Author: RR

Anticonvulsant Prophylaxis and Steroid Use in Adults with Metastatic Brain Tumors ASCO and SNO Endorsement of the Congress of Neurological Surgeons Guidelines

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SUMMARY: Brain metastases are the most common intracranial tumors in adults in the United States. In patients with systemic malignancies, brain metastases occur in 10-30% of adults, with Lung, Breast, and Melanoma continuing to be the leading cause of brain metastases. The incidence of brain metastases may be on the rise due to both improved imaging techniques, as well as better control of extracerebral disease from advances in systemic therapy.

The Congress of Neurological Surgeons (CNS) developed a series of guidelines for the treatment of adult patients with metastatic brain tumors, including systemic therapy and supportive care topics. The ASCO/SNO (Society of NeuroOncology) Expert Panel determined that the recommendations from the CNS anticonvulsants and steroids guidelines, published January 9, 2019, are clear, thorough, and based on the most relevant scientific evidence. ASCO/SNO endorsed these two CNS guidelines with minor alterations. This guideline was developed by a multidisciplinary Expert Panel that included a patient representative and an ASCO guidelines staff member with health research methodology expertise.

Guideline Questions

CNS Anticonvulsant Guideline

1) Do prophylactic antiepileptic drugs decrease the risk of seizures in nonsurgical patients with brain metastases who are otherwise seizure free?

2) Do prophylactic antiepileptic drugs decrease the risk of seizures in patients with brain metastases and no prior history of seizures in the postoperative setting?

CNS Steroids Guideline

1) Do steroids improve neurologic symptoms and/or quality of life in patients with metastatic brain tumors compared with supportive care only or other treatment options?

2) If steroids are administered, what dose should be given?

Target Population

Adults with metastatic brain tumors.

Target Audience

Medical oncologists, Neurologists, and others who provide care for adults with metastatic brain tumors.

Recommendations

CNS Anticonvulsants Guideline: 

1) Prophylactic antiepileptic drugs are not recommended for routine use in patients with brain metastases who did not undergo surgical resection and who are otherwise seizure free.

2) Routine postcraniotomy antiepileptic drug use for seizure-free patients with brain metastases is not recommended.

CNS Steroids Guideline: Steroid Therapy Versus No Steroid Therapy

Patients with asymptomatic brain metastases without mass effect:

Insufficient evidence exists to make a treatment recommendation for this clinical scenario.

Patients with brain metastases with mild symptoms related to mass effect:

1) Corticosteroids are recommended to provide temporary symptomatic relief of symptoms related to increased intracranial pressure and edema secondary to brain metastases. It is recommended for patients who are symptomatic from metastatic disease to the brain that a starting dose of Dexamethasone 4 to 8 mg/day be considered. Patients with brain metastases with moderate to severe symptoms related to mass effect

2) Corticosteroids are recommended to provide temporary symptomatic relief of symptoms related to increased intracranial pressure and edema secondary to brain metastases. If patients exhibit severe symptoms that are consistent with increased intracranial pressure, it is recommended that higher doses, such as Dexamethasone 16 mg/day or more, be considered.

Choice of steroid:

If corticosteroids are administered, Dexamethasone is the best drug choice, given the available evidence.

Duration of corticosteroid administration:

Corticosteroids, if administered, should be tapered as rapidly as possible, but no faster than clinically tolerated, on the basis of an individualized treatment regimen and a full understanding of the long-term sequelae of corticosteroid therapy.

ASCO/SNO Expert Panel comment: The Panel’s expert opinion is that, given the important adverse effects of steroids, the minimum effective dose (often no more than 4 mg) should be used where possible and night-time doses of steroids should be avoided to minimize toxicity.

Note regarding CNS Level 3 recommendation classification: CNS defines a Level 3 recommendation as, one based on “Evidence from case series, comparative studies with historical controls, case reports, and expert opinion, as well as significantly flawed randomized controlled trials”

Anticonvulsant Prophylaxis and Steroid Use in Adults With Metastatic Brain Tumors: ASCO and SNO Endorsement of the Congress of Neurological Surgeons Guidelines. Chang SM, Messersmith H, Ahluwalia M, et al. J Clin Oncol 2019;37:1130-1135

Association between Androgen Deprivation Therapy and Diagnosis of Alzheimer Disease or Dementia in Patients with Prostate Cancer

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 174,650 new cases of Prostate cancer will be diagnosed in 2019 and 31,620 men will die of the disease. The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide). The first-generation Androgen Receptor (AR) inhibitors act by binding to the Androgen Receptor (AR) and prevent the activation of the AR and subsequent up-regulation of androgen responsive genes. They may also accelerate the degradation of the AR. These agents have a range of pharmacologic activity from being pure anti-androgens to androgen agonists. The second-generation, anti-androgen agents include, ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide) and ERLEADA® (Apalutamide). ZYTIGA® inhibits CYP17A1 enzyme and depletes adrenal and intratumoral androgens, thereby impairing AR signaling. XTANDI® and ERLEADA® compete with Testosterone and Dihydrotestosterone and avidly binds to the Androgen Receptor, thereby inhibiting AR signaling, and in addition inhibits translocation of the AR into the nucleus and thus inhibits the transcriptional activities of the AR.

