Safety of Direct Oral Anticoagulants in Central Nervous System Malignancies

Patients with brain tumors are at high risk for thromboembolic complications and frequently require anticoagulation. Direct oral anticoagulants (DOACs) are a less burdensome treatment for cancer‐associated thrombosis with safety and efficacy comparable to those of low molecular weight heparin (LMWH); however, there are few data to support the use of DOACs in patients with brain tumors. The purpose of this study was to better understand the safety profile of anticoagulants in patients with primary and metastatic brain tumors, with particular interest in the safety and efficacy of DOACs. Our hypothesis was that DOACs are as safe and effective as LWMH in this population. This study was conducted through a single‐center retrospective chart review of 125 patients with primary and metastatic brain tumors on anticoagulation. Our primary outcomes were major bleeding and intracranial hemorrhage (ICH), with secondary outcomes of minor bleeding and recurrent thrombosis. The rate of major bleeding was 26% in the LMWH group versus 9.6% in the DOAC group (p = .03). The rate of ICH was 15% in the LMWH group versus 5.8% in the DOAC group (p = .09). The severity of ICH in both groups was low with median Common Terminology Criteria for Adverse Events version 5 scores of 2 in the LMWH group and 3 in the DOAC group. The rates of minor bleeding and recurrent thrombosis were low in both groups. Our conclusion is that DOAC use in patients with brain tumors is not associated with increased rates of major bleeding compared with LMWH and is a safe and effective option.Implications for PracticePatients with brain tumors are at high risk for venous thromboembolism and frequently require anticoagulation. Direct oral anticoagulants (DOACs) are less burdensome than low molecular weight heparin (LMWH) for treatment of thromboembolism, but there is concern in the community over increased risk of bleeding. This study provides much‐needed objective evidence that there are fewer major bleeding events in patients with brain tumors on DOACs compared to LMWH with similar efficacy. As the paradigm of anticoagulation in patients with cancer shifts from LWMH toward DOACs, this work is particularly meaningful as it suggests DOACs are safe and effective for patients with brain tumors.     

Treatment of Cancer‐Associated Venous Thromboembolism with Low‐Molecular‐Weight Heparin or Direct Oral Anticoagulants: Patient Selection,Controversies, and Caveats

The treatment of venous thromboembolism (VTE) in patients with cancer is challenging because these patients have increased risks of both recurrent VTE and major bleeding, along with patient‐specific and cancer‐related factors that influence the approach to treatment. Historically, anticoagulant therapy with low‐molecular‐weight heparin (LMWH), given for both initial and long‐term treatment, has been the preferred approach recommended by practice guidelines. Most recently, the National Comprehensive Cancer Network (NCCN) guidelines indicate that the direct oral anticoagulants (DOACs) apixaban, edoxaban, or rivaroxaban are preferred for patients without gastric or gastroesophageal lesions. DOACs have been associated with an increased risk of major bleeding in patients with gastrointestinal and possibly genitourinary cancers, and DOACs should either not be used (especially in those with intact intraluminal tumors) or be used with caution in patients with these cancers. Fatal or life‐threatening bleeding occurs with similar frequency with DOACs or LMWH, and most major bleeding with DOACs can be managed with transfusion and standard measures. The patient''s willingness and ability to comply with LMWH injections, and their treatment preference, should also be considered. Patients with cancer who have VTE should be treated with anticoagulation for a minimum of 6 months. Anticoagulation should be continued indefinitely while cancer is active or under treatment or if there are persistent risk factors for recurrent VTE. This article summarizes the evidence from clinical trials of LMWH and DOACs that underpins the NCCN guideline recommendations, addresses several controversies and caveats regarding anticoagulant treatment, and offers evidence‐based, practical suggestions on patient selection for treatment with DOACs.Implications for PracticeSeveral randomized trials support the addition of direct oral anticoagulants (DOACs) to the therapeutic armamentarium for cancer‐associated venous thromboembolism (VTE). These agents come with unique risks and patient‐ and cancer‐specific variables that must be evaluated during the course of a patient''s cancer care. This narrative review discusses findings from clinical trials of low‐molecular‐weight heparin and DOACs for the treatment of cancer‐associated VTE, evidence that supports the recent National Comprehensive Cancer Network guideline recommendations. A personalized approach to treatment is proposed that addresses patient selection for treatment with DOACs, factors that influence efficacy and safety, controversies and caveats, and suggestions for their resolution in clinical practice.     

