In the Clinic: Annals Sweta Kakaraparthi 1/23/15

In the Clinic: Annals Sweta Kakaraparthi 1/23/15

Case Scenerio 56 year old female with breast cancer presents to the clinic for her 3 month followup! She is concerned about blood clots and asks you about her risk as well as preventive measures! WHAT WOULD YOU DO?

Prophylaxis against Thromboembolism in Cancer Patients: In the Clinic

Dan L. Longo, M.D., Editor Prophylaxis against Venous Thromboembolism in Ambulatory Patients with Cancer Jean M. Connors, M.D. Tn engl j med 370;26 nejm.org june 26, 2014!! 2013 by American Society of Clinical Oncology! Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update!.! Gary H. Lyman, Alok A. Khorana, Nicole M. Kuderer, Agnes Y. Lee, Juan Ignacio Arcelus, Edward P. Balaban, Jeffrey M. Clarke, Christopher R. Flowers, Charles W. Francis, Leigh E. Gates, Ajay K. Kakkar, Nigel S. Key, Mark N. Levine, Howard A. Liebman, Margaret A. Tempero, Sandra L. Wong, Ann Alexis Prestrud and Anna Falanga! +!

Introduction Risk of thromboembolism is 4-7 times higher in cancer patients! Venous Thromboembolism is the second leading cause of death in patients with cancer! Mucin production, Exposure of tissue factor-rich surfaces, local hypoxia, etc.! Prophylactic anticoagulation in patients with cancer: Surgery and Hospitalized patients

Risk and Rates of Venous Thromboembolism Risk depends on type of cancer, treatments and presence/absence of coexisting disease! Khorana score! According to this model, 0.3% among low risk patients; 2.0% in intermediate risk patients and 6.7% among high-risk patients over 2.5 month period

Table 1. Risk-Assessment Model for Venous Thromboembolism, According to the Khorana Score.* Variable Type of cancer Points Odds Ratio (95% CI) Stomach or pancreatic 2 4.3 (1.2 15.6) Lung, lymphoma, gynecologic, bladder, or testicular 1 1.5 (0.9 2.7) Platelet count 350,000/mm 3 1 1.8 (1.1 3.2) Hemoglobin <10 g/dl 1 2.4 (1.4 4.2) White-cell count >11,000/mm 3 1 2.2 (1.2 4.0) BMI 35 1 2.5 (1.3 4.7) * Data are from Khorana et al. 18 The aggregate score is calculated by adding the individual component points. Complete blood counts before treatment should be used. An aggregate score of 0 indicates low risk, an aggregate score of 1 or 2 indicates intermediate risk, and an aggregate score of 3 or more indicates high risk. The body-mass index (BMI) is the weight in kilograms divided by the square of the height in meters. Odds ratios are based on data from the derivation cohort. CI denotes confidence interval.

Other risk factors Prolonged immobilization! Use of hormone therapy and angiogenesis inhibitors.! History of deep-vein thrombosis, vascular compression due to tumor or adenopathy,! Known inherited thrombophilia.

Introduction: Ambulatory Setting Empiric prophylaxis against venous thromboembolism in ambulatory patients remains controversial

Guidelines: ASCO 1. Routine pharmacologic thromboprophylaxis is not recommended in cancer outpatients.!! 2. Based on limited RCT data, clinicians may consider LMWH prophylaxis on a case-by-case basis in highly selected outpatients with solid tumors receiving chemotherapy. Consideration of such therapy should be accompanied by a discussion with the patient about the uncertainty concerning benefits and harms as well as dose and duration of prophylaxis in this setting.!! 3. Patients with multiple myeloma receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone should receive pharmacologic thromboprophylaxis with either aspirin or LMWH for lower-risk patients and LMWH for higher-risk patients.!

