Tag: General Medical Oncology & Hematology

SUMMARY: Platelets are often transfused preemptively to reduce the risk for spontaneous bleeding in patients who are thrombocytopenic following chemotherapy or hematopoietic stem cell transplantation. In the United States, a little over 2 million platelet units are transfused annually. The risks associated with platelet transfusion such as febrile and allergic reactions, Transfusion Related Acute Lung Injury and infections, have to be taken into consideration before transfusion is planned. Further, unlike other blood products, platelets must be stored at room temperature and this limits the platelet unit shelf life to only 5 days, to prevent the risk for bacterial growth during storage. This in turn is an additional burden to the hospital blood banks. The AABB (American Association of Blood Banks) commissioned and funded the development of platelet transfusion guidelines with the help of 21 experts from various specialties of medicine, after a systematic review of 17 randomized controlled trials and 53 observational studies. A platelet unit in this guideline refers to 1 apheresis platelet unit or a pool of 4-6 whole blood derived platelet concentrates, containing approximately 3- 4 x 10¹¹ platelets. Thrombocytopenia refers to a platelet count below the lower limit of the normal range used by the laboratory performing the count. Six recommendations were made for 4 different clinical settings.

Hospitalized Adult Patients with Therapy-Induced Hypoproliferative Thrombocytopenia

Recommendation 1: The AABB recommends that platelets should be transfused prophylactically to reduce the risk for spontaneous bleeding in hospitalized adult patients with therapy-induced hypoproliferative thrombocytopenia. The AABB recommends transfusing hospitalized adult patients with a platelet count of 10 × 10⁹ cells/L or less to reduce the risk for spontaneous bleeding. The AABB recommends transfusing up to a single apheresis unit or equivalent. Greater doses are not more effective, and lower doses equal to one half of a standard apheresis unit are equally effective.

Adult Patients Having Minor Invasive Procedures

Recommendation 2: The AABB suggests prophylactic platelet transfusion for patients having elective central venous catheter placement with a platelet count less than 20 × 10⁹ cells/L.

Recommendation 3: The AABB suggests prophylactic platelet transfusion for patients having elective diagnostic lumbar puncture with a platelet count less than 50 × 10⁹ cells/L.

Adult Patients Having Major Elective Non-neuraxial Surgery

Recommendation 4: The AABB suggests prophylactic platelet transfusion for patients having major elective non-neuraxial surgery with a platelet count less than 50 × 10⁹ cells/L.

Recommendation 5: The AABB recommends against routine prophylactic platelet transfusion for patients who are non-thrombocytopenic and have cardiac surgery with cardiopulmonary bypass. The AABB suggests platelet transfusion for patients having bypass who exhibit perioperative bleeding with thrombocytopenia and/or evidence of platelet dysfunction.

Adult Patients Receiving Antiplatelet Therapy Who Have Intracranial Hemorrhage (Traumatic or Spontaneous)

Recommendation 6: The AABB cannot recommend for or against platelet transfusion for patients receiving antiplatelet therapy who have intracranial hemorrhage (traumatic or spontaneous).

The authors acknowledge that the platelet transfusion threshold recommendations made by the various medical specialty societies, may be different, but the evidence based recommendations provided herein, will complement clinical judgment, as individualized decisions are made, to transfuse platelets. Kaufman RM, Djulbegovic B, Gernsheimer T, et al. Ann Intern Med. 2015;162:205-213.

SUMMARY: CHOOSING WISELY® is a quality improvement initiative led by the American Board of Internal Medicine Foundation in collaboration with leading medical societies in the United States such as the American Society of Hematology (ASH). This organization was established to improve quality of medical care, after it was noted that about 25% of the tests ordered at the time of hospital admission and 65% of the tests ordered on subsequent days were avoidable. Further, there is ample evidence to suggest that reducing unneeded investigations can decrease costs, increase patient satisfaction and quality of care. CHOOSING WISELY® has challenged medical societies to identify 5 tests, procedures or treatments, within each specialty's clinical domain, that are offered to patients, despite the lack of evidence demonstrating its benefit. The goal is to make positive changes in the actual delivery of patient care. The 2014 Task Force was comprised of 13 individuals representing a broad spectrum of hematologic expertise including malignant, benign, adult, and pediatric specialists. The five final recommendations of the 2014 ASH Choosing Wisely Campaign are summarized below. Practicing hematologists should give due consideration to these recommendations which are evidence based and cost effective.

