Publications by authors named "Marc Van Den Eynde"

45 Publications

Fortnightly or fractionated weekly docetaxel-cisplatin-5-FU as first-line treatment in advanced gastric and gastroesophageal junction adenocarcinoma: The randomized phase II DoGE study.

Cancer Med 2021 May 31. Epub 2021 May 31.

Department of Medicine, Gastrointestinal Unit, Institut Jules Bordet, Université Libre de Bruxelles, Bruxelles, Belgium.

Background: While docetaxel/cisplatin/5-fluorouracil (DCF) outperforms CF in first-line gastric adenocarcinoma, toxicity remains an issue.

Methods: This multicenter phase II trial randomized chemonaïve metastatic gastric adenocarcinoma patients to fractionated weekly DCF (D 40 mg/m , C 35 mg/m², F 1800 mg/m² over 24 h, on days 1 and 8 every 3 weeks, arm (1) or fortnightly DCF (D 50 mg/m , C 50 mg/m², F 2000 mg/m² over 48 h every 2 weeks, arm (2). Prophylactic granulocyte colony-stimulating factor (G-CSF) was not allowed. The primary endpoint was the rate of febrile neutropenia within the first six treatment weeks (early FN).

Results: A total of 106 eligible patients were recruited. The early and overall FN rates were 9.5% and 17% in arm 1, respectively, and 5.9% and 8% in arm 2, respectively. Grade ≥3 toxicities occurred in 81% of patients in arm 1 and 90% of patients in arm 2, the most common being neutropenia (33% vs. 61%), fatigue (27% vs. 25%), vomiting (21% vs. 12%), anorexia (19% vs. 18%), and diarrhea (17% vs. 10%). Median progression-free survival and overall survival were 5.1 (95% CI, 3.2-6.5) and 8.2 months (95% CI, 6.0-14.5), respectively, in arm 1 and 5.2 (95% CI, 3.0-6.9) and 11.9 months (95% CI, 7.4-15.9), respectively, in arm 2.

Conclusions: Fractionated weekly and fortnightly DCF regimens are associated with a low risk of early FN, and a better hematological toxicity profile as compared to historical DCF without compromising efficacy. Both regimens offer greater convenience removing the need for systematic use of prophylactic G-CSF.
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http://dx.doi.org/10.1002/cam4.3976DOI Listing
May 2021

Avelumab and cetuximab as a therapeutic combination: An overview of scientific rationale and current clinical trials in cancer.

Cancer Treat Rev 2021 Jun 2;97:102172. Epub 2021 Mar 2.

Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy.

Treatment outcomes have improved with the advent of immune checkpoint inhibitors and small molecule inhibitors. However, many patients do not respond with single agents. Consequently, ongoing research is focused on the use of combination therapies to increase clinical efficacy by potential synergistic effects. Here, we outline ongoing trials and review the rationale and evidence for the combination of avelumab, an anti-programmed death ligand 1 (PD-L1) immunoglobulin G1 (IgG1) monoclonal antibody (mAb), with cetuximab, an anti-epidermal growth factor receptor (EGFR) IgG1 mAb. Avelumab is approved as a monotherapy for the treatment of Merkel cell carcinoma and urothelial carcinoma, and in combination with axitinib for renal cell carcinoma; cetuximab is approved in combination with chemotherapy for the treatment of squamous cell carcinoma of the head and neck (SCCHN) and RAS wild-type metastatic colorectal cancer, and in combination with radiation therapy for SCCHN. Avelumab binds to PD-L1 expressed on tumor cells and immune regulatory cells, thus blocking its interaction with programmed death 1 and reventing T-cell suppression; cetuximab inhibits the EGFR signaling pathway, inhibiting proliferation and inducing apoptosis. Both therapies have complementary mechanisms of action and may also activate the immune system to induce innate effector function through the binding of their Fc regions to natural killer (NK) cells. Furthermore, cetuximab combined with chemotherapy has been shown to induce immunogenic cell death and leads to an increase in tumor-infiltrating CD8+ T and NK cells, which should synergize with the immunostimulatory effects of avelumab. Prospective studies will investigate this combination and inform future treatment strategies.
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http://dx.doi.org/10.1016/j.ctrv.2021.102172DOI Listing
June 2021

Prediction of tumor response and patient outcome after radioembolization of hepatocellular carcinoma using 90Y-PET-computed tomography dosimetry.

Nucl Med Commun 2021 Jul;42(7):747-754

Departments of Nuclear Medicine.

Aim: 90Y-radioembolization using glass or resin microspheres is increasingly used for the treatment of hepatocellular carcinoma (HCC). The aim of this retrospective study is to determine the prognostic relevance of dosimetric parameters defined with 90Y-PET-CT obtained immediately after radioembolization.

Methods: Forty-five HCC patients, mostly with multiple lesions, were treated by radioembolization between 2011 and 2017. After treatment, all underwent a 90Y PET-CT with time of flight reconstruction (90Y-TOF-PET-CT). Tumor absorbed dose and cumulative tumor dose-volume histogram were calculated using a dose point Kernel convolution algorithm. The radiological tumor response was assessed using modified (m)-RECIST criteria. Progression-free-survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox regression analysis.

Results: Twenty-six patients were treated with glass microspheres (73 lesions) and nineteen with resin microspheres (60 lesions). Thresholds of 118 and 61 Gy for glass and resin microspheres respectively correlate well with radiological response with a positive predictive value (PPV) of 98 and 80% and discriminate patient outcome with regard to PFS (P = 0.03 and 0.005) and OS (P = 0.003 and 0.007). Using dose volume histogram, a minimal absorbed dose of 40 Gy in 66% of the tumor volume (defined as D66) was highly predictive of radiological response (PPV = 94%), PFS (P < 0.001) and OS (P = 0. 008), for either device.

Conclusion: Dosimetric parameters obtained using 90Y-PET-CT are predictive of tumor response, PFS and OS. In clinical practice, a systematic dosimetric evaluation using 90Y PET should be implemented to help predicting patient outcomes.
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http://dx.doi.org/10.1097/MNM.0000000000001395DOI Listing
July 2021

Trifluridine/tipiracil in patients with metastatic gastroesophageal junction cancer: a subgroup analysis from the phase 3 TAGS study.

