used for feature selection. Based on the GradientBoostingSurvivalAnalysis classifier, different machine learning models were trained and tested to predict OS and PFS. Model performances were assessed using the C-index and Kaplan–Meier curves. SHAP analysis was applied to allow for post hoc interpretability. Results. A total of 107 radiomics features were extracted from each of the GTV and RPV. Fourteen subgroups of features were selected: clinical, GTV, RPV, clinical & GTV, clinical & GTV & RPV, GTV-volume and RPV-volume both for OS and PFS. Subsequently, 14 Gradient Boosting Survival Analysis models were trained and tested. In the testing dataset, the clinical & GTV model demonstrated the highest performance for OS (C-index: 0.72) among all other models, while for PFS, the clinical model exhibited a superior performance (C-index: 0.70). Conclusions. An integrated approach, combining clinical and radiomics features, excels in predicting OS, whereas clinical features demonstrate strong performance in PFS prediction. [ABSTRACT FROM AUTHOR]

Simple Summary: The prognosis of metastatic colorectal cancer patients remains poor despite the increased number of active treatments. This particularly applies to patients with chemorefractory disease. Biomarkers that could help prognostication and management decisions in this setting are lacking. This is the study with the largest panel (n = 182) of circulating cytokines ever assessed in metastatic colorectal cancer. By analyzing 196 chemorefractory colorectal cancer patients with available plasma samples, we showed that high concentrations of IGFBP-1 and/or IGFBP-2 were associated with shorter overall survival. These results are consistent with the extensive literature supporting an association between the IGF pathway and colorectal cancer. Further research is needed to validate our findings in larger independent series, and to elucidate the biological mechanisms underlying the prognostic effect of these cytokines. Circulating cytokines could be optimal biomarkers for prognostication and management decisions in colorectal cancer (CRC). Chemorefractory CRC patients with available plasma samples were included in this study. In the discovery cohort (n = 85), 182 circulating cytokines were tested with a semi-quantitative multiplex assay, and prognostic cytokines were analyzed in the validation cohort (n = 111) by ELISA. Overall survival (OS) was the primary outcome measure, with the false discovery rate (FDR) method (significance level of <0.01) being used to correct for multiple comparisons. Four cytokines were associated with OS in the discovery cohort: insulin-like growth factor-binding protein 1 (IGFBP-1) (HR 2.1 [95%CI: 1.58–2.79], FDR < 0.001), insulin-like growth factor-binding protein 2 (IGFBP-2) (HR 1.65 [95%CI: 1.28–2.13], FDR = 0.006), serum amyloid A (SAA) (HR 1.84 [95%CI: 1.39–2.43], FDR < 0.001), and angiotensin II (HR 1.65 [95%CI: 1.29–2.1], FDR = 0.006). Of these, IGFBP-1 (HR 2.70 [95%CI: 1.56–4.76], FDR = 0.007) and IGFBP-2 (HR 3.33 [95%CI: 1.64–6.67], FDR = 0.008) were confirmed to be independently associated with OS in the validation cohort. Patients with high concentrations of IGFBP-1 and/or IGFBP-2 had a median OS of 3.0 months as compared with 6.9 months for those with low concentrations of both cytokines (HR 2.44 [95%CI: 1.52–4.0], FDR = 0.002) Validation of circulating IGFBP-1 and IGFBP-2 as independent prognostic biomarkers for chemorefractory CRC in larger, independent series is warranted. [ABSTRACT FROM AUTHOR]

Background A minority of phase III trials in gastrointestinal oncology are positive. We assessed the association between their outcome and the level and characteristics of preexisting evidence. Methods EMBASE, PubMed, and proceedings from international meetings were searched for phase III gastrointestinal cancer trials (gastroesophageal, hepatocellular, biliary tract, pancreatic, small bowel, colorectal, anal, stromal, and neuroendocrine) between January 2000 and June 2020. Trials investigating anticancer drugs for advanced disease, with superiority design and standard treatments as control were eligible. The highest level of preexisting evidence was retrieved from the main study report. Results A total of 193 phase III trials were included, and 69 (35.8%) met their primary endpoint. Positivity rates were as follows: gastroesophageal 37%, colorectal 48%, pancreatic 17.1%, hepatocellular 20%, neuroendocrine 75%, and both biliary tract and GIST 60%. No information about preexisting evidence was found for 44 trials (22.8%). For the remaining 149, preexisting evidence consisted of phase II studies in 123 cases (82.6%) and phase I studies in 26 cases (17.4%). The probability of success was 34.1%, 35.8%, and 35.7%, respectively (P  = .934). No parameter from prior studies predicted the outcome of phase III trials except β <.2 (P  = .048). A numerically increased success rate was observed for phase III trials preceded by positive phase II studies (41.9% vs 18.5%, P  = .2). Conclusions There does not appear to be an association between level of prior evidence and success of phase III gastrointestinal cancer trials. These data, along with the high phase III failure rate, highlight the need to improve the drug development process in this setting. [ABSTRACT FROM AUTHOR]

Background: Surgery is a curative treatment for patients with locally advanced colon cancer, but recurrences are frequent for those with stage III disease. FOLFOX adjuvant chemotherapy has been shown to improve recurrence-free survival and overall survival by more than 20% and is nowadays considered a standard of care. However, the vast majority of patients will not benefit from receiving cytotoxic drugs because they have either already been cured by surgery or because their tumor cells are resistant to the chemotherapy, for which predictive factors are still not available.Methods/design: PePiTA is a prospective, multicenter, non-randomised trial built on the hypothesis that preoperative chemosensitivity testing using FDG-PET/CT before and after one course of FOLFOX can identify the patients who are unlikely to benefit from 6 months of adjuvant FOLFOX treatment for stage III colon cancer.Discussion: PePiTA is the first study to use the primitive tumor chemosensitivity assessed by metabolic imaging as a guidance for adjuvant therapy in colon cancer. It could pave the way for tailoring the treatment and avoiding useless toxicities for the patients and inadequate expenses for the society. It could also give an interesting insight into tumoral heterogeneity, resistance to chemotherapy, genetic predisposants to oxaliplatin toxicity and immune response to cancer.Eudract Number: 2009-011445-13 TRIAL REGISTRATION: ClinicalTrials.gov number, NCT00994864. [ABSTRACT FROM AUTHOR]

