Rekha Parameswaran

Safe and effective use of rivaroxaban for treatment of cancer-associated venous thromboembolic disease: a prospective cohort study

Low-molecular weight heparin (LMWH) has been the standard of care for treatment of venous thromboembolism (VTE) in patients with cancer. Rivaroxaban was approved in 2012 for the treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT), but no prior studies have been reported specifically evaluating the efficacy and safety of rivaroxaban for cancer-associated thrombosis (CAT). Under a Quality Assessment Initiative (QAI), we established a Clinical Pathway to guide rivaroxaban use for CAT and now report a validation analysis of our first 200 patients. A 200 patient cohort with CAT (PE or symptomatic, proximal DVT), whose full course of anticoagulation was with rivaroxaban, were accrued. In competing risk analysis, primary endpoints at 6 months included new or recurrent PE or symptomatic proximal lower extremity DVT, major bleeding, clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban, or death. In competing risk analysis, the 6 months cumulative incidence of new or recurrent VTE was 4.4 % (95 % CI = 1.4–7.4 %), major bleeding was 2.2 % (95 % CI = 0−4.2 %) and all-cause mortality 17.6 % (95 % CI = 11.7–23.0 %). In this cohort of 200 patients with active cancer and CAT the rates of new or recurrent VTE and major bleeding were comparable to the cancer subgroup analysis from the EINSTEIN studies. The results of our Clinical Pathway provide guidance on Rivaroxaban use for treatment of CAT, and suggest that safety and efficacy is preserved, compared with past-published experience with LMWH.

Unstable Angina Associated With Cisplatin and Carboplatin in a Patient With Advanced Melanoma

Several classes of antineoplastic agents are associated with cardiac toxicities ranging from acute and delayed cardiomyopathy to myocardial ischemia. Although the risk of cardiotoxicity due to anthracyclines and fluorouracil is well recognized, descriptions of cardiac events associated withplatinumagentsare lesscommon. AMEDLINEdatabasesearchvia PubMed (on the terms carboplatin, cisplatin, angina, myocardial ischemia) revealed four case reports describing cardiac toxicity attributable to carboplatin and more than 10 cases associated with cisplatin. We contributeacaseofunstableanginaassociatedwithbothcisplatinandcarboplatin in a patient with advanced melanoma.

Enoxaparin dose reduction for thrombocytopenia in patients with cancer: a quality assessment study

The development of thrombocytopenia in the setting of therapeutic anticoagulation for venous thromboembolic disease (VTE) is common in cancer patients, but guidelines for management are based on limited past data and have not been validated. In 2011, Memorial Sloan Kettering Cancer Center (MSKCC) implemented the following guidelines in this setting: administer full dose enoxaparin for a platelet count > 50,000/mcL, half-dose enoxaparin for a platelet count of 25,000–50,000/mcL, and hold anticoagulation for a platelet count < 25,000/mcL. We now report validation of safety and efficacy of these guidelines. As a Quality Assessment Initiative, we evaluated our guidelines for adult cancer patients at MSKCC who were on therapeutic-dose enoxaparin for VTE during the years 2011 through 2013 and experienced at least one 7-day period of thrombocytopenia (platelet count ≤ 50,000/mcL). We assessed adherence to the enoxaparin dose modification guidelines, major bleeding, clinically relevant non-major bleeding, recurrent VTE, and mortality during the thrombocytopenic episodes. We identified 99 patients with 140 episodes of thrombocytopenia of 7 or more days. The median duration of these thrombocytopenic episodes was 12 days. The enoxaparin dose was modified in 133 of the 140 episodes (95%), reflecting satisfactory adherence to our institutional guidelines. There were no recurrent VTE events or major bleeding episodes when the anticoagulant dose was reduced or held. In this cohort, there was only one major bleeding episode, a trauma-associated retroperitoneal hemorrhage that occurred on the third day of a thrombocytopenic episode, prior to enoxaparin dose modification. There were 13 clinically relevant non-major bleeding episodes. Lastly, 10 patients died of cancer-related causes during an episode of thrombocytopenia. This Quality Assessment Initiative supports the safety and efficacy of our guidelines for therapeutic enoxaparin dose modification.