Androgen Deprivation Therapy (ADT) is often recommended alone or as a part of multimodality therapy, as ADT reduces the likelihood of cancer progression and/or mortality, in high-risk localized, locally advanced, recurrent, or metastatic Prostate cancer. ADT however can be associated with side effects such as fatigue, loss of muscle mass, impotence, anemia, osteoporosis, depression, etc., which in turn can have a significant negative impact on an individual’s quality of life. ADT has also been associated with cognitive dysfunction and there has been conflicting evidence establishing an association between ADT use and diagnosis of Alzheimer disease or Dementia. It has been postulated that lower testosterone levels impair neuron growth and axonal regeneration, in addition to accumulation of abnormally folded β-amyloid protein. With the earlier introduction of ADT in the course of disease progression for patients with Prostate cancer, it is important to discuss the association between ADT and Dementia with patients, which in turn can improve shared decision making around the risks and benefits of ADT in Prostate cancer.

The present study was conducted to analyze the association between ADT exposure and diagnosis of Alzheimer disease or Dementia, among elderly men with Prostate cancer. The authors in this retrospective cohort study used data from the NCI’s Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, and the participants included 154,089 elderly men with newly diagnosed Prostate cancer, between 1996 and 2003. The analyses were conducted in 2018 and patients receiving ADT within 2 years of Prostate cancer diagnosis were identified. In this study, 62,330 men received ADT within 2 years of Prostate cancer diagnosis, and 91,759 men did not receive ADT. Mean follow up was 8.3 years, and survival analysis was used to determine association between ADT exposure and diagnosis of Alzheimer disease or Dementia.

The researchers noted that exposure to ADT, compared with no ADT exposure, was associated with a diagnosis of Alzheimer disease (13.1% vs 9.4%; HR=1.14; P<0.001) and Dementia (21.6% vs 15.8%; HR=1.20; P<0.001). There was a dose-response relationship and patients who received more than 8 doses of ADT were at a significantly higher hazard of diagnosis of both Alzheimer disease and Dementia, than those receiving fewer doses ADT.

The authors concluded that over a follow-up period of at least 10 years, ADT exposure among elderly patients with Prostate cancer was associated with subsequent diagnosis of Alzheimer disease or Dementia. They added that clinicians should carefully weigh the long-term risks and benefits of ADT, in patients with a prolonged life expectancy, and stratify patients based on Dementia risk, prior to ADT initiation. Association Between Androgen Deprivation Therapy Use and Diagnosis of Dementia in Men With Prostate Cancer. Jayadevappa R, Chhatre S, Malkowicz SB, et al. JAMA Netw Open. 2019;2(7):e196562. doi:10.1001/jamanetworkopen.2019.6562

Survival Benefit with KEYTRUDA® After Locally Ablative Therapy (LAT) for Oligometastatic NSCLC

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2019, about 228,150 new cases of lung cancer will be diagnosed and 142,670 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas.

It is estimated that approximately 7% of patients with NSCLC present with a limited number of metastatic foci (oligometastatic). Several retrospective studies have shown that the use of Locally Ablative Therapy (LAT) to all sites of disease in oligometastatic NSCLC is associated with a significant improvement in Progression Free Survival (PFS) and Overall Survival (OS), when compared with historical data. Preclinical evidence had suggested that chemotherapy and radiotherapy may upregulate PD-L1 expression in tumor cells. Therefore, incorporating immunotherapy along with LAT has been an area of active research. In the PACIFIC trial, consolidation therapy with PD-L1 inhibitor IMFINZI® (Durvalumab), following chemoradiation, significantly improved PFS and OS among patients with locally advanced NSCLC suggesting that there is a strong biological rationale for the use of immunotherapy in patients with minimal residual disease state.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. The primary objective of this study was to evaluate whether the addition of KEYTRUDA® after Locally Ablative Therapy (LAT) improves outcomes among patients with oligometastatic NSCLC, compared with historical data.

The authors conducted a single arm Phase II trial at an academic referral cancer center, and 51 eligible patients with oligometastatic NSCLC (no more than 4 metastatic sites) were enrolled. Enrolled patients had oligometastatic disease at diagnosis (synchronous disease) or who developed oligometastatic disease after initial definitive therapy (metachronous disease). There was no limit on the number of prior therapies, although patients could not have received prior therapy with a Programmed Death 1 (PD-L1) inhibitor. Any form of Locally Ablative Therapy (LAT) was acceptable and LATs included Surgery, Chemoradiotherapy, Stereotactic radiotherapy, and/or Interventional ablation. Forty five of the 51 patients enrolled received KEYTRUDA® within 4 to 12 weeks of completing LAT. Patients received KEYTRUDA® 200 mg IV every 21 days, for 8 cycles and were allowed to continue therapy for a total of 16 cycles in the absence of progressive disease or untoward toxicities. The median age was 64 years and patients were eligible regardless of their PD-L1 or molecular target status. Thirty-two patients had adequate tissue for assessment of PD-L1 status, and 29 patients had adequate tissue for assessment of CD8 T-cell infiltration. In patients undergoing testing, 34% had results positive for PD-L1 (1% or more) and 52% had CD8 T-cell infiltration of greater than 2.5%. Patients received a median of 11 cycles of KEYTRUDA®.