ASH recommendation #1: In patients with a first VTE (Venous ThromboEmbolism) provoked by a major, transient VTE risk factor such as surgery, trauma, or an intravascular catheter, do not treat with an anticoagulant for more than 3 months. There is a low risk of VTE recurrence after three months in this setting and anticoagulation for VTE continued beyond three months may be associated with increased bleeding risk, particularly in the elderly and those with comorbidities. This recommendation is not applicable to patients with non-major, transient VTE risk factors such as travel-associated immobility, pregnancy or hormone use. Women who experience a first VTE during pregnancy should receive anticoagulation until at least six weeks post-partum, for a minimum total duration of three months or longer. VTEs occurring in the context of estrogen supplements are associated with a low recurrence rate following discontinuation of hormonal therapy/oral contraceptives and three months of anticoagulation may be adequate. However, the optimal duration of anticoagulation for VTEs provoked by hormones or by travel remains unclear and should be determined on a on a case-by-case basis.

ASH recommendation #2: Routine transfusion of PRBC for chronic anemia or uncomplicated pain crises in patients with sickle cell disease is not recommended as these patients who are predominantly African Americans, are at an especially higher risk for alloimmunization to minor blood group antigens, which can result in delayed-hemolytic transfusion reactions, as well as difficulty finding compatible blood when necessary. The baseline hemoglobin values range between 7 and 10g/dL in stable patients with severe sickle cell disease and these patients are often able to tolerate a 1-2g/dL decreases in their hemoglobin values following IV hydration. Further, data does not strongly support that episodic red cell transfusion reduces pain during acute vaso-occlusive crises. Moreover, iron overload from repeated transfusions can cause significant morbidity and mortality in patients with sickle cell disease.

ASH recommendation #3: Unlike in other lymphoproliferative diseases, routine surveillance CT scans are not recommended in patients with asymptomatic, early stage chronic lymphocytic leukemia (CLL). Both the Rai and Binet staging systems are based on physical exam findings and complete blood counts and prognosis can be assessed with molecular mutational analyses. CT scans are therefore not necessary and can be potentially harmful, by exposing patients to radiation and may also trigger additional workup to evaluate incidental findings (Cascade effect), that may not be of importance.

ASH recommendation #4: Do not test or treat for suspected Heparin-Induced Thrombocytopenia (HIT) in patients with a Low pretest probability of HIT. The 4Ts is a pretest scoring system for HIT and incorporates 4 components of HIT which include magnitude of thrombocytopenia, timing of thrombocytopenia with respect to heparin exposure, thrombosis or other sequelae of HIT and likelihood of other causes of thrombocytopenia. The 4Ts score is the sum of the values for each of the 4 categories. A score of 0-3 is classified as Low, 4-5 as Intermediate and 6-8 as High pretest probability for HIT. The negative predictive value of a Low 4T’s score is close to 100% in adults. Further, Enzyme ImmunoAssays (EIA) for HIT have a high false positive rate and a positive EIA HIT test results in a patient with a Low 4T’s score is much more likely to represent a false positive value than true positive. Confirmatory testing with serotonin release assays are not easily available and can be expensive. Misdiagnosing HIT can harm patients by denying them a heparin preparation in the future and the use of alternative, expensive anticoagulants such as Argatroban in these thrombocytopenic patients can be associated with a higher risk of bleeding. For these reasons, testing for HIT is only cost-effective when the pre-test probability of HIT is greater than 8%, which corresponds to an Intermediate or High 4T’s score

ASH recommendation #5: Do not treat patients with Immune Thrombocytopenic Purpura (ITP) in the absence of bleeding or a very low platelet count. ITP is often a temporary condition in children and resolves without treatment and treatment is not recommended in childhood ITP unless there is bleeding or risk factors for bleeding. ITP in adults is usually a chronic disease with remissions and exacerbations and patients with a platelet count of 30,000/microL or more and with no bleeding, can be observed without intervention. Steroids can impair glucose metabolism, increase infection risk, cause adrenal suppression and in children can cause growth impairment. Splenectomy is associated with perioperative risks and small risk of life threatening infections. Rituximab can cause Hepatitis B reactivation and TPO receptor agonists are only cost-effective in the setting of severe ITP, refractory to other treatment interventions.