Potential intrinsic resistance mechanisms to regorafenib were explored after short exposure (3 days) on five CRC cell lines (HCT-116, SW1116, LS-1034, SW480, Caco-2). The observation of senescence-like features led to the investigation of a drug-initiated phenotype switch. Following long-term exposure (12 months) of HCT-116 and SW480 cell lines to regorafenib, we developed resistant models to explore acquired resistance. SW480 cells demonstrated senescent-like properties, including a cell arrest in the late G2/prophase cell cycle stage and a statistically significant decrease in the expression of G1 Cyclin-Dependent Kinase inhibitors and key cell cycle regulators. A specific senescence-associated secretome was also observed. In contrast, HCT-116 treated cells presented early senescent features and developed acquired resistance triggering EMT and a more aggressive phenotype over time. The gained migration and invasion ability by long-exposed cells was associated with the increased expression level of key cellular and extracellular EMT-related factors. The PI3K/AKT pathway was a significant player in the acquired resistance of HCT-116 cells, possibly related to a PI3KCA mutation in this cell line. Our findings provide new insights into the phenotypic plasticity of CRC cells able, under treatment pressure, to acquire a stable TIS or to use an early senescence state to undergo EMT. [ABSTRACT FROM AUTHOR]

In the phase II multicohort CheckMate 142 study, nivolumab plus low-dose (1 mg/kg) ipilimumab provided robust and durable clinical benefit with a manageable safety profile in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) at 13.4- and 25.4-month median follow-up (Overman MJ, Lonardi S, Wong KYM et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36:773-779. Overman MJ, Lonardi S, Wong KYM, et al. Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: long-term follow-up. J Clin Oncol. 2019;37:635). Here, we present results from the 4-year follow-up of these patients. Patients received nivolumab (3 mg/kg) plus low-dose (1 mg/kg) ipilimumab every 3 weeks (four doses) followed by nivolumab (3 mg/kg) every 2 weeks until disease progression. Primary endpoint was investigator-assessed objective response rate (ORR; as per RECIST version 1.1). A total of 119 patients were treated; 76% had ≥2 prior lines of therapy. Median follow-up was 50.9 months (range 46.9-62.7 months). Median duration of therapy was 24.9 months [95% confidence interval (CI) 15.8-33.2 months]. Investigator-assessed ORR increased from 55% (95% CI 45% to 64%) at 13.4 months to 65% (95% CI 55% to 73%) at 50.9 months with a disease control rate of 81% (95% CI 72% to 87%). The complete response rate increased from 3% at 13.4 months to 13% at 50.9 months. Partial responses were observed in 52% of patients; 21% had stable disease, and 12% had progressive disease. Median time to response was 2.8 months (range 1.1-37.1 months), and median duration of response was not reached (range 1.4+ to 58.0+ months). At data cut-off, 37 (48%) patients had ongoing responses. Median progression-free survival was not reached [95% CI 38.4 months-not estimable (NE)], and median overall survival was not reached (95% CI NE). Grade 3-4 treatment-related adverse events (TRAEs) were observed in 32% of patients; 13% of patients had any-grade TRAEs leading to discontinuation. The results confirm long-term benefit of nivolumab plus low-dose ipilimumab for previously treated patients with MSI-H/dMMR mCRC. The safety profile was manageable with no new safety signals. • In previously treated MSI-H/dMMR mCRC, nivolumab plus ipilimumab showed durable benefit with 4 years of follow-up. • ORR was 65%. The 48-month rates of progression-free survival and overall survival were 53% and 71%, respectively. • Significant and clinically meaningful improvements in quality of life were largely maintained with continuous treatment. • No new safety signals were identified, with a low rate (13% of patients) of any-grade TRAEs leading to discontinuation. • These results show the long-term benefit of nivolumab plus low-dose ipilimumab in previously treated MSI-H/dMMR mCRC. [ABSTRACT FROM AUTHOR]

Small cell carcinoma of the pancreas (SCCP) is a rare and aggressive tumor, which accounts for 1 to 1.4 percent of all pancreatic malignancies. Forty-two cases of SCCP have been reported in the literature but only twenty-three of these have sufficient clinical and pathological data for meaningful analysis. In these published reports, SCCP was more common in men, with an M/F ratio of 2.83, and most commonly affected individuals during the sixth decade (range, 37-75 years). The hormonal profile in patients with SCCP was generally normal and paraneoplasic syndrome was rarely described. Serum or histological concentrations of neuron-specific enolase (NSE) were increase/positive in all cases where values were specified, and NSE could therefore be used as a tumor marker for diagnosis and/or assessment of treatment effect in patients with SCCP. In ninety-one percent of cases, the tumor was associated with metastatic dissemination at initial diagnosis. Prognosis was poor with a median survival of 3 months (range, 0.5-50months). There is no consensus about the management of SCCP because of the small number of cases. There was a significant increase in median survival, from 1 to 6 months, in treated patient compared to patients treated only by symptomatic management. Chemotherapy was the most common treatment with the combination of cisplatinletoposide most frequently prescribed. There was no significant difference in survival between patients treated by chemotherapy alone versus chemotherapy with local treatment (radiation therapy or surgery). [ABSTRACT FROM AUTHOR]

