Edoxaban for 12 Months Versus 3 Months in Patients With Cancer With Isolated Distal Deep Vein Thrombosis (ONCO DVT Study): An Open-Label, Multicenter, Randomized Clinical Trial.

BACKGROUND: The optimal duration of anticoagulation therapy for isolated distal deep vein thrombosis in patients with cancer is clinically relevant, but the evidence is lacking. The prolonged anticoagulation therapy could have a potential benefit for prevention of thrombotic events; however, it could also increase the risk of bleeding. METHODS: In a multicenter, open-label, adjudicator-blinded, randomized clinical trial at 60 institutions in Japan, we randomly assigned patients with cancer with isolated distal deep vein thrombosis, in a 1-to-1 ratio, to receive either a 12-month or 3-month edoxaban treatment. The primary end point was a composite of a symptomatic recurrent venous thromboembolism (VTE) or VTE-related death at 12 months. The major secondary end point was major bleeding at 12 months, according to the criteria of the International Society on Thrombosis and Haemostasis. The primary hypothesis was that a 12-month edoxaban treatment was superior to a 3-month edoxaban treatment with respect to the primary end point. RESULTS: From April 2019 through June 2022, 604 patients were randomized, and after excluding 3 patients who withdrew consent, 601 patients were included in the intention-to-treat population: 296 patients in the 12-month edoxaban group and 305 patients in the 3-month edoxaban group. The mean age was 70.8 years, 28% of the patients were men, and 20% of the patients had symptoms of deep vein thrombosis at baseline. The primary end point of a symptomatic recurrent VTE event or VTE-related death occurred in 3 of the 296 patients (1.0%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 0.13; 95% CI, 0.03-0.44). The major secondary end point of major bleeding occurred in 28 of the 296 patients (9.5%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 1.34; 95% CI, 0.75-2.41). The prespecified subgroups did not affect the estimates on the primary end point. CONCLUSIONS: In patients with cancer with isolated distal deep vein thrombosis, 12 months was superior to 3 months for an edoxaban treatment with respect to the composite outcome of a symptomatic recurrent VTE or VTE-related death. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03895502.

Myocarditis associated with immune-checkpoint inhibitors diagnosed by cardiac magnetic resonance imaging.

Myocarditis associated with immune-checkpoint inhibitors (ICIs) is a rare, but critical adverse event. Although endomyocardial biopsy (EMB) is the standard for diagnosis of myocarditis, there is a possibility of false negatives due to sampling errors and local nonavailability of EMB, which may hamper the appropriate diagnosis of myocarditis. Therefore, an alternative criterion based on cardiac magnetic resonance imaging (CMRI) combined with clinical presentation has been proposed, but not emphasized sufficiently. We report a case of myocarditis after ICIs administration, which was diagnosed using CMRI in a 48-year-old male with lung adenocarcinoma. CMRI provides an opportunity to diagnose myocarditis during cancer treatment.

Relevance of Non-Bridging Therapy with Heparin during Temporary Interruption of Direct Oral Anticoagulants in Patients with Cancer-Associated Venous Thromboembolism.

Objectives: To evaluate the relevance of non-bridging therapy with unfractionated heparin during the temporary, pre-procedural interruption of direct oral anticoagulants (DOACs) in patients with cancer-associated venous thromboembolism (VTE). Materials and Methods: This retrospective study included 142 patients with cancer and VTE who required temporary interruption of DOACs before invasive procedures. Data, including rates of VTE recurrence, non-major bleeding, and major bleeding, were compared between patients who received or not received alternative therapy with unfractionated heparin during interruption. Results: Sixty-eight patients were prescribed heparin, while 74 were not. There were no differences in age, body mass index, white blood cell count, hemoglobin level, or platelet count between the groups. VTE recurrence was observed in four (6%) and one (1%) patient in the heparin bridging and non-bridging groups, respectively (risk ratio [RR]: 4.4, 95% confidence interval [CI]: 0.50-38.0, p=0.19). Non-major bleeding occurred in three (4%) and two (3%) patients in the bridging and non-bridging groups (RR: 1.6, 95%CI: 0.28-9.48, p=0.67), while major bleeding occurred in 0 (0%) and three patients (4%) (p=0.25), respectively. Conclusion: Our findings confirm the relevance of non-bridging therapy with unfractionated heparin for reducing VTE risk during DOAC interruption in patients with cancer.

