Hematopoietic Growth Factor Usage in Patients with Solid Tissue Malignancies

Transcription

1 hematology Board Review Manual Statement of Editorial Purpose The Hospital Physician Hematology Board Review Manual is a study guide for fellows and practicing physicians preparing for board examinations in hematology. Each manual reviews a topic essential to the current practice of hematology. PUBLISHING STAFF PRESIDENT, Group PUBLISHER Bruce M. White editorial director Debra Dreger Associate EDITOR Rita E. Gould assistant EDITOR Farrawh Charles Hematopoietic Growth Factor Usage in Patients with Solid Tissue Malignancies Series Editor: Eric D. Jacobsen, MD Instructor in Medicine, Harvard Medical School, Department of Medical Oncology, Brigham & Women s Hospital and Dana-Farber Cancer Institute, Boston, MA Contributor: Rushdia Zareen Yusuf, MBBS, MPH Fellow, Department of Medical Oncology, Brigham & Women s Hospital and Dana-Farber Cancer Institute, Boston, MA executive vice president Barbara T. White executive director of operations Jean M. Gaul PRODUCTION Director Suzanne S. Banish PRODUCTION associate Kathryn K. Johnson ADVERTISING/PROJECT director Patricia Payne Castle sales & marketing manager Deborah D. Chavis NOTE FROM THE PUBLISHER: This publication has been developed without involvement of or review by the American Board of Internal Medicine. Endorsed by the Association for Hospital Medical Education Table of Contents Introduction Neutropenia Anemia Thrombocytopenia Conclusion References Cover Illustration by Christine Armstrong Copyright 2007, Turner White Communications, Inc., Strafford Avenue, Suite 220, Wayne, PA ,. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications. The preparation and distribution of this publication are supported by sponsorship subject to written agreements that stipulate and ensure the editorial independence of Turner White Communications. Turner White Communications retains full control over the design and production of all published materials, including selection of topics and preparation of editorial content. The authors are solely responsible for substantive content. Statements expressed reflect the views of the authors and not necessarily the opinions or policies of Turner White Communications. Turner White Communications accepts no responsibility for statements made by authors and will not be liable for any errors of omission or inaccuracies. Information contained within this publication should not be used as a substitute for clinical judgment. hematology Volume 2, Part 4

2 HEMATOLOGY BOARD REVIEW MANUAL Hematopoietic Growth Factor Usage in Patients with Solid Tissue Malignancies Rushdia Zareen Yusuf, MBBS, MPH INTRODUCTION Hematopoiesis refers to the process in which circulating blood cells are formed in the bone marrow (Figure). Glycoprotein molecules known as hematopoietic growth factors control the process of hematopoiesis, which includes the differentiation, proliferation, and survival of precursor cells. Hematopoietic growth factors also govern the function of mature blood cells. In patients with cancer, hematopoiesis may be interrupted due to infiltration of the bone marrow with cancer cells or suppression of hematopoiesis due to chemotherapy. As a result, insufficient production of blood cells or production of abnormal cells occurs, which is manifested as neutropenia, anemia, and thrombocytopenia. Different chemotherapeutic agents also suppress hematopoiesis to varying degrees by mechanisms identical to those by which they affect cell kill in rapidly dividing tumors. Hematopoietic growth factors, including granulocyte colony-stimulating factors (G-CSFs), granulocyte macrophage colony-stimulating factors (GM-CSFs), and erythropoietin, are used in such circumstances to treat or, in some cases, prevent the resulting neutropenia and anemia. The purpose of this review is to discuss the physiology of hematopoiesis and the role of hematopoietic growth factors in the process. Furthermore, the use of growth factors in patients with solid tissue malignancies will be reviewed, with cases provided to illustrate important facets of supportive care. In addition, this review will include a discussion of the evidence behind recent revision of guidelines for the use of erythropoiesisstimulating agents (ESAs) as they apply to patients with cancer and the potential uses of thrombopoietin mimetic molecules currently in development. NEUTROPENIA Transient neutropenia can result from numerous viral, bacterial, and rickettsial infections as well as from the administration of nonchemotherapeutic drugs. Hospital Physician Board Review Manual Several primary neutropenic disorders also exist that can cause neutropenia in the absence of infection or the use of drugs. This review focuses on neutropenia associated with solid malignancies, which is caused by tumors infiltrating the bone marrow or by interruption of hematopoiesis in cancer patients, most likely the result of either cancer pathophysiology or due to chemotherapy administered for the treatment of the cancer. NEUTROPENIA PROPHYLAXIS Neutropenia is defined as an absolute neutrophil count (ANC) below 1500 cells/µl. The ANC is defined as the percentage of neutrophils and band forms multiplied with the leukocyte count (expressed as cells/µl). Normal ranges vary by laboratory but are generally between 1500 and 8000 neutrophils/µl and band forms/µl of blood. An ANC between 1500 and 1000 cells/µl is defined as mild neutropenia. Values between 500 and 1000 cells/µl is considered moderate neutropenia, whereas an ANC below 500 cells/µl is considered severe neutropenia. 1 Patients undergoing chemotherapy may receive either primary or secondary prophylaxis for neutropenia. Primary prophylaxis is defined as the administration of synthetic G-CSFs or GM-CSFs after the first cycle of chemotherapy, whereas secondary prophylaxis is the administration of G-CSFs or GM-CSFs after the second and subsequent cycles of chemotherapy. Secondary prophylaxis is instituted only if the patient has developed febrile neutropenia after the first cycle. The following will discuss how these factors affect hematopoiesis and how synthetic G-CSF and GM-CSF are used to address neutropenia in patients with solid malignancies. Granulocyte Colony-Stimulating Factor Physiology. G-CSF is a myeloid growth factor produced by monocytes, macrophages, endothelial cells, and fibroblasts in response to the presence of interleukin (IL)-1, tumor necrosis factor (TNF), endotoxin, and neutropenia. This factor functions through the G-CSF receptor, expressed on immature and mature granulocytes, and, to a lesser extent, on monocytes and macrophages. G-CSF acts on late myeloid progenitors or hematology Volume 2, Part 4