High-throughput sequencing technologies are increasingly used in research but limited data are available on the feasibility and value of these when routinely adopted in clinical practice. We analyzed all consecutive cancer patients for whom genomic testing by a 48-gene next-generation sequencing (NGS) panel (Truseq Amplicon Cancer Panel, Illumina) was requested as part of standard care in one of the largest Belgian cancer networks between 2014 and 2019. Feasibility of NGS was assessed in all study patients, while the impact of NGS on the decision making was analyzed in the group of gastrointestinal cancer patients. Tumor samples from 1064 patients with varying tumor types were tested, the number of NGS requests increasing over time (p <.0001). Success rate and median turnaround time were 91.4% and 12.5 days, respectively, both significantly decreasing over time (p ≤.0002). Non-surgical sampling procedure (OR 7.97, p <.0001), tissue from metastatic site (OR 2.35, p =.0006) and more recent year of testing (OR 1.79, p =.0258) were independently associated with NGS failure. Excluding well-known actionable or clinically relevant mutations which are recommended by international guidelines and commonly tested by targeted sequencing, 57/279 (20.4%) assessable gastrointestinal cancer patients were found to have tumors harboring at least one actionable altered gene according to the OncoKB database. NGS results, however, had a direct impact on management decisions by the treating physician in only 3 cases (1.1%). Our findings confirm that NGS is feasible in the clinical setting with acceptably low failure rates and rapid turnaround time. In gastrointestinal cancers, however, NGS-based multiple-gene testing adds very little to standard targeted sequencing, and in routine practice the clinical impact of NGS panels including genes which are not routinely recommended by international guidelines remains limited. [ABSTRACT FROM AUTHOR]

Background: The benefit of surgery in patients with non-colorectal non-neuroendocrine liver metastases (NCRNNELM) remains controversial. At the population level, several statistical prognostic factors and scores have been proposed but inconsistently verified. At the patient level, no selection criteria have been demonstrated to guide individual therapeutic decision making. We aimed to evaluate potential individual selection criteria to predict the benefit of surgery in patients undergoing treatment for NCRNNELM. Methods: Data for 114 patients undergoing surgery for NCRNNELM were reviewed. In this population, we identified an early relapse group (ER), defined as patients with unresectable recurrence < 1 year postoperatively who did not benefit from surgery (N = 28), and a long-term survival group (LTS), defined as patients who were recurrence-free ≥ 5 years postoperatively and benefited from surgery (N = 20). Clinicopathologic parameters, the Association Française de Chirurgie (AFC) score, and a modified 4-point Clinical Risk Score (mCRS) (excluding CEA level) were analyzed and compared between LTS and ER groups. Results: The majority of patients were female and a majority had an ASA score ≤ 2 at the time of liver surgery. The median age was 55 years. Almost half of the patients (46%) presented with a single-liver metastasis. Intermediate- and low-risk AFC scores represented 40% and 60% of the population, respectively. Five- and 10-year overall survival (OS) and disease-free survival (DFS) rates were 56% and 27%, and 30% and 12%, respectively. Negative prognostic factors were the size of liver metastases > 50 mm and delay between primary and NCRNNELM <24 months for OS and DFS, respectively. AFC score was not prognostic while high-risk mCRS (scores 3–4) was predictive for the poorer OS. The clinicopathologic parameters were similar in the ER and LTS groups, except the presence of N+ primary tumor, and the size of liver metastases was significantly higher in the ER group. Conclusion: In patients with resectable NCRNNELM, no predictive factors or scores were found to accurately preoperatively differentiate individual cases in whom surgery would be futile from those in whom surgery could be associated with a significant oncological benefit. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy represents a promising option for treatment of hepatocellular carcinoma (HCC) in cirrhotic patients but its efficacy is currently inconsistent and unpredictable. Locoregional therapies inducing immunogenic cell death, such as transarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT), have the potential to act synergistically with immunotherapy. For the development of new approaches combining locoregional treatments with immunotherapy, a better understanding of the respective effects of TACE and SIRT on recruitment and activation of immune cells in HCC is needed. To address this question, we compared intra-tumor immune infiltrates in resected HCC after preoperative treatment with TACE or SIRT.Methods: Data fromr patients undergoing partial hepatectomy for HCC, without preoperative treatment (SURG, n = 32), after preoperative TACE (TACE, n = 16), or preoperative SIRT (n = 12) were analyzed. Clinicopathological factors, tumor-infiltrating lymphocytes (TILs), CD4+ and CD8+ T cells, and granzyme B (GZB) expression in resected HCC, and postoperative overall and progression-free survival were compared between the three groups.Results: Clinicopathological and surgical characteristics were similar in the three groups. A significant increase in TILs, CD4+ and CD8+ T cells, and GZB expression was observed in resected HCC in SIRT as compared to TACE and SURG groups. No difference in immune infiltrates was observed between TACE and SURG patients. Within the SIRT group, the dose of irradiation affected the type of immune infiltrate. A significantly higher ratio of CD3+ cells was observed in the peri-tumoral area in patients receiving < 100 Gy, whereas a higher ratio of intra-tumoral CD4+ cells was observed in patients receiving > 100 Gy. Postoperative outcomes were similar in all groups. Irrespective of the preoperative treatment, the type and extent of immune infiltrates did not influence postoperative survival.Conclusions: SIRT significantly promotes recruitment/activation of intra-tumor effector-type immune cells compared to TACE or no preoperative treatment. These results suggest that SIRT is a better candidate than TACE to be combined with immunotherapy for treatment of HCC. Evaluation of the optimal doses for SIRT for producing an immunogenic effect and the type of immunotherapy to be used require further evaluation in prospective studies. [ABSTRACT FROM AUTHOR]