Prospective evaluation of the relationship between response and exposure of total and unbound erlotinib in non-small cell lung cancer patients.

PURPOSE: To evaluate the relationship between treatment efficacy and exposure of total and unbound erlotinib in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations. PATIENTS AND METHODS: EGFR-tyrosine kinase inhibitor naïve NSCLC patients were enrolled, and erlotinib was started at 150 mg/day. Total and unbound exposure of erlotinib were prospectively evaluated. RESULTS: Of the 70 enrolled patients, 61 had EGFR-activating mutations (30 patients with exon 19 deletions, 31 patients with L858R). The median area under the concentration-time curve from 0 to 24 h (AUC0-24) of total and unbound erlotinib on day 1 was 37,004 ng·h/mL (range, 9683-63,257 ng·h/mL) and 2338 ng·h/mL (581-5904 ng·h/mL), respectively. The median progression-free survival (PFS) was 10.9 months, and PFS did not differ between each tertile of total and unbound AUC0-24 on day 1 in 59 patients with EGFR-activating mutations. The worst grade of skin toxicities was significantly correlated with total trough concentration at steady state (Ctrough,ss) at each visit for 3 months after the initiation of erlotinib treatment (P < 0.0001). Total and unbound Ctrough,ss on day 7-15 in 20 patients whose dose was reduced due to intolerable toxicities was significantly higher than those in 48 patients whose dose was unchanged for 3 months (P = 0.0046, 0.0008). CONCLUSION: The lack of relationship between efficacy and exposure of total and unbound erlotinib demonstrates that the standard dose of 150 mg/day is sufficient for the treatment of NSCLC harboring EGFR-activating mutations, despite wide inter-individual variability in exposure and dose reduction. CLINICAL TRIALS REGISTRATION NUMBER: UMIN000012862.

Effective collaboration between hematologists and cardiologists facilitated successful control of reversible dasatinib-related pulmonary arterial hypertension and treatment-free remission of chronic myeloid leukemia: a case report.

The BCR-ABL1 tyrosine kinase inhibitor dasatinib is effective in chronic myeloid leukemia (CML) treatment. The major known adverse effects of dasatinib include pleural effusion and pulmonary arterial hypertension (PAH); however, the underlying mechanisms remain unclear. This case report describes a two-step dasatinib dose reduction decided by multi-disciplinary collaboration between cardiologists and hematologists for the management of PAH that led to treatment-free remission (TFR), suggesting an important improvement in the field. Herein, a 43-year-old woman with CML was administered 100 mg of dasatinib daily as a first-line therapy from May 2014. There were no evident abnormalities on her electrocardiogram and transthoracic echocardiography (TTE) charts before she started taking dasatinib. She developed leg edema in June 2015, and the TTE showed a high transtricuspid pressure gradient value. Based on these findings, we diagnosed PAH and right-sided heart failure due to dasatinib. However, since it was confirmed that the molecular response (MR4.5) (International Scale: BCR-ABL1IS ≤ 0.0032%) was sustained, the hematologist decided to reduce the dasatinib dose to 70 mg after thorough deliberations with the cardiologists. After the dose reduction, the PAH improved immediately; however, it was observed again in 2017, which improved with a second dose reduction to 50 mg. Additionally, cardiovascular drug therapy was initiated. The PAH was exacerbated again in 2018 with sustained MR4.5. Hence, we decided to discontinue dasatinib as the MR4.5 had been sustained over 4 years. After the discontinuation of dasatinib, PAH improved again, and near MR4.0 (BCR-ABL1IS ≤ 0.01%) level has been sustained for several years now. Thereafter, no apparent deterioration in PAH was observed. We present a case of reversible dasatinib-induced PAH. Successful management of recurrent PAH was possible with several dose reductions, and TFR was achieved. This was partly due to effective collaboration between the hematologists and cardiologists. If needed, dose reduction as a treatment strategy may be considered before discontinuing dasatinib.

Assessment of Pazopanib-Related Heart Failure in Patients With Advanced Soft Tissue Sarcoma　- A Single Institute Analysis.

