ANEMIAS AND OTHER RED CELL DISORDERS - PART 3 ppt

66 OVERVIEW OF ANEMIA SECTION I Inflammatory cytokines disrupt erythropoiesis through effects additional to those on hepcidin and iron metabolism. IL-6 directly suppresses erythropoietin production, creating a state of relative erythropoietin deficiency for a given degree of anemia. 25 Other inflammatory cytokines likely contribute to suppressed erythropoietin production as well. At the distal end of the erythropoietic pathway, inflammatory cytokines suppress erythropoietin responsiveness of hematopoietic precursor cells. IL-1β, IFN-γ , and TNF-α play very prominent roles in this respect. When added to in vitro cultures of erythropoietic precursors, IFN-γ promotes apoptosis of these cells in direct opposi- tion to erythropoietin activity. 26 Other cytokines including TNF-α directly amplify this detrimental effect on hematopoiesis. 27 This pernicious result of inflammatory cytokines is compounded by a shortening in the half-life of circulating red cells. The anemia induced by inflammatory cells is therefore multifactorial in origin. Reactive oxygen species (ROS) generated as part of the chronic inflammatory state probably further exacerbate anemia in cancer patients. 28 ROS include a host of injurious compounds such as superoxide, the hydroxyl radical, and nitric oxide. Although nitric oxide is a very important biological second messenger, out of context the molecule is a potent oxidizing agent. These agents can injure cells by promoting production of lipid and protein peroxides as well as DNA cross-links. 29 Heavy oxidant damage leads to cell necrosis. Less severe injury triggers apoptosis with eventual cell death. Hematopoietic precursor cells are very sensitive to oxidant assault. Erythroid precursors appear to be particularly susceptible to this form of injury, perhaps because of their abundant iron content. Iron is a natural catalyst in the formation of ROS. Cells have a number of defenses against oxidant injury including enzymes such as superoxide dismutase, glutathione peroxidase, and glutathione reductase. Some of these defensive parapets are breached under the assault of cancer and cancer-induced pro-oxidants. 30 These perturbations likely contribute to the hemolysis and ineffective erythropoiesis that frequently characterize cancer-related anemia. Cancer-related anemia is a complex, multifactorial process. Dysregulation of iron metabolism due to hepcidin overproduction contributes heavily to the phenomenon, but is not the sole factor in the pathogenesis of cancer anemia. Direct suppression of hematopoiesis by inflammatory cytokines is also a key piece of the puzzle. Finally, oxidant compounds of various sorts injure hematopoietic cells, further exacerbating the problem. The complex nature of anemia in cancer means that no single or simple solution to the issue exists. ᭿ TREATMENT OF ANEMIA IN CANCER Elimination of the cancer and cure of the patient is the ultimate goal of any cancer treatment. As noted earlier, this goal often is frustratingly elusive, particularly with respect to the most common tumors such as lung, breast, and gastrointestinal malignancies. In these circumstances, problems such as anemia that diminish quality of life (QoL) assume much larger roles in management decisions. CHAPTER 5 CANCER AND ANEMIA 67 TRANSFUSIONS For cancer patients not deficient in iron, folate, or cobalamin, blood transfusion is the most clear-cut way to correct an anemia. Transfusion also is relatively straight- forward. In the late 1980s in the United States, an estimated one million units of blood were transfused yearly to correct or moderate the severity of anemia in patients with cancer. 31 This figure represented nearly 10% of the nation’s blood supply. The end of the 1980s also brought about an unparalleled trial to the practice of blood transfusion. Blood-borne infection has always been a transfusion risk. Infection with hepatitis viruses, cytomegalovirus, and even malaria were well-known problems within the medical community. However, the entry of the human HIV virus into the blood supply raised concern to the point of crisis. The mysterious nature of the infection struck fear into the hearts of patients and physicians alike. The terror gripped even many blood donors who, for instance, irrationally believed that HIV might be contracted merely by giving blood. The net result was a one of the greatest crises to confront modern medicine. The advent of effective screening procedures virtually eliminated HIV from the nation’s blood supply. 