The two Primary efficacy end points were Progression Free Survival (PFS) from the start of Locally Ablative Therapy (PFS-L) and PFS from the start of KEYTRUDA® therapy (PFS-P). This study was powered for comparison with historical data on the first efficacy end point. Secondary outcomes included Overall Survival, Safety, and Quality of Life, as measured by the Functional Assessment of Cancer Therapy–Lung (FACT-L) instrument.

After a median follow-up of 23.2 months for surviving patients, the median PFS from the start of Locally Ablative Therapy (PFS-L) was 19.1 months, which was a statistically significant improvement from the historical median of 6.6 months (P=0.005). The median PFS from the start of KEYTRUDA® therapy (PFS-P) was 18.7 months. The mean Overall Survival rate at 12 months was 90.9% and at 24 months was 77.5%. The Progression Free Survival from the start of Locally Ablative Therapy (PFS-L) was not influenced by PD-L1 expression or CD8 T-cell tumor infiltration. Quality of Life as measured by the FACT-L scores at cycles 8 and 16 were not significantly different from FACT-L scores at baseline.

The authors concluded that KEYTRUDA® after Locally Ablative Therapy for oligometastatic NSCLC was associated with a clinically and statistically significant improvement in Progression Free Survival, compared with historical data, without a decrement in Quality of Life. They added that the Overall Survival data is encouraging but will require further follow up. Pembrolizumab After Completion of Locally Ablative Therapy for Oligometastatic Non–Small Cell Lung Cancer: A Phase 2 Trial. Bauml JM, Mick R, Ciunci C, et al. JAMA Oncol. Published online July 11, 2019. doi:10.1001/jamaoncol.2019.1449

ASCO/ASH Update on Erythropoiesis Stimulating Agents for Cancer-Associated Anemia

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SUMMARY: The American Society of Clinical Oncology (ASCO) along with American Society of Hematology (ASH) updated recommendations for use of Erythropoiesis Stimulating Agents (ESAs) in patients with cancer. The primary literature review included 15 meta-analyses of Randomized Clinical Trials and two Randomized Clinical Trials. These recommendations were developed using a systematic review of the literature from January, 2010, through May, 2018, and clinical experience.

Guideline question: When and how should Erythropoiesis Stimulating Agents (ESAs) be used to manage anemia in adults with cancer?

Target population: Adults with Cancer and Anemia.

Target audience: Oncologists, Hematologists, Oncology Nurses, Oncology Pharmacists, and other health care professionals who care for patients with cancer, and patients with cancer.

RECOMMENDATIONS

Clinical question 1: To reduce the need for RBC transfusions, should ESAs be offered to patients who have chemotherapy-associated anemia?

Recommendation 1.1. Depending on clinical circumstances, ESAs may be offered to patients with chemotherapy-associated anemia whose cancer treatment is not curative in intent and whose hemoglobin has declined to less than 10 g/dL. RBC transfusion is also an option, depending on the severity of the anemia or clinical circumstances

Recommendation 1.2. ESAs should not be offered to patients with chemotherapy-associated anemia whose cancer treatment is curative in intent

Clinical question 2: To reduce the need for RBC transfusions, should ESAs be offered to anemic patients with cancer who are not receiving concurrent myelosuppressive chemotherapy?

Recommendation 2.1. ESAs should not be offered to most patients with nonchemotherapy-associated anemia

Recommendation 2.2. ESAs may be offered to patients with lower risk MyeloDysplastic Syndromes and a serum Erythropoietin level 500 IU/L or less.

Clinical question 3: What special considerations apply to adult patients with nonmyeloid hematologic malignancies who are receiving concurrent myelosuppressive chemotherapy?

Recommendation 3. In patients with Myeloma, Non-Hodgkin Lymphoma, or Chronic Lymphocytic Leukemia, clinicians should observe the hematologic response to cancer treatment before considering an ESA. Particular caution should be exercised in the use of ESAs concomitant with treatment strategies and diseases where risk of thromboembolic complications is increased (see Recommendations 4 and 6). In all cases, blood transfusion is a treatment option that should be considered

Clinical question 4: What examinations and diagnostic tests should be performed before making a decision about using an ESA to identify patients who are likely to benefit from an ESA?

Recommendation 4. Before offering an ESA, clinicians should conduct an appropriate history, physical examination, and diagnostic tests to identify alternative causes of anemia aside from chemotherapy or an underlying hematopoietic malignancy. Such causes should be appropriately addressed before considering the use of ESAs. Suggested baseline investigations include thorough drug exposure history, peripheral blood smear review, analyses where indicated, for Iron, TIBC, Ferritin, Transferrin saturation, Folate, Vitamin B12, or Hemoglobinopathy screening, assessment of Reticulocyte count, occult blood loss and renal Insufficiency and baseline Erythropoietin level and TSH. Investigations may also include Direct Antiglobulin Testing (eg, Coombs test) for patients with Chronic Lymphocytic Leukemia, Non-Hodgkin Lymphoma, or a history of autoimmune disease.