Gastric Cancer 2021 Jul 13;24(4):970-977. Epub 2021 Mar 13.

University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium.

Background: Patients with advanced gastroesophageal junction cancer (GEJC) have poor survival outcomes, and GEJC-specific data from trials evaluating agents in gastric cancers (GCs) as a whole are lacking. Trifluridine/tipiracil (FTD/TPI) was approved for previously treated metastatic GC or GEJC (mGC/mGEJC) based on results of the phase 3 TAGS trial. Subgroup analyses by primary tumor type (GC or GEJC) in TAGS are reported here.

Methods: Pa tients with mGC/mGEJC treated with  ≥ 2 prior chemotherapy regimens were randomized (2:1) to receive FTD/TPI or placebo, plus best supportive care. A pre-planned sub-analysis was performed to evaluate efficacy and safety outcomes by primary tumor type (GEJC or GC).

Results: Of 507 randomized patients, 145 (29%) had GEJC and 360 (71%) had GC as the primary disease site. Baseline characteristics were generally similar between the GEJC and GC subgroups, except that more patients in the GEJC subgroup had received  ≥ 3 prior regimens (72 vs. 59% in the GC subgroup). Survival benefit with FTD/TPI was observed in both subgroups. The overall survival hazard ratio for FTD/TPI vs placebo was 0.75 (95% CI 0.50-1.11) and 0.67 (95% CI 0.52-0.87) in the GEJC and GC subgroups, respectively. Grade ≥ 3 adverse events of any cause were reported in 75 (77%) and 192 (81%) FTD/TPI-treated patients in the GEJC and GC subgroups, respectively. No new safety concerns were noted with FTD/TPI.

Conclusion: As in patients with GC, FTD/TPI showed an efficacy benefit in patients with GEJC in the TAGS trial, along with demonstrating a manageable safety profile.
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http://dx.doi.org/10.1007/s10120-021-01156-xDOI Listing
July 2021

The absence of benefit of perioperative chemotherapy in initially resectable peritoneal metastases of colorectal cancer origin treated with complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: A retrospective analysis.

Eur J Surg Oncol 2021 Jul 3;47(7):1661-1667. Epub 2021 Feb 3.

Department of Surgical Oncology, Institut J. Bordet, Université Libre de Bruxelles, Brussels, Belgium. Electronic address:

Introduction: The aim of this study was to compare the outcome of patients with peritoneal metastasis (PM) of colorectal origin treated with complete cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with or without perioperative systemic chemotherapy (PCT+/PCT-).

Patients And Methods: Retrospective analysis of 125 patients treated with complete CRS (R0/R1) and HIPEC for PM from colorectal origin in two Belgian academic centers between 2008 and 2017. Disease-free survival (DFS) and overall survival (OS) were assessed with regard to PCT. Statistical analyses were adjusted for non-balanced survival risk factors.

Results: The PCT+ group (n = 67) received at least 5 cycles of PCT and the PCT-group (n = 56) did not receive PCT. The groups were well balanced for all prognostic factors except presentation of synchronous disease (more in PCT+). Survival analysis was adjusted to peritoneal cancer index and presentation of synchronous disease. After a median follow-up of 54±5-months, the 1, 3, 5-years OS in the PCT+ group were 98%, 59% and 35% compared to 97%, 77% and 56% in the PCT-group (HR = 1.46; 95% CI:0.87-2.47; p = 0.155). The 1,3 and 5 years DFS in the PCT+ group were 47%, 13% and 6% compared to 58%, 29% and 26% respectively in the PCT- (HR = 1.22; 95% CI:0.78-1.92; p = 0.376).

Conclusion: This study does not show any clear benefit of PCT in carefully selected patients undergoing R0/R1 CRS and HIPEC for colorectal PM. The ongoing CAIRO6 trial randomizing CRS/HIPEC versus CRS/HIPEC and PCT will probably clarify the role of PCT in patients with resectable PM.
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http://dx.doi.org/10.1016/j.ejso.2021.01.018DOI Listing
July 2021

Multiverse of immune microenvironment in metastatic colorectal cancer.

Oncoimmunology 2020 09 29;9(1):1824316. Epub 2020 Sep 29.

INSERM, Laboratory of Integrative Cancer Immunology, Paris, France.

The comprehensive analysis of patients with a complete resection of all metastases reveals the heterogeneity of the colorectal metastatic disease and its clinical impact. Complex tumor immune interrelations shape the metastatic landscape, not only in terms of number and size of lesions, or mutational pattern, but also in terms of immune cell infiltrate. Significantly higher densities of T-cells and lower density of B-cells were quantified in the tumor microenvironment of metastases compared with primary tumors. A high T cell infiltration and Immunoscore measured in the least-infiltrated metastasis were associated with a significantly lower number of metastases, larger metastasis, and prolonged survival while patients with increased metastatic burden had a lower Immunoscore. Immunoscore was evaluated on a biopsy, in a random metastasis or as the mean value of all metastases significantly predicting outcome. However, the most immune-infiltrated metastasis was not significantly predicting outcome, whereas the least immune-infiltrated metastasis was best in predicting clinical outcome. A good likelihood of concordance of Immunoscore was observed between one biopsy and complete metastasis, but the overall intra-metastatic immune infiltrate might be better estimated with multiple biopsies or sampling of larger tumor areas. This intra-metastatic adaptive immune reaction increases following aneoadjuvant treatment containing anti-EGFR monoclonal antibody, an effect that is currently therapeutically evaluated in clinical trials to improve the survival of metastatic patients.
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http://dx.doi.org/10.1080/2162402X.2020.1824316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781760PMC
September 2020

Joint Belgian recommendation on screening for DPD-deficiency in patients treated with 5-FU, capecitabine (and tegafur).

Acta Clin Belg 2021 Jan 11:1-7. Epub 2021 Jan 11.

Department of Gastroenterology, UZ Gent, Gent.

