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Continue NCCN Clinical Practice Guidelines in Oncology™ Cancer- and Chemotherapy- Induced Anemia V.2.2010 www.nccn.org Version 2.2010, 08/17/09 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. Practice Guidelines in Oncology – v.2.2010 Guidelines Index Anemia Table of Contents Discussion, ReferencesCancer- and Chemotherapy-Induced AnemiaNCCN ® NCCN Cancer- and Chemotherapy-Induced Anemia Panel Members George M. Rodgers, III, MD, PhD/Chair Huntsman Cancer Institute at the University of Utah Pamela Sue Becker, MD, PhD Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance Charles L. Bennett, MD, PhD, MPP Robert H. Lurie Comprehensive Cancer Center of Northwestern University Peter F. Coccia, MD UNMC Eppley Cancer Center at The Nebraska Medical Center ‡ ‡ Þ ‡ † ‡ David Cella, PhD Robert H. Lurie Comprehensive Cancer Center of Northwestern University Asher Chanan-Khan, MD Roswell Park Cancer Institute Charles Cleeland, PhD The University of Texas M. D. Anderson Cancer Center � � € Joseph Rosenthal, MD City of Hope ‡ ‡ ‡ † ‡ € Comprehensive Cancer Center Rowena N. Schwartz, PharmD The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Richard S. Stein, MD Vanderbilt-Ingram Cancer Center Ravi Vij, MD Siteman Cancer Center at Barnes- Jewish Hospital and Washington University School of Medicine Gordana Vlahovic, MD Duke Comprehensive Cancer Center Alva B. Weir III, MD St. Jude Children's Research Hospital/University of Tennessee Cancer Institute б � * ‡ Hematology/Hematology oncology † Medical oncology Bone marrow transplantation Þ Internal medicine # Nursing Pharmacotherapy � Psychiatry/Psychology € Pediatric oncology * Writing Committee Member � б Benjamin Djulbegovic, MD, PhD H. Lee Moffitt Cancer Center & Research Institute Jeffrey A. Gilreath, PharmD Huntsman Cancer Institute at the University of Utah Eric H. Kraut, MD Weei-Chin Lin, MD, PhD University of Alabama at Birmingham Comprehensive Cancer Center Ursula Matulonis, MD Dana-Farber/Brigham and Women’s Cancer Center Michael Millenson, MD Fox Chase Cancer Center Denise Reinke, APRN, BC, AOCN # University of Michigan Comprehensive Cancer Center † ‡ ‡ † ‡ † ‡ Þ � б The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute Continue * NCCN Guidelines Panel Disclosures Version 2.2010, 08/17/09 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. Practice Guidelines in Oncology – v.2.2010 Guidelines Index Anemia Table of Contents Discussion, ReferencesCancer- and Chemotherapy-Induced AnemiaNCCN ® Table of Contents NCCN Cancer- and Chemotherapy-Induced Anemia Panel Members Guidelines Index Print the Anemia Guideline Summary of the Guidelines Updates Screening Evaluation and Risk Assessment (ANEM-1 Cancer-Related Anemia (Non-Treatment Related) (ANEM-2 Symptomatic Treatment and Evaluation (ANEM-6 Comparison of Risks and Benefits of ESA Use Versus Red Blood Cell Transfusion � ) ) ) � � � � Myelosuppressive Chemotherapy-Induced Anemia (ANEM-3 Symptom Assessment (ANEM-3 Evaluation for Symptomatic Anemia Risk (ANEM-4 ) ) ) � � � Asymptomatic Treatment and Evaluation (ANEM-5 Response Assessment (ANEM-7 ) ) Erythropoietic Therapy - Dosing and Titration (ANEM-A (ANEM-B Parenteral Iron Preparations (ANEM-C ) ) ) These guidelines are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. These guidelines are copyrighted by National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2009 For help using these documents, please click here Discussion References Clinical Trials: Categories of Evidence and Consensus: NCCN The believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. To find clinical trials online at NCCN member institutions, All recommendations are Category 2A unless otherwise specified. See NCCN click here: nccn.org/clinical_trials/physician.html NCCN Categories of Evidence and Consensus Version 2.2010, 08/17/09 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. Practice Guidelines in Oncology – v.2.2010 Guidelines Index Anemia Table of Contents Discussion, ReferencesCancer- and Chemotherapy-Induced AnemiaNCCN ® UPDATES Summary of the Guidelines Updates ANEM-3 