3 Pluripotent stem cell Unipotent stem cell Proerythroblast Lymphoblast Myeloblast Monoblast Megakaryoblast Early normoblast Neurtrophil promyelocyte Eosinophil promyelocyte Basophil promyelocyte Intermediate normoblast Neutrophil myelocyte Eosinophil myelocyte Basophil myelocyte Promonocyte Late normoblast Prolymphocyte Neutrophil metamyelocyte Eosinophil metamyelocyte Basophil metamyelocyte Megakaryocyte Reticulocyte Neutrophil stab cell Eosinophil stab cell Basophil stab cell Erythrocyte Lymphocyte Neutrophil Eosinophil Basophil Monocyte Platelets Figure. Schema of the hematopoietic system. (Adapted from Burkitt HG, Young B, Heath JW. Wheater s functional histology: a text and colour atlas. 3rd ed. New York: Churchill Livingstone; 1993:56. Copyright 1993, with permission from Elsevier.) Hospital Physician Board Review Manual

4 Table. Chemotherapeutic Regimens Associated with at Least 20% Incidence of Neutropenia* Cancer Type Regimen Bladder Breast Lung Non-Hodgkin s lymphoma Testicular colony-forming units and increases production of neutrophils by increasing the number of cell divisions and decreasing the transit time through the bone marrow. G-CSF is essential for maintaining normal neutrophil levels and for increasing neutrophil counts in response to infections. Some of the effects of G-CSF are dose dependent. At low levels, G-CSF attracts neutrophils and, in higher concentrations, it immobilizes them. G-CSF also increases the affinity of L-selectin on neutrophils for its ligand on endothelial cells and hence helps neutrophils attach to endothelium. G-CSF increases the expression of Carboplatin and paclitaxel Methotrexate, vinblastine, doxorubicin, and cisplatin Paclitaxel, doxorubicin, and cyclophosphamide administered every 2 wk for adjuvant therapy Doxorubicin and paclitaxel or doxorubicin, paclitaxel, and cyclophosphamide for first-line treatment of metastatic disease Docetaxel for second-line treatment of metastatic disease Topotecan or topotecan plus paclitaxel for advanced disease Cyclophosphamide, doxorubicin, and vincristine for advanced disease Gemcitabine, ifosfamide, and vinorelbine or docetaxel and carboplatin for non small cell lung cancer Relapsed disease: Vincristine, doxorubicin, prednisolone, etoposide, cyclophosphamide, bleomycin (VAPEC-B) Etoposide, methylprednisolone, cytarabine, cisplatin (ESHAP) Dexamethasone, cisplatin, and cytarabine (DHAP) Ifosfamide, cyclophosphamide, and etoposide with or without rituximab Vinblastine, ifosfamide, and cisplatin for the treatment of advanced disease Data from Smith TJ, Khatcheressian J, Lyman GH, et al update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24: ; and National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Myeloid growth factors. V Available at myeloid_growth.pdf. Accessed 14 Nov *This list is not intended to be comprehensive; all available evidence should be reviewed prior to making treatment decisions. All dose-dense regimens (eg, paclitaxel every 2 wk for adjuvant treatment of breast cancer or cyclophosphamide, doxorubicin, oncovin, and prednisone every 2 wk for non-hodgkin s lymphoma) should be supported with myeloid growth factors. cluster of differentiation (CD) molecules, CD11b/CD18, and helps neutrophil migration to tissues as well as increases resultant phagocytosis, production of free oxygen radicals and hence bactericidal and fungicidal activity and antibody mediated cellular cytotoxicity. Besides its direct effects on neutrophil numbers and function, G-CSF also inhibits lipopolysaccharide triggered release of TNF, IL-1β, IL-12, and IL-18 by monocytes. This ultimately results in a decreased T-1 helper cell (TH-1) response and an increased TH-2 cell response. 2,3 The increase in TH-2 cell response acts to check neutrophil activation. Therapeutic indications. If synthetic G-CSF (filgrastim) is administered to patients receiving chemotherapy, it shortens the duration of neutropenia, hospitalization for febrile neutropenia, and the number of days for which antimicrobials may have to be used. However, it does not decrease infection-related or overall mortality, nor does it impact response rate to antibiotics. 4 Pegylated filgrastim (pegfilgrastim)has also been shown to decrease the rate of the development of febrile neutropenia, hospitalization from febrile neutropenia, and the use of intravenous antibiotics. 5 Not all patients receiving chemotherapy are eligible according to guidelines (which take cost-effectiveness into account) to receive primary prophylaxis against febrile neutropenia with G-CSF. 6 Patients younger than age 70 years who are receiving a chemotherapeutic regimen that is associated with at least 20% incidence of neutropenia should receive a synthetic G-CSF for primary prophylaxis. 7 Several regimens known to cause neutropenia are listed in the 2006 American Society of Clinical Oncology (ASCO) guidelines and in the National Comprehensive Cancer Network (NCCN) guidelines on myeloid growth factors (Table). 1,7 However, patient characteristics should also be considered when determining whether a patient should receive primary prophylaxis for neutropenia. For example, the threshold of when to administer G-CSF should be lower in patients older than age 70 years. These patients should receive prophylactic G-CSF with all moderately toxic chemotherapeutic regimens. Patients who have poor performance status, serious comorbidities, history of infectious complications not related to cancer, bone marrow involvement with cancer, and poor nutritional status also may be given primary prophylaxis based on the clinician s judgment. Regarding secondary prophylaxis, G-CSF should be administered in patients who developed an episode of febrile neutropenia after their first cycle of chemotherapy and in whom reduction in the dose of or delay of subsequent chemotherapy may affect overall or disease-free survival (eg, lymphomas, testicular cancers). Filgrastim has indications for use in various other hematology Volume 2, Part 4