Fluoropyrimidines such as 5-Fluorouracil (5-FU), capecitabine and tegafur are drugs that are often used in the treatment of maliginancies. The enzyme dihydropyrimidine dehydrogenase (DPD) is the first and rate limiting enzyme of 5-FU catabolism. Genetic variations within the DPYD gene (encoding for DPD protein) can lead to reduced or absent DPD activity. Treatment of DPD deficient patients with fluoropyrimidines can result in severe and, rarely, fatal toxicity. Screening for DPD deficiency should be implemented in practice. The available methods in routine to screen for DPD deficiency were analyzed and discussed in several group meetings involving members of the oncological, genetic and toxicological societies in Belgium: targeted genotyping based on the detection of 4 DPYD variants and phenotyping, through the measurement of uracil and dihydrouracil/uracil ratio in plasma samples. The main advantage of targeted genotyping is the existence of prospectively validated genotype-based dosing guidelines. The main limitations of this approach are the relatively low sensitivity to detect total and partial DPD deficiency and the fact that this approach has only been validated in Caucasians so far. Phenotyping has a better sensitivity to detect total and partial DPD deficiency when performed in the correct analytical conditions and is not dependent on the ethnic origin of the patient. In Belgium, we recommend phenotype or targeted genotype testing for DPD deficiency before starting 5-FU, capecitabine or tegafur. We strongly suggest a stepwise approach using phenotype testing upfront because of the higher sensitivity and the lower cost to society.
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http://dx.doi.org/10.1080/17843286.2020.1870855DOI Listing
January 2021

Immunity to live: an immunopathoscore using the consensus Immunoscore to best define the risk of recurrence and death in stage IV metastatic patients.

Oncoimmunology 2020 10 13;9(1):1826133. Epub 2020 Oct 13.

Laboratory of Integrative Cancer Immunology, INSERM, Paris, France.

The consensus Immunoscore is a routine assay quantifying the adaptive immune response within the tumor microenvironment. Its evaluation in the primary tumor of patients with stages I/II/III colorectal cancer (CRC) has prognostic value that has been confirmed in multiple studies. For metastatic patients, the evaluation of the consensus Immunoscore within resected metastases also significantly predicts the recurrence and survival of Stage IV patients. Since recurrence rates post-surgery are still very high, it is important to best evaluate risk parameters using the main patho-molecular and immune parameters. After preoperative treatment and curative resection of 582 metastases from 221 patients, clinico-pathological parameters, mutation, and Immunoscore within metastases were assessed. Immunoscore and clinico-pathological parameters (number of metastases, surgical margin, histopathological growth pattern, and steatohepatitis) were associated with relapse in multivariable analysis. A Pathological Score (PS) that combines relevant clinico-pathological factors for relapse and Immunoscore was significantly ( < .0001) associated with Time to recurrence. In multivariable analysis, only Immunoscore ( < .001) and mutations (= .03) were prognostic and significantly associated with overall survival. Thus, among all parameters clinically relevant in the metastatic settings, PS and Immunoscore allow the stratification of stage IV CRC patients and identify patients with higher risk of recurrence. Immunoscore remained the major prognostic factor for overall survival (OS). In its latest edition, the WHO classification of Digestive System Tumors introduced for the first time the immune response as an essential and desirable diagnostic criterion for CRC. These novel results highlight the clinical utility of Immunoscore in Stage IV patients.
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http://dx.doi.org/10.1080/2162402X.2020.1826133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561331PMC
October 2020

Metastasis immune-based scores predict patient survival.

Oncoimmunology 2020 08 20;9(1):1806000. Epub 2020 Aug 20.

Laboratory of Integrative Cancer Immunology, INSERM, Paris, France.

Treatment of metastatic colorectal cancer is based upon the assumption that metastases are homogeneous within a patient. A comprehensive analysis of all metastases of each patient revealed the heterogeneity of the colorectal metastatic disease and its clinical impact. Complex tumor-immune interrelations shape the metastatic landscape. Adaptive immune cells and Immunoscore quantified in a random metastatic biopsy predict clinical outcome and their evaluation in the tumor microenvironment of the least infiltrated metastasis most accurately predict long-term survival. The adaptive immune cell infiltration was more informative than tumor regression and pathological response to predict long-term survival. These results highlight the clinical utility of Immunoscore for patient management. The immune response within the tumor microenvironment is an essential diagnostic criterion for colorectal cancer that has recently been integrated into the international WHO classification of Digestive System Tumors.
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http://dx.doi.org/10.1080/2162402X.2020.1806000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458633PMC
August 2020

Prognostic assessment of resected colorectal liver metastases integrating pathological features, RAS mutation and Immunoscore.

J Pathol Clin Res 2021 01 9;7(1):27-41. Epub 2020 Sep 9.

Department of Pathology, Cliniques Universitaires Saint-Luc/Université Catholique de Louvain (UCLouvain), Brussels, Belgium.

Surgical resection of colorectal liver metastases combined with systemic treatment aims to maximize patient survival. However, recurrence rates are very high postsurgery. In order to assess patient prognosis after metastasis resection, we evaluated the main patho-molecular and immune parameters of all surgical specimens. Two hundred twenty-one patients who underwent, after different preoperative treatment, curative resection of 582 metastases were analyzed. Clinicopathological parameters, RAS tumor mutation, and the consensus Immunoscore (I) were assessed for all patients. Overall survival (OS) and time to relapse (TTR) were estimated using the Kaplan-Meier method and compared by log-rank tests. Cox proportional hazard models were used for uni- and multivariate analysis. Immunoscore and clinicopathological parameters (number of metastases, surgical margin, histopathological growth pattern, and steatohepatitis) were associated with relapse in multivariate analysis. Overall, pathological score (PS) that combines relevant clinicopathological factors for relapse, and I, were prognostic for TTR (2-year TTR rate PS 0-1: 49.8.% (95% CI: 42.2-58.8) versus PS 2-4: 20.9% (95% CI: 13.4-32.8), hazard ratio (HR) = 2.54 (95% CI: 1.82-3.53), p < 0.0000; and 2-year TTR rate I 0: 25.7% (95% CI: 16.3-40.5) versus I 3-4: 60% (95% CI: 47.2-76.3), HR = 2.87 (95% CI: 1.73-4.75), p = 0.0000). Immunoscore was also prognostic for OS (HR [I 3-4 versus I 0] = 4.25, 95% CI: 1.95-9.23; p = 0.0001). Immunoscore (HR [I 3-4 versus I 0] = 0.27, 95% CI: 0.12-0.58; p = 0.0009) and RAS mutation (HR [mutated versus WT] = 1.66, 95% CI: 1.06-2.58; p = 0.0265) were significant for OS. In conclusion, PS including relevant clinicopathological parameters and Immunoscore permit stratification of stage IV colorectal cancer patient prognosis in terms of TTR and identify patients with higher risk of recurrence. Immunoscore remains the major prognostic factor for OS.
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http://dx.doi.org/10.1002/cjp2.178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737782PMC
January 2021