ANEM-5 ANEM-6 ANEM-A 3 of 5 ANEM-B 1 of 2 ANEM-C 2 of 3 � � � For cancer treatment goals, “curative” was clarified as “chemotherapy with curative intent” and “non-curative” was clarified as “chemotherapy with non-curative intent”. The following footnotes were added to the page. Footnote ‘f’: Footnote ‘j’: “Recommendations for administering parenteral iron products” table was revised: For all preparations, the following statement was added, “Examples of adverse events associated with FDA approved doses of parenteral iron preparations include: hypotension, hypertension, nausea, vomiting, diarrhea, pain, fever, dyspnea, pruritis, headaches, and dizziness.” Iron dextran, dosage was clarified as “Total dose infusion given over several hours” and a corresponding statement “Dose = 0.0442 (Desired Hgb - Observed Hgb) X LBW + (0.26X LBW ) LBW = Lean Body Weight. If dose exceeds 1000 mg, remaining dose may be given after 4 wks if inadequate hemoglobin response” was added. Ferric gluconate, dose was clarified as “Maximum dose = 250 mg per infusion” Iron sucrose, dose was clarified as “Maximum dose = 300-400 mg per infusion” � � � � � � An example of therapy with curative intent includes adjuvant chemotherapy. Fatigue (FACT-F) and Anemia (FACT-An) subscales of the Functional Assessment of Cancer Therapy (FACT) and Brief Fatigue Inventory (BFI) are examples of standardized measures for assessing patient-reported fatigue. For asymptomatic, risk factors present for development of symptomatic anemia: treatment recommendation for “no iron deficiency” was added. For absolute iron deficiency, “after 4 weeks” was added to “hemoglobin increases” and “hemoglobin does not increase”. For functional iron deficiency, ferritin level was changed from “< 300 ng/mL” to “ ” and “ IV iron supplementation” was added to the “erythropoietic therapy” option. Symptomatic, a statement “Ensure iron studies (iron panel- serum iron, total iron binding capacity, serum ferritin) do not indicate absolute iron deficiency” was added to “consider erythropoietic therapy” treatment option for clarification. Cancer Patient Survival Bullet 1 was modified by adding, “One analysis in patients with cancer not receiving active therapy found decreased survival in ESA treated patients.” Bullet 2, two new references of meta-analysis on survival confirming an increased mortality risk with the use of ESAs were added. Risks of the use of ESA in the cancer setting: “increased” was added to “thrombotic events”. Benefits of the use of ESA in the cancer setting: “avoidance of red blood cell transfusion” was modified as “transfusion avoidance” Risks of the use of red blood cell transfusion: “febrile and non- hemolytic” were added as examples of transfusion reactions. � � � � � � � � � 800 ng/mL Consider � � Changes in the 1.2010 version of the Cancer- and Chemotherapy-Induced Anemia Guidelines from the 3.2009 version include: Changes in the 2.2010 version of the Cancer- and Chemotherapy-Induced Anemia Guidelines from the 1.2010 version include: ANEM-3 � Footnote ‘g’ was revised as follows: “For patients receiving chemotherapy for breast, advanced head and neck, lymphoid, non-small cell lung, and cervical cancers with non-curative intent, ESAs should ” be used with caution. Some studies have demonstrated an increase in mortality for patients with these tumor types who are treated with ESAs. See manuscript (MS-6) for detailed discussion and references. Version 2.2010, 08/17/09 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. Practice Guidelines in Oncology – v.2.2010 Guidelines Index Anemia Table of Contents Discussion, ReferencesCancer- and Chemotherapy-Induced AnemiaNCCN ® Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. aThe NCCN Cancer- and Chemotherapy-Induced Anemia Guidelines were formulated in reference to adult patients. b c d Transplant-related anemia is not included. The following studies should have been completed if clinically indicated: reticulocyte count, iron studies, B12/folate, stool guaiac, LDH, fractionated bilirubin, bone marrow examination, direct Coombs test, Hb electrophoresis, creatinine and/or creatinine