The role of direct oral anticoagulants in the management of cancerassociated thrombosis

Cancer patients are at an increased risk of venous thromboembolism (VTE). The current standard initial treatment of an acute episode of VTE in cancer patients consists of the administration of three to six months of subcutaneous low molecular weight heparin (LMWH) at a dose adjusted to the body weight. The efficacy and safety profile of LMWHs are well established, but a drawback of these agents is that they require daily subcutaneous administration. In addition, they are mainly cleared through the kidneys, and their use in patients with severe renal insufficiency may require dose reduction or monitoring of the anti-Xa activity. To address the issues with LMWH, several direct oral anticoagulants (DOAC) have been developed for the treatment of VTE. In contrast to LMWHs and vitamin K antagonist, DOACs directly interfere with thrombin or activated factor X (FXa). DOACs have now become standard treatment options in the general management of VTE, but until recently, there were no results of clinical trials specifically assessing the role of DOACs in the treatment of cancer-associated thrombosis. Recently, the Hokusai VTE cancer study and preliminary data from the Select-D trial demonstrated that DOACs are non-inferior to LMWH in preventing recurrent VTE. However, both studies also show that this comes at the cost of an increased rate of both major and clinically-relevant non-major bleeding. Especially in the subgroup of patients with gastrointestinal cancer, the benefit in VTE recurrence with the DOAC seems to be outbalanced by a significantly increased bleeding risk. Based on the available results, DOACs might represent an interesting alternative for LMWH in certain subgroups of patients, but with an important list of exceptions. It seems reasonable not to use DOACs in patients with a high bleeding risk, and especially in patients with gastrointestinal cancer, DOACs should not be the first-line choice. In summary, while LMWHs are currently the standard of care in the acute management of cancer-associated thrombosis, the advent of DOACs is welcomed for patients at a low bleeding risk who are in need of long-term anticoagulatio

The role of direct oral anticoagulants in the management of cancerassociated thrombosis

Cancer patients are at an increased risk of venous thromboembolism (VTE). The current standard initial treatment of an acute episode of VTE in cancer patients consists of the administration of three to six months of subcutaneous low molecular weight heparin (LMWH) at a dose adjusted to the body weight. The efficacy and safety profile of LMWHs are well established, but a drawback of these agents is that they require daily subcutaneous administration. In addition, they are mainly cleared through the kidneys, and their use in patients with severe renal insufficiency may require dose reduction or monitoring of the anti-Xa activity. To address the issues with LMWH, several direct oral anticoagulants (DOAC) have been developed for the treatment of VTE. In contrast to LMWHs and vitamin K antagonist, DOACs directly interfere with thrombin or activated factor X (FXa). DOACs have now become standard treatment options in the general management of VTE, but until recently, there were no results of clinical trials specifically assessing the role of DOACs in the treatment of cancer-associated thrombosis. Recently, the Hokusai VTE cancer study and preliminary data from the Select-D trial demonstrated that DOACs are non-inferior to LMWH in preventing recurrent VTE. However, both studies also show that this comes at the cost of an increased rate of both major and clinically-relevant non-major bleeding. Especially in the subgroup of patients with gastrointestinal cancer, the benefit in VTE recurrence with the DOAC seems to be outbalanced by a significantly increased bleeding risk. Based on the available results, DOACs might represent an interesting alternative for LMWH in certain subgroups of patients, but with an important list of exceptions. It seems reasonable not to use DOACs in patients with a high bleeding risk, and especially in patients with gastrointestinal cancer, DOACs should not be the first-line choice. In summary, while LMWHs are currently the standard of care in the acute management of cancer-associated thrombosis, the advent of DOACs is welcomed for patients at a low bleeding risk who are in need of long-term anticoagulation. ACKNOWLEDGEMENT: This article was previously published in the Belgium Journal of Medical Oncology (BELG J MED ONCOL 2019;13(2):46-53

Real life safety and effectiveness of nivolumab in older patients with non-small cell lung cancer: Results from the Belgian compassionate use program.