Clinical question 5: Among adult patients who receive an ESA for chemotherapy-associated anemia, do Darbepoetin, Epoetin beta and alfa originator, and currently available biosimilars of Epoetin alfa differ with respect to safety or efficacy?

Recommendation 5. The Expert Panel considers Epoetin beta and alfa, Darbepoetin, and biosimilar Epoetin alfa to be equivalent with respect to effectiveness and safety

Clinical question 6: Do ESAs increase the risk of thromboembolism?

Recommendation 6. ESAs increase the risk of thromboembolism, and clinicians should carefully weigh the risks of thromboembolism and use caution and clinical judgment when considering use of these agents

Clinical question 7: Among adult patients who will receive an ESA for chemotherapy-associated anemia, what are recommendations for ESA dosing and dose modifications?

Recommendation 7. It is recommended that starting and modifying doses of ESAs follow FDA guidelines

Clinical question 8: Among adult patients who will receive an ESA for chemotherapy-associated anemia, what is the recommended target HgB level?

Recommendation 8. HgB may be increased to the lowest concentration needed to avoid or reduce the need for RBC transfusions, which may vary by patient and condition

Clinical question 9: Among adult patients with chemotherapy-associated anemia who do not respond to ESA therapy (less than 1 to 2 g/dL increase in HgB or no decrease in transfusion requirements), does continuation of ESA therapy beyond 6-8 weeks provide a benefit?

Recommendation 9. ESAs should be discontinued in patients who do not respond within 6-8 weeks. Patients who do not respond to ESA treatment should be reevaluated for underlying tumor progression, Iron deficiency, or other etiologies for anemia

Clinical question 10: Among adult patients with chemotherapy-associated anemia, does Iron supplementation concurrent with an ESA reduce transfusion requirements?

Recommendation 10. Iron replacement may be used to improve HgB response and reduce RBC transfusions for patients receiving ESA with or without iron deficiency. Baseline and periodic monitoring of Iron, total Iron-Binding Capacity, Transferrin saturation, or Frritin levels is recommended

Management of cancer-associated anemia with erythropoiesis-stimulating agents: ASCO/ASH clinical practice guideline update. Bohlius J, Bohlke K, Castelli R, et al. Blood Advances 2019;3:1197-1210

Dramatic Increase in ColoRectal Cancer Incidence among Young Adults

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 145,600 new cases of CRC will be diagnosed in the United States in 2019 and about 51,020 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Even though the incidence of Colorectal cancer (CRC) in the United States has been rapidly declining overall, primarily driven by screening, the incidence however has been increasing among adults younger than 50 years of age, according to data in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. Based on these findings, the American Cancer Society in 2018 updated its guidelines to include a “qualified recommendation” to begin CRC screening at the age of 45 yrs. The US Preventive Services Task Force (USPSTF) and other major US organizations have however not yet changed their recommendations. The increase in the incidence of CRC in young adults has been attributed to western style, high carbohydrate, high fat, low fiber diet, which can initiate inflammation and proliferation in the colonic mucosa within two weeks. Other lifestyle factors associated with CRC include obesity, high consumption of processed meat and alcohol, low levels of physical activity and cigarette smoking.

The authors in this publication performed a retrospective study examining the National Cancer Data Base (NCDB) registry to determine whether the trends seen through 2013, as published from SEER program had continued to worsen through 2015 (the most recent available data from the NCDB). The National Cancer Data Base is one of the largest cancer registries in the world and includes more than 70% of newly diagnosed cancer cases in the United States and more than 34 million historical records. The researchers also examined available demographic and socioeconomic factors to determine whether they were related to CRC in young adults and further compared clinical characteristics of CRC tumors among age groups, to determine whether younger patients had differences in clinical presentation. A total of 1,185,763 cases were included in the study of whom 130,165 patients were diagnosed at an age younger than 50 yrs and 1,055,598 patients were diagnosed at the age of 50 yrs or older. The proportion of patients diagnosed before the age of 50 yrs was chosen as the Primary endpoint, as most current guidelines recommend screening starting at an age of 50 yrs.

The proportion of the total number of patients diagnosed with CRC under the age of 50 yrs rose from 10% in 2004 to 12.2% in 2015 (P<0.0001). Younger adults presented with more advanced stage of disease (Stage III/IV) than those 50 yrs or older (51.6% versus 40.0% respectively). When racial and ethnic groups were stratified by sex, among men with a diagnosis of CRC before age 50, non‐Hispanic whites showed a proportional increase in diagnosis (P<0.0001), whereas among women, both Hispanic whites (P<0.05) and non‐Hispanic whites (P<0.001) had increases in the proportion of CRC diagnosed before age 50. The rates of CRC diagnosis in young adults increased over time, regardless of income level (P<0.001).The highest proportion of young adult CRC diagnoses occurred in the highest income group. The proportion of CRC cases diagnosed in younger individuals rose in urban areas (P<0.001), but not in rural areas.