Skin necrosis induced by generic enoxaparin

To the Editor: Heparin-induced skin necrosis is a rare complication of heparin or low molecular weight heparins (LMWH) [1]. Cases generally are associated with antibodies to the heparin:platelet factor 4 complex and/or heparin-induced thrombocytopenia (HIT) [2]. A recent review identified only 25 cases of skin necrosis associated with LMWH through May, 2009 [3]. In July 2010, the Food and Drug Administration (FDA) approved generic enoxaparin sodium [4]. At our institution, we observed four cases of enoxaparin-induced skin necrosis in the initial 18-months since switching from the branded LovenoxVR to generic enoxaparin (Sandoz). As we had not observed any cases in several years previously, this raised a concern of a greater risk of heparin-induced skin necrosis with the generic formulation. Case 1: A 67-year-old female with metastatic uterine carcinosarcoma was on therapeutic LovenoxVR for over 3 weeks for a deep vein thrombosis (DVT). Within 24 hr of transitioning to generic enoxaparin, she developed necrotic lesions at the injection sites (Fig. 1A,B). The Heparin-Dependent Antibody (HDA) test (GTIVR PF4 EnhancedVR ) was negative. Scarring persisted for over 6 months. Case 2: A 49-year-old male with metastatic colorectal adenocarcinoma tolerated a single unfractionated heparin infusion in an intra-hepatic artery infusion pump for localized chemotherapy delivery as well as brief exposure to generic enoxaparin prophylaxis during hospitalization. Ten days later, he was readmitted for infection and the first three doses of prophylactic generic enoxaparin resulted in injection site necrosis (Fig. 1C,D). HDA assay was strongly positive, (optical density, OD: 2.637), but he did not develop thrombocytopenia or thrombosis. Case 3: A 57-year-old female with metastatic colorectal adenocarcinoma underwent insertion of an intra-hepatic artery infusion pump. On post-operative day 1, the patient was placed on prophylactic generic enoxaparin sodium. On Day 13 of enoxaparin, the patient developed two local skin necrosis reactions. HDA assay was positive (OD: 3.217), as was the serotonin release assay. However, the patient neither developed thrombocytopenia nor thrombosis. Case 4: A 30-year-old woman, with steroid-controlled chronic immune thrombocytopenic purpura, was found to have a proximal DVT and was started on enoxaparin treatment. Beginning on Day 3, she developed inflamed injection site reactions, which progressed over the subsequent several days to necrosis. Her heparin dependent antibody assay was negative (OD: 0.199) and she did not develop thrombocytopenia nor new thrombosis. Hyperpigmented skin changes persisted beyond 6 months. Generic enoxaparin has quickly achieved widespread use for thrombosis prophylaxis and treatment due to its reduced cost. Our cluster of cases raises a question of possible increased risk of skin necrosis with generic enoxaparin compared with brand named LovenoxVR . To the best of our knowledge, these are the first reported cases attributed to generic enoxaparin. It is noteworthy that in just one institution we observed four cases in the first 18 months since introduction of generic enoxaparin. Several characteristics of our four cases are distinct from previously published cases. Most cases of heparin-induced skin necrosis have been associated with HDA, and/or thrombocytopenia [3,5]. In contrast, none of our patients exhibited thrombocytopenia, new thrombosis, or clinical HIT, and only 2 of our 4 cases exhibited a positive HDA assay. Further, in two cases the skin necrosis developed outside the usual time-frame of HIT of 5–15 days of exposure (Cases no. 1 and 4) [5]. These novel features suggest a novel mechanism of the pathology. In 2010, the FDA approved generic enoxaparin sodium injection under the FDA’s Abbreviated New Drug Application pathway (4). Approval was based on in vitro analysis and immunogenicity studies in healthy volunteers with only limited human clinical trial experience. An FDA bulletin claimed, “With the FDA approach, there is no scientific need to perform additional clinical studies to demonstrate equivalence of clinical effectiveness and safety of generic enoxaparin to Lovenox” [4]. A full discussion of the appropriateness of the FDA approval process in the case of generic enoxaparin is beyond the scope of this brief report. However, our four cases of skin necrosis raise the possibility that an increased risk of this relatively uncommon, but potentially severe adverse event, may exist and was not identified in the abbreviated approval process.