Hicks LK, Bering H, Carson KR, et al. Prepublished online December 3, 2014; doi:10.1182/blood-2014-09-599399

SUMMARY: Radiation Therapy involves the use of X-Rays, gamma rays and charged particles for cancer treatment. External-beam radiation therapy is most often delivered using a linear accelerator in the form of Photon beams (either x-rays or gamma rays). Photons have no mass and are packets of energy of an electromagnetic wave. Electrons and Protons are charged particles and Electrons are considered light particles whereas Protons are considered heavy particles. Electron beams are used to irradiate skin and superficial tumors, as they are unable to penetrate deep into the tissues. The different types of external beam radiation treatments include 3-Dimensional Conformal Radiation Therapy (3D-CRT) meant to deliver radiation to very precisely shaped target areas, IMRT or Intensity Modulated Radiation Therapy which allows different areas of a tumor or nearby tissues to receive different doses of radiation, Image Guided Radiation Therapy (IGRT) which allows reduction in the planned volume of tissue to be treated as changes in a tumor size are noted during treatment, Stereotactic RadioSurgery (SRS) which can deliver one or more high doses of radiation to a small tumor, Stereotactic Body Radiation Therapy (SBRT) or CYBERKNIFE® which is similar to SRS but also takes the normal motion of the body into account while treating malignancies involving the lung and liver and Proton Beam therapy. Proton beams unlike Photons, enter the skin and travel through the tissues and deposit much of their energy at the end of their path (known as the Bragg peak) and deposit less energy along the way. This is unlike Photons which deposit energy all along the path through the tissues and the deposited dose decreases with increasing depth. As a result, with Proton beam therapy, normal tissues are exposed to less radiation compared with Photons. Despite this advantage, tissue heterogeneity such as organ motion, tumor volume changes during treatment can have a significant negative impact on target coverage for Proton beam therapy and can result in damage to the surrounding tissues and potential complications. The authors in this review discussed the clinical applications of Proton therapy in Adult and Pediatric malignancies. Pediatric patients with malignancies have greater benefit with Proton beam therapy, with a statistically significant lower risk of secondary malignancies and less damage to the developing tissues and organs, compared to Photon therapy (External Beam Radiation Therapy). This clinical benefit may be less so in adult malignancies in spite of superior dosimetry, compared to external beam radiation, as adults are less prone to secondary malignancies compared to children.

ADULT MALIGNANCIES

Prostate Cancer: Majority of the patients receiving Proton beam treatment in the United States have prostate cancer. Several randomized trials have concluded that higher radiation dose to the prostate gland leads to better tumor control. Proton beam therapy may deliver this promise, but with associated toxicities, in particular rectal bleeding. This is by virtue of the anatomy of the prostate gland which is deep in the pelvis. Outcomes and patient reported side effects were similar when men with prostate cancer were treated with similar doses of radiation using either Proton beam therapy or External beam radiation therapy. The American Society of Therapeutic Radiology and Oncology (ASTRO) has recommended that Proton beam therapy for patients with prostate cancer should be offered in the context of a clinical trial or registry, as there is not enough evidence suggesting clinical benefit in this patient population.

Breast Cancer: Proton beam therapy may be of value in select situations, such as patients with bilateral implants after mastectomy and in clinical scenarios where cardiac or pulmonary risks with Photon therapy are not acceptable. This is because of a significant reduction in the radiation doses to the heart, lung and contralateral breast with Proton therapy compared to Photon therapy.

Lung Cancer: Proton beam therapy for NSCLC (Non Small Cell Lung Cancer) is in the early stages of evaluation and has the advantage of reduced radiation to the normal lung and heart. This may be relevant in patients with inoperable early stage NSCLC with poor lung function, prior chest irradiation or in those with multifocal lung cancers requiring more than one treatment course. Proton therapy can be of significant value in patients with Stage IIIA NSCLC who in addition to chemoradiation may be candidates for pneumonectomy, thus sparing the contralateral lung from radiation related toxicities.

Head and Neck Cancers: Proton therapy may be of value in nasopharyngeal carcinoma and malignancies involving the oropharynx and paranasal sinuses. Proton therapy limits the radiation dose to the brain stem, optic structures, mandible and salivary glands, decreasing the risk of xerostomia and osteoradionecrosis of the mandible.

GI Malignancies: Proton beam therapy is the preferable treatment for hepatocellular carcinoma in patients with Child-Pugh class B and class C cirrhosis, as it is able to spare more liver tissue from radiation.