It was concluded that based on this study, that the proportion of individuals diagnosed with CRC at an age younger than 50 years, has continued to increase over the past decade in the US. Younger adults also present with more advanced disease and Health Care Providers should be mindful of these data, when screening guidelines are discussed with patients. This study however does not capture oncogenic mutations or tumor laterality, which are known to affect the prognosis. The authors pointed out that the National Cancer Data Base which provided the patient information for this study currently captures laterality only for paired organs. Recent trends in the age at diagnosis of colorectal cancer in the US National Cancer Data Base, 2004‐2015. Virostko J, Capasso A, Yankeelov TE, et al. First published: 22 July 2019. https://doi.org/10.1002/cncr.32347

Platelet Antibody Testing in Patients with ITP

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SUMMARY: Immune Thrombocytopenic Purpura (ITP), also referred to as Idiopathic Thrombocytopenic Purpura, is an autoimmune disorder characterized by a low platelet count and an increased risk of bleeding. The diagnosis of ITP is established based on a platelet count of less than 100×109/L and exclusion of other causes of thrombocytopenia. Infection with the Hepatitis C Virus should be considered in all patients with acute ITP. The autoantibodies identified in patients with ITP are often directed against platelet glycoprotein IIb/IIIa, although antibodies directed against glycoprotein Ib/IX have also been detected. The glycoprotein complex IIb/IIIa plays an important role in platelet adhesion by binding fibrinogen, fibronectin, vitronectin, and von Willebrand factor. Glycoprotein Ib/IX is the main receptor for von Willebrand factor. Platelet autoantibodies destroy platelets resulting in persistent thrombocytopenia. Platelet autoantibodies have also been implicated in impaired platelet production by megakaryocytes.Series-of-Events-in-ITP

There are presently no reliable diagnostic tests or standard biomarkers to diagnose ITP. A response to immunosuppressive therapy remains the most useful diagnostic and therapeutic strategy in patients suspected with ITP. The utility of platelet autoantibody tests in ITP remains unclear, as the sensitivity and specificity of these tests is variable.

This study was conducted to understand the role of platelet autoantibody testing in patients with suspected ITP. Investigators extracted data from three online databases, Ovid Medline, PubMed, and Web of Science and conducted a systematic review and meta-analysis of 18 studies that included a total of 1170 patients with ITP and 225 controls without ITP. The analysis included studies that tested at least 20 or more ITP patients, for autoantibodies against the major platelet antigens GPIIb/IIIa or GPIb/IX, either directly on the platelet surface or indirectly in serum or plasma.

Pooled estimates for sensitivity and specificity were calculated and it was noted that the sensitivity and specificity of direct antiplatelet autoantibody testing for either antiglycoprotein IIb/IIIa or antiglycoprotein Ib/IX were 53% and 93%, respectively. For indirect testing, the pooled estimates for the sensitivity and specificity were 18% and 96%, respectively.

It was concluded from this study that platelet autoantibody testing in ITP patients has a high specificity but low sensitivity. A positive autoantibody test can help confirm a diagnosis of ITP, but a negative test does not rule out ITP. The sensitivity and specificity of platelet autoantibody testing in immune thrombocytopenia: a systematic review and meta-analysis of a diagnostic test. Vrbensky JR, Moore JE, Arnold DM, et al. J Thromb Haemost. 2019;17:787-794

Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. About 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. Approximately 50% of all breast cancers are Estrogen Receptor (ER) positive, HER2-negative, axillary node-negative tumors. Patients with early stage breast cancer often receive adjuvant chemotherapy. The Oncotype DX breast cancer assay, is a multigene genomic test that analyzes the activity of a group of 21 genes and is able to predict the risk of breast cancer recurrence and likelihood of benefit from systemic chemotherapy, following surgery, in women with early stage breast cancer. Chemotherapy recommendations for Hormone Receptor positive, HER negative, early stage breast cancer patients, are often made based on tumor size, grade, ImmunoHistoChemical (IHC) markers such as Ki-67, nodal status and Oncotype DX Recurrence Score (RS) assay.

Oncotype Dx assay categorizes patients on the basis of Recurrence Scores into Low risk (less than 18), Intermediate risk (18-30), and High risk (31 or more). It has been unclear whether patients in the Intermediate risk group benefited from the addition of chemotherapy to endocrine therapy. TAILORx was specifically designed to address this question and provide a very definitive answer. In this study, the Intermediate risk Recurrent Score (18-30) was changed to 11-25, to account for exclusion of higher-risk patients with HER2-positive disease and to minimize the potential for under treatment.