clearance. There is no clear evidence that erythropoietin levels are predictive of response. Objective physical symptoms may include peripheral edema, sustained tachycardia, and tachypnea and other subjective physical symptoms may include chest pain, dyspnea on exertion, orthostatic lightheadedness/near syncope or syncope, and fatigue. PRESENTATIONa,b Hemoglobin (Hb) < 11 g/dL Myelosuppressive chemotherapy-induced anemia Anemia related to other causes: � � � � � � � Bleeding Hemolysis Nutritional deficiency Hereditary Renal dysfunction Iron deficiency Radiation therapy alone Treat as indicated � � CBC with indices Review of peripheral smear, as clinically indicated SCREENING EVALUATIONc ANEM-1 Cancer-related anemia (non- treatment related) See ANEM-2 RISK ASSESSMENT � � � � Acuity Severity Mild (Hb 10-11 g/dL) Moderate (Hb 8-10 g/dL) Severe (Hb < 8 g/dL) Symptoms-physiological Cardiac symptoms Pulmonary symptoms Comorbidities Cardiac history/decompensation Chronic pulmonary disease Cerebral vascular disease � � � � � � � � d See Symptom Assessment (ANEM-3) Version 2.2010, 08/17/09 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. Practice Guidelines in Oncology – v.2.2010 Guidelines Index Anemia Table of Contents Discussion, ReferencesCancer- and Chemotherapy-Induced AnemiaNCCN ® Inadequate data to make recommendations: encourage enrollment in clinical trials Cancer-related anemiae (non- treatment related) Myelodysplastic syndromes See NCCN Myelodysplastic Syndromes Guidelines Solid tumors Hematologic malignancies � � � Treat underlying disease per NCCN guideline Transfuse as indicated based upon symptoms and institutional or published guidelines Erythropoiesis-stimulating agents (ESAs) are not indicated See NCCN Guidelines Table of Contents � � Treat underlying hematologic malignancy per NCCN guideline Transfuse as indicated based upon symptoms and institutional or published guidelines See NCCN Guidelines Table of Contents For patients with good prognosis and persistent transfusion- dependent anemia following response to treatment Anemia corrected Observe Other hematologic malignancies ePatients with terminal cancer who are not receiving chemotherapy should not be treated with ESAs. (See manuscript for detailed discussion and references.) Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. ANEM-2 TREATMENT CANCER-RELATED ANEMIA (NON-TREATMENT RELATED) CANCER TYPE Version 2.2010, 08/17/09 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. Practice Guidelines in Oncology – v.2.2010 Guidelines Index Anemia Table of Contents Discussion, ReferencesCancer- and Chemotherapy-Induced AnemiaNCCN ® f j An example of therapy with curative intent includes adjuvant chemotherapy. . Fatigue (FACT-F) and Anemia (FACT-An) subscales of the Functional Assessment of Cancer Therapy (FACT) and Brief Fatigue Inventory (BFI) are examples of standardized measures for assessing patient-reported fatigue. gFor patients receiving chemotherapy for breast, advanced head and neck, lymphoid, non-small cell lung, and cervical cancers with non-curative intent, ESAs should be used with caution. Some studies have demonstrated an increase in mortality for patients with these tumor types who are treated with ESAs. See manuscript ( ) for detailed discussion and references. h iOther anemia-related symptoms include: decreased activity level, and decreased performance status. MS-6 See Comparison of Risks and Benefits of ESA Use Versus Red Blood Cell Transfusion (ANEM-B) ANEM-3 Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Immediate correction not required Immediate correction required Transfuse as indicated based on institutional or published guidelines Complete symptom assessment: Peripheral edema Sustained tachycardia Tachypnea Other subjective physical symptoms may include: Chest pain Dyspnea on exertion Orthostatic lightheadedness/near syncope or syncope Fatigue i � � Objective physical symptoms may include: � � � � � � � j SYMPTOM ASSESSMENT Symptomatic Asymptomatic MYELOSUPPRESSIVE CHEMOTHERAPY-INDUCED ANEMIA Cancer treatment goals Chemotherapy with curative intentf Chemotherapy with