BACKGROUND: Heart failure (HF) is one of the potential adverse events of pazopanib treatment for soft tissue sarcoma (STS), but detailed reports of such HF cases are scarce. This study determined the incidence and risk factors of HF following pazopanib treatment for STS at our Institute and the clinical outcomes.Methods and Results:This study retrospectively analyzed the cases of STS patients treated with pazopanib (n=151) between 2012 and 2020. HF occurred in 6 patients (3.9%) at the median onset of 137 (range 14-468) days after the treatment initiation. When their HF was diagnosed, pazopanib was interrupted in all 6 patients. No patients experienced HF-related death, and HF development was not a significant factor for poor overall survival. The cumulative doses of anthracyclines (>225 mg/m2) before pazopanib initiation (83% vs. 37%, P=0.031), pazopanib initiation at age ≥60 years (83% vs. 35%, P=0.026), and the baseline B-type natriuretic peptide (BNP) concentration (≥50 pg/mL) before pazopanib (67% vs. 11%, P=0.002) initiation were predictive factors for post-pazopanib treatment HF. CONCLUSIONS: The study findings highlight the effect of past anthracycline exposure and baseline BNP for pazopanib-associated HF. Although the study patients' clinical outcomes were generally favorable, periodic monitoring of cardiac function using ultrasonic echocardiography or serum markers is essential to detect events early and begin therapeutic intervention appropriately under a cardiologist's instructions.

Myocardial dysfunction caused by abemaciclib: a case report.

A 68-year-old female patient with metastatic breast cancer presented 12 weeks after starting chemotherapy with abemaciclib and fulvestrant with breathlessness, peripheral edema, and weight gain. Brain natriuretic peptide (BNP) and troponin I levels were raised above normal, and chest radiography revealed an increase in the cardiothoracic ratio from 47% before chemotherapy to 55%. The transthoracic echocardiogram showed a reduction in left ventricular ejection fraction from 76% before chemotherapy to 68%. Contrast-enhanced cardiac magnetic resonance imaging (MRI) revealed delayed accumulation in the interventricular septum. Under the diagnosis of abemaciclib-induced myocardial dysfunction and heart failure, abemaciclib was discontinued, and enalapril and furosemide were started. Two months later, imaging revealed a cardiothoracic ratio of 47% with a left ventricular ejection fraction of 73%. A cardiac MRI after three months was normal. This case report demonstrates that cardiac dysfunction caused by abemaciclib is reversible if detected early and treated appropriately.

A Rare Case of Reversible Cardiac Dysfunction Associated with Tegafur/Gimeracil/Oteracil (S-1) Therapy.

For the past 20 years, S-1 has been used in the treatment of many types of cancer. However, the clinical importance of myocardial dysfunction attributed to S-1 remains to be unclear. Thus, in this study, we report on a patient with myocardial dysfunction associated with S-1.S-1 postoperative chemotherapy for gastric cancer was included as a treatment for a 65-year-old man. On day 8, S-1 treatment was discontinued after the patient developed an oral ulcer. He was then admitted to the hospital because of diarrhea caused by S-1. At approximately the same time, he developed dyspnea, and his chest X-rays revealed perihilar vascular engorgement and cardiac enlargement. Although his brain natriuretic peptide was 595.8 pg/mL, troponin I and creatine phosphokinase were unremarkable. Electrocardiograms showed no change in atrial fibrillations or new ST-T wave change. As per his transthoracic echocardiogram, noted were expansion of the left ventricle, global hypokinesis, and reduced left ventricular ejection fraction (approximately 40%). The patient was then diagnosed with S-1-related myocardial dysfunction. Furosemide, human atrial natriuretic peptide, dobutamine, enalapril, spironolactone, and bisoprolol were administered. Thirteen days after being diagnosed with heart failure, his symptoms disappeared, his echocardiogram showed that the left ventricular ejection fraction had increased to 65%, and the cardiothoracic ratio improved to 47% according to his chest X-rays.S-1-related myocardial dysfunction may be reversible, as it can improve after approximately 2 weeks.

Examining the Beneficial Aspects of Nutritional Guidance Using Estimated Daily Salt Intake in Cancer Patients with Ischemic Heart Disease.