Brain Tumors: Meningiomas are ideal tumors for Proton beam therapy, with less cerebral adverse events and therefore has a positive impact on quality of life of patients. Clinical trials are underway to test this hypothesis.

PEDIATRIC TUMORS

Medulloblastoma- CranioSpinal Irradiation: There is a significant long term advantage with Proton CranioSpinal Irradiation compared to conventional or IMRT photon CSI. There is a 6-12 times lower risk of secondary malignancies due to lower radiation doses to normal tissues. This is more relevant because craniospinal axis irradiation results in the most exposure of a childs tissue to radiation.

Rhabdomyosarcoma: This is the most common soft tissue sarcoma in children arising in the head and neck region and Proton therapy can significantly reduce the mean doses to the retina, optic nerve, parotid and cochlea.

Ependymoma, Craniopharyngioma, Retinoblastoma and Glioma: Proton therapy for these tumors has been associated with lower acute and long term toxicities as well lower risk of secondary malignancies.

The authors concluded that the most benefit for Proton beam therapy is in pediatric malignancies, no significant benefit in skin cancer and marginal benefit in adult lung and prostate cancer. With ongoing advances in the delivery of Proton therapy such as Intensity Modulated Proton Therapy (IMPT) and other expensive therapeutic interventions, economics will take precedence, until and unless a clear clinical benefit is proven. Mitin T and Zietman AL. J Clin Oncol 2014;32:2855-2863

SUMMARY:Carcinoma of Unknown Primary Site (CUPS) is a heterogeneous clinical pathologic syndrome for which the anatomical site of origin of the primary tumor is clinically undetectable. CUPS accounts for approximately 2% of all advanced malignances annually. The American Cancer Society estimates that about 31,430 cases of Cancer of Unknown Primary site will be diagnosed in 2014 in the United States. The pathobiology of tumors from unknown primary sites is similar to those with detectable primary tumors and therefore may respond to therapies similar to those with easily detectable primary tumors. Historically, the treatment approach for patients with CUPS included broad spectrum empiric chemotherapy. Histological evaluation of the biopsy tissue alone has been the standard practice for decades. With the availability of gene expression profiling assays and advances in ImmunoHistoChemistry staining as well as imaging technology, predicting the tissue of origin of the primary tumor and tailoring therapy accordingly, has improved overall survival in this patient population. Evaluation of a patient with CUPS starts with gathering and incorporating medical information which includes the patient’s gender, medical history, clinical findings and sites of metastases. A CT scan of the chest, abdomen and pelvis with IV and oral contrast is recommended, although PET (Positron Emission Tomography) or an MRI can be performed in those with renal insufficiency or iodine allergy. PET scan is recommended for those with cervical lymphadenopathy with squamous histology, to help determine the extent of the disease and treatment planning for radiation. PET imaging is also helpful for patients with solitary metastases before locoregional therapies are planned, as well as assessing response in patients with predominantly bone only disease. In women presenting with isolated axillary lymphadenopathy, adenocarcinoma histology, negative mammograms and ultrasound, MRI of the breasts is indicated. With the exception of those patients with CUPS who present with cervical lymphadenopathy, diagnostic procedures such as bronchoscopy, EGD and colonoscopy are not recommended in asymptomatic patients. Tumor markers in general do not have diagnostic value in patients with CUPS although they could be utilized to monitor response to treatment. However, PSA when elevated in a male with adenocarcinoma and osteoblastic metastases, is suggestive of a prostate primary. Similarly an elevated Beta HCG and AFP in a patient with undifferentiated or poorly differentiated carcinoma, is suggestive of an extragonadal germ cell tumor and an elevated AFP is also helpful in making a diagnosis of Hepatoma. Approximately 60% of the patients with CUPS have well or moderately differentiated adenocarcinoma on light microscopy, 30% have poorly differentiated carcinoma or adenocarcinoma, 5% have poorly differentiated or undifferentiated malignancy and 5% have squamous cell carcinoma. Following histological evaluation on light microscopy, the biopsy specimen is further tested using ImmunoHistoChemical stains, using peroxidase labeled antibodies against tumor specific antigens, taking advantage of the similarities in the tumor profiles of primary and metastatic malignancies. After delineating a tumor as carcinoma, lymphoma, sarcoma or melanoma, additional IHC testing can help identify tumors such as a lung primary (postive Thyroid Transcription Factor 1-TTF1and positive CytoKeratin 7- CK7), lower gastrointestinal cancers (positive CK20, positive CDX2 and negative CK7) or a breast primary (positive CK7 and positive Mammaglobin). Tissue-of-Origin molecular profiling is based on the principle that in patients with CUPS, molecular signatures of metastatic tumors are similar to their primary tumor. Tissue-of-Origin molecular profiling is performed using tools such as DNA microarray, quantitative real time polymerase chain reaction assay (rt-PCR) or assays based on messenger RNA (mRNA) or microRNA. These tests are cost-effective and 70% – 90% accurate. This study can be performed on formalin-fixed samples as well as samples from fine needle aspiration. Even though platinum based chemotherapy has been the default regimen for patients with CUPS, histological evaluation of biopsy tissue by light microscopy, IHC testing and molecular profiling assay may complement each other and help guide the Health Care Provider to select site specific therapy. The survival outcomes of CUPS patients with a Tissue-of-Origin molecularly diagnosed profile are comparable to those with similar type advanced cancer with a known primary. The authors concluded that with additional molecular insights into tumor biology and availability of newer therapeutic agents, patients with CUPS and known primary tumors may eventually be treated alike. Varadhachary, GR and Raber, MN. N Engl J Med 2014; 371:757-765