TAILORx ((Trial Assigning Individualized Options for Treatment) is a phase III, randomized, prospective, non-inferiority trial, and is the largest breast cancer treatment trial ever conducted, and the first precision medicine trial ever done, according to the authors. In this study, 10,273 women, 18-75 years of age, with hormone receptor-positive, HER2-negative, axillary node-negative breast cancer were enrolled. Patients had tumors 1.1-5.0 cm in size (or 0.6-1.0 cm and intermediate/high grade). Patients were divided into three groups based on their Recurrence Score. Women with a Low Recurrence Score of 0-10 received endocrine therapy alone and those with a High Recurrence Score of 26-100 received endocrine therapy in combination with standard adjuvant chemotherapy. Patient with Intermediate Recurrence Score of 11-25 (N=6711) were randomly assigned to receive endocrine therapy alone or endocrine therapy and adjuvant chemotherapy. Patients were followed up for 9 years. The Primary endpoint was invasive Disease Free Survival, defined as recurrence of cancer in the breast, regional lymph nodes, and/or distant organs, a second primary cancer in the opposite breast or another organ, or death from any cause. Results reported in June 2018 showed that while most women with an Intermediate Recurrence Score of 11-25 did not benefit from chemotherapy, women 50 years or younger with a Recurrence Score of 16-25 did indeed benefit from adjuvant chemotherapy.

The authors in this publication provided additional results from the same data set showing that adding “Clinical Risk” provides additional prognostic information. The investigators used a binary classification system from the MINDACT trial (Microarray in Node-Negative Disease May Avoid Chemotherapy), which used a 70-gene assay, and divided patients into high or low “Clinical Risk” based on tumor size and histologic grade. Clinical Risk was defined as low if the tumor was 3 cm or less in diameter and had a low histologic grade, 2 cm or less and had an intermediate histologic grade, or 1 cm or less in diameter and had a high grade. The Clinical Risk was defined as high if the low-risk criteria were not met. This additional reporting provided prognostic information about recurrent risk, but not benefits of chemotherapy particularly in the Intermediate Recurrence Score group.TAILORx-HR-Positive-HER-Negative-Early-Stage-Breast-Cancer

Among women who were 50 years of age or younger with a low Recurrence Score, the distant recurrence rate at 9 years was less than 5%, irrespective of Clinical Risk, and about 5% among those with an intermediate Recurrence Score with low Clinical Risk. However in sharp contrast, among women 50 years of age or younger, with high Clinical Risk and an intermediate Recurrence Score who had received endocrine therapy alone, the rate of distant recurrence at 9 years was 12.3%, compared with 6.1% among women who had received adjuvant chemotherapy. It is possible that younger women with a Recurrence Score of 11-25 and high Clinical Risk, receiving endocrine therapy alone, may have been undertreated with Tamoxifen, and the authors speculated that based on previously published studies, adding Ovarian Suppression and an Aromatase Inhibitor might result in risk reduction, equivalent to that observed using adjuvant chemotherapy.

The authors concluded that these new findings complement the original, definitive TAILORx conclusion and integration of genomic (Recurrence Score) and Clinical Risk may provide a more accurate estimate of prognosis for individual patients, than could be provided by either the genomic or clinical information alone. They added that this Clinical Risk stratification facilitates more refined estimates of absolute chemotherapy benefit for women 50 years of age or younger, with a Recurrence Score 16-25. Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer. Sparano JA, Gray RJ, Ravdin PM, et al. N Engl J Med 2019;380:2395-2405

Vitiligo Associated with Reduced Risk of Internal Malignancies

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SUMMARY: Vitiligo is a common acquired skin disorder affecting 1% of the population worldwide. Vitiligo is generally considered to be an autoimmune disorder and is characterized by destruction of melanocytes resulting in patchy loss of skin pigmentation. CD8 positive T cells have been implicated in the progression of Vitiligo. Approximately 15-25% of individuals with Vitiligo are also affected by at least one other autoimmune disorder, such as autoimmune Thyroid disease, Rheumatoid arthritis, type 1 Diabetes, Psoriasis, Pernicious anemia, Addison disease, or Systemic Lupus Erythematosus.

There is epidemiologic evidence demonstrating reduced risks of both Melanoma and non-Melanoma skin cancers (NMSCs) in patients with Vitiligo, suggesting that Vitiligo-associated autoimmunity exerts immune surveillance on skin cells other than melanocytes. Further, it has been shown that the occurrence of de novo Vitiligo following treatment with Immune Checkpoint Inhibitors may be a surrogate marker for improved survival in patients with advanced Melanoma. This suggests that increased T-cell activity following blockade of immune checkpoints, targets cancer cells as well as melanocytes in the skin.

The benefit of increased T-cell activity on cancers of internal organs in patients with Vitiligo, however has been unclear. In this publication, the authors evaluated whether autoreactive T-cell responses to melanocytes in patients with Vitiligo would affect tumor immunosurveillance in different internal organs.

We conducted a nationwide population-based cohort study to explore the risk of internal malignancies in patients with Vitiligo using the 10-year Korean National Health Insurance (NHI) claims database from 2007-2016. This study included 101,078 patients with Vitiligo and 202,156 controls without Vitiligo. Patients were 20 years or older with Vitiligo and had at least two contacts with a physician. The authors examined the overall risk for the development of internal malignancies and organ-specific cancer risks in each group.