Multicenter International Society for Immunotherapy of Cancer Study of the Consensus Immunoscore for the Prediction of Survival and Response to Chemotherapy in Stage III Colon Cancer.

J Clin Oncol 2020 11 8;38(31):3638-3651. Epub 2020 Sep 8.

Princess Margaret Cancer Centre, UHN, Toronto, Ontario, Canada.

Purpose: The purpose of this study was to evaluate the prognostic value of Immunoscore in patients with stage III colon cancer (CC) and to analyze its association with the effect of chemotherapy on time to recurrence (TTR).

Methods: An international study led by the Society for Immunotherapy of Cancer evaluated the predefined consensus Immunoscore in 763 patients with American Joint Committee on Cancer/Union for International Cancer Control TNM stage III CC from cohort 1 (Canada/United States) and cohort 2 (Europe/Asia). CD3+ and cytotoxic CD8+ T lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The primary end point was TTR. Secondary end points were overall survival (OS), disease-free survival (DFS), prognosis in microsatellite stable (MSS) status, and predictive value of efficacy of chemotherapy.

Results: Patients with a high Immunoscore presented with the lowest risk of recurrence, in both cohorts. Recurrence-free rates at 3 years were 56.9% (95% CI, 50.3% to 64.4%), 65.9% (95% CI, 60.8% to 71.4%), and 76.4% (95% CI, 69.3% to 84.3%) in patients with low, intermediate, and high immunoscores, respectively (hazard ratio [HR; high low], 0.48; 95% CI, 0.32 to 0.71; = .0003). Patients with high Immunoscore showed significant association with prolonged TTR, OS, and DFS (all < .001). In Cox multivariable analysis stratified by participating center, Immunoscore association with TTR was independent (HR [high low], 0.41; 95% CI, 0.25 to 0.67; .0003) of patient's sex, T stage, N stage, sidedness, and microsatellite instability status. Significant association of a high Immunoscore with prolonged TTR was also found among MSS patients (HR [high low], 0.36; 95% CI, 0.21 to 0.62; .0003). Immunoscore had the strongest contribution χ2 proportion for influencing survival (TTR and OS). Chemotherapy was significantly associated with survival in the high-Immunoscore group for both low-risk (HR [chemotherapy no chemotherapy], 0.42; 95% CI, 0.25 to 0.71; = .0011) and high-risk (HR [chemotherapy no chemotherapy], 0.5; 95% CI, 0.33 to 0.77; = .0015) patients, in contrast to the low-Immunoscore group ( > .12).

Conclusion: This study shows that a high Immunoscore significantly associated with prolonged survival in stage III CC. Our findings suggest that patients with a high Immunoscore will benefit the most from chemotherapy in terms of recurrence risk.
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http://dx.doi.org/10.1200/JCO.19.03205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605397PMC
November 2020

A Diagnostic Biopsy-Adapted Immunoscore Predicts Response to Neoadjuvant Treatment and Selects Patients with Rectal Cancer Eligible for a Watch-and-Wait Strategy.

Clin Cancer Res 2020 10 15;26(19):5198-5207. Epub 2020 Jul 15.

Laboratory of Integrative Cancer Immunology, INSERM UMRS1138, Immunology and Cancer Department, Cordeliers Research Center, Paris, France.

Purpose: No biomarker to personalize treatment in locally advanced rectal cancer (LARC) is currently available. We assessed in LARC whether a diagnostic biopsy-adapted immunoscore (IS) could predict response to neoadjuvant treatment (nT) and better define patients eligible to an organ preservation strategy ("Watch-and-Wait").

Experimental Design: Biopsies from two independent cohorts ( = 131, = 118) of patients with LARC treated with nT followed by radical surgery were immunostained for CD3 and CD8 T cells and quantified by digital pathology to determine IS. The expression of immune-related genes post-nT was investigated ( = 64 patients). Results were correlated with response to nT and disease-free survival (DFS). The IS prognostic performance was further assessed in a multicentric cohort ( = 73 patients) treated by Watch-and-Wait.

Results: IS positively correlated with the degree of histologic response ( < 0.001) and gene expression levels for Th1 orientation and cytotoxic immune response, post-nT ( = 0.006). IS high identified patients at lower risk of relapse or death compared with IS low [HR, 0.21; 95% confidence interval (CI), 0.06-0.78; = 0.009]. Prognostic performance of IS for DFS was confirmed in a validation cohort. IS was an independent parameter, more informative than pre- ( < 0.001) and post-nT ( < 0.05) imaging to predict DFS. IS combined with imaging post-nT discriminated very good responders that could benefit from organ preservation strategy. In the "Watch-and-Wait" cohort ( = 73), no relapse was observed in patients with IS high (23.3%).

Conclusions: IS predicts response to nT and survival in patients with LARC treated by surgery. Its usefulness in the selection of patients eligible for a Watch-and-Wait strategy is strongly suggested.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0337DOI Listing
October 2020

Analytical validation of the Immunoscore and its associated prognostic value in patients with colon cancer.

J Immunother Cancer 2020 05;8(1)

Laboratory of Integrative Immunology and cancerology, INSERM, University of Paris, Cordeliers Research centre, Immunomonitoring Platform, Laboratory of Immunology, AP-HP (Assistance Publique-Hôpitaux de Paris) Hôpital Européen Georges Pompidou, Paris, France

Background: New and fully validated tests need to be brought into clinical practice to improve the estimation of recurrence risk in patients with colon cancer. The aim of this study was to assess the analytical performances of the Immunoscore (IS) and show its contribution to prognosis prediction.