Oesophago-gastric cancers (OGCs) are aggressive tumours. While better peri-operative strategies, increased number of cytotoxic agents and availability of targeted therapies have improved survival, there remains an unmet need for novel treatment approaches. Immune checkpoint inhibitors (ICIs) have marked a new era in cancer management with unprecedented results in several malignancies. Although OGC lagged behind other solid tumours, evidence has increasingly accumulated supporting the contention that modulation of the anti-cancer host immune response may be beneficial for at least some patients. Many trials have been completed in Eastern and Western countries, some of these leading to the approval of ICIs in the refractory setting, and favorable opinion from regulatory agencies is expected also in treatment-naïve, advanced OGC. Furthermore, studies are evaluating ICIs in the early stage setting and exploring the potential of combination treatments. In this article we discuss the biological bases underlying the successful development of ICIs in OGC and review the available data on PD-1 and PD-L1 monoclonal antibodies in this disease. Also, we present ongoing clinical trials of these ICIs that could shape the future treatment landscape of OGC. [ABSTRACT FROM AUTHOR]

Purpose: Reported outcomes of patients with intra-hepatic cholangiocarcinoma (IH-CCA) treated with radioembolization are highly variable, which indicates differences in included patients' characteristics and/or procedure-related variables. This study aimed to identify patient- and treatment-related variables predictive for radioembolization outcome. Methods: This retrospective multicenter study enrolled 58 patients with unresectable and chemorefractory IH-CCA treated with resin 90Y-microspheres. Clinicopathologic data were collected from patient records. Metabolic parameters of liver tumor(s) and presence of lymph node metastasis were measured on baseline 18F-FDG-PET/CT. 99mTc-MAA tumor to liver uptake ratio (TLRMAA) was computed for each lesion on the SPECT-CT. Activity prescription using body-surface-area (BSA) or more personalized partition-model was recorded. The study endpoint was overall survival (OS) starting from date of radioembolization. Statistical analysis was performed by the log-rank test and multivariate Cox's proportional hazards model. Results: Median OS (mOS) post-radioembolization of the entire cohort was 10.3 months. Variables associated with significant differences in terms of OS were serum albumin (hazard ratio (HR) = 2.78, 95%CI:1.29–5.98, p = 0.002), total bilirubin (HR = 2.17, 95%CI:1.14–4.12, p = 0.009), aspartate aminotransferase (HR = 2.96, 95%CI:1.50–5.84, p < 0.001), alanine aminotransferase (HR = 2.02, 95%CI:1.05–3.90, p = 0.01) and γ-GT (HR = 2.61, 95%CI:1.31–5.22, p < 0.001). The presence of lymph node metastasis as well as a TLRMAA < 1.9 were associated with shorter mOS: HR = 2.35, 95%CI:1.08–5.11, p = 0.008 and HR = 2.92, 95%CI:1.01–8.44, p = 0.009, respectively. Finally, mOS was significantly shorter in patients treated according to the BSA method compared to the partition-model: mOS of 5.5 vs 14.9 months (HR = 2.52, 95%CI:1.23–5.16, p < 0.001). Multivariate analysis indicated that the only variable that increased outcome prediction above the clinical variables was the activity prescription method with HR of 2.26 (95%CI:1.09–4.70, p = 0.03). The average mean radiation dose to tumors was significantly higher with the partition-model (86Gy) versus BSA (38Gy). Conclusion: Radioembolization efficacy in patients with unresectable recurrent and/or chemorefractory IH-CCA strongly depends on the tumor radiation dose. Personalized activity prescription should be performed. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor-T cells (CAR-Ts) are an exciting new cancer treatment modality exemplified by the recent regulatory approval of two CD19-targeted CAR-T therapies for certain B cell malignancies. However, this success in the hematological setting has yet to translate to a significant level of objective clinical responses in the solid tumor setting. The reason for this lack of translation undoubtedly lies in the substantial challenges raised by solid tumors to all therapies, including CAR-T, that differ from B cell malignancies. For instance, intravenously infused CAR-Ts are likely to make rapid contact with cancerous B cells since both tend to reside in the same vascular compartments within the body. By contrast, solid cancers tend to form discrete tumor masses with an immune-suppressive tumor microenvironment composed of tumor cells and non-tumor stromal cells served by abnormal vasculature that restricts lymphocyte infiltration and suppresses immune function, expansion, and persistence. Moreover, the paucity of uniquely and homogeneously expressed tumor antigens and inherent plasticity of cancer cells provide major challenges to the specificity, potency, and overall effectiveness of CAR-T therapies. This review focuses on the major preclinical and clinical strategies currently being pursued to tackle these challenges in order to drive the success of CAR-T therapy against solid tumors. [ABSTRACT FROM AUTHOR]

Background: Adjuvant therapy improves the prognosis of stage II & III colon cancer patients. Unfortunately, most patients do not benefit from this treatment. PePITA (NCT00994864) is a prospective, multicenter, non-randomized study whose primary objective is to predict the outcome of adjuvant therapy in colon cancer.Methods: The primary objective was to determine the prognostic and predictive value of circulating tumor cell (CTC) detection before therapy and after one course of preoperative FOLFOX.Results: Out of the 58 first patients accrued in PePiTA trial, 36 patients participated in the CTC companion study, of whom 32 had at least one evaluable sample. Only 5 patients (14, 95% CI = 5-30%) had ≥1 CTC/22.5 ml blood in at least one of the two timepoints with 2 patients having ≥1 CTC/22.5 ml at baseline (6, 95% CI: 1-19%). The detection rate of patients with CTCs at baseline being lower than expected, the inclusion of patients in the PePiTA CTC substudy was stopped. The limited sample size did not allow us to investigate the prognostic and predictive value of CTCs in locally advanced colon cancer.Conclusions: Our data illustrate the need for further standardized studies in order to find the most reliable prognostic/predictive biomarker in early-stage colon cancer.Trial Registration: This trial was prospectively registered at Jules Bordet institute ( NCT00994864 ) on the October 14, 2009. [ABSTRACT FROM AUTHOR]