BACKGROUND The outcomes associated with nutritional guidance for patients with ischemic heart disease undergoing cancer treatment have not been explored. We examined the effects of nutritional guidance using estimated daily salt intake in cancer patients with ischemic heart disease. MATERIAL AND METHODS We examined the data from physical examinations and laboratory assessments of 27 patients with suspected excessive salt intake who underwent coronary angiography for the first time and received nutritional guidance on their next visit to the Department of Cardiology of Shizuoka Cancer Center between May 2018 and March 2020. Salinity measurement was not used in the nutritional guidance method, but the patients were instructed to reduce consumption of salt-containing foods. We compared the frequency of the estimated daily salt intake with the frequency of categories requiring salt control (food, cooking, and table salts). RESULTS The median age of the participants was 74 (range, 63-86) years. The estimated daily salt intake and the rate of change in the triglyceride level were negatively correlated (r=-0.61, P<0.01). The estimated daily salt intake was reduced in 16 cases; there was a relative decrease in the frequency of food intake among categories requiring salt control compared with that in the nonimproved cases (P<0.01). No difference was found between the cancer stage and the affected site of the digestive system in either group (P=0.64, P=0.39). CONCLUSIONS Nutritional guidance on dietary habits without using salinity measurement was beneficial in preventing ischemic heart disease and food intake reduction in cancer patients.

Cancer-associated cerebral infarction during direct oral anticoagulant treatment in cancer patients: a case series.

The effect of direct oral anticoagulants (DOACs) on cancer-associated cerebral infarction (CI) is unclear. We present the clinical course of 20 consecutive patients with cancer-associated CI that developed during treatment with DOACs. The incidence rate of cancer-associated CI during the treatment with DOACs was 3.4%. The median modified Rankin scale (mRS) and Karnofsky performance status (KPS) after CI were 5 and 30, respectively. The median survival time after CI was 1 month. In the group in which the thrombus due to venous thromboembolism (VTE) was reduced before CI, the median mRS, KPS, and prognosis after CI were significantly better than in those of the group with unchanged thrombus. Cancer-associated CI also developed in patients taking DOACs and those who did not show VTE recurrence. When the VTE thrombus decreased or disappeared with DOAC treatment, the clinical course after cancer-associated CI was improved.

Use of direct oral anti-coagulants for the treatment of venous thromboembolism in patients with advanced cancer: a prospective observational study.

BACKGROUND: The efficacy of direct oral anti-coagulants (DOACs) for the treatment of venous thromboembolism (VTE) in Japanese patients with advanced cancer is largely unknown. METHODS: This prospective single-center observational study enrolled Japanese patients with unresectable advanced cancer who started DOAC treatment for new-onset VTE between December 2015 and May 2018. Patients were followed for 3 months to evaluate bleeding and VTE recurrences. The primary study endpoint was major and non-major bleeding. RESULTS: One hundred and forty-five of 147 enrolled patients were analyzed. Of these, 8 [5.5%, 95% confidence interval (CI) 2.8-10.5] and 29 patients (20%, 95% CI 14.3-27.2) experienced major and non-major bleeding, respectively. Patients with bleeding were more likely to have a poor performance status (PS) [hazard rate (HR) 2.04, 95% CI 1.15-3.63] and more frequent use of non-steroidal anti-inflammatory drugs (NSAIDs) (HR 2.75, 95% CI 1.62-4.67) relative to those without bleeding. In a multivariate analysis, combined DOAC and NSAID use correlated significantly with bleeding (odds ratio 4.63, 95% CI 1.70-12.9, p = 0.003). Among 105 of 145 patients included in the VTE recurrence assessment, 9 experienced a VTE recurrence (8.6%, 95% CI 4.6-15.5). CONCLUSIONS: Our findings confirm the risk of bleeding during DOAC treatment for VTE in Japanese patients with advanced cancer, particularly those with poor PS and those using NSAIDs. The risk of bleeding in these patients may be reduced by avoiding the combined use of DOACs and NSAIDs.

Crizotinib-induced simultaneous multiple cardiac toxicities.

Crizotinib is a receptor tyrosine kinase inhibitor that has several targets, including c-ros oncogene 1 and the MET proto-oncogene. Considering its known cardiac toxicity, bradycardia is often investigated following treatment with crizotinib. Our patients had bradycardia, QT prolongation, ventricular rhythm, ventricular fibrillation, and pericarditis simultaneously. The cardiotoxicity of crizotinib can sometimes be simultaneous; thus, intensive observation is needed.

A Patient with a Massive Single Cardiac Metastasis of Lung Adenocarcinoma, Diagnosed via a Biopsy.

A patient with a history of lung adenocarcinoma was admitted because of palpitation. Transthoracic echocardiogram revealed a mass (74×42 mm) in the right ventricle. Computed tomography showed a tumor lesion in the right ventricular cavity but no other distant metastasis. Coronary angiography revealed well-developed small branches to the tumor. After right heart catheterization, a pathological analysis of a tumor biopsy demonstrated adenocarcinoma. We diagnosed the patient with right ventricular metastasis of lung cancer. With large cardiac metastasis, a tumor biopsy with a right heart catheter may help obtain a pathological diagnosis and also serve as a re-biopsy to confirm the gene mutation status.