5 cancer settings not related to solid malignancies, such as in acute myeloid leukemia (AML). In addition, filgrastim is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia in symptomatic patients with congenital neutropenia cyclic neutropenia or idiopathic neutropenia. A discussion of the role of filgrastim support in these other settings is beyond the scope of this review. Dosing and side effects. Filgrastim should be administered 24 to 72 hours after chemotherapy for both primary and secondary prophylaxis. The recommended dose is 5 µg/kg/day, and it can be administered subcutaneously or intravenously. Filgrastim should be administered daily until the ANC is greater than at least 500 cells/µl. Many oncologists continue until the ANC exceeds 1000 cells/µl. For ease of administration, the patient can be given 6-mg pegfilgrastim once after chemotherapy. Pegfilgrastim is a G-CSF in which polyethylene glycol is bound to the methionine at the amino terminal of filgrastim. Filgrastim has a half-life in vivo of 3 hours, while pegfilgrastim has a half-life in vivo of 40 hours. 8 Filgrastim has a shorter half-life because it is cleared by the kidneys and by receptors on the surface of neutrophils, whereas pegfilgrastim is cleared only by the latter. 9 Side effects of filgrastim or pegfilgrastim treatment include bone pain due to marrow expansion in about 30% of recipients. Headache and fatigue are also common side effects. Rare but potentially serious side effects are splenic rupture and adult respiratory distress syndrome. Use of G-CSF in any form is contraindicated in patients with sickle cell disease, as these growth factors may precipitate sickle cell crisis. 10 Filgrastim and pegfilgrastim have not been evaluated in the setting of chemotherapeutic agents that cause delayed myelosuppression (eg, mitomycin C, nitrosoureas). Additionally, filgrastim has not been studied in patients receiving concurrent radiation therapy nor has pegfilgrastim been studied for the mobilization of stem cells for transplant. Filgrastim and pegfilgrastim are not contraindicated in any solid malignancies. It is unknown how diet and vitamin supplements interact with filgrastim and pegfilgrastim. However, current evidence indicates that no nutritional supplementation in addition to a balanced diet is essential for the action of either of these growth factors. Granulocyte Macrophage Colony-Stimulating Factor GM-CSF is a glycoprotein that is constitutively expressed by monocytes, macrophages, endothelial cells, and fibroblasts. IL-1 and TNF increase its production. GM-CSF acts on granulocyte-macrophage colonyforming units and increases the number of circulating monocytes and neutrophils. It also increases the bactericidal and fungicidal activity of neutrophils. In addition, it increases the maturation and proliferation of dendritic cells and increases antigen presentation by both dendritic cells and macrophages. 11 Therapeutic indications. Synthetic GM-CSF (sargramostim) is approved in the United States to shorten the time for neutrophil recovery in patients who have been induced for AML or who have undergone autologous and allogeneic bone marrow transplantation. It is also indicated for the mobilization of peripheral blood stem cells in patients who are undergoing autologous transplants. A discussion of the role of growth factor support in these other settings is beyond the scope of this review. Sargramostim does not have approval for use in primary or secondary prophylaxis of chemotherapy-induced neutropenia but it has a category 2 recommendation in the NCCN guidelines for use in this setting. 1 Dosing and side effects. Sargramostim is administered at a dose of 250 mg/m 2 /day via an intravenous infusion over 2 to 24 hours (duration of infusion varies by indication) or subcutaneously. 1,11 Like filgrastim and pegfilgrastim, sargramostim is contraindicated in sickle cell disease, and it has not been evaluated in the setting of chemotherapeutic agents that cause delayed myelosuppression. Patients taking sargramostim may develop myalgias (up to 20%), arthralgias (up to 15%), fluid retention (up to 8%), and dyspnea (up to 13%). The side effects are more common with higher doses exceeding 500 mg/m 2 /day. Fever is also a commonly reported side effect and can occur in up to 20% of patients, which can be a confounding factor if used to treat febrile neutropenia. 12 CASE 1 A 35-year-old man with no significant past medical history presents to his primary care physician with shortness of breath, fevers, and night sweats of 2-weeks duration. Diagnostic work-up reveals a large mediastinal mass, which on biopsy is consistent with primary mediastinal B cell lymphoma. A treatment plan is formulated, which consists of 6 cycles of cyclophosphamide, doxorubicin, oncovin, prednisone, and rituximab (CHOP-R) every 3 weeks, followed by radiation to the site of the mass. The patient tolerates the first infusion of chemotherapy well but presents with a fever of F and an ANC of 200 cells/ml on day 7 of the cycle. What is the role for synthetic G-CSF or GM-CSF in the management of this patient? The case patient did not receive primary prophylaxis Hospital Physician Board Review Manual