Background: The prognostic value of body composition in cancer patients has been widely studied during the last decade. The main finding of these studies is that sarcopenia, or skeletal muscle depletion, assessed by CT imaging correlates with a reduced overall survival (OS). By contrast, the prognostic value of fat mass remains ill-defined. This study aims to analyze the influence of body composition including both muscle mass and adipose tissue on OS in a homogeneous population of advanced colorectal cancer (CRC) patients.Methods: Among 235 patients with chemorefractory advanced CRC included in the SoMore and RegARd-C trials, body composition was assessed in 217 patients on baseline CT images. The relationship between body composition (sarcopenia, muscle density, subcutaneous and visceral fat index and density), body mass index (BMI) and OS were evaluated.Results: Patients with a higher BMI had a better OS (≥30 versus < 30, HR: 0.50; 0.33-0.76). Those with low muscle index and muscle density had an increased mortality (HR: 2.06; 1.45-2.93 and HR: 1.54; 1.09-2.18, respectively). Likewise, low subcutaneous and visceral fat index were associated with an increased risk of dying (HR: 1.63; 1.23-2.17 and 1.48; 1.09-2.02 respectively), as were a high subcutaneous and visceral adipose tissue density (HR: 1.93; 1.44-2.57 and 2.40; 1.79-3.20 respectively). In multivariate analysis, a high visceral fat density was the main predictor of poor survival.Conclusions: Our results confirm the protective role of obesity in CRC patients at an advanced stage, as well as the negative prognostic impact of muscle depletion on survival. More importantly, our data show for the first time that visceral adipose tissue density is an important prognostic factor in metastatic CRC.Trial Registration: NCT01290926 , 07/02/2011 and NCT01929616 , 28/08/2013. [ABSTRACT FROM AUTHOR]

Differentiated-type Intraepithelial Neoplasia (DIN) is defined as HPV-negative squamous intraepithelial proliferation with abnormal keratinocyte differentiation and basal cell atypia, originally described in the vulva, with following descriptions in the oral cavity. DIN occurring in the anus is quite rare, and to the best of our knowledge, only one publication reported it. In this report, we describe the clinicopathological features of this entity on anal margin, associated with invasive squamous cell carcinoma. In addition, using the next generation sequencing (NGS) technique, we have demonstrated TP53 mutation in the invasive component but not in the associated DIN-like lesion, where p53 immunohistochemical expression was restricted to basal layers. [ABSTRACT FROM AUTHOR]

Background/Purpose Preoperative selective internal radiation therapy (SIRT) may improve the results of partial hepatectomy (PH) or radiofrequency destruction (RF) for hepatocellular carcinoma (HCC) in patients with cirrhosis. The aim of this study was to evaluate the feasibility and safety of this combined approach. Methods Patients with cirrhosis and HCC selected for PH or RF were prospectively included and systematically proposed for preoperative SIRT. Feasibility and safety of SIRT and post-SIRT PH or RF were assessed. Results Thirty patients were included. SIRT was contraindicated in seven, due to lack of access to tumour artery or to hepato-pulmonary shunts. SIRT was performed in 23 patients without significant complications. Post-SIRT, surgery was refuted in seven patients, due to tumour progression or the patient's deteriorating condition. After surgery, major complications were observed in 2/16 patients (12.5%) and one patient died 52 days post-surgery. A major tumour pathological response was seen in most patients who underwent surgery after SIRT. Conclusions On intention-to-treat basis, the overall feasibility of combining preoperative SIRT and surgery was limited. Preoperative SIRT did not increase expected operative morbidity, but post-SIRT, a third of patients were refuted for surgery. Accurate selection criteria and potential long-term oncological benefit of this approach remains to be determined. ClinicalTrials.gov NCT01686880 . [ABSTRACT FROM AUTHOR]

Current guidelines recommend radical resection for stage I rectal cancer. However, since screening programs are being installed, an increasing number of cancers are being detected in early stages. Endoscopic resection is often performed at the time of diagnosis. This systematic review was undertaken to review the evidence on endoscopic approach vs. radical resection for stage I rectal cancer. Recommendations were issued based on the GRADE methodology and risk stratification used in clinical practice. A systematic search (until March 2015) identified 2 meta-analyses and 1 additional randomized trial. For the primary outcomes (overall survival, disease-free survival, local recurrence-free survival and metastasis-free survival) no evidence could be found on the superiority of local or radical resection. Secondary outcomes (blood loss, hospital stay, operative time, number of permanent stomas and perioperative deaths) were in favour of local resection. The authors strongly recommend radical resection for T2 rectal cancer, but consider ‘en bloc’ local resection sufficient for pT1 sm1 rectal cancers when confirmed pathologically. Discussion by a multidisciplinary team and adequate surveillance remain mandatory. [ABSTRACT FROM AUTHOR]