Treatment of cancer-associated venous thromboembolism in the age of direct oral anticoagulants

Anticoagulation for cancer-associated venous thromboembolism (VTE) can be challenging due to complications—including bleeding and potential drug–drug interactions with chemotherapy—associated with vitamin K antagonists and inconvenience of low-molecular-weight heparin (LMWH). Direct oral anticoagulants (DOACs) could partially overcome these issues, but until recently there were no large clinical trials assessing their efficacy and safety in cancer patients. This review summarizes clinical treatment guidelines, prior clinical and real-world evidence for anticoagulant choice, recent clinical trials assessing DOACs for cancer-associated VTE (i.e. Hokusai-VTE Cancer, SELECT-D, CARAVAGGIO, and ADAM VTE), and special considerations for DOAC use. Based on established data, clinical guidelines recommend patients with cancer-associated VTE receive LMWH treatment of at least 3–6 months. Nevertheless, LMWH is underused and associated with poor compliance and persistence in these patients relative to oral anticoagulants. Clinical data supporting DOAC use in cancer patients are becoming available. In Hokusai-VTE Cancer, edoxaban was noninferior to dalteparin for the composite of recurrent VTE and major bleeding (12.8% versus 13.5%), with numerically lower recurrent VTE (7.9% versus 11.3%) and significantly higher major bleeding (6.9% versus 4.0%); only patients with gastrointestinal cancer had significantly higher risk of bleeding with edoxaban. In SELECT-D, rivaroxaban had numerically lower VTE recurrence (4% versus 11%), comparable major bleeding (6% versus 4%), and numerically higher clinically relevant nonmajor bleeding (13% versus 4%) versus dalteparin. Most bleeding events were gastrointestinal or urologic; patients with esophageal/gastroesophageal cancer had higher rates of major bleeding with rivaroxaban (36% versus 11%). For comparison of apixaban versus dalteparin, CARAVAGGIO is ongoing, and preliminary results from ADAM VTE are favorable. This review concludes that DOACs appear to be reasonable alternatives to LMWH for treatment of cancer-associated VTE. In patients with gastrointestinal cancer, DOAC use should be considered on a case-by-case basis with consideration of the relative risks and benefits.     

Practice patterns and outcomes of direct oral anticoagulant use in myeloproliferative neoplasm patients

Myeloproliferative neoplasms (MPNs) are characterized by an increased risk of thrombosis and bleeding. Vitamin K antagonists (VKAs) are the historic anticoagulant recommended for use in MPNs. Direct oral anticoagulants (DOACs) are being increasingly used in general and cancer populations. However, DOAC safety and efficacy in MPN patients remains unclear. We characterized real-world practice patterns of DOAC use in MPN patients and evaluated thrombosis and bleeding risk. We conducted a retrospective cohort study of 133 MPN patients prescribed DOACs for venous thromboembolism (VTE), atrial fibrillation, or arterial thromboembolism (ATE). Practice patterns including duration of anticoagulation, dosing, and concomitant use of antiplatelet/cytoreductive agents, were heterogeneous among MPN patients. The 1-year cumulative incidence of thrombosis and bleeding on DOAC was 5.5% (1.5–9.5%) and 12.3% (6.4–18.2%) respectively. In comparison, reported bleeding rates in MPN patients on DOAC and VKAs are 1–3%. On multivariable analysis, prior history of thrombosis, use of dabigatran or edoxaban, and younger age were significantly associated with a higher risk of recurrent thrombosis, while leukocytosis was associated with a higher risk of bleeding on DOAC. The higher-than-expected bleeding rate found in our study indicates the continued need for rigorous evaluation of DOACs in this population.Subject terms: Myeloproliferative disease, Medical research     

Nivolumab VERSUS Cabozantinib as Second-Line Therapy in Patients With Advanced Renal Cell Carcinoma: A Real-World Comparison

BackgroundTyrosine-kinase inhibitors (TKIs) still represent a first-line option for selected patients with metastatic Renal Cell Carcinoma (mRCC). We aimed to compare the real-world efficacy of nivolumab or cabozantinib as second-line therapy in specific mRCC subpopulations.Patients and MethodsWe retrospectively collected data from 11 centers from Italy, Spain and US. Overall Survival (OS) and Progression-Free Survival (PFS) were analyzed using Kaplan-Meier curves. Cox proportional models were used at univariate and multivariate analyses.ResultsWe collected data from 343 patients with mRCC, 123 (36%) treated with cabozantinib and 220 (64%) with nivolumab. The median OS resulted longer, but not statistically significant, with nivolumab in patients aged >70 years (21.4 vs. 15.4 months, P = .746), treated with first-line pazopanib (26.8 vs. 11.6 months, P = .450), or with good (47.0 vs. 15.5 months, P = .285) or intermediate-risk criteria (14.4 vs. 11.0 months, P = .357), while it was longer, but even not statistically significant, for cabozantinib in patients who received previous sunitinib (25.7 vs. 21.7 months, P = .638) or with bone metastases (28.4 vs. 24.4 months, P = .871). The median PFS was significantly longer with cabozantinib in patients with clear cell histology (7.8 vs. 5.4 months, P = .026) and in patients with good risk features (12.3 vs. 5.7 months, P = .022).ConclusionsNivolumab and cabozantinib resulted active in mRCC patients, showing distinct results when stratified into clinico-pathological features.     