6 with either filgrastim or pegfilgrastim because febrile neutropenia occurs in less that 20% of patients receiving CHOP-R every 3 weeks and he does not have any host factors that would place him at increased risk of febrile neutropenia or its complications. Given that he developed febrile neutropenia after the first cycle of CHOP-R and that his disease is a potentially curable one in which delay of chemotherapy may decrease survival, secondary prophylaxis is appropriate. 13 The patient should not receive sargramostim because it is not indicated for this setting. CASE CONTINUED The case patient receives 1 dose of pegfilgrastim 24 hours after receiving a cycle of CHOP-R. He does not develop subsequent fever during this session or the remaining 5 cycles. Although filgrastim is an acceptable choice, its use requires administering 1 subcutaneous injection of filgrastim every 24 hours until ANC reaches at least 500 cells/ml or, preferably, 1000 cells/ml. Hence, pegfilgrastim is the most convenient option for this patient. ANEMIA Patients with cancer develop anemia from several causes. Two major causes are the infiltration of bone marrow with cancer itself and the treatment (chemotherapy with or without radiation therapy) that they are receiving. Patients can develop anemia from other causes, such as nutritional deficiencies (iron, vitamin B 12, and folate) or hemolysis. These causes must be ruled out before transfusion or growth factors are instituted. Historically, transfusion of packed red blood cells (RBCs) was the method used for replacing hemoglobin. In the 1980s, greater awareness of the risks associated with transfusion (especially infection) and the limited blood supply made it necessary to consider alternatives, such as growth factors to stimulate erythropoiesis. According to the NCCN guidelines on anemia, 14 normal values for hemoglobin are between 12 and 16 g/dl for women and between 14 and 18 g/dl for men. Mild anemia is defined as hemoglobin levels below normal but above 10 g/dl, moderate anemia is defined as a hemoglobin level between 8 and 10 g/dl, severe anemia is defined as a hemoglobin value between 6.5 and 7.9 g/dl, and life-threatening anemia is defined as a hemoglobin value below 6.5 g/dl. 14 ERYTHROPOIETIN Erythropoietin is a glycoprotein molecule that is secreted by interstitial fibroblasts in the kidney and, to a small extent (< 10%), by the liver. It acts on erythroid colony-forming units via a cell surface receptor and causes maturation of these progenitor cells into normoblasts and RBCs. The primary stimulus for the production of erythropoietin is hypoxia, which is sensed by an oxygen sensor present in the kidneys (likely a cytochrome-like molecule). The oxygen sensor responds to hypoxia by removing repression from the transcription of the erythropoietin gene and by leading to new protein synthesis. 15 The erythropoietin receptor is also found in several other tissues. The function of erythropoietin on these tissues is still being determined. ANEMIA TREATMENT There are 2 synthetic ESAs available in the United Stages, epoetin alfa and darbepoetin alfa. Epoetin alfa is 1 of 3 recombinant human erythropoietin molecules available commercially. Epoetin alfa and epoetin beta (not available in the United States) are made in Chinese hamster ovary cells. Darbepoetin is recombinantly manufactured erythropoietin that has a higher molecular weight and a half-life that is 3 times longer in vivo than epoetin alfa. These agents do not address the underlying cause of the anemia; however, they are used to increase the level of hemoglobin and decrease the number of transfusions that would otherwise be required. Both epoetin alfa and darbepoetin have US Food and Drug Administration (FDA) approval for treating anemia in patients undergoing chemotherapy. Neither agent is approved for use in cancer patients who are not actively undergoing chemotherapy ( 6 wk after treatment with chemotherapy or radiation). 14,16 The use of ESAs for treating anemia associated with cancer in conditions, such as myelodysplastic syndrome (MDS) and multiple myeloma, lymphoma, and chronic lymphoid leukemias has been extensively studied; however, specific recommendations for the use of ESAs in these conditions are beyond the scope of this review. The following discussion will focus on the recent evidence that forms the basis of recommendations for administering ESAs in patients who have chemotherapy-induced anemia. Chemotherapy-Induced Anemia Several trials have demonstrated the efficacy of ESAs in increasing hemoglobin levels and decreasing transfusion requirements in patients with solid tissue malignancies. A 2006 meta-analysis examining the efficacy of ESAs in either preventing or treating anemia in patients with cancer reviewed data from 57 randomized controlled trials that included 9533 patients. The trials studied the hematology Volume 2, Part 4

7 use of ESAs (epoetin alfa or beta or darbepoetin) in combination with RBC transfusions versus the use of RBC transfusions alone. The cohort included patients with cancer who were not undergoing active treatment or who were undergoing active chemotherapy, radiation therapy, or both. Patients who received epoetin alfa and darbepoetin had a 36% lower risk of transfusion than the control group (relative risk, 0.64 [95% confidence interval {CI}, ]). However, the hazard ratio for overall survival in the treatment group versus the control group was 1.08 (95% CI, ), which was not significant. Evaluation of the risk of thromboembolic phenomenon revealed a relative risk of 1.67 (95% CI, ) in the treatment group as compared with the control group. 17 Although this trial demonstrated that ESAs are efficacious in reducing the risk of requiring transfusions in cancer patients, these findings do not allow distinctions to be made between patients who are not undergoing chemotherapy and those who are receiving therapy, as the control and study groups were heterogeneous. However, there are several randomized controlled trials that have studied the use of epoetin and darbepoetin in breast cancer, small cell lung cancer (SCLC) and non small cell lung cancer (NSCLC), and head and neck cancer patients being treated with chemotherapy These studies, among others, contributed data to the recently revised ASCO/American Society of Hematology (ASH) guidelines on anemia. 25 Breast cancer. A randomized controlled trial comparing overall survival at 12 months in patients with metastatic breast cancer who were undergoing first-line chemotherapy was stopped early by the data safety monitoring board due to a statistically significant increase in mortality in the treatment group. Patients had been administered epoetin at baseline and during the study if hemoglobin levels were below 13 g/dl in order to achieve a target hemoglobin level between 12 and 14 g/dl. Although the control group differed from the treatment group in that it had better Eastern Cooperative Oncology Group (ECOG) performance status, longer disease-free survival, and longer time since diagnosis, the overall survival remained significantly worse in the treatment group despite adjustment for these factors. 