SUMMARY: According to the American Cancer Society, tobacco use is responsible for nearly 1 in 5 deaths in the United States and accounts for at least 30% of all cancer deaths. Smokeless tobacco products are a major source of cancer causing nitrosamines and increase the risk of developing cancer of the oropharynx, esophagus, and pancreas. Cigarette smoke contains more than 7,000 chemicals, many of which are toxic and some linked to cancer. E-cigarettes were first developed in China and were introduced to the U.S. market in 2007. When a smoker inhales through the mouth piece of an E-cigarette, the air flow triggers a sensor that switches on a small lithium battery powered heater, which in turn vaporizes liquid nicotine along with PolyEthylene Glycol (PEG) present in a small cartridge. The PEG vapor looks like smoke. The potent liquid form of nicotine extracted from tobacco is tinctured with fragrant flavors such as chocolate, cherry and bubble gum, coloring substances, as well other chemicals and these e-liquids are powerful neurotoxins. With the rapid growth of the E-cigarette industry and the evidence of potential dangers and risk to public health, particularly children, experts from the world's leading lung organizations were compelled to release a position statement on electronic cigarettes, specifically focusing on their potential adverse effects on human health and calling on government organizations to ban or restrict the use of E-cigarettes, until their impact on health is better understood. With epidemiological data demonstrating that nicotine use is a gateway to the use of cocaine and marijuana and subsequent lifelong addiction, the Forum of International Respiratory Societies (FIRS), an organization composed of the world's leading international respiratory societies including American Thoracic Society (ATS) and the American College of Chest Physicians (ACCP), made the following recommendations. The position statement of the Forum of International Respiratory Societies (FIRS) on electronic nicotine delivery devices includes the following:

• The safety of electronic cigarettes has not been adequately demonstrated.

• The addictive power of nicotine and its untoward effects should not be underestimated.

• The potential benefits of electronic nicotine delivery devices, including harm reduction and as an aid to smoking cessation, have not been well studied.

• Potential benefits to an individual smoker should be weighed against harm to the population of increased social acceptability of smoking and use of nicotine.

• Health and safety claims regarding electronic nicotine delivery devices should be subject to evidentiary review.

• Adverse health effects for third parties exposed to the emissions of electronic cigarettes cannot be excluded.

• Electronic nicotine delivery devices should be restricted or banned, at least until more information about their safety is available.

• If electronic nicotine delivery devices are permitted, they should be regulated as medicines and subject to the same evidentiary review of other medicines.

• If electronic nicotine delivery devices are not regulated as medicines, they should be regulated as tobacco products.

• Research, supported by sources other than the tobacco or electronic cigarette industry, should be carried out to determine the impact of electronic nicotine delivery devices on health in a wide variety of settings.

• The use and population effects of electronic nicotine delivery devices should be monitored.

• All information derived from this research should be conveyed to the public in a clear manner.

Schraufnagel DE, Blasi F, Drummond MB, et al. on behalf of the Forum of International Respiratory Societies. Am J Respir Crit Care Med. First published online 09 Jul 2014 as DOI: 10.1164/rccm.201407-1198PP