Analysis of Toxicity and Clinical Outcomes in Full Versus Reduced Starting Dose Cabozantinib in Metastatic Renal Cell Carcinoma Patients

BackgroundFull dose cabozantinib for metastatic renal cell carcinoma (mRCC) is 60 mg, but adverse events (AEs) may require dose reductions. Limited data exist comparing efficacy among cabozantinib doses. We compared AEs and clinical outcomes in mRCC patients treated with full vs. reduced starting cabozantinib dose.MethodsWe performed a retrospective analysis of 87 mRCC patients treated with cabozantinib at Winship Cancer Institute from 2016 to 2019. Overall survival (OS), progression-free survival (PFS), and objective response (OR) rate measured clinical outcomes. AEs were collected from clinic notes and the most common were hypertension, mucositis/hand-foot skin reaction (HFSR), or gastrointestinal toxicity. Univariate analysis (UVA) between starting doses and AEs with clinical outcomes was performed using logistic regression model. Multivariable analysis was also performed using Cox proportional hazard model.ResultsMost patients were men (71%) with clear-cell RCC (72%). The majority were IMDC intermediate (58%) or poor (35%) risk. One third received first-line cabozantinib and 64% had ≥3 baseline metastatic sites. Most patients (68%) required dose reduction from 60 mg or started at reduced dose without escalation. Reduced dose patients were more likely to have ≥3 distant metastatic sites (70% vs. 58%) and ≥2 prior lines of systemic therapy (50% vs. 40%) compared to full dose patients. UVA revealed a trend towards shorter OS (HR: 1.78, P = .095), PFS (HR: 1.50, P = .107), and lower chance of OR (HR:0.42, P = .149) among reduced dose patients. This trend did not hold in Multivariable analysis (OS HR: 1.20, P = .636; PFS HR: 1.23, P = .4662). Mucositis/HFSR and hypertension were significantly associated with improved outcomes in UVA.ConclusionsAlthough we found a trend favoring full dose cabozantinib, this is likely due to worse baseline disease characteristics among patients starting on a reduced dose. Hypertension and mucositis/HFSR may be associated with improved outcomes. Larger studies are warranted to validate these findings.     

Overall survival analysis of EXAM,a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma

BackgroundPrimary analysis of the double-blind, phase III Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial demonstrated significant improvement in progression-free survival with cabozantinib versus placebo in patients with progressive medullary thyroid cancer (MTC). Final analysis of overall survival (OS), a key secondary endpoint, was carried out after long-term follow-up.Patients and methodsEXAM compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomized (2:1) to cabozantinib (140 mg/day) or placebo. Final OS and updated safety data are reported.ResultsMinimum follow-up was 42 months. Kaplan–Meier analysis showed a 5.5-month increase in median OS with cabozantinib versus placebo (26.6 versus 21.1 months) although the difference did not reach statistical significance [stratified hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.64–1.12; P = 0.24]. In an exploratory assessment of OS, progression-free survival, and objective response rate, cabozantinib appeared to have a larger treatment effect in patients with RET M918T mutation–positive tumors compared with patients not harboring this mutation. For patients with RET M918T-positive disease, median OS was 44.3 months for cabozantinib versus 18.9 months for placebo [HR, 0.60; 95% CI, 0.38–0.94; P = 0.03 (not adjusted for multiple subgroup analyses)], with corresponding values of 20.2 versus 21.5 months (HR, 1.12; 95% CI, 0.70–1.82; P = 0.63) in the RET M918T–negative subgroup. Median treatment duration was 10.8 months with cabozantinib and 3.4 months with placebo. The safety profile for cabozantinib remained consistent with that of the primary analysis.ConclusionThe secondary end point was not met in this final OS analysis from the trial of cabozantinib in patients with metastatic, radiographically progressive MTC. A statistically nonsignificant increase in OS was observed for cabozantinib compared with placebo. Exploratory analyses suggest that patients with RET M918T–positive tumors may experience a greater treatment benefit with cabozantinib.Trial Registration NumberNCT00704730     