Aspirin Is Associated with Improved Survival in Severely Thrombocytopenic Cancer Patients with Acute Myocardial Infarction

BACKGROUND Patients with hematologic malignancies are at risk for severe thrombocytopenia (sTP). The risk and benefit of aspirin are not known in thrombocytopenic cancer patients experiencing acute myocardial infarction (AMI). MATERIALS AND METHODS Medical records of patients with hematologic malignancies diagnosed with AMI at Memorial Sloan Kettering Cancer Center during 2005-2014 were reviewed. sTP was defined as a platelet count <50,000 cells per µL within 7 days of AMI. RESULTS Of 118 patients with hematologic malignancies who had AMI, 58 (49%) had sTP. Twenty-five patients (43%) with sTP received aspirin as a treatment for AMI. Compared with patients without sTP with AMI, patients with sTP with AMI were less likely to receive aspirin (83% vs. 43%; p = .0001) and thienopyridine treatment (27% vs. 3%; p = .0005). During median follow-up of 3.7 years after AMI, survival was lower in patients with sTP than in those with no sTP (23% vs. 50% at 1 year; log rank p = .003). Patients with sTP who received aspirin for AMI had improved survival compared with those who did not (92% vs. 70% at 7 days, 72% vs. 33% at 30 days, and 32% vs. 13% at 1 year; log rank p = .008). In multivariate regression models, aspirin use was associated with improved 30-day survival both in the overall patient cohort and in sTP patients. No fatal bleeding events occurred. Major bleeding was not associated with sTP or aspirin use. CONCLUSION Treatment of AMI with aspirin in patients with hematologic malignancies and sTP is associated with improved survival without increase in major bleeding. The Oncologist 2017;22:213-221Implications for Practice: In patients with hematologic malignancies and acute myocardial infarction with severe thrombocytopenia (platelet count < 50,000 cells/µL), guideline-recommended medical therapy is often withheld because of the fear of major bleeding. In this study, aspirin therapy was associated with improved survival without an increase in major bleeding in this high-risk patient cohort.

Indications for and complications of transfusion and the management of gynecologic malignancies

Anemia, which is highly prevalent in oncology patients, is one of the most established negative prognostic factors for several gynecologic malignancies. Multiple factors can cause or contribute to the development of anemia in patients with gynecologic cancers; these factors include blood loss (during surgery or directly from the tumor), renal impairment (caused by platinum-based chemotherapy), and marrow dysfunction (from metastases, chemotherapy, and/or radiation therapy). Several peri- and intra-operative strategies can be used to optimize patient management and minimize blood loss related to surgery. Blood transfusions are routinely employed as corrective measures against anemia; however, blood transfusions are one of the most overused healthcare interventions. There are safe and effective evidence-based blood transfusion strategies used in other patient populations that warrant further investigation in the surgical oncology setting. Blood is a valuable healthcare resource, and clinicians can learn to use it more judiciously through knowledge of the potential risks and complications of blood interventions, as well as the ability to properly identify the patients most likely to benefit from such interventions.

Managing the risks of cardiac therapy in cancer patients.

The purpose of this review was to highlight the more commonly used cardiac medications that should be closely monitored or possibly discontinued during cancer therapy. Often, older cancer patients are taking multiple pharmacotherapy agents for the treatment or prevention of cardiac disease when they face decisions about cancer treatment. Concurrent administration of drugs can result either in increased toxicity or decreased efficacy of either therapy. The benefits of the cardiac medications must be weighed against the effects of cancer therapy, and the role of drug metabolism also must be considered. For example, the benefits of cardiac medications such as anti-platelet agents, important in treating coronary artery disease, and anti-thrombotic agents, important for stroke prevention in atrial fibrillation, must be evaluated against an increased risk of bleeding during cancer therapy. It should be noted that some cardiac medications which act on hormonal receptors can theoretically stimulate growth of certain cancers. The concomitant management of cardiac therapy and cancer therapy is a common challenge in todays aging population.

Romiplostim management of chemotherapy-induced thrombocytopenia.

10134Background: Chemotherapy-induced thrombocytopenia (CIT) is a common toxicity of cancer therapy, often leading to delay or reduction in chemotherapy. We conducted a randomized open-label phase ...

Corrigendum to “Indications for and complications of transfusion and the management of gynecologic malignancies” [Gynecol. Oncol. 146 (2017) 416–426]

a Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA b Hematology and Coagulation Laboratory Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA c Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA d Department of Medicine, Weill Cornell Medical College, New York, NY, USA e Transfusion Medicine Service, Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA f Hematology Service, Department of Medicine, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA g Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY, USA