Table 2. Comparison of Recommendations Regarding Prophylaxis against Venous Thromboembolism.* Potential Indication Treatment of multiple myeloma with tha lido mide or lenalidomide with high-dose dexamethasone, doxorubicin, combi nation chemotherapy, or other risk factors Cancer associated with high risk of venous thromboembolism (pancreatic or gastric) Recommended Use of Prophylaxis Author ACCP ASCO NCCN Yes Suggest Yes Yes With other risk factors Yes Suggest Consider Consider Without other risk factors Consider No Consider Consider Cancer associated with intermediate risk of venous thromboembolism (lung, ovarian, primary central nervous system, bladder, lymphoma) With other risk factors Consider Suggest Consider No Without other risk factors No No Consider No Cancer associated with low risk of venous thromboembolism With other risk factors Consider Suggest Consider No Without other risk factors No No Consider No * Consensus guidelines of professional societies are not always explicit. Variations in the strength of recommendations exist because data are limited and often recommendations are extrapolated from other patient populations. All societies agree that high-risk patients with multiple myeloma should receive prophylaxis, although the wording of the American College of Chest Physicians (ACCP) is suggest, or a weak recommendation based on limited data. For other patient groups, yes indicates a definitive recommendation; suggest, a weak recommendation; and consider, a possible benefit but with no supporting data and therefore uncertainty regarding benefit. The ACCP 11 suggests the use of prophylaxis in patients with solid tumors, a low bleeding risk, and additional risk factors for venous thromboembolism. According to other societies and clinicians, additional risk factors for venous thromboembolism include previous venous thromboembolism, inherited thrombophilia, the use of hormonal therapy, the presence of metastatic disease, vascular compromise by tumor or lymphadenopathy, and a high Khorana risk score. The Amer i can Society of Clinical Oncology (ASCO) suggests that the use of prophylaxis should be considered on a case-by-case basis in highly selected outpatients who have solid tumors and are receiving chemotherapy, and the uncertainty of risks and benefits should be discussed. The National Comprehensive Cancer Network (NCCN) advises that prophylaxis against venous thromboembolism should not be used outside the setting of a clinical trial, although it can be considered for patients with a Khorana score of 3 or higher. Bleeding risk must be assessed and considered. High-risk factors for bleeding include a recent episode of major active bleeding or bleeding at a critical site, a platelet count of less than 50,000 per cubic millimeter, and the presence of untreated central nervous system metastases. The risk for the individual patient should be assessed, and the risk benefit ratio should be discussed with that patient.

Society Guidelines For patients with an increased risk of venous thromoboembolism, such as those with a Khorana score of 3 or higher or patients with pancreatic, lung, or stomach cancer, the ASCO and NCCN guidelines recommend conversations with the individual patient about the risks and benefits of prophylactic anticoagulation! ACCP guidelines recommend the use of prophylactic lowmolecular-weight heparin or unfractionated heparin.!

Literature Analysis 3 systematic reviews considering the ambulatory setting and 9 RCTs.! Two RCTs, SAVE-ONCO (Evaluation of AVE5026 in the Prevention of Venous Thromboembolism in Cancer Patients Undergoing Chemotherapy) and PROTECHT (Prophylaxis of Thromboembolism During Chemotherapy) included patients with a variety of solid tumors.! FRAGEM (Gemcitabine With or Without Dalteparin in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer) and PROSPECT-CONKO 004 (Chemotherapy With or Without Enoxaparin in Pancreatic Cancer) included only patients with pancreatic cancer.! The PRODIGE (Dalteparin Low Molecular Weight Heparin for Primary Prophylaxis of Venous Thromboembolism in Brain Tumour Patients) trial examined anticoagulation for patients with glioma. Two recent trials evaluated thromboprophylaxis in multiple myeloma.

Systemic Reviews Two systematic reviews identified RCTs comparing LMWH prophylaxis in the outpatient setting with placebo or no prophylaxis.! Estimated risk ratios (RRs) across trials indicated decreases in symptomatic VTE events with LMWH thromboprophylaxis of 0.53 (95% CI, 0.39 to 0.72) and 0.54 (95% CI, 0.31 to 0.95),! Neither meta-analysis noted a statistically significant increase in bleeding with LMWH! The absolute differences in symptomatic VTE event rates between treated and control patients were < 5% in most trials. Among the three systematic reviews, the absolute risk differences in VTE were 1.5%, 2.8%, and 1.7% with estimates of the number needed to treat (NNT) of 67, 36, and 59 to prevent one symptomatic VTE event across the included trials