Thromboembolism Incidence and Risk Factors in Multiple Myeloma After First Exposure to Immunomodulatory Drug–Based Regimens

BackgroundWe evaluated time to thromboembolism (TE) and risk factors in multiple myeloma (MM) patients after first exposure to immunomodulatory therapy, stratified by thromboprophylaxis.Patients and MethodsWe retrospectively analyzed adult MM patients who received immunomodulatory therapy with or without dexamethasone between February 2012 and October 2017. Thromboprophylaxis included aspirin, anticoagulants (low-molecular-weight heparin, direct oral anticoagulants, or warfarin), or none. Primary endpoint was time to on-treatment TE by thromboprophylaxis type. Time to TE using death as a competing risk censored at 12 months was used in univariate and multivariable analyses to identify risk factors.ResultsOf 485 evaluable patients, 57% were white and 36% African American; median age was 66. Most received lenalidomide (97.5%) and dexamethasone (90%). Half presented with ≥ 1 comorbidities. Sixty-nine had no documented receipt of prophylaxis, 357 aspirin, and 59 anticoagulation. More patients receiving anticoagulants had ≥ 1 comorbidities compared to aspirin or no-prophylaxis groups (P < .001). There was no difference in 12-month estimated cumulative incidence of TE (7.3%; 95% confidence interval, 5.2-9.9) between thromboprophylaxis groups (none 4.4%, aspirin 8.5%, anticoagulant 3.4%) (P = .24). In multivariable analyses, male sex (hazard ratio, 2.50; 95% confidence interval, 1.21-5.17; P = .014) and presence of any comorbidity (hazard ratio, 2.35; 95% confidence interval, 1.17-4.73; P = .016) were associated with TE incidence; thromboprophylaxis type was not (P = .12).ConclusionMale sex and presence of any comorbidity were associated with time to TE. There were no differences in TE incidence between thromboprophylaxis groups despite a higher proportion of those in the anticoagulant group having ≥ 1 comorbidities.     

Cancer effect on periprocedural thromboembolism and bleeding in anticoagulated patients

BackgroundPatients with active cancer are often on chronic anticoagulation and frequently require interruption of this treatment for invasive procedures. The impact of cancer on periprocedural thromboembolism (TE) and major bleeding is not known.Patients and methodsTwo thousand one hundred and eighty-two consecutive patients referred for periprocedural anticoagulation (2484 procedures) using a standardized protocol were followed forward in time to estimate the 3-month incidence of TE, major bleeding and survival stratified by anticoagulation indication. For each indication, we tested active cancer and bridging heparin therapy as potential predictors of TE and major bleeding.ResultsCompared with patients without cancer, active cancer patients (n = 493) had more venous thromboembolism (VTE) complications (1.2 % versus 0.2 % ; P = 0.001), major bleeding (3.4 % versus 1.7 % ; P = 0.02) and reduced survival (95 % versus 99 % ; P < 0.001). Among active cancer patients, only those chronically anticoagulated for VTE had higher rates of periprocedural VTE (2 % versus 0.16 % ; P = 0.002) and major bleeding (3.7 % versus 0.6 % ; P < 0.001). Bridging with heparin increased the rate of major bleeding in cancer patients (5 % versus 1 % ; P = 0.03) without impacting the VTE rate (0.7 % versus 1.4 % , P = 0.50).ConclusionsCancer patients anticoagulated for VTE experience higher rates of periprocedural VTE and major bleeding. Periprocedural anticoagulation for these patients requires particular attention to reduce these complications.     

Primary Tumor Shrinkage and the Effect on Metastatic Disease and Outcomes in Patients With Advanced Kidney Cancer With Intermediate or Poor Prognosis Treated With Nivolumab Plus Ipilimumab or Cabozantinib