Characteristics of cellular composition in malignant pericardial effusion and its association with the clinical course of carcinomatous pericarditis.

To date, the cellular composition of malignant pericardial effusion (MPE) and its association with the clinical course of carcinomatous pericarditis remain unclear. We aimed to determine the MPE cellular composition and its association with carcinomatous pericarditis. Forty-four cases indicated for pericardial drainage due to symptomatic carcinomatous pericarditis were retrospectively reviewed; the blood cell count and composition of MPE were examined. The most dominant cells in MPE were neutrophils. The appearance ratio of an atypical cell in cytologically positive MPE was 95.5%. Low neutrophil and high lymphocyte counts were significantly associated with good effusion failure-free survival at 1 month. The survival after pericardial drainage was significantly shorter when the neutrophil/lymphocyte ratio was 3.5 or more (P = 0.041). Patients whose performance status improved due to drainage had significantly high leukocyte counts in MPE (P = 0.02). Prediction of the course of drainage through basic examination of MPE cellular composition might be beneficial in clinical practice.

Chemotherapy-induced cardiomyopathy caused by Pemetrexed.

Chemotherapy-related cardiac toxicity is a rare but serious adverse event in patients with cancer. Thus far, no case of serious cardiac toxicity of pemetrexed has been reported. We describe the case of a patient with advanced lung cancer and cardiomyopathy due to pemetrexed. A 59-year-old woman visited our hospital, and we found abnormal findings on a chest radiograph. She was diagnosed as having stage IV lung adenocarcinoma. Chemotherapy with cisplatin and pemetrexed every 3 weeks was initiated. After four cycles of chemotherapy, maintenance chemotherapy with pemetrexed was administered every 3 weeks. During the seventeenth cycle of pemetrexed, she had shortness of breath in her daily life. A chest radiograph showed an enlarged cardiothoracic ratio (66%), and the transthoracic echocardiogram demonstrated expansion of the left ventricle (diastolic diameter, 67 mm), severe global hypokinesis, and reduced left ventricular ejection fraction (28%). The coronary angiogram showed no coronary constriction. There was no delayed accumulation on the contrast-enhanced cardiac magnetic resonance imaging scan. After right heart catheterization, pathological results of a myocardial biopsy from the ventricular septum indicated no cardiac muscle hypertrophy, cardiac fibrosis, inflammatory cell infiltration, or myocyte disarray. Eventually, she was diagnosed as having pemetrexed-induced cardiomyopathy. Pemetrexed was discontinued, and furosemide, enalapril, and carvedilol were started. Then her symptoms and cardiac function improved. Early detection and discontinuation of causative agents are the most important treatment strategies in similar patients. Diuretics, angiotensin-conversion enzyme inhibitors, and beta-blockers may be effective for treating heart failure.

Effect of Switching from the Initial Direct Oral Anticoagulant to Another One on Exacerbation of Venous Thromboembolism in Patients with Cancer: A Retrospective Study.

Objective: To determine the effect of switching from the initial direct oral anticoagulant (DOAC) to another DOAC on exacerbation of deep vein thrombosis (DVT). Materials and Methods: We retrospectively reviewed the data of patients with advanced cancer who experienced exacerbated DVT during initial treatment with DOAC due to new venous thromboembolism (VTE). After switching to another DOAC for VTE recurrence, changes in the thrombus and bleeding were evaluated for 3 months. Eighteen patients met these criteria. We compared the effect of anticoagulant switching on the switched-drug group in those 18 patients with the effect of no anticoagulant switching on the single-drug group of patients (n=78) with a similar background. Results: The recurrence rate of VTE in the switched-drug group was 6%. Non-major bleeding occurred in 11% of patients. Recurrent VTE occurred in 6% of patients in both the switched-drug and single-drug groups, respectively [risk ratio (RR): 0.9, 95% confidence interval (CI): 0.11-7.6]. Non-major bleeding occurred in 11% and 14% of patients in the switched-drug and single-drug groups, respectively (RR: 0.79, 95%CI: 0.19-3.2). Conclusion: Switching DOAC may be a treatment option for exacerbation of DVT in patients with advanced cancer.