Methods: Immunohistochemical staining of CD3+ and CD8+ T cells on adjacent sections of colon cancer tissues were quantified in the core of the tumor and its invasive margin with dedicated IS modules integrated into digital pathology software. Staining intensity across samples collected between 1989 and 2016 (n=595) was measured. The accuracy of the IS workflow was established by comparing optical and automatic counts. Analytical precision of the IS was evaluated within individual tumor block on distant sections and between eligible blocks. The IS interlaboratory reproducibility (n=100) and overall assay precision were assessed (n=3). Contribution of the IS to prediction of recurrence based on clinical and molecular parameters was determined (n=538).

Results: Optical and automatic counts for CD3+ or CD8+ were strongly correlated (r=0.94, p<0.001 and r=0.92, p<0.001, respectively). CD3 and CD8 staining intensities were not altered by the age of the tumor block over a period of 30 years. Neither the position of tested tissue sections within a tumor block nor the selection of the tissue blocks affected the IS. Reproducibility of the IS was not affected by multiple variables (eg, antibody lots, DAB revelation kits, immunohistochemistry automates and operators). Interassay repeatability of the IS was 100% and interlaboratory reproducibility between two testing centers was 93%. Finally, in a case series of patients with stage II-III colon cancer, the relative proportion of variance for time to recurrence was greatest for the IS (53% of prognostic variability) in a model that included IS, T-stage, microsatellite instability status and total number of lymph nodes.

Conclusion: IS is a robust and validated clinical assay leveraging immune scoring to predict recurrence risk of patient with localized colon cancer. The strong and independent prognostic value of IS should pave the way for it use in clinical practice.
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http://dx.doi.org/10.1136/jitc-2019-000272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253006PMC
May 2020

HER2 as a Predictive Biomarker and Treatment Target in Colorectal Cancer.

Clin Colorectal Cancer 2020 06 8;19(2):65-72. Epub 2020 Feb 8.

Institut Roi Albert II, Service d'Oncologie Médicale, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (POLE MIRO), Université Catholique de Louvain, Brussels, Belgium.

The prognosis of metastatic colorectal cancer (mCRC) is poor. Cetuximab and panitumumab, 2 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs), improve the overall survival of patients with RAS wild-type mCRC. However, not all patients with RAS wild-type mCRC will respond to anti-EGFR mAbs. Several retrospective trials suggest that human epidermal growth factor receptor 2 (HER2) amplification could be a predictive biomarker of resistance to anti-EGFR mAbs in patients with metastatic RAS and RAF wild-type mCRC. Dual HER2 inhibition with trastuzumab plus lapatinib or pertuzumab has shown promising preliminary anti-tumoral efficacy in RAS wild-type mCRC. Although these findings need to be confirmed in randomized trials, the data strongly support that HER2 is an actionable gene in CRC and provide the scientific rationale to test HER2 status on a routine basis in this disease. In this review, we discuss the predictive value of HER2 activation in CRC as well as its potential role as a treatment target.
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http://dx.doi.org/10.1016/j.clcc.2020.02.007DOI Listing
June 2020

Immunotherapy with immune checkpoint inhibitors in colorectal cancer: what is the future beyond deficient mismatch-repair tumours?

Gastroenterol Rep (Oxf) 2020 Feb 25;8(1):11-24. Epub 2019 Nov 25.

Institut de Recherche Clinique et Expérimentale (Pole MIRO), UCLouvain, Brussels, Belgium.

Following initial success in melanoma and lung tumours, immune checkpoint inhibitors (ICIs) are now well recognized as a major immunotherapy treatment modality for multiple types of solid cancers. In colorectal cancer (CRC), the small subset that is mismatch-repair-deficient and microsatellite-instability-high (dMMR/MSI-H) derive benefit from immunotherapy; however, the vast majority of patients with proficient MMR (pMMR) or with microsatellite stable (MSS) CRC do not. Immunoscore and the consensus molecular subtype classifications are promising biomarkers in predicting therapeutic efficacy in selected CRC. In pMRR/MSS CRC, biomarkers are also needed to understand the molecular mechanisms governing immune reactivity and to predict their relationship to treatment. The continuous development of such biomarkers would offer new perspectives and more personalized treatments by targeting oncological options, including ICIs, which modify the tumour-immune microenvironment. In this review, we focus on CRC and discuss the current status of ICIs, the role of biomarkers to predict response to immunotherapy, and the approaches being explored to render pMMR/MSS CRC more immunogenic through the use of combined therapies.
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http://dx.doi.org/10.1093/gastro/goz061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034232PMC
February 2020

Chimeric Antigen Receptor-T Cells for Targeting Solid Tumors: Current Challenges and Existing Strategies.

BioDrugs 2019 Oct;33(5):515-537

Celyad SA, Mont-Saint-Guibert, Belgium.

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.
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http://dx.doi.org/10.1007/s40259-019-00368-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790340PMC
October 2019

Impact of Primary Tumour Location and Early Tumour Shrinkage on Outcomes in Patients with RAS Wild-Type Metastatic Colorectal Cancer Following First-Line FOLFIRI Plus Panitumumab.

Drugs R D 2019 Sep;19(3):267-275

Tagestherapiezentrum, Interdisziplinäres Tumorzentrum, Universitätsmedizin Mannheim, Mannheim, Germany.

Objective: Data from a trial of first-line panitumumab plus FOLFIRI (folinic acid, infusional 5-fluorouracil and irinotecan) in metastatic colorectal cancer were retrospectively analysed to investigate the effects of primary tumour location and early tumour shrinkage on outcomes.

Methods: Patients with RAS wild-type metastatic colorectal cancer from a single-arm, open-label phase II study (NCT00508404) were included. Tumours located from the splenic flexure to rectum and in the caecum to transverse colon were defined as left- and right-sided, respectively. Baseline characteristics were summarised by primary tumour location and the effects of primary tumour location on outcomes-including objective response rate, resection rate, depth of response, duration of response and progression-free survival-were analysed. Progression-free survival and objective response rate were analysed by early tumour shrinkage status.