BackgroundImmune checkpoint inhibitor (ICI)-based combinations have become the first-line standard of care in metastatic renal cell carcinoma (mRCC), but their activity on the primary tumor is still one of the most debated issues.Patients and MethodsThe aim of our analysis was to evaluate the primary tumor's response to first-line therapy with cabozantinib or nivolumab+ipilimumab, and its correlation with metastatic response and with patient outcomes.ResultsSixty-seven mRCC patients met the criteria for inclusion in the final analysis (30 treated with cabozantinib and 37 with nivolumab+ipilimumab). In the overall population, the primary tumor control rate (PTCR) was 90.9%; no complete responses (CR) were achieved. A significant correlation was found between the baseline size of the primary tumor's longest diameter and its response according to RECIST v1.1 criteria at the time of the second radiological assessment (rs = -0.351; P = .049). Moreover, a significant correlation between the type of primary tumor response and the response of the metastases was observed in the overall population (rs = 0.50; two-sided P < 0.001). There was also a significant correlation between primary tumor response and 1-year survival rate (P = .002), even when adjusted for the IMDC prognostic group and type of therapy (HR = 8.70; 95%CI, 2.52-30.05; P = .001).ConclusionExtension of the primary tumor did not affect patient survival, while its response was significantly related to the response on metastatic disease and survival. No significant differences in terms of primary tumor shrinkage were identified between treatment with nivolumab+ipilimumab or cabozantinib in this cohort.     

Risk of Atrial Fibrillation and Bleeding Diathesis Associated With Ibrutinib Treatment: A Systematic Review and Pooled Analysis of Four Randomized Controlled Trials

BackgroundClinical trials raised concern that ibrutinib may increase the risk of atrial fibrillation/flutter (Afib/Aflutter) and major bleeding. However, the association has not been statistically validated, and there is no consensus regarding optimal management of anticoagulation among patients receiving ibrutinib who develop Afib/Aflutter. We performed a systematic review and pooled analysis to precisely assess the risk of Afib/Aflutter and bleeding associated with ibrutinib treatment in patients with hematologic malignancies.Patients and MethodsWe searched PubMed, EMBASE, Cochrane Database, and meeting abstracts up to May 15, 2016, for randomized controlled trials comparing ibrutinib to chemotherapy, monoclonal antibody, or a combination. Primary outcomes were serious Afib/Aflutter and major bleeding. Secondary outcomes were all-grade Afib/Aflutter and bleeding. We calculated the Mantel-Haenszel risk ratio (RR) and estimated the effect of the treatments using a fixed-effects model.ResultsIbrutinib treatment was associated with a significantly higher incidence of serious Afib/Aflutter (3.03% vs. 0.80%, RR = 3.80, 95% confidence interval [CI] = 1.56-9.29, P = .003), all-grade Afib/Aflutter (8.18% vs. 0.93%, RR = 8.81, 95% CI = 2.70-28.75, P = .0003), and all-grade bleeding (4.85% vs. 1.55%, RR = 2.93, 95% CI = 1.14-7.52, P = .03) compared to control treatments. The observed between-treatment difference in major bleeding rates was not statistically significant (3.69% vs. 2.13%, RR = 1.72, 95% CI = 0.95-3.11, P = .07). The risk of these adverse events was not different between subgroups on the basis of pathology, treatment setting, dose, and duration of ibrutinib exposure.ConclusionThe risks of Afib/Aflutter and all-grade bleeding were significantly higher in the ibrutinib group. These results indicate the need for vigilant monitoring while the patient is receiving ibrutinib therapy, and careful assessment of the risks and benefits of anticoagulation is required.     

Primary Thromboprophylaxis and the Risk of Venous Thromboembolic Events in Patients With Testicular Germ Cell Tumors Treated With Cisplatinum-Based Chemotherapy

BackgroundCisplatinum-based chemotherapy is associated with an increased risk of venous thromboembolism (VTE). We hypothesized that primary thromboprophylaxis in patients with testicular germ cell tumors (GCT) undergoing cisplatinum-based chemotherapy can reduce the risk of VTE.Patients and MethodsIn this single-center retrospective cohort study, we investigated the increased use of primary thromboprophylaxis between January 2000 and December 2021 at our institution and its effect on the risk of VTE. Patients with GCT undergoing adjuvant or curative cisplatinum-based chemotherapy were included.ResultsThree hundred forty-six patients with GCT initiating a cisplatinum-based therapy were included in the study, of whom 122 (35%) were treated in the adjuvant and 224 (65%) in the curative setting, respectively. VTE events occurred in 49 (14.2%) patients. In univariable competing risk analysis, a higher clinical tumor stage and large retroperitoneal lymphadenopathy (RPLND >5 cm) were the strongest predictors of an elevated VTE risk (SHR for stage IIC - IIIC: 2.6 (95%CI: 5.0-24.7, P < .001), SHR for RPLN: 2.36 (95%CI: 1.27-4.4, P < .007)). The proportion of patients receiving primary thromboprophylaxis strongly increased over time and reached 100% in CS IIC-III patients from 2019 onwards. After adjusting for tumor stage, primary thromboprophylaxis was associated with a 52% relatively lower risk of VTE (SHR = 0.48, 95% CI: 0.24-0.97; P = .032).ConclusionIn this retrospective cohort study, we showed that TGCT patients undergoing cisplatinum-based chemotherapy have a lower VTE risk when receiving primary thromboprophylaxis. For the duration of chemotherapy, primary thromboprophylaxis should be considered on a risk-benefit ratio.     