18 This trial was one of the several trials that demonstrated a possible increased mortality in patients receiving ESAs for a high target hemoglobin level. Small cell and non small cell lung cancer. In another randomized controlled trial designed to study the efficacy and safety of darbepoetin in previously untreated patients with extensive stage SCLC, 596 previously untreated patients with SCLC who had hemoglobin levels between 9 and 13 g/dl and who were receiving chemotherapy were randomized to receive darbepoetin or placebo. Patients were treated to a target hemoglobin level of 13 g/dl. The median survival time was 40 weeks in both groups (hazard ratio for death, 0.93 [95% CI, ]). At least 1 transfusion was administered to 17% of patients in the darbepoetin group and 39% of patients in the placebo group (hazard ratio, 0.4 [95% CI, ]). 19 This study s findings were important because they demonstrated no increase in mortality from darbepoetin in this homogenous population. In an earlier double-blind, randomized, placebocontrolled trial that included both SCLC and NSCLC patients receiving chemotherapy, 320 anemic patients who had hemoglobin levels of 11 g/dl or less were randomized to receive darbepoetin or placebo every week for a total of 12 weeks. The primary endpoint was RBC transfusions received. Patients were also assessed for quality of life as a secondary endpoint. Transfusions were required by 27% of patients in the treatment group and 52% of patients in the placebo group (P < 0.001). The treatment group also had better improvement in Functional Assessment of Cancer Therapy (FACT) fatigue scores (56% versus 44% in the placebo group; P = 0.019). Adverse effects were similar in the 2 groups. 20 The mean hemoglobin level was 9.93 g/dl in the control group and g/dl in the darbepoetin group. This study established efficacy of darbepoetin in patients with hemoglobin levels below 12 g/dl, which was shown by the decrease in transfusions required by the treatment group with no increased mortality (14% in the darbepoetin group and 12% in the placebo group; no deaths were attributable to the treatment drug.) Head and neck cancer. At least 4 trials studied the effect of ESAs on survival in patients with head and neck cancer receiving chemotherapy, radiotherapy, or both. In a 2004 study, patients with inoperable squamous cell head and neck cancer who were receiving definitive radiation therapy or definitive chemoradiotherapy for locoregional control and had hemoglobin levels between 9 and 13.5 g/dl for men and between 9 and 12 g/dl for women were randomized to receive either epoetin with their treatment plan or the treatment plan alone. Epoetin was continued until the level of hemoglobin reached 14 g/dl in women and 16 g/dl in men. After 148 patients had been accrued to the study, the data monitoring committee terminated further accrual because it was extremely unlikely that the primary endpoint of the study (locoregional control) would be impacted by the study drug. The 1-year actuarial locoregional control rate in 135 evaluable patients was 63% in the group receiving epoetin and 70% in the control group, which was not a significant difference. The Hospital Physician Board Review Manual

8 treatment group had a significant increase in their mean hemoglobin levels as compared with the control group. 21 In contrast to the following study, this trial failed to show a benefit of epoetin on locoregional control. In a 2002 study, 191 patients were treated with neoadjuvant chemoradiation therapy followed by surgery. For the purpose of data analysis, the patients were divided into 4 groups. Of these, 2 groups are important to this discussion: patients who had pretreatment hemoglobin levels below 14.5 g/dl either received epoetin (treatment group; n = 57) or did not receive epoetin (control group; n = 88). Two-year locoregional control was 95% in the treatment group and 72% in the control group. Two-year overall survival was 88% in the treatment group and 60% in the control group. This trial demonstrated benefit in locoregional control; however, it was not a randomized trial. 22 In a 2003 multicenter, double-blind, placebocontrolled, randomized trial, 351 anemic patients (hemoglobin levels < 12 g/dl in women and < 13 g/dl in men) with carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx who were receiving either postoperative radiation therapy or definitive radiation therapy were randomized to receive erythropoietin or placebo. The primary endpoint was locoregional progressionfree survival, which was poorer in the treatment group as compared with the control group (relative risk, 1.69 [95% CI, ]; P = 0.007). 23 The more recent DAHANCA-10 study also randomized 522 patients with head and neck cancer who were undergoing radiation therapy and had a baseline hemoglobin level below 14.5 g/dl to receive either darbepoetin or placebo. A planned interim analysis showed significantly worse locoregional control in the treatment group versus the control group. This study together with the previously discussed study 23 contributed to the concern that the use of ESAs may actually worsen tumor control and survival. 24 The trials discussed above provide mixed evidence about the effect of ESAs on survival and locoregional control, which, as noted earlier, was considered in the recent revision of the ASCO/ASH guidelines on the use of ESAs. Quality of life. It has been proposed that the effects of ESAs may improve fatigue and, by association, quality of life of cancer patients receiving chemotherapy. In 1 randomized, double-blind, placebo-controlled trial, 375 patients with solid or nonmyeloid malignancies receiving chemotherapy who had hemoglobin levels of 10.5 g/dl or less or who had a decrease in their hemoglobin levels of at least 1.5 g/dl since beginning chemotherapy (hemoglobin level 12.5 g/dl in the latter case) were randomized to receive epoetin alfa at 150 to 300 U/kg or placebo. The primary endpoint was measurement of reduction in transfusions; a secondary endpoint assessed quality of life using the FACT scale. Transfusion requirements were significantly decreased in the treatment group. All primary anemia and cancerspecific quality of life domains, including energy level, ability to perform daily activities, and fatigue, were significantly greater for epoetin alfa patients versus placebo patients. 