Background: CP-4126 (gemcitabine elaidate, previously CO-101) is a lipid-drug conjugate of gemcitabine designed to circumvent human equilibrative nucleoside transporter1-related resistance to gemcitabine. The purpose of this study was to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of CP-4126, and to describe its pharmacokinetic profile.Methods: Eligible patients with advanced refractory solid tumours, and adequate performance status, haematological, renal and hepatic function, were treated with one of escalating doses of CP-4126 administered by a 30-min intravenous infusion on days 1, 8 and 15 of a 28-day cycle. Blood and urine samples were collected to determine the pharmacokinetics (PKs) of CP-4126.Results: Forty-three patients, median age 59 years (range 18-76; male = 27, female = 16), received one of ten dose levels (30-1600 mg/m(2)). Dose-limiting toxicities included grade 3 anaemia, grade 3 fatigue and grade 3 elevation of transaminases. The MTD and RP2D were 1250 mg/m(2) on basis of the toxicity and PK data. CP-4126 followed dose-dependent kinetics and maximum plasma concentrations occurred at the end of CP-4126 infusion. Seven patients achieved stable disease sustained for ≥3 months, including two patients with pancreatic cancer who had progressed on or after gemcitabine exposure.Conclusions: CP-4126 was well tolerated with comparable toxicity profile to gemcitabine. Future studies are required to determine its anti-tumour efficacy, either alone or in combination with other cytotoxic chemotherapy regimens. [ABSTRACT FROM AUTHOR]

Purpose: To compare various computed tomography (CT) parameters to the positronemission tomographywith computed tomography (PET-CT) response, with or without PET guidance for the response assessment of colorectal cancer (CRC) metastases treated by Y90 radioembolization. Methods: Thirty-six CRC metastases were retrospectively evaluated on 18F-Fluoro-Deoxy-Glucose PET-CT and contrast-enhanced computed tomography (CECT) performed at baseline and 2-3months after Y90 radioembolization. Results: Median SUVmax values decreased from 11.39 to 6.71 after radioembolization (Pb.001), and 23/36 (64%)metastases were categorizedmetabolic responses according to European Organisation for Research and Treatment of Cancer criteria. Only a decrease of the mean attenuation in the structural (Pb.001) and metabolic active volume (Pb.001) was observed. The change in these criteriawas correlatedwith the change of SUVmax. [ABSTRACT FROM AUTHOR]

Background: Potentially myelosuppressive doublet and triplet chemotherapy combination regimens are considered the most active treatments in gastric cancer. This multicenter prospective observational study was designed to gain insight into the chemotherapy regimens being used in Europe and to evaluate neutropenia management in patients identified as at high risk for febrile neutropenia (FN). Methods: Eligible patients had gastric cancer, were scheduled for ≥ 3 cycles of myelosuppressive chemotherapy, and had an investigator-assessed overall FN risk ≥ 20 %. Data were collected for up to ten cycles. The primary endpoint was the proportion of patients who received granulocyte colony stimulating factor (G-CSF) primary prophylaxis (defined as G-CSF initiated on days 1-7 of cycle 1). Secondary endpoints included FN incidence, chemotherapy administration, and G-CSF use. Results: Of 199 patients who met the eligibility criteria and started at least one cycle of chemotherapy, mean age was 63 years, 76 % were men, 83 % had an ECOG score of 0 or 1, 54 % had metastatic disease, and 24 % had received prior chemotherapy. A total of 27 different backbone regimens were given; the most common regimen was modified docetaxel, cisplatin, and 5-fluorouracil (DCF). Despite all patients having been identified as having a ≥ 20 % FN risk, only 70 (35 %) received G-CSF primary prophylaxis. FN occurred in 14 patients overall (7 %). Most FN events occurred in patients who received DCF/modified DCF (9/14 events, 64 %). Conclusions: The results of this study reveal a high use of myelotoxic treatment regimens in gastric cancer in Europe and low adherence to clinical practice guidelines for the use of primary and secondary G-CSF prophylaxis for FN. [ABSTRACT FROM AUTHOR]

Liver metastases in colorectal cancer patients decreases the expected 5 year survival rates by a factor close to nine. It is generally accepted that resection of liver metastases should be attempted whenever feasible. This manuscript addresses the optimal therapeutic plan regarding timing of resection of synchronous liver metastases and the use of chemotherapy in combination with resection of synchronous metachronous liver metastases. The aim is to pool all published results in order to attribute a level of evidence to outcomes and identify lacking evidence areas. A systematic search of guidelines, reviews, randomised controlled, observational studies and updating a meta-analysis was performed. Data were extracted and analysed. Data failed to demonstrate an effect of timing of surgery or use of chemotherapy on overall survival. Concomitant resection of liver metastases and the primary tumour may result in lower postoperative morbidity. Systemic peri-operative chemotherapy may improve progression free survival compared to surgery alone. [ABSTRACT FROM AUTHOR]

Background Metastatic colorectal cancer (mCRC) may present various behaviours that define different courses of tumor evolution. There is presently no available tool designed to assess tumor aggressiveness, despite the fact that this is considered to have a major impact on patient outcome. Methods/design CORIOLAN is a single-arm prospective interventional non-therapeutic study aiming mainly to assess the natural tumor metabolic progression index (TMPI) measured by serial FDG PET-CT without any intercurrent antitumor therapy as a prognostic factor for overall survival (OS) in patients with mCRC. Secondary objectives of the study aim to test the TMPI as a prognostic marker for progression-free survival (PFS), to assess the prognostic value of baseline tumor FDG uptake on PFS and OS, to compare TMPI to classical clinico-biological assessment of prognosis, and to test the prognostic value on OS and PFS of MRI-based apparent diffusion coefficient (ADC) and variation of vADC using voxel-based diffusion maps. Additionally, this study intends to identify genomic and epigenetic factors that correlate with progression of tumors and the OS of patients with mCRC. Consequently, this analysis will provide information about the signaling pathways that determine the natural and therapy-free course of the disease. Finally, it would be of great interest to investigate whether in a population of patients with mCRC, for which at present no known effective therapy is available, tumor aggressiveness is related to elevated levels of circulating tumor cells (CTCs) and to patient outcome. Discussion Tumor aggressiveness is one of the major determinants of patient outcome in advanced disease. Despite its importance, supported by findings reported in the literature of extreme outcomes for patients with mCRC treated with chemotherapy, no objective tool allows clinicians to base treatment decisions on this factor. The CORIOLAN study will characterize TMPI using FDG-PET-based metabolic imaging of patients with chemorefractory mCRC during a period of time without treatment. Results will be correlated to other assessment tools like DW-MRI, CTCs and circulating DNA, with the aim to provide usable tools in daily practice and in clinical studies in the future. [ABSTRACT FROM AUTHOR]