32 The psychological damage was done however, leaving blood transfusion under a pall of suspicion that persists to this day. In addition to infection risk, transfusions pose other problems for cancer patients. Repeated blood transfusions can produce iron overload and a host of consequent problems including heart and liver failure. No transfusion is a perfect antigenic match between donor and recipient. In particular, matching for minor red cell antigens is not routine, in contrast to the case with the major antigens ABO and Rh. Repeated transfusions can generate an immune response to minor antigens called alloimmunization. Alloimmunization complicates crossmatching and can render a patient refractory to transfusion due to the inability to identify compatible units of blood. In addition to these woes, cancer patients face a further burden related to an immune defense system weakened by the cancer itself or the chemotherapy used to treat the cancer. Immune- competent lymphocytes transferred from the blood donor in the transfused blood can trigger an immune attack against the recipient, producing graft-versus-host disease (GVHD). GVHD complicates the management of these already ill patients and at times is fatal. All transfusion products given to cancer patients should be irradiated to kill any lymphocytes and eliminate the risk of GVHD. These problems gave justifiable pause to the issue of transfusion in cancer patients. One of the few publishedassessments oftransfusion practicein cancerpatients showed that although 20% of patients in the late 1980s received a transfusion in the course of their care, the hemoglobin threshold used for those transfusions was quite low, often under 8 g/dL. 33 Concerns about transfusion safety intersected with a reduction in blood supply to impair patient well-being by lowering to a tenuous point the hemoglobin threshold used as a transfusion trigger. The advent of recombinant human erythropoietin (rHuEpo) provided an alternative to blood transfusion for management of anemia in these patients. With the exception of life-threatening or severe anemia (Hb <8 g/dL), rHuEpo products have superseded blood transfusion as the standard of care for these patients. 34 68 OVERVIEW OF ANEMIA SECTION I ERYTHROPOIESIS-STIMULATING AGENTS The search for alternatives to blood transfusion for the management of anemia intersected with the first great success in the genetic engineering of a drug, namely the production of rHuEpo. Patients with anemia due to renal failure were the first to reap a benefit from this marvel of recombinant DNA technology. Following this initial success, rHuEpo found a niche in the treatment of many other forms of anemia, including that seen in cancer patients. Cancer itself commonly produces anemia. The addition of chemotherapy raises the proportion from a minority to a large plurality or even a majority, depending on the nature of the drugs used in the particular treatment regimen. Agents in the cisplatin family of drugs are the most likely to produce anemia in cancer patients. 35 These drugs are mainstays in the treatment of many of the most aggressive malignancies, including cancers of the lung and GI tract. That being said, myelosuppressive chemotherapy agents of every class produce some degree of anemia. The advent of erythropoiesis-stimulating agents (ESAs; so called because some are modifications of natural erythropoietin) provided a new option for the treatment of anemia in cancer that is free of the risks associated with blood transfusion. The first approval in the United States for ESA treatment of cancer-related anemia came in 1993. This practice subsequently found favor in Europe and the rest of the world and is currently the standard of care. Since 1989 three ESAs have been approved and marketed for use in cancer anemia: epoetin alfa, epoetin beta, and darbepoetin alfa. Epoetin alfa and epoetin beta are cloned versions of natural human erythropoietin and are marketed by different pharmaceutical companies. 36,37 Darbepoetin alfa is a version of human erythropoietin engineered to have five glycosylation side chains rather than the three that occur normally. 38 The therapeutic half-life of this product substantially exceeds that of natural human erythropoietin. 39 ESAs are effective with either intravenous or subcutaneous administration (Table 5-4). However, the magnitude of the hematopoietic response differs dramati- cally for the two routes of delivery. Intravenous administration produces a sharp peak in the plasma drug level followed by a rapid decline. Erythroid precursors have relatively few erythropoietin receptors, generally as few as 1000 per cell. 40 This small number of receptors exists only during the BFU-E and CFU-E stages of development, a fairly narrow window in the progression of the erythroid lineage. Intravenously administered ESAs quickly saturate the erythropoietin receptors existing at the time of injection but dissipate before the next cohort of immature cells reach a receptive phase of development. Therefore, much of the intravenously administered ESA is effectively wasted. In contrast, drug delivered subcutaneously forms a small depot. The ESA seeps from the depot site into the circulation, providing a more sustained presence of drug in the plasma. The drug does not attain the high peak plasma concentration seen with intravenous administration. However, with a miniscule number of erythropoietin receptors that are quickly