26 Vansteenkiste et al 20 conducted a double-blind, placebo-controlled, randomized trial that revealed similar improvement in quality of life with darbepoetin. Other data from open-label, community-based studies and systematic reviews also suggest an improvement in quality of life with administration of ESAs in patients being treated for cancer. 17,27 29 Crawford et al 30 examined the relationship between hemoglobin levels and improvement in quality of life among anemic cancer patients undergoing chemotherapy. They used data from 2 open-label community-based trials and showed that the maximal incremental gain in quality of life occurs in patients whose hemoglobin increases from 11 g/dl to 12 g/dl. However, the FDA recently (8 November 2007) issued a new alert warning to health care professionals that there was evidence indicating that the increasing hemoglobin levels to more than 12 g/dl can decrease survival and increase tumor progression, as was discussed above. The warning also indicated that increased risk of tumor progression and decreased survival had not been excluded when ESAs were used to maintain the hemoglobin between 10 and 12 g/dl. 31 The risk/benefit ratio would have to be considered carefully before ESAs were prescribed to improve quality of life in patients receiving chemotherapy. Summary. Epoetin alfa, epoetin beta, and darbepoetin are considered equivalent in regards to their efficacy and safety profiles. 25 These ESAs can be used in patients with solid tumors who are undergoing chemotherapy and whose hemoglobin levels have decreased below or are likely to decrease below towards 10 g/dl. For patients with solid malignancies who are receiving chemotherapy and who have a hemoglobin level between 10 and 12 g/dl that is not decreasing towards 10 g/dl, the decision to institute ESAs is a clinical one. Physicians must bear in mind the comorbidities of the patient (eg, cardiovascular disease) and the symptoms resulting from anemia (eg, fatigue) before deciding whether to start ESAs. 25 Dosing and Side Effects Patients can receive epoetin 3 times per week at 150 U/kg of body weight. The dose can be increased to hematology Volume 2, Part 4

9 300 U/kg 3 times weekly if an increase is not seen after 2 months of initiation of the epoetin. If an increase of 1 to 2 g/dl is not seen in the hemoglobin levels 2 months after escalating the dose, epoetin should be discontinued. Epoetin can also be administrated once weekly at doses of 40,000 U. If there is no response in 1 month, then the dose can be increased to 60,000 U/wk. Epoetin can be administered subcutaneously or intravenously. 25 Darbepoetin can be administered at 2.25 µg/kg/wk or 500 µg every 3 weeks as a subcutaneous injection. It can also be administered intravenously at the physician s discretion. 25 The dose can be increased to 4.5 µg/kg if there is an increase of less than 1 g/dl in the hemoglobin levels after 6 weeks. 25 The ASCO/ASH guidelines also recommend dose reduction in ESAs if the hemoglobin levels increase by more than 1 g/dl in 2 weeks or if the hemoglobin levels approach 12 g/dl with epoetin and exceeds 11 g/dl for darbepoetin. ESAs need to be held if the hemoglobin increases above 12 g/dl. Epoetin and darbepoetin can cause iron deficiency and iron stores should be repleted in all patients receiving these drugs. Arthralgias and headaches are other common side effects. Less common but more serious are risks of congestive heart failure (incidence of up to 9%) and thrombotic events such as deep venous thrombosis, acute myocardial infarction, stroke, and hypertension. Risk for developing deep venous thrombosis is approximately 5%, less than 1% for acute myocardial infarction and stroke, and approximately 20% for hypertension. 32 Anemia Not Attributable to Chemotherapy A phase III study was conducted to assess the efficacy and safety of darbepoetin for treating anemia in cancer patients who were not actively receiving chemotherapy. Patients (n = 985) who were diagnosed with cancer (18% of patients had NSCLC, 13% had breast cancer, and 11% had prostate cancer) and who had hemoglobin levels of 11 g/dl or less were randomized to receive darbepoetin (6.75 µg/kg every 4 wk for a total of 16 wk) or placebo. The primary endpoint was the occurrence of blood transfusions between weeks 5 and 17 of the study, with a hazard ratio of 0.85 (95% CI, ). There were more deaths in the darbepoetin group than the placebo group (26% versus 20%). This study, however, was not designed to study mortality as an endpoint. 33 Another study addressed the effect of epoetin alfa on the quality of life in patients with NSCLC. Patients with hemoglobin levels less than 12.1 g/dl who were not receiving any chemotherapy or radiation therapy were randomized to receive epoetin alfa every week for 12 weeks or placebo. If the hemoglobin level increased to more than 14 g/dl at any time, the study drug was withheld and reinitiated when the hemoglobin level fell to less than 12 g/dl with a 25% decrease in dose. An interim analysis performed after 70 patients had been accrued to the trial revealed a statistically significant decrease in survival in the treatment arm (63 versus 129 days). The Steering Committee closed the study to accrual. Quality-of-life data could not be analyzed due to small study numbers. 34 However, it appears that epoetin and darbepoetin can impact survival adversely in patients with cancer who are not being actively treated. Currently, the ASCO/ASH guidelines recommend against treating anemia in these patients using ESAs, 25 and the FDA has not approved the use of ESAs in this setting. 16 Cancer patients with anemia not attributable to chemotherapy should undergo routine work-up of anemia to determine if the anemia has a treatable cause. 