It was noted that after the analysis was adjusted for age, sex, and comorbidities, the overall risk of internal malignancies was significantly lower in patients with Vitiligo than in controls (HR=0.86; P<0.001). This risk reduction was more so in men than in women and younger patients 20-30 yrs old with Vitiligo, had notably reduced risk than patients 40 yrs or older. With regards to organ-specific malignancies, patients with Vitiligo had a remarkably decreased risk of cancer in the Colon and Rectum (HR=0.62; P<0.001), Ovary (HR=0.62; P<0.001), and Lung (HR=0.75; P<0.001).

It was concluded that Vitiligo was associated with a reduced risk of internal malignancies overall. The authors from the findings of this study postulated that autoimmune diseases, including Vitiligo, may provide immune surveillance for the development of cancer beyond the targeted organ. Markedly Reduced Risk of Internal Malignancies in Patients With Vitiligo: A Nationwide Population-Based Cohort Study. Bae JM, Chung KY, Yun SJ, et al. J Clin Oncol 2019;37:903-911

Low Provider Knowledge Associated with Less Lung Cancer Screening

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2019, about 228,150 new cases of lung cancer will be diagnosed and 142,670 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. In the National Lung Screening Trial (NLST) with Low Dose CT (LDCT) screening for lung cancer, there was a 20% reduction in mortality. Following the publication of the results of NLST and NCCN issued guideline in 2011, the United States Preventive Services Task Force (USPSTF) recommended Lung Cancer screening with Low Dose CT scan in high risk patients. CMS in 2015 determined that there was sufficient evidence to reimburse for this preventive service.

Despite the evidence and recommendation along with supportive public policies, screening with LDCT has not been adequately implemented in the US healthcare system. (A low-dose CT scan will typically deliver 1-4 millisieverts of radiation exposure, whereas a conventional CT scan typically delivers between 5-20 millisieverts).Health Care Providers play a key role because LDCT is currently the only cancer screening modality required by CMS to have a shared decision-making conversation with the patient for reimbursement, making it crucial for providers to have knowledge of the screening recommendations, CMS coverage criteria, and evidence for screening. Low Health Care Provider knowledge of the Lung Cancer Screening (LCS) guidelines represents a potential barrier to implementation.

The authors in this study tested the hypothesis that low provider knowledge of Lung Cancer Screening guidelines is associated with less provider-reported screening with LDCT. The researchers from February thru May 2017 surveyed/invited 625 providers who routinely perform health screenings or care for patients at high risk of lung cancer, out of whom responses from 378 providers were analyzed. Health Care Providers were emailed internet-based questionnaire and participating providers included those who practiced general Internal Medicine/Family Medicine, Pulmonology, Hematology/Oncology, and Gynecology, within an academic medical center (Vanderbilt University Medical Center [VUMC]) and its affiliated Veterans Health Administration (VHA), including hospital-based and community-based practices. A medicine Grand Rounds at VUMC focused on Lung Cancer Screening (LCS) prior to this survey. Eligible providers included Attending physicians, Physicians in training, Physician Assistants, and Nurse Practitioners, who reported providing healthcare services to patients aged more than 50 in the year before the study. The questionnaire was terminated if respondents did not meet these criteria. Approximately 47% were Attending physicians, 43% were Physicians in training and 10% were Nurse Practitioners/Physician Assistants. Questionnaire Content included six multiple-choice items based on the USPSTF and CMS coverage criteria for Lung Cancer Screening. They included the following:

1) Initial age of screening eligibility (correct answer: 55 years)

2) Upper age limit at which a patient is no longer eligible for screening (correct answer: either 77 or 80 years)

3) Minimum smoking exposure (correct answer: 30 pack-years)

4) Smoking status (correct answer: current and former smokers)

5) Screening frequency (correct answer: yearly)

6) Screening for patients who were not surgical candidates (correct answer: no)

High LCS knowledge was defined as correctly identifying 3 major criteria to identify screening candidates: initial age of screening eligibility, minimum smoking exposure, and smoking status. Low LCS knowledge was defined as not correctly identifying these 3 criteria. The Primary outcome was self-reported order/referral of LDCT within the past year. Secondary outcomes were self-reported ordering of non-recommended LCS tests such as chest X Ray and sputum cytology.

On analysis it was noted that 59% of the providers reported ordering/referring for LDCT within the past year. Overall 62% of the provider’s demonstrated low LCS knowledge and the odds of ordering/referring for LDCT were 76% lower for providers with low LCS knowledge than for those with high LCS knowledge. Providers with low LCS knowledge had a 2.7 higher odds of ordering a screening chest radiograph, than providers with high LCS knowledge. The ordering/referring rates for LDCT were highest among general Internal Medicine/Primary Care Providers (75.9%), followed by Pulmonologists (74.4%), Hematologists/Oncologists (39.7%), and Gynecologists (2.1%). After adjusting for other variables, all provider types were less likely than general Internists/Primary Care Providers to order/refer for LDCT.