Background: Metastatic colorectal cancer (mCRC) may present various behaviours that define different courses of tumor evolution. There is presently no available tool designed to assess tumor aggressiveness, despite the fact that this is considered to have a major impact on patient outcome. Methods/Design: CORIOLAN is a single-arm prospective interventional non-therapeutic study aiming mainly to assess the natural tumor metabolic progression index (TMPI) measured by serial FDG PET-CT without any intercurrent antitumor therapy as a prognostic factor for overall survival (OS) in patients with mCRC. Secondary objectives of the study aim to test the TMPI as a prognostic marker for progression-free survival (PFS), to assess the prognostic value of baseline tumor FDG uptake on PFS and OS, to compare TMPI to classical clinico-biological assessment of prognosis, and to test the prognostic value on OS and PFS of MRI-based apparent diffusion coefficient (ADC) and variation of vADC using voxel-based diffusion maps. Additionally, this study intends to identify genomic and epigenetic factors that correlate with progression of tumors and the OS of patients with mCRC. Consequently, this analysis will provide information about the signaling pathways that determine the natural and therapy-free course of the disease. Finally, it would be of great interest to investigate whether in a population of patients with mCRC, for which at present no known effective therapy is available, tumor aggressiveness is related to elevated levels of circulating tumor cells (CTCs) and to patient outcome. Discussion: Tumor aggressiveness is one of the major determinants of patient outcome in advanced disease. Despite its importance, supported by findings reported in the literature of extreme outcomes for patients with mCRC treated with chemotherapy, no objective tool allows clinicians to base treatment decisions on this factor. The CORIOLAN study will characterize TMPI using FDG-PET-based metabolic imaging of patients with chemorefractory mCRC during a period of time without treatment. Results will be correlated to other assessment tools like DW-MRI, CTCs and circulating DNA, with the aim to provide usable tools in daily practice and in clinical studies in the future. [ABSTRACT FROM AUTHOR]

Purpose: To compare the performance of eight metabolic indices for the early assessment of tumour response in patients with metastatic colorectal cancer (mCRC) treated with chemotherapy. Methods: Forty patients with advanced mCRC underwent two FDG PET/CT scans, at baseline and on day 14 after chemotherapy initiation. For each lesion, eight metabolic indices were calculated: four standardized uptake values (SUV) without correction for the partial volume effect (PVE), two SUV with correction for PVE, a metabolic volume (MV) and a total lesion glycolysis (TLG). The relative change in each index between the two scans was calculated for each lesion. Lesions were also classified as responding and nonresponding lesions using the Response Evaluation Criteria In Solid Tumours (RECIST) 1.0 measured by contrast-enhanced CT at baseline and 6-8 weeks after starting therapy. Bland-Altman analyses were performed to compare the various indices. Based on the RECIST classification, ROC analyses were used to determine how accurately the indices predicted lesion response to therapy later seen with RECIST. Results: RECIST showed 27 responding and 74 nonresponding lesions. Bland-Altman analyses showed that the four SUV indices uncorrected for PVE could not be used interchangeably, nor could the two SUV corrected for PVE. The areas under the ROC curves (AUC) were not significantly different between the SUV indices not corrected for PVE. The mean SUV change in a lesion better predicted lesion response without than with PVE correction. The AUC was significantly higher for SUV uncorrected for PVE than for the MV, but change in MV provided some information regarding the lesion response to therapy (AUC >0.5). Conclusion: In these mCRC patients, all SUV uncorrected for PVE accurately predicted the tumour response on day 14 after starting therapy as assessed 4 to 6 weeks later (i.e. 6 to 8 weeks after therapy initiation) using the RECIST criteria. Neither correcting SUV for PVE nor measuring TLG improved the assessment of tumour response compared to SUV uncorrected for PVE. The change in MV was the least accurate index for predicting tumour response. [ABSTRACT FROM AUTHOR]

Purpose: Medical oncology needs early identification of patients that are not responding to systemic therapy. F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) performed before and early during treatment has been proposed for this purpose. However, the best way to assess the change in FDG uptake between two scans has not been identified. We studied cutoff thresholds to identify responding tumours as a function of the method used to measure tumour uptake. Methods: The study included 28 metastatic colorectal cancer (mCRC) patients who underwent 2 FDG PET/CT scans (baseline and at day 14 of the first course of polychemotherapy). For 78 tumour lesions, 4 standardized uptake value (SUV) indices were measured: maximum SUV (SUV) and mean SUV in a region obtained using an isocontour (SUV), with each of these SUV normalized either by the patient body weight (BW) or body surface area (BSA). The per cent change and absolute change in tumour uptake between the baseline and the early PET scans were measured based on these four indices. These changes were correlated to the RECIST 1.0-based response using contrast-enhanced CT at baseline and at 6-8 weeks on treatment. Results: The 78 tumours were classified as non-responding (NRL, n = 58) and responding lesions (RL, n = 20). Receiver-operating characteristic (ROC) curves characterizing the performance in NRL/RL classification using early FDG PET uptake had areas under the curve between 0.75 and 0.84, without significant difference between the indices. The cutoff threshold in FDG uptake per cent change to get a 95 % sensitivity of RL detection depended on the way uptake was measured: −14 % (specificity of 53 %) and −22 % (specificity of 64 %) for SUV and SUV, respectively. Thresholds expressed as absolute SUV decrease instead of per cent change were less sensitive to the SUV definition: an SUV decline by 1.2 yielded a sensitivity of RL detection of 95 % for SUV and SUV. For a given cutoff threshold, the sensitivity was the same whatever the normalization (by BSA or BW). Conclusion: A 14 % drop of tumour FDG SUV, 22 % drop of SUV or 1.2 drop of SUV or SUV after one single course of polychemotherapy predicts objective response in mCRC lesions with a high sensitivity, potentially allowing the early identification of non-responding patients. [ABSTRACT FROM AUTHOR]