14,25 Other Potential Uses of ESAs The use of ESAs in patients with anemia of chronic disease, anemia of chronic renal insufficiency, HIV positive patients with anemia, and surgical patients who are donating blood for possible autologous transfusions has been studied extensively. A discussion of these topics is beyond the scope of this review. CASE 2 A 65-year-old woman with stage III breast cancer is receiving neoadjuvant chemotherapy with dose-dense paclitaxel, doxorubicin, and cyclophosphamide. At an office visit for her third scheduled cycle of doxorubicin and cyclophosphamide, she complains of increasing fatigue. Her physical examination is unremarkable. There is no discernable pallor. However, her complete blood count reveals a hemoglobin value of 12 g/dl. Is this patient a candidate for treatment with recombinant erythropoietin? None of the randomized studies discussed above showed an increase in overall survival in patients being treated for cancer when they were administered ESAs to increase their hemoglobin levels above 12 g/dl In fact, as discussed in detail above there is a suggestion of poorer outcome. 18 The ASCO/ASH guidelines and the FDA recommend using ESAs for patients receiving chemotherapy when their hemoglobin levels are less than 10 g/dl or decreasing towards the value; this patient does not meet these criteria. 16,25 In this case, the patient should undergo routine work-up of anemia to determine if there is a more common and readily 10 Hospital Physician Board Review Manual

10 treatable cause of her anemia, such as iron, vitamin B 12, or folate deficiency. If the patient s hemoglobin level had been less than 10 g/dl, she would have been a candidate for either epoetin or darbepoetin to potentially decrease transfusion requirements and fatigue. THROMBOCYTOPENIA Thrombocytopenia results from various causes. In the setting of cancer, thrombocytopenia is the result of decreases in cell division and death of progenitor cells (Figure). Platelets are responsible for primary hemostasis and hence deficiency leads to the presence of petechiae, epistaxis, ecchymosis, and gingival bleeding. Patients are considered thrombocytopenic when platelet counts are below 150,000 cells/µl. Platelet counts below 10,000 cells/µl or 20,000 cells/µl constitutes severe thrombocytopenia and is associated with lifethreatening hemorrhage. Moderate thrombocytopenia occurs when platelet counts are between 20,000 and 50,000 cells/µl and is associated with bleeding only in the setting of surgery and trauma. Patients with platelet counts of at least 50,000 cells/µl but less than 150,000 cells/µl have mild thrombocytopenia and are usually asymptomatic. 35 TREATMENT OF THROMBOCYTOPENIA In patients receiving chemotherapy, it is prudent to attempt increasing platelet counts when the level decreases below 20,000 cells/µl. Increasing platelet counts is performed using platelet transfusions because the growth factors associated with thrombopoiesis have severe side effects. Efforts to develop safer and more efficacious platelet growth factors have spanned decades. These efforts as well as the compounds currently in development will be discussed in the following section. 35 THROMBOPOIETIC AGENTS Interleukin-11 IL-11 is a multifunctional hematopoietic growth factor that works with other growth factors (eg, IL-3) to cause a multiprogenitor proliferative effect on the bone marrow. In regards to platelets, IL-11 has been shown to stimulate megakaryocyte progenitor cells in the bone marrow and increase their ploidy, with resultant increase in peripheral platelet counts. Oprelvekin is the recombinant form of IL-11 and is the only FDA-approved agent for preventing severe thrombocytopenia and reducing the need for platelet transfusions. Oprelvekin has been shown in studies to increase platelet counts in patients with bone marrow failure (aplastic anemia, MDS, chemotherapy-induced bone marrow or graft failure). In 1 particular study, 33 patients who had one of the aforementioned bone marrow failure syndromes were treated with oprelvekin, and 9 of these patients had a hematologic response. One patient suffered a transient ischemic attack and a second patient developed supraventricular tachycardia. Randomized clinical trials established the efficacy of oprelvekin in primary and secondary prevention of chemotherapy-induced thrombocytopenia. 36,37 Due to the side effects associated with oprelvekin (eg, nausea, vomiting, diarrhea, fever, vasodilation and resultant syncope) and the relative ease of using platelet transfusions instead, oprelvekin is not routinely used in clinical practice. 38 Developing Therapies Thrombopoietin is a 332 amino acid glycoprotein that creates thrombopoietic stimulus on cells of the megakaryocytic lineage; it causes the most potent stimulus of endomitosis and polyploidy in megakaryocytes. In addition, thrombopoietin also acts on mature megakaryocytes to cause platelet shedding. 35 Thrombopoietin was purified and cloned in Since then, several attempts at developing a recombinant homologue have occurred, which resulted in 3 different families of thrombopoietin molecules: recombinant thrombopoietin molecules, peptide molecules (which are not homologous to human thrombopoietin but activate its receptor), and nonpeptide molecules (which function similarly to peptide molecules). All are geared towards increasing platelet counts in a variety of patient populations. 39 First-generation recombinant thrombopoietin mimetic molecules. Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) was developed in the 1990s and was clinically studied in various clinical settings, including: in collecting platelets via apheresis from healthy donors; 40 in stage III or IV lung cancer being treated with carboplatin and paclitaxel; 41,42 in reducing dose-limiting toxicity (not efficacy) in patients receiving induction and consolidation therapy for AML (M3 and M7 types excluded); 43 in breast cancer patients who underwent autologous stem cell collection and then received STAMP V chemotherapy (myeloablative chemotherapy consisting of cyclophosphamide, thiotepa and carboplatin); 44 in patients with MDS and aplastic anemia; 45 and in patients with refractory chronic idiopathic thrombocytopenic purpura (ITP). 46 Likewise, recombinant thrombopoietin also was studied in the 1990s to determine its efficacy in sarcoma patients and its utility for mobilizing CD34+ progenitor cells when combined with G-CSF. 47 Although results with recombinant thrombopoietin and PEG-rHuMGDF were hematology Volume 2, Part 4 11