non- curative intentg ESAs are not indicated Risk/benefit ratio should be carefully assessed on an individual basis; ESAs may be appropriate based on a thorough risk/benefit discussion and patient preference h See Treatment (ANEM-6) See Evaluation for Symptomatic Anemia Risk (ANEM-4) NCCN ® Version 2.2010, 08/17/09 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. Practice Guidelines in Oncology – v.2.2010 Guidelines Index Anemia Table of Contents Discussion, ReferencesCancer- and Chemotherapy-Induced AnemiaNCCN ® Asymptomatic EVALUATION FOR SYMPTOMATIC ANEMIA RISK AMONG CANCER PATIENTS RECEIVING MYELOSUPPRESSIVE CHEMOTHERAPY WITHOUT CURATIVE INTENT Evaluate risk factors for developing symptomatic anemia: History of prior myelosuppressive therapy (eg, bone marrow transplant) History of radiotherapy > 20% of skeleton Myelosuppression potential of current therapy Schedule Agents Hemoglobin level � � � � � � Transfusion in past 6 mo Duration Comorbidities Cardiac history/decompensation Chronic pulmonary disease Cerebral vascular disease � � � � � � Risk factors present Risk factors not present See Treatment (ANEM-5) See Treatment (ANEM-5) Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. ANEM-4 Version 2.2010, 08/17/09 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. Practice Guidelines in Oncology – v.2.2010 Guidelines Index Anemia Table of Contents Discussion, ReferencesCancer- and Chemotherapy-Induced AnemiaNCCN ® TREATMENT Asymptomatic; Risk factors present for development of symptomatic anemia Asymptomatic; Risk factors not present for symptomatic anemia development of Observation or Iron studies: Iron panel (serum iron, total iron binding capacity, serum ferritin) Observation ADDITIONAL EVALUATION Periodic re-evaluation for symptoms and risk factors TREATMENT REGIMEN See Response Assessment ANEM-7( ) Absolute iron deficiency (ferritin < 30 ng/mL and < 15%)transferrin saturation Functional iron deficiency f 800( erritin ng/mL and transferrin saturation < 20%) � IV or oral iron supplementationm Hemoglobin increases after 4 wks Hemoglobin does not increase after 4 wks Observation See Functional iron deficiency pathway below e h Patients with terminal cancer who are not receiving chemotherapy should not be treated with ESAs. (See manuscript for detailed discussion and references.) considering use of ESAs, evaluate the risk factors for thrombosis: history of thromboembolism, heritable mutation, hypercoagulability, elevated pre-chemotherapy platelet counts, hypertension, steroids, prolonged immobilization, recent surgery, certain therapies for multiple myeloma, hormonal agents, etc. ( ) IV iron appears to have superior efficacy and should be considered for supplementatio See manuscript for detailed discussion and references.) . Five randomized trials which evaluated IV iron with the use of ESA included patients with serum ferritin values ranging from 100 ng/mL to 900 ng/mL. (See manuscript for references.) . Patients with previous risk factors for thrombosis may be at higher risk for thrombosis with the use of ESAs. Ifk n l m n. Oral iron has been more commonly used but is less effective. ( � � See Comparison of Risks and Benefits of ESA Use Versus Red Blood Cell Transfusion (ANEM-B See NCCN Venous Thromboembolic Disease Guidelines See Parenteral Iron Preparations (ANEM-C ) ) See Adverse Effects of Erythropoietic Therapy (ANEM-A 3 of 5). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Periodic re- evaluation for symptoms and risk factors ANEM-5 CANCER PATIENTS RECEIVING MYELOSUPPRESSIVE CHEMOTHERAPY WITHOUT CURATIVE INTENT Consider IV iron supplementationm,n h + erythropoietic therapye,k,l after patient counseling regarding risks and benefits of ESAs See Erythropoietic Therapy - Dosing and Titration (ANEM-A) No iron deficiency f( erritin > 800 ng/mL or transferrin saturation 20%)� IV or oral iron supplementation is not needed Consider erythropoietic therapye,k,l after patient counseling regarding risks and benefits of ESAsh See Erythropoietic Therapy - Dosing and Titration (ANEM-A) Version 2.2010, 08/17/09 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of N