Results: Primary tumour location was determined in 52/69 (75%) patients with RAS wild-type metastatic colorectal cancer; 45 (87%) had left-sided disease. Median progression-free survival was longer in patients with left-sided tumours (11.2 vs. 7.2 months for right-sided disease) and more of these patients experienced early tumour shrinkage ≥ 30% (53% vs. 29%). Early tumour shrinkage ≥ 30% was associated with improved progression-free survival irrespective of tumour location. More patients with early tumour shrinkage ≥ 30% achieved a partial or complete response. Objective response rate, duration of response, depth of response and resection rates were similar in patients with left- and right-sided tumours.

Conclusions: This analysis has confirmed a prognostic effect of primary tumour location in patients with RAS wild-type metastatic colorectal cancer receiving first-line panitumumab plus FOLFIRI. Early tumour shrinkage was associated with improved progression-free survival irrespective of tumour location. In right-sided disease, early tumour shrinkage may identify a subgroup of patients who might respond to panitumumab. CLINICALTRIALS.

Gov Identifier: NCT00508404.
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http://dx.doi.org/10.1007/s40268-019-0278-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738356PMC
September 2019

CTCs as a prognostic and predictive biomarker for stage II/III Colon Cancer: a companion study to the PePiTA trial.

BMC Cancer 2019 Apr 3;19(1):304. Epub 2019 Apr 3.

Medical Oncology Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.

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.
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http://dx.doi.org/10.1186/s12885-019-5528-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446374PMC
April 2019

The Link between the Multiverse of Immune Microenvironments in Metastases and the Survival of Colorectal Cancer Patients.

Cancer Cell 2018 12;34(6):1012-1026.e3

INSERM, Laboratory of Integrative Cancer Immunology, Sorbonne Université, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot; Centre de Recherche des Cordeliers, 75006 Paris, France. Electronic address:

Treatment of metastatic colorectal cancer is based upon the assumption that metastases are homogeneous within a patient. We quantified immune cell types of 603 whole-slide metastases and primary colorectal tumors from 222 patients. Primary lesions, and synchronous and metachronous metastases, had a heterogeneous immune infiltrate and mutational diversity. Small metastases had frequently a low Immunoscore and T and B cell score, while a high Immunoscore was associated with a lower number of metastases. Anti-epidermal growth factor receptor treatment modified immune gene expression and significantly increased T cell densities in the metastasis core. The predictive accuracy of the Immunoscore from a single biopsy was superior to the one of programmed cell death ligand 1 (PD-L1). The immune phenotype of the least-infiltrated metastasis had a stronger association with patient outcome than other metastases.
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http://dx.doi.org/10.1016/j.ccell.2018.11.003DOI Listing
December 2018

Evolution of Metastases in Space and Time under Immune Selection.

Cell 2018 10 11;175(3):751-765.e16. Epub 2018 Oct 11.

INSERM, Laboratory of Integrative Cancer Immunology, Sorbonne Université, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Centre de Recherche des Cordeliers, 75006 Paris, France. Electronic address:

We examined how the immune microenvironment molds tumor evolution at different metastatic organs in a longitudinal dataset of colorectal cancer. Through multiplexed analyses, we showed that clonal evolution patterns during metastatic progression depend on the immune contexture at the metastatic site. Genetic evidence of neoantigen depletion was observed in the sites with high Immunoscore and spatial proximity between Ki67 tumor cells and CD3 cells. The immunoedited tumor clones were eliminated and did not recur, while progressing clones were immune privileged, despite the presence of tumor-infiltrating lymphocytes. Characterization of immune-privileged metastases revealed tumor-intrinsic and tumor-extrinsic mechanisms of escape. The lowest recurrence risk was associated with high Immunoscore, occurrence of immunoediting, and low tumor burden. We propose a parallel selection model of metastatic progression, where branched evolution could be traced back to immune-escaping clones. The findings could inform the understanding of cancer dissemination and the development of immunotherapeutics.
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http://dx.doi.org/10.1016/j.cell.2018.09.018DOI Listing
October 2018

International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study.

Lancet 2018 05 10;391(10135):2128-2139. Epub 2018 May 10.

Department of Pathology and Laboratory Medicine, University Health Network, Toronto, ON, Canada.

Background: The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer.

Methods: An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance.

Findings: Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0·97 for colon tumour; r=0·97 for invasive margin; p<0·0001). In the training set, patients with a high Immunoscore had the lowest risk of recurrence at 5 years (14 [8%] patients with a high Immunoscore vs 65 (19%) patients with an intermediate Immunoscore vs 51 (32%) patients with a low Immunoscore; hazard ratio [HR] for high vs low Immunoscore 0·20, 95% CI 0·10-0·38; p<0·0001). The findings were confirmed in the two validation sets (n=1981). In the stratified Cox multivariable analysis, the Immunoscore association with time to recurrence was independent of patient age, sex, T stage, N stage, microsatellite instability, and existing prognostic factors (p<0·0001). Of 1434 patients with stage II cancer, the difference in risk of recurrence at 5 years was significant (HR for high vs low Immunoscore 0·33, 95% CI 0·21-0·52; p<0·0001), including in Cox multivariable analysis (p<0·0001). Immunoscore had the highest relative contribution to the risk of all clinical parameters, including the American Joint Committee on Cancer and Union for International Cancer Control TNM classification system.

Interpretation: The Immunoscore provides a reliable estimate of the risk of recurrence in patients with colon cancer. These results support the implementation of the consensus Immunoscore as a new component of a TNM-Immune classification of cancer.

Funding: French National Institute of Health and Medical Research, the LabEx Immuno-oncology, the Transcan ERAnet Immunoscore European project, Association pour la Recherche contre le Cancer, CARPEM, AP-HP, Institut National du Cancer, Italian Association for Cancer Research, national grants and the Society for Immunotherapy of Cancer.
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http://dx.doi.org/10.1016/S0140-6736(18)30789-XDOI Listing
May 2018

Celyad's novel CAR T-cell therapy for solid malignancies.