Clinical Trials: Solid Tumor The PROTECHT and SAVE-ONCO trials evaluated thromboprophylaxis in ambulatory patients with cancer receiving chemotherapy for locally advanced or metastatic solid tumors.! ENDPOINT: composite of symptomatic VTEs and arterial thromboembolic events during treatment and follow-up! In PROTECHT trial, 3.9% of patients in the control arm experienced events compared with 2.0% of patients treated with nadroparin for an NNT of 53. Major bleeding rates were not different between the arms.! In SAVE-ONCO, fewer symptomatic VTE events occurred in patients who received semuloparin (1.2%) compared with placebo (3.4%; HR, 0.36; 95% CI, 0.21 to 0.60; P <.001). The absolute risk difference for VTE events was 2.2% for an NNT of 45. Major bleeding was similar across arms

Clinical Trials: Solid Tumors The PROTECHT [Prophylaxis of Thromboembolism during Chemotherapy] study randomly assigned 1150 ambulatory patients with cancer to receive prophylactic nadroparin or placebo.! The SAVE-ONCO trial randomly assigned 3212 ambulatory patients receiving chemotherapy for locally advanced solid tumors or metastatic cancer to receive a prophylactic dose of semuloparin or placebo.

Clinical trials: Solid tumors In the PROTECHT trial, the subjects were not separated prospectively according to risk of venous thromboembolism! Clinical trials vs. Real world retrospective analysis

Clinical Trials: Solid Tumors Two double-blind RCTs of ambulatory patients with metastatic breast carcinoma (TOPIC-1) or stage III/IV non small-cell lung carcinoma (TOPIC-2) compared certoparin 3,000 IU subcutaneously once daily with placebo for 6 months.! The primary outcome was symptomatic or asymptomatic VTE.

Clinical Trials: Pancreatic Cancer FRAGEM and PROSPECT-CONKO trials enrolled patients with advanced pancreatic neoplasms.! The FRAGEM trial was a phase IIb RCT of 123 patients with advanced pancreatic cancer receiving gemcitabine-based chemotherapy comparing thromboprophylaxis with therapeutic doses of dalteparin up to 12 weeks,! VTE over the course of the study was reduced from 28% to 12%, with a relative risk of 0.42 (95% CI, 0.19 to 0.94; P =.039). No differences in rates of major bleeding or mortality between study arms were observed.

Glioma The PRODIGE trial included 186 patients with newly diagnosed grade 3 or 4 glioma and was terminated early.! Patients were randomly assigned to dalteparin or placebo for 6 months, and therapy could continue for an additional 6 months.! VTE events occurred in nine patients (9%) in the dalteparin arm compared with 13 patients (15%) in the placebo arm (HR, 0.51; 95% CI, 0.19 to 1.40; P =.29). Five patients in the dalteparin arm experienced intracranial bleeding by 12 months compared with one in the control arm

Conclusion: Solid Tumors Overall, the Panel concluded that offering all patients with solid malignancies anticoagulation for thromboprophylaxis in the ambulatory setting is not justified based on the available clinical trial data and the heterogeneity of this patient population.

Multiple Myeloma Two RCT substudies assessed different thromboprophylaxis strategies in patients with newly diagnosed multiple myeloma receiving lenalidomide- or thalidomide-based treatment! Either enoxaparin (at a dose of 40 mg subcutaneously daily or the equivalent) or warfarin is recommended, although INR targets differ (ASCO guidelines recommend 1.5 and NCCN and ACCP guidelines recommend 2.0 to 3.0).!

Bleeding risk Closely monitored, and anticoagulation therapy can be withheld if there are changes in renal function or the platelet count that suggest an increased risk of bleeding.! All guidelines suggest withholding any dose of anticoagulation drug if the platelet count is less than 50,000! However, for very high-risk patients, the continued use of prophylactic anticoagulation therapy can be considered if the platelet count is more than 30,000

Conclusion Increased use of prophylaxis against venous thromoboembolism in high-risk ambulatory patients with cancer who are eligible for this therapy could lead to improved outcomes.! Need for further studies