Managing thromboembolic disease in the cancer patient: efficacy and safety of antithrombotic treatment options in patients with cancer

Management of thromboembolic disease in patients with cancer can be challenging. Patients with cancer who have established thrombosis are at increased risk of recurrent VTE and of anticoagulant-associated bleeding compared to patients with no cancer. The optimal treatment of VTE in patients with cancer should lower the risk of recurrent VTE without increasing the risk of bleeding and ideally improve a patient's quality of life. Initial treatment of VTE in patients with cancer should be with LMWH, which may be administered, subcutaneously, at home. The current standard of care for long-term treatment of VTE remains oral anticoagulant, which should be administered for as long as the cancer is active. However, the use of oral anticoagulants can be problematic in these patients due to possible anorexia and vomiting. The efficacy and safety of long-term treatment of VTE in cancer patients with LMWH is currently under investigation.     

Impact of Body Mass Index on Outcomes in an Asian population of Advanced Renal Cell Carcinoma and Urothelial Carcinoma Treated With Immune Checkpoint Inhibitors

ObjectivesTo clarify the impact of body mass index (BMI) on treatment outcomes including survival, tumor response, and adverse events (AEs) in patients with advanced renal cell carcinoma (RCC) or urothelial carcinoma (UC) treated with immune checkpoint inhibitors (ICIs) in an Asian population.MethodsWe retrospectively evaluated 309 patients with advanced RCC or UC who received ICIs between September 2016 and July 2021. The patients were divided into high- (i.e., ≥25 kg/m²) and low-BMI (<25 kg/m²) groups according to the BMI at the time of treatment initiation.ResultsOverall, 57 patients (18.4%) were classified into the high-BMI group. In RCC patients treated with ICIs as first-line therapy or UC treated with pembrolizumab, progression-free survival (PFS) (p = 0.309; p = 0.842), overall survival (OS) (p = 0.701; p = 0.983), and objective response rate (ORR) (p = 0.163; p = 0.553) were comparable between the high- and low-BMI groups. In RCC patients treated with nivolumab monotherapy as later-line therapy, OS (p = 0.101) and ORR (p = 0.102) were comparable, but PFS was significantly longer in the high-BMI group (p = 0.0272). Further, multivariate analysis showed that BMI was not an independent factor of PFS or OS in all the treatment groups (any, p>0.05). As for AE profiles, in nivolumab monotherapy, the rate was significantly higher in the high-BMI group (p = 0.0203), whereas in the other two treatments, the rate was comparable.ConclusionsBMI was not associated with survival or response rates of advanced RCC or UC patients treated with ICIs in an Asian population. AEs might frequently develop in high-BMI patients with RCC in nivolumab monotherapy.     

Management of venous thromboembolism in high-grade glioma: Does low molecular weight heparin increase intracranial bleeding risk?

BackgroundVenous thromboembolism (VTE) occurs in up to 30% of patients with high-grade glioma (HGG). Concern for increased risk of intracranial hemorrhage (ICH) with therapeutic anticoagulation (AC) complicates VTE treatment. Some retrospective studies have reported an increased risk of ICH associated with therapeutic AC; however, effective alternatives to AC are lacking. The aim of our study is to assess the risk of ICH in HGG patients with VTE on low molecular weight heparin (LMWH).MethodsWe performed a retrospective matched cohort study of HGG patients from January 2005 to August 2016. Blinded review of neuroimaging for ICH was performed. For analysis of the primary endpoint, estimates of cumulative incidence (CI) of ICH were calculated using competing risk analysis with death as competing risk; significance testing was performed using the Gray’s test. Median survival was estimated using the Kaplan-Meier method.ResultsTwo hundred twenty patients were included, 88 (40%) with VTE treated with LMWH, 22 (10%) with VTE, not on AC, and 110 (50%) without VTE. A total of 43 measurable ICH was recorded: 19 (26%) in LMWH, 3 (14%) in VTE not on AC, and 21 (19%) in non-VTE cohort. No significant difference was observed in the 1-year CI of ICH in the LMWH cohort and non-AC with VTE group (17% vs 9%; Gray’s test, P = .36). Among patients without VTE, the 1-year CI of ICH was 13%. Median survival was similar among all 3 cohorts.ConclusionsOur data suggest that therapeutic LMWH is not associated with substantially increased risk of ICH in HGG patients.     