To compare real life effectiveness and safety of nivolumab in patients with non-small cell lung cancer (NSCLC), according to age and Eastern Cooperative Group performance status (ECOG-PS). We performed a retrospective analysis of patients treated with nivolumab for NSCLC within a Belgian compassionate use program from July 2015 until December 2016. Safety and effectiveness were compared between patients aged ≥70 years and < 70 years and between ECOG-PS 0/1 and ≥ 2. A total of 324 patients with NSCLC were included. There was no significant difference between older (≥70) and younger (<70 years) patients with regards to progression free survival (PFS) (4 months (95%CI 2.6;4.8) versus 3.7 months (95%CI 1;7), p = 0.483) and overall survival (OS) (9.3 months (95% CI 5.5;13.1 months) versus 8.4 months (95%CI 6.3; 10.5), p = 0,638). Patients with an ECOG-PS ≥2 had a significant lower median PFS and OS compared to patients with an ECOG-PS 0-1 (2.2 (95%CI 1.4; 2.9) versus 5.6 months (95%CI 4.1; 7.1), p = 0.001 and 3.4 (95%CI 2.3; 4.5) versus 11.1 months (95%CI 8.9; 13.2), p < 0.001 respectively). No significant difference in all grades or grade 3/4 adverse events (AEs) were observed between the different age groups (p = 0.526 and p = 0.603 respectively). Patients with an ECOG-PS 0/1 had significantly more all grades AEs (p = 0.009) but no difference in grade 3/4 AEs was observed (p = 0.406) compared to ECOG-PS ≥2. This real life retrospective study confirms that safety and effectiveness of nivolumab is similar between different age groups, but that effectiveness is driven by performance status

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

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

Regorafenib assessment guided by metabolic imaging in refractory advanced colorectal cancer (aCRC): REGARD-C study.

Background: Regorafenib, an oral multi-tyrosine kinase inhibitor that shares with sorafenib several targets on tumor angiogenesis, oncogenesis, and tumor microenvironment, was recently approved for patients (pts) with pretreated advanced colorectal cancer (aCRC). The drug improves the pts’ outcome, but with significant toxicities, underscoring the need to identify those who will not benefit. A previous study (SoMore trial) showed that early FDGPET-based metabolic response assessment (MRA) may adequately discriminate pts with chemorefractory aCRC unlikely to benefit from a sorafenib-capecitabine combination. RegARd-C aims to explore early MRA in pts treated with regorafenib as a clinical tool to spare pts from needless toxicity from a drug that gives them little or no benefit and as a translational tool to guide comprehensive genomic and epigenetic research on the determinants of drug resistance. Methods: RegARd-C’s (EUDRACT 2012-005655-16) is a multi-centric prospective study. Its primary objective is to identify in a population of pts with pretreated aCRC, those who will not benefit from regorafenib given at 160 mg/day, three weeks/4. Baseline PET is repeated at D14 of the first treatment course. MRA results are blinded for the investigators. Tumor tissues, optionally obtained from a PET-measurable lesion, and blood samples (at baseline; after the first chemotherapy course; and every two months) are collected. Overall survival (OS) is the primary endpoint and will be correlated with metabolic parameters, and genetic, epigenetic and molecular aberrations assessed from tumor biopsies and blood samples using gene expression and methylation profiling, RNA and exome sequencing. As the study is exploratory, no formal hypothesis was formulated. We arbitrarily decided to have a sample size of 105 evaluable pts with 70 pts as a derivation set and 35 pts as a validation set. Taking into account an expected 20-25% drop-out rate, between 124 and 140 pts will be accrued.This sample size is, however, sufficient to validate the hypothesis generated by the SoMore study, which found a prognostic impact of homogeneous metabolic response on OS, with an estimated HR of 0.59. RegARd-C has accrued 76 pts since August 2013.info:eu-repo/semantics/publishe