It was concluded that results of this study suggests that the referring provider knowledge of LCS guidelines is low and providers with low guideline knowledge were less likely to order LDCT lung screening. The authors recommended that strategies to advance effective evidence-based LCS should incorporate provider education and healthcare system interventions, to facilitate the appropriate identification of candidates for Lung Cancer Screening. Low Provider Knowledge Is Associated With Less Evidence-Based Lung Cancer Screening. Lewis JA, Chen H, Weaver KE, et al. J Natl Compr Canc Netw 2019;17:339-346

Darolutamide in Nonmetastatic Castration-Resistant Prostate Cancer

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 174,650 new cases of Prostate cancer will be diagnosed in 2019 and 31,620 men will die of the disease. The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide). The median duration of response is approximately 1 year and majority of these patients progress to Castration Resistant Prostate Cancer (CRPC). The mechanism of resistance to Androgen Deprivation Therapy (ADT) include reactivation of Androgen Receptor signaling through persistent adrenal androgen production, modification of the biologic characteristics of Androgen Receptors, intratumoral testosterone production and parallel steroidogenic pathways. Progression to Castration Resistant Prostate Cancer (CRPC) often manifests itself with a rising PSA (Prostate Specific Antigen), and watchful waiting is recommended in men with non-metastatic CRPC. However, those with a rapidly rising PSA on ADT (doubling time of less than 8-10 months), are at significantly greater risk of developing metastases and death.MOA-of-Androgen-Receptor-Targeted-Agents

The Androgen-Receptor inhibitors ERLEADA® (Apalutamide) and XTANDI® (Enzalutamide) have recently been approved for the treatment of nonmetastatic CRPC. However, patients who may already be experiencing adverse effects from their ongoing ADT may experience additional toxicities from these agents. There is therefore an unmet need for therapies with improved safety and toxicity profiles.

Darolutamide is a nonsteroidal AR antagonist with a unique molecular structure that is distinct from other AR antagonists and exhibits tighter binding affinity to the AR than ERLEADA® and XTANDI®, resulting in strong androgen inhibitory activity. Darolutamide and its major metabolite are full antagonists and retain their activity against known AR mutations shown to enable resistance to first- and second-generation ADTs. Additionally, Darolutamide has low penetration of the blood-brain barrier and low binding affinity for Gamma AminoButyric Acid type A receptors, which in turn reduces the risk of CNS-related Adverse Events such as seizures, and results in less severe toxic effects than ERLEADA® and XTANDI®, in patients with CRPC. Darolutamide and its active metabolite have been shown to inhibit testosterone-induced translocation of AR to the nucleus, thus decreasing activation of genes required for the growth and survival of prostate tumor cells.

Based on the significant antitumor activity of Darolutamide in Phase I and II studies, as well as favorable side effect profile, the authors conducted a multinational, randomized, double-blind, placebo-controlled, Phase III trial (ARAMIS- Androgen Receptor Antagonizing Agent for Metastasis-free Survival), involving 1509 patients with nonmetastatic, Castration-Resistant Prostate Cancer (CRPC) and a Prostate Specific Antigen doubling time of 10 months or less and a baseline PSA level of at least 2 ng/ml. Patients were randomly assigned in a 2:1 ratio to receive Darolutamide 600 mg orally twice daily or placebo. Patients continued to receive ADT (Luteinizing Hormone Releasing Hormone agonist or antagonist) throughout the trial. The median patient age was 74 years, median time from initial diagnosis was 85 months and approximately 30% of patients were on a bone-sparing agent. The Primary end point was Metastasis-Free Survival, with the presence of metastasis determined by Independent Central Review of radiographic imaging, every 16 weeks. Secondary end points included Overall Survival, Time to pain progression, Time to first symptomatic skeletal event and Time to first cytotoxic chemotherapy. The median follow up was 17.9 months.

The median Metastasis-Free Survival was 40.4 months with Darolutamide, as compared with 18.4 months with placebo (Hazard Ratio for metastasis or death in the Darolutamide group=0.41; P<0.001). This treatment benefit with Darolutamide was consistently favorable across all prespecified subgroups, including in patients with PSA doubling times of 6 months or less or more than 6 months. Darolutamide was also associated with improved Overall Survival, with a lower risk of death (HR=0.71; P=0.045) and longer time to pain progression (40.3 months versus 25.4 months, HR=0.65; P<0.001), compared to the placebo group. The median time to PSA progression was 33.2 months with Darolutamide and 7.3 months with placebo (Hazard ratio for PSA progression or death=0.13; P<0.001). The time to first cytotoxic chemotherapy and time to first symptomatic skeletal event also favored Darolutamide. Adverse Events overall were reported by 83.2% of the patients who received Darolutamide and 76.9% of the patients who received placebo, and patient-reported quality of life was similar in the Darolutamide and placebo group.

It was concluded that among patients with nonmetastatic CRPC, Metastasis-Free Survival was significantly longer with Darolutamide compared with placebo, with similar incidence of Adverse Events and Quality of Life outcomes. Darolutamide in Nonmetastatic Castration-Resistant Prostate Cancer. Fizazi K, Shore N, Tammela TL, et al., for the ARAMIS Investigators. N Engl J Med 2019;380:1235-1246