Curr Res Transl Med 2018 05 4;66(2):53-56. Epub 2018 Apr 4.

Celyad, Mont-Saint-Guibert, Belgium. Electronic address:

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.
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http://dx.doi.org/10.1016/j.retram.2018.03.001DOI Listing
May 2018

Comprehensive Intrametastatic Immune Quantification and Major Impact of Immunoscore on Survival.

J Natl Cancer Inst 2018 01;110(1)

Laboratory of Integrative Cancer Immunology, INSERM, UMRS1138, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, Paris, France; Inovarion, Paris, France; Department of Medical Oncology, Cliniques Universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole MIRO), Institut Roi Albert II, Université Catholique de Louvain, Brussels, Belgium; Department of Immunology, HEGP, Assistance Publique-Hopitaux de Paris, Paris, France; AstraZeneca, Cambridge, UK; Departments of General and Digestive Surgery, HEGP, AP-HP, Assistance Publique-Hopitaux de Paris, Paris, France; Grand Hopital de Charleroi, Charleroi, Belgium.

Background: This study assesses how the metastatic immune landscape is impacting the response to treatment and the outcome of colorectal cancer (CRC) patients.

Methods: Complete curative resection of metastases (n = 441) was performed for two patient cohorts (n = 153). Immune densities were quantified in the center and invasive margin of all metastases. Immunoscore and T and B cell (TB) score were analyzed in relation to radiological and pathological responses and patient's disease-free (DFS) and overall survival (OS) using multivariable Cox proportional hazards models. All statistical tests were two-sided.

Results: The spatial distribution of immune cells within metastases was nonuniform. Patients, as well as metastases of the same patient, had variable immune infiltrates and response to therapy. A beneficial response was statistically significantly associated with increased immune densities. Among all metastases, Immunoscore (I) and TB score evaluated in the least immune-infiltrated metastases were the strongest predictors for DFS and OS (five-year follow-up, Immunoscore: I 3-4: DFS rate = 27.9%, 95% CI = 15.2 to 51.3; vs I 0-1-2: DFS rate = 12.3%, 95% CI = 4.9 to 30.6; HR = 0.45, 95% CI = 0.28 to 0.70, P = .02; I 3-4: OS rate = 64.6%, 95% CI = 46.6 to 89.6; vs I 0-1-2: OS rate = 32.5%, 95% CI = 17.2 to 61.4; HR = 0.32, 95% CI = 0.15 to 0.66, P = .001, C-index = 65.9%; five-year follow-up, TB score: TB 3-4: DFS rate = 25.7%, 95% CI = 14.2 to 46.6; vs TB 0-1-2: DFS rate = 5.0%, 95% CI = 0.8 to 32.4; HR = 0.36, 95% CI = 0.22 to 0.57, P < .001; TB 3-4: OS rate = 63.7%, 95% CI = 46.4 to 87.5; vs TB 0-1-2: OS rate: 21.4%, 95% CI = 9.2 to 49.8; HR = 0.25, 95% CI = 0.12 to 0.51, P < .001, C-index = 67.8%). High TB score and Immunoscore patients had a median survival of 70.5 months, while low patients survived only 25.1 to 38.3 months. Nonresponding patients with high-immune infiltrates had prolonged DFS (HR = 0.28, 95% CI = 0.15 to 0.52, P = .001) and OS (HR = 0.25, 95% CI = 0.1 to 0.62, P = .001). The immune parameters remained the only statistically significant prognostic factor associated with DFS and OS in multivariable analysis (P < .001), while response to treatment was not.

Conclusions: Response to treatment and prolonged survival of metastatic CRC patients were statistically significantly associated with high-immune densities quantified into the least immune-infiltrated metastasis.
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http://dx.doi.org/10.1093/jnci/djx123DOI Listing
January 2018

Radiological imaging markers predicting clinical outcome in patients with metastatic colorectal carcinoma treated with regorafenib: post hoc analysis of the CORRECT phase III trial (RadioCORRECT study).

ESMO Open 2016 13;1(6):e000111. Epub 2017 Feb 13.

Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.

Objective: To identify imaging markers predicting clinical outcomes to regorafenib in metastatic colorectal carcinoma (mCRC).

Methods: The RadioCORRECT study is a post hoc analysis of a cohort of patients with mCRC treated within the phase III placebo-controlled CORRECT trial of regorafenib. Baseline and week 8 contrast-enhanced CT were used to assess response by RECIST 1.1, changes in the sum of target lesion diameters (ΔSTL), lung metastases cavitation and liver metastases density. Primary and secondary objectives were to develop ex novo univariable and multivariable models to predict overall survival (OS) and progression-free survival (PFS), respectively.

Results: 202 patients were enrolled, 134 (66.3%) treated with regorafenib and 68 (33.7%) with placebo. In the univariate analysis, PFS predictors were lung metastases cavitation at baseline (HR 0.50, 95% CI 0.27 to 0.92, p=0.03) and at week 8 (HR 0.58, 95% CI 0.36 to 0.93, p=0.02). Baseline cavitation (HR 0.23, 95% CI 0.08 to 0.66, p=0.007), RECIST 1.1 (HR 0.23, 95% CI 0.14 to 0.4, p <0.0001) and ΔSTL (HR 1.16, 95% CI 1.06 to 1.27, p=0.002) predicted OS. We found an increase of 9% of diameter as the best threshold for discriminating OS (HR 2.64, 95% CI 1.61 to 4.34, p <0.001). In the multivariate analysis, baseline and week 8 cavitation remained significant PFS predictors. Baseline cavitation, RECIST 1.1 and ΔSTL remained predictors of OS in exploratory multivariable models. Assessment of liver metastases density did not predict clinical outcome.

Conclusions: RECIST 1.1 and ΔSTL predict favourable outcome to regorafenib. In contrast to liver metastases density that failed to be a predictor, lung metastases cavitation represents a novel radiological marker of favourable outcome that deserves consideration.
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http://dx.doi.org/10.1136/esmoopen-2016-000111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548980PMC
February 2017

Surgical Treatment of Colorectal Cancer with Peritoneal and Liver Metastases Using Combined Liver and Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Report from a Single-Centre Experience.