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

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

Long-acting octreotide as secondary prevention of chemotherapy-induced diarrhea

Introduction : Chemotherapy-induced diarrhea (CID) is one of the most disturbing side effects of chemotherapy with respect to the patient’s quality of life, often dose-limiting if not calling into question the entire therapeutic strategy. CID prevention could enhance treatment safety and outcome by enabling the administration of optimal therapeutic doses. Diarrhea prevention is a major challenge for future oncological therapies, as CID is a frequent side effect of modern biological agents. In this multicentric, Belgian, prospective non-randomized trial, we tested the secondary prevention of CID with long-acting octreotide (LAO) in patients receiving cytotoxic chemotherapy associated with a high risk of digestive toxicity. Methods : In the study’s observational phase, all patients treated with a high-risk chemotherapy regimen were prospectively screened after having provided written consent. Patients experiencing a CID = 2 were proposed to enter the interventional phase, after having signed a second informed consent. They received a monthly Sandostatin LAR30 IM injection and the next chemotherapy course was administered with a 25% dose decrease. If no grade = 2 CID occurred, subsequent chemotherapy doses were increased to the initial 100% values. The main endpoint of the study was the diarrhea control rate for patients participating in the interventional phase of the study and receiving the optimal dose of chemotherapy for a minimum of 2 cycles. The statistical plan used a 2-step Simon design, with a first step after successful secondary CID prevention in 19 out of 25 patients. LAO would be considered as efficient in secondary prevention of CID if no diarrhea > grade 1 had been observed in at least 62 out of 79 patients treated with full-dose chemotherapy. Results : From March 2007 to March 2009, a total of 57 patients were included in the trial. The study was terminated before reaching its target size population because of poor accrual. 29 patients did not develop any CID and participated only in the observational phase. Of the 28 patients included in the interventional part after the first onset of a = grade 2 CID, 5 patients (17.8%, 95% CI = 6.1% - 36.9%) experienced no improvement after a 25% decrease in chemotherapy dose. 9 patients (32.1%, 95% CI = 15.9% - 52.4%) did not continue for the following reasons : rapid tumor progression (7), local reaction after LAO injection (1) and refusal (1). The screen failure rate is thus 14/28 (50%, 95% CI = 30.6% - 69.4%). Of the 14 patients whose CID was resolved after chemotherapy dose reduction, only 2 experienced a = grade 2 CID recurrence after receiving full dose chemotherapy. The remaining 12 patients were treated at the optimal chemotherapy dose without significant digestive side effects (85.7%, 95% CI = 57.2% - 98.2%). The overall success rate of the tested strategy is 12/28 (42.8%, 95% CI = 24.5% - 62.8%). Conclusions : While this trial did not recruit enough patients to answer the study question, available data suggest that LOA is very effective in allowing the return to optimal doses of chemotherapy in patients whose moderate to severe CID was improved after an initial chemotherapy dose reduction. Moreover, the high rate of screen failures emphasizes the need for more aggressive management of acute CID in addition to secondary prevention

Regorafenib assessment guided by metabolic imaging in refractory advanced colorectal cancer (aCRC): REGARD-C study.

Background: Regorafenib, an oral multi-tyrosine kinase inhibitor that shares with sorafenib several targets on tumor angiogenesis, oncogenesis, and tumor microenvironment, was recently approved for patients (pts) with pretreated advanced colorectal cancer (aCRC). The drug improves the pts’ outcome, but with significant toxicities, underscoring the need to identify those who will not benefit. A previous study (SoMore trial) showed that early FDGPET-based metabolic response assessment (MRA) may adequately discriminate pts with chemorefractory aCRC unlikely to benefit from a sorafenib-capecitabine combination. RegARd-C aims to explore early MRA in pts treated with regorafenib as a clinical tool to spare pts from needless toxicity from a drug that gives them little or no benefit and as a translational tool to guide comprehensive genomic and epigenetic research on the determinants of drug resistance. Methods: RegARd-C’s (EUDRACT 2012-005655-16) is a multi-centric prospective study. Its primary objective is to identify in a population of pts with pretreated aCRC, those who will not benefit from regorafenib given at 160 mg/day, three weeks/4. Baseline PET is repeated at D14 of the first treatment course. MRA results are blinded for the investigators. Tumor tissues, optionally obtained from a PET-measurable lesion, and blood samples (at baseline; after the first chemotherapy course; and every two months) are collected. Overall survival (OS) is the primary endpoint and will be correlated with metabolic parameters, and genetic, epigenetic and molecular aberrations assessed from tumor biopsies and blood samples using gene expression and methylation profiling, RNA and exome sequencing. As the study is exploratory, no formal hypothesis was formulated. We arbitrarily decided to have a sample size of 105 evaluable pts with 70 pts as a derivation set and 35 pts as a validation set. Taking into account an expected 20-25% drop-out rate, between 124 and 140 pts will be accrued.This sample size is, however, sufficient to validate the hypothesis generated by the SoMore study, which found a prognostic impact of homogeneous metabolic response on OS, with an estimated HR of 0.59. RegARd-C has accrued 76 pts since August 201