Background: Induction chemotherapy has been suggested to impact on preoperative chemoradiation efficacy in locally advanced rectal cancer (LARC). To evaluate in LARC patients, the feasibility and efficacy of a short intense course of induction oxaliplatin before preoperative chemoradiotherapy (CRT). Patients and methods: Patients with T2-T4/N+ rectal adenocarcinoma were randomly assigned to arm A—preoperative CRT with 5-fluorouracil (5-FU) continuous infusion followed by surgery—or arm B—induction oxaliplatin, folinic acid and 5-FU followed by CRT and surgery. The primary end point was the rate of ypT0-1N0 stage achievement. Results: Fifty seven patients were randomly assigned (arm A/B: 29/28) and evaluated for planned interim analysis. On an intention-to-treat basis, the ypT0-1N0 rate for arms A and B were 34.5% (95% CI: 17.2% to 51.8%) and 32.1% (95% CI: 14.8% to 49.4%), respectively, and the study therefore was closed prematurely for futility. There were no statistically significant differences in other end points including pathological complete response, tumor regression and sphincter preservation. Completion of the preoperative CRT sequence was similar in both groups. Grade 3/4 toxicity was significantly higher in arm B. Conclusions: Short intense induction oxaliplatin is feasible in LARC patients without compromising the preoperative CRT completion, although the current analysis does not indicate increased locoregional impact on standard therapy. [ABSTRACT FROM PUBLISHER]

Although the treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, it is entering a new era with the development of new strategies and trial designs. Because there is an increasing number of novel therapeutic agents and potential combinations available to test in patients with PDAC, the identification of robust prognostic and predictive markers and of new targets and relevant pathways is a top priority as well as the design of adequate trials incorporating molecular-driven hypothesis. We presently report a consensus strategy for research in pancreatic cancer that was developed by a multidisciplinary panel of experts from different European institutions and collaborative groups involved in pancreatic cancer. The expert panel embraces the concept of exploratory early proof of concept studies, based on the prediction of response to novel agents and combinations, and randomised phase II studies permitting the selection of the best therapeutic approach to go forward into phase III, where the recommended primary end point remains overall survival. Trials should contain as many translational components as possible, relying on standardised tissue and blood processing and robust biobanking, and including dynamic imaging. Attention should not only be paid to the pancreatic cancer cells but also to microenvironmental factors and stem/stellate cells. [ABSTRACT FROM PUBLISHER]

Abstract: Background: Identifying new prognostic factors is important for guiding treatments and preventing metastasis in cancer. Vagal nerve activity may predict prognosis in cancer due to its roles in modulating inflammation, sympathetic activity and oxidative stress. This study tested the relationship between heart rate variability (HRV), a vagal nerve index, and the colon cancer (CC) marker carcinoembryonic antigen (CEA), in an ‘historical prospective’ design. Methods: We examined data of 72 CC patients, without inflammatory or cardiac diseases, of whom 38 had baseline electrocardiograms (ECG) and 12month CEA levels. We measured HRV (SDNN, RMSSD) from brief archived ECG. Multiple confounders were considered. Results: Controlling for effects of tumor stage and treatment-orientation, baseline HRV predicted CEA levels at 12months (r=−.43, p=.006). Patients with SDNN<20ms had significantly higher CEA at 12months than those with SDNN>20ms. Conclusion: These preliminary results showed that higher HRV predicts lower levels of a tumor marker, one year later, independent of confounders. This supports the hypothesized role of vagal activity in tumor modulation. Replication in larger samples is needed. [Copyright &y& Elsevier]

Sorafenib (twice daily [bid]) plus capecitabine (2 weeks on schedule/1 week off schedule) safety and pharmacokinetics were investigated in patients with advanced solid tumors (N = 35). Cohort 1 (n = 13) included sorafenib 200 mg bid and capecitabine 1050 mg/m2 bid; cohort 2 (n = 4), sorafenib 400 mg bid and capecitabine 1050 mg/m2 bid; cohort 3 (n = 6), sorafenib 200 mg bid and capecitabine 1050 mg/m2 bid (cycles 1 and 2), then 400 mg bid and capecitabine 1050 mg/m2 bid (cycle 3 onwards); and cohort 4 (n = 12), sorafenib 400 mg bid and capecitabine 850 mg/m2 bid. The combination of sorafenib and capecitabine was generally well tolerated. Most frequent drug-related adverse events were hand-foot skin reaction (HFSR, 89%), diarrhea (71%), and fatigue (69%). The HFSR was dose-limiting toxicities in 6 patients. Sorafenib exposure (Cmax and AUC0–12) was unaffected by concomitant capecitabine. Concomitant sorafenib moderately increased capecitabine and 5-fluorouracil (metabolite) exposure when the capecitabine dose was 1050 mg/m2 bid. Simultaneous administration of 400 mg bid sorafenib and 850 mg/m2 bid capecitabine, however, had only minor effects on the exposure to capecitabine and 5-fluorouracil. Based on the overall toxicity profile and pharmacokinetic parameters, the recommended phase 2 doses were therefore sorafenib 400 mg bid and capecitabine 850 mg/m2 bid, as scheduled above. [ABSTRACT FROM PUBLISHER]