Treatment of venous thrombosis in cancer patients: practical aspects

The risk of venous thromboembolism (VTE) is increased in association with malignancy, and has a potential to produce significant morbidity and mortality. Treatment of such patients with anticoagulants is associated with both benefit and a high rate of complications. In the early phase, the treatment is usually achieved with low molecular weight heparin (LMWH), which has a number of advantages over unfractionated heparin (UFH): once or twice daily administration, no necessary laboratory monitoring, lesser risk of bleeding and no drugs interactions. Nevertheless, the UFH is the anticoagulant of choice when a rapid anticoagulant effect or stop of anticoagulant effect is required, in the treatment of massive pulmonary embolism or severe renal insufficiency. Prolonged anticoagulation with LMWH (over 3 or 6 months) appears to be beneficial on survival for such patients. The subject of anticoagulation in patients with primary or secondary brain tumours is controversial. The long-term anticoagulation mainly use LMWH or vitamin K antagonist. The last ones are more difficult to use because of an unpredictable response with higher rate of recurrence and bleeding. The optimal duration of treatment is not known but the patients should be treated for at least 6 months, even at least 12 months after a second episode of venous thromboembolism. On the primary prevention in high-risk surgical oncology, the LMWH are at least as effective and safer as UFH when the optimal dose was administered. For the medical patients, the use of prophylactic anticoagulant treatment is less clear except the patients who are bedridden for prolonged periods of time. For the secondary prevention, the LMWH seems to be more effective over vitamin K antagonists. For these patients, the anticoagulant therapy is recommended indefinitely or until cancer is resolved.     

Direct oral anticoagulants in patients with hematologic malignancies

The anticoagulant treatment for patients with hematologic malignancies is low molecular weight heparin (LMWH), which is considered the safest in this particular patients setting. Although direct oral anticoagulants (DOACs) have proven their efficacy and safety in patients with cancer, their use can be challenging in patients with hematologic malignancies due to the peculiarity of these neoplasms: high thrombotic risk, possible onset of thrombocytopenia and concomitant anticancer therapies. The aim of our study was to evaluate the efficacy and safety of DOACs for venous thromboembolism or atrial fibrillation in patients with hematologic malignancies and plasmatic DOACs level during anticancer therapy and at time of bleeding or thrombotic complications. We evaluated patients with hematologic malignancies treated with DOACs for venous thromboembolism or atrial fibrillation—therapy was maintained until the platelet count was ≥50 × 10⁹/L. In case of concomitant anticancer treatment and haemorrhagic or thrombotic events, we checked DOACs plasma levels (trough and peak). The patients evaluated were 135: 104/135 were on anticancer therapy. We did not observe either thrombotic or major haemorrhagic adverse events. Minor bleedings occurred in 10 patients and clinical relevant non-major (CRNM) in two patients. There was a statistically significant correlation between bleedings and myelodysplastic syndrome. DOACs resulted effective and safe in patients with hematologic malignancies. DOACs plasma level can be helpful in suggesting an early dose adjustment to prevent haemorrhagic adverse event in patients on concomitant anticancer therapy. Larger prospective studies including hematologic patients are warranted to confirm the safety and efficacy of DOACs.     

Prevalence and Clinical Significance of Incidental and Clinically Suspected Venous Thromboembolism in Lung Cancer Patients

BackgroundIt is unclear what proportion of VTE events in lung cancer patients are incidentally discovered and whether incidental events affect mortality.Patients and MethodsWe conducted a retrospective cohort study of lung cancer patients seen at the University of Rochester between January 1, 2006 and December 31, 2008 with the goal of quantifying and characterizing VTE events. Multiple clinical variables and mortality outcomes were compared using Kaplan-Meier survival analysis and multivariate Cox proportional hazards.ResultsThe study population consisted of 207 subjects with lung cancer. The median age was 66 years and 55% were female (n = 115). Thirty-one patients (14.9%) experienced at least 1 VTE event with 32.2% (10/31) of these incidentally discovered. Incidental events comprised 29.4% (n = 5) of pulmonary embolisms, 11.1% (n = 2) of deep vein thrombosis, and 100% (n = 3) of visceral events. The median survival for patients with incidental VTE was 23.4 months (95% confidence interval [CI], 4.8-32.1) compared with 45.8 months (95% CI, 34.1-56.8) in patients without VTE (HR 2.4; 95% CI, 1.2-4.9; P = .01), but in a subgroup analysis of stage IV patients overall survival was not significantly different (HR, 0.94; P = .33). Patients with clinically suspected VTE had the lowest median survival at 13.1 months (95% CI, 6.4-18.9) which was significantly lower than patients without VTE (HR, 2.7; 95% CI, 1.6-4.5; P = .002), but not significantly different from patients with incidental VTE (HR, 1.2; 95% CI, 0.4-2.0; P = .7). In multivariate analysis, occurrence of VTE (HR, 2.3; 95% CI, 1.3-3.8; P = .002) was significantly associated with mortality when adjusting for age, stage, and histology.ConclusionsOne-third of VTE events in lung cancer patients are incidentally discovered and VTE has negative clinical effect in lung cancer patients.     