11 encouraging in these various clinical circumstances, reports that neutralizing antibodies to PEG-rHuMGDF had developed, thus causing aplastic anemia, led to abandonment of further development of both types of agents. 48 Second-generation recombinant thrombopoietin mimetic molecules. Subsequently various peptide and nonpeptide compounds with thrombopoietic activity have been tested in clinical trials, as there is a probability that these will not be associated with neutralizing antibodies. 49 For example, AMG 531 is a peptide compound that has been tested in phase I and II clinical trials in patients who have chronic ITP. In a phase I trial, 24 patients who had received at least 1 treatment for ITP were treated with AMG 531. In a phase II trial, the patients were randomly assigned to receive AMG 531 or placebo via 6 weekly subcutaneous injections. There were no major side effects and platelet counts increased in both phase I and phase II trial patients receiving the drug. 50 Currently, phase 2 studies are enrolling patients with chemotherapy-induced thrombocytopenia and MDS. Development of this and other peptide and nonpeptide thrombopoietic compounds is ongoing and one can envision uses in settings similar to those in which PEG-rHuMGDF and thrombopoietin were tested. CONCLUSION Growth factors are all commonly used in patients with cancer for the amelioration of bone marrow failure. Guidelines are available to direct clinical practice, but a review of the available evidence is also essential to understand the nuances of when these agents are optimally used for greatest benefit in patients experiencing neutropenia and anemia due to bone marrow failure. REFERENCES 1. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Myeloid growth factors. V Available at Accessed 14 Nov Möhle R, Kanz L. Hematopoietic growth factors for hematopoietic stem cell mobilization and expansion. Semin Hematol 2007;44: Rutella S. Granulocyte colony-stimulating factor for the induction of T-cell tolerance. Transplantation 2007;84(1 Suppl):S Garciá-Carbonero R, Mayordomo JI, Tornamira MV, et al. Granulocyte colony-stimulating factor in the treatment of high-risk febrile neutropenia: a multicenter randomized trial. J Natl Cancer Inst 2001;93: Vogel CL, Wojtukiewicz MZ, Carroll RR, et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol 2005;23: Lyman GH, Kuderer NM, Djulbegovic B. Prophylactic granulocyte colonystimulating factor in patients receiving dose-intensive cancer chemotherapy: a meta-analysis. Am J Med 2002;112: Smith TJ, Khatcheressian J, Lyman GH, et al update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24: Phillips MS. Pegfilgrastim. Clin J Oncol Nurs 2003;7. Available at www. ons.org/publications/journals/cjon/volume7/issue2/ asp. Accessed 14 Nov Holmes FA, O Shaughnessy JA, Vukelja S, et al. Blinded randomized multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high risk stage II or stage III/IV breast cancer. J Clin Oncol 2002;20; Blau CA. Adverse effects of G-CSF in sickle cell syndromes [editorial]. Blood 2001;97: Fleetwood AJ, Cook AD, Hamilton JA. Functions of granulocyte macrophage colony-stimulating factor. Crit Rev Immunol 2005;25: Buchner T, Hiddemann W, Koenigsmann M, et al. Recombinant human granulocyte macrophage colony-stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse. Blood 1991;78: Berghmans T, Paesmans M, Lafitte JJ, et al. Therapeutic use of granulocyte and granulocyte-macrophage colony-stimulating factors in febrile neutropenic cancer patients. A systematic review of the literature with metaanalysis. Support Care Cancer 2002;10: National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Cancer- and treatment-related anemia. Available at www. nccn.org/professionals/physician_gls/pdf/anemia.pdf. Accessed 25 Oct Lappin T. The cellular biology of erythropoietin receptors. Oncologist 2003;8 Suppl 1: US Food and Drug Administration. Information for healthcare professionals erythropoiesis stimulating agents (ESA) [Aranesp (darbepoetin), Epogen (epoetin alfa), and Procrit (epoetin alfa)]. Center for Drug Evaluation and Research. Available at RHE2007HCP.htm. Accessed 25 Oct Bohlius J, Wilson J, Seidenfeld J, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev 2006;3:CD Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol 2005;23: AMGEN. Aranesp study showing no negative impact on survival in SCLC presented at World Conference on Lung Cancer. Available at www. amgen.com/media/media_pr_detail.jsp?year=2007&releaseid= Accessed 25 Oct Vansteenkiste J, Pirker R, Massuti B, et al; Aranesp Study Group. Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 2002;94: Machtay M, Pajak T, Suntharalingam M, et al. Definitive radiotherapy ± erythropoietin for squamous cell carcinoma of the head and neck: preliminary report of RTOG Int J Radiat Oncol Biol Phys 2004;60 (Suppl 1):S Glaser CM, Millesi W, Kornek GV, et al. Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys 2001;50: Henke M, Laszig R, Rübe C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003;362: Danish Head and Neck Cancer Group. Interim Analysis of DAHANCA 10: study of the importance of novel erythropoiesis stimulating protein (Aranesp) for the effect of radiotherapy in patients with primary squamous cell carcinoma of the head and neck. Available at dahanca.dk/get_media_file.php?mediaid=125. Accessed 5 Dec Rizzo JD, Somerfield MR, Hagerty KL, et al. American Society of Clinical Oncology/American Society of Hematology 2007 clinical practice guideline update on the use of epoetin and darbepoetin. J Clin Oncol 2007;25:[Epub ahead of print]. 26. Littlewood TJ. Efficacy and quality of life outcomes of epoetin-alpha in a double-blind, placebo-controlled, multicentre study of cancer patients 12 Hospital Physician Board Review Manual