Ann Surg Oncol 2016 12 19;23(Suppl 5):666-673. Epub 2016 Sep 19.

Hepatobiliary Surgery Unit, Department of Abdominal Surgery and Transplantation, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.

Background: Chemotherapeutic advances have enabled successful cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) expansion in treating metastatic colorectal cancer.

Objectives: The aims of this study were to evaluate the safety of combining liver surgery (LS) with HIPEC and CRS (which remains controversial) and its impact on overall survival (OS) rates.

Methods: From 2007 to 2015, a total of 77 patients underwent CRS/HIPEC for peritoneal carcinomatosis (PC) of colorectal cancer. Twenty-five of these patients underwent concomitant LS for suspicion of liver metastases (LM; group 2), and were compared with patients who underwent CRS/HIPEC only (group 1). Demographic and clinical data were reviewed retrospectively.

Results: Among the group 2 patients, two underwent major hepatectomies, six underwent multiple wedge resections, 16 underwent single wedge resections (one with radiofrequency ablation), and one underwent radiofrequency ablation alone. For groups 1 and 2, median peritoneal cancer index was 6 and 10 (range 0-26; p = 0.08), complication rates were 15.4 and 32.0 % (Dindo-Clavien ≥3; p = 0.15), and median follow-up was 34.2 and 25.5 months (range 0-75 and 3-97), respectively. One group 2 patient died of septic shock after 66 days. Pathology confirmed LM in 21 patients in group 2 (four with benign hepatic lesions were excluded from long-term outcome analysis). Two-year OS rates were 89.5 and 70.2 % (p = 0.04), and 2-year recurrence-free survival rates were 38.3 and 13.4 % (p = 0.01) in groups 1 and 2, respectively.

Conclusions: Simultaneous surgery for colorectal LM and PC is both feasible and safe, with low postoperative morbidity. Further longer-term studies would help determine its impact on patient survival.
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http://dx.doi.org/10.1245/s10434-016-5543-2DOI Listing
December 2016

Regorafenib induced severe toxic hepatitis: characterization and discussion.

Liver Int 2016 11 6;36(11):1590-1594. Epub 2016 Sep 6.

Service d'Oncologie médicale, Cliniques Universitaires Saint-Luc, Université catholique de Louvain (UCL), Brussels, Belgium.

Background: Regorafenib is the first small-molecule multikinase inhibitor which showed survival benefits in pretreated metastatic colorectal cancer (mCRC) patients. Besides classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect.

Material And Methods: Patients with refractory mCRC treated with regorafenib in our institution were reviewed. Severe treatment-related liver toxicity was investigated. Clinical history, liver histology and genetic assessment (sequence analysis) of cytochrome P3A4 (CYP3A4) and uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) involved in regorafenib metabolization were here reported for patients with severe hepatotoxicity.

Results: Among the 93 reviewed patients, 3 presented severe and icteric toxic hepatitis which was fatal for 1 patient. Histopathological liver lesions were different depending on the onset of hepatotoxicity (acute or subacute): acinar zone 3 necrosis in case of acute symptoms, and portal tract inflammation with porto-central bridging and fibrosis in the delayed presentation. None of the patients had CYP3A4 gene mutations. Similar polymorphisms in UGT1A9 gene promoter region (UGT1A9 variant -118T [rs3832043]) were found in both patients who presented acute hepatitis. Moreover, it appears retrospectively that both of them already experienced significant toxicity under irinotecan-based chemotherapy.

Conclusion: This is the first report of severe hepatotoxicity with available liver histology and genetic assessment of enzymes involved in regorafenib metabolization. This report also reminds the importance of close liver tests monitoring during regorafenib treatment.
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http://dx.doi.org/10.1111/liv.13217DOI Listing
November 2016

Monitoring metabolic response using FDG PET-CT during targeted therapy for metastatic colorectal cancer.

Eur J Nucl Med Mol Imaging 2016 Sep 12;43(10):1792-801. Epub 2016 Apr 12.

Nuclear Medicine Department, Institut Jules Bordet, Université libre de Bruxelles, 1 rue Héger-Bordet, 1000, Brussels, Belgium.

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.
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http://dx.doi.org/10.1007/s00259-016-3365-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969337PMC
September 2016

Long-acting octreotide as secondary prevention of chemotherapy-induced diarrhea: proof of concept.

Minerva Chir 2016 Jan 15. Epub 2016 Jan 15.

Department of medical oncology, Antwerp University Hospital, Antwerp, University of Antwerp, Antwerp, Belgium -

Background: The aim of this study is to investigate the role of Octreotide LAR in secondary prevention in patients with chemotherapy-induced diarrhea.

Methods: In this study, patients experiencing CID ≥ grade 2 received 30 mg long-acting octreotide as a monthly injection and the next chemotherapy dose was administrated with a 25% dose decrease. If no CID ≥ grade 2 occurred, subsequent chemotherapy doses were increased to the initial 100% values. The primary endpoint of the study was the diarrhea control rate (< grade 2) for patients receiving the optimal dose of chemotherapy for a minimum of 2 cycles.

Results: Twenty-nine patients were included. Ten patients experienced no improvement or ended the study very early after the first injection of octreotide LAR. Nineteen patients had a reduction in the grade of diarrhea after the first administration of Octreotide LAR and a reduced chemotherapy dose. Seven of them (24%) did not reach the end of the study because of disease progression (6) or lost in follow-up (1). Ultimately 12 patients (41%) continued the study till the end. In ten of these twelve patients, there was a significant and persisting reduction of diarrhea while receiving full dose chemotherapy.

Conclusion: This study suggests that monthly injections with long-acting octreotide might be used as a secondary prevention of chemotherapy-induced diarrhea. Its usefulness and optimal dosage in secondary prevention in combination with antidiarrheal agents needs further research.
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January 2016

The Prognostic Significance of Metabolic Response Heterogeneity in Metastatic Colorectal Cancer.

PLoS One 2015 30;10(9):e0138341. Epub 2015 Sep 30.

Nuclear Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.

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 NCT01290926.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0138341PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589397PMC
May 2016