Computed Tomography Characteristics of Unresectable Primary Renal Cell Carcinoma Treated With Neoadjuvant Sunitinib

IntroductionIn patients with locally advanced and metastatic RCC, selection criteria for nephrectomy are imprecise. Neoadjuvant sunitinib might downsize unresectable tumors and enable nephrectomy. CT scans of unresectable primary RCCs before and after neoadjuvant sunitinib were retrospectively reviewed to identify radiographic features associated with patient selection for surgery.Patients and MethodsCT scans of 27 patients with RCC (31 tumors) treated with neoadjuvant sunitinib were performed as part of a prospective clinical trial. After neoadjuvant sunitinib, tumors were surgically resected in 13 patients (17 tumors) and not resected in 14 patients (14 tumors). Response to treatment with sunitinib was assessed with Response Evaluation Criteria in Solid Tumors and MASS criteria.ResultsOn the contrast-enhanced CT scan before nephrectomy compared with the baseline CT scan, 88% of resected tumors demonstrated decreased size (median decrease 26%; −2.0 cm; P < .001), 88% had decreased attenuation (median decrease 30%; −27 Hounsfield units; P = .004), and 76% had increased necrosis (P < .001). Response to sunitinib was significantly more favorable (according to MASS criteria) in resected than in nonresected tumors (P = .005). In addition, the degree of baseline necrosis was less in tumors subsequently resected than in nonresected tumors (P = .05). Multivariate analysis showed that higher tumor attenuation after 2 cycles of sunitinib therapy and a favorable response (MASS criteria) after 2 cycles of sunitinib therapy were independent predictors of subsequent tumor resection.ConclusionIn unresectable primary RCC tumors, changes in select CT parameters after 2 cycles of neoadjuvant sunitinib might be associated with the potential for surgical resection.     

Neoadjuvant Sunitinib Decreases Inferior Vena Caval Thrombus Size and Is Associated With Improved Oncologic Outcomes: A Multicenter Comparative Analysis

BackgroundWe analyzed outcomes of neoadjuvant sunitinib in patients with renal-cell carcinoma (RCC) and inferior vena caval (IVC) tumor and compared outcomes to patients who did not undergo neoadjuvant therapy before surgery.Patients and MethodsWe performed a multicenter retrospective comparison of RCC patients with IVC tumor who underwent neoadjuvant sunitinib before surgery versus those who did not. Response to sunitinib was defined by Response Evaluation Criteria in Solid Tumors (RECIST). Primary outcome was cancer-specific survival. Secondary outcomes included overall survival. Multivariate analysis was performed to identify risk factors associated with primary and secondary outcomes. Kaplan-Meier analysis compared survival in neoadjuvant and primary surgery groups.ResultsData of 53 patients were analyzed (19 neoadjuvant sunitinib, 34 primary surgery; median follow-up, 58 months). Eighteen (9 in each group, P = .143) had metastatic RCC. There was no difference in IVC tumor level between the 2 groups (P = .76). After neoadjuvant sunitinib, median primary tumor decreased size from 8.1 to 6.8 cm, and IVC tumor decreased by 1.3 cm. IVC tumor level decreased in 8 (42.1%) of 19 and was stable in 10 (52.6%) of 19; 5 (26.3%) of 19 experienced partial response. Similar proportions of patients underwent robot-assisted or minimally invasive approaches (P = .351), and no differences were noted in complications (P = .194). Multivariate analysis showed neoadjuvant sunitinib was associated with improved cancer-specific survival (odds ratio = 3.28; P = .021). Kaplan-Meier analysis demonstrated significantly longer median cancer-specific survival (72 vs. 38 months, P = .023) for neoadjuvant sunitinib.ConclusionNeoadjuvant sunitinib was associated with a reduction in primary tumor and thrombus size as well as improved survival. Further investigation is needed to determine the utility of neoadjuvant sunitinib in RCC with IVC tumor.