saturated, peak plasma drug levels are less important than drug duration in the plasma. CHAPTER 5 CANCER AND ANEMIA 69 TABLE 5-4 KEY MANAGEMENT POINTS WITH CANCER ANEMIA Issue Comments ESA support r Myeloid cancers such as acute leukemia are not eligible r Hemoglobin ≤ 11 g/dL r Best results with low serum erythropoietin r Replace iron if necessary r Twelve-week therapeutic trial r Validated only for anemia associated with chemotherapy r Transfusions as necessary r Higher hemoglobin values correlate with improved quality of life r Possible higher rate of thrombovascular events r Effect on survival is unsettled Transfusion r Indicated for severe anemia (Hb less than 8 g/dL) r Can be given along with ESA therapy r Transfusion products should be irradiated ESA use differs in the settings of anemia due to CKD and cancer-related anemia both with respect to drug dose and interval between drug administrations. The anemia of CKD most closely approximates pure erythropoietin deficiency, meaning that ESA use in this setting produces the most robust erythropoietic response. The complicated nature of cancer-related anemia means that erythropoiesis in response to ESA treatment often is blunted and sometimes absent. Drug doses required for an acceptable response usually exceed by twofold or more than those needed to treat CKD. Administration of ESAs for cancer-related anemia initially followed a thrice in a week (TIW) schedule. This routine grew out of the treatment approach for CKD where the first patients treated with ESAs underwent hemodialysis three times a week. TIW dosing in the hemodialysis setting matched a pre-existing requirement for medical encounters. Furthermore, this schedule appeared appropriate for the known short half-life of epoetin alfa and epoetin beta. A TIW treatment schedule is extremely inconvenient for people with cancer- related anemia who, unlike their CKD counterparts, have no reason for such fre- quent medical attention. Experimentation with dosing schedules showed that effective hemoglobin rises occurred with once-weekly administration of these ESAs if the drug dose was sufficiently high. 41 Treatment of cancer-related anemia gradually shifted to the more convenient weekly schedule. The engineering of darbepoetin alfa grew out of an effort to address the issue of dosing interval with the ESAs. Experiments with erythropoietin devoid of carbohydrate side chains showed the importance of glycosylation in erythropoietin biology. The bare erythropoietin protein disappears quickly from the circulation, apparently due to rapid degradation of the protein. 42 Nonglycosylated erythropoietin 70 OVERVIEW OF ANEMIA SECTION I consequently has little activity in the whole animal despite an excellent in vitro activity profile. Since erythropoietin without carbohydrate side chains has a short half-life in the circulation, the possibility existed that extra carbohydrate side chains might prolong the agent’s survival in the circulation. The genetic modification of erythropoietin structure in darbepoetin alfa produces five rather than three carbohydrate side chains. The drug does indeed have a longer activity profile than the previously existing ESAs. The initial administration schedule for darbepoetin alfa was weekly. Higher dosing later allowed administration of darbepoetin once in 3 weeks for cancer-related anemia. 43 This is a far more palatable schedule for patients since obligate medical encounters for chemotherapy often are once every 3 weeks. Experience with ESAs to treat cancer-related anemia has led to consensus definitions of drug efficacy. A positive response commonly is defined as an increase in hemoglobin level by 1–2 g/dL over the treatment course. The maximum hemoglobin level attained varies depending on the starting baseline hemoglobin value. Hemoglobin increments of less than 1 g/dL are unlikely to produce a clinically mean- ingful response (see below). The hematopoietic response to ESAs in cancer-related anemia is irregular both in magnitude and rate of onset. Up to 40% of patients fail to respond significantly to these agents. The basis of this heterogeneity is unclear. The fact that cancer-related anemia often displays a chronic inflammatory state with substantial cytokine activation makes plausible the contention that a storm of circulating cytokines sometimes overwhelms erythropoiesis activation by ESAs. Therapeutic approaches that include efforts at cytokine suppression might prove beneficial to patients who are otherwise refractory to ESAs. Predictive markers to identify patients who a priori will not respond to ESAs would provide valuable direction in the targeting of ESA therapy. Such markers currently are nonexistent. One possible approach to improving the therapeutic profile of ESAs is the administration of supplemental iron. Most patients with cancer-related anemia are not truly iron deficient. As noted earlier, however, hepcidin overexpression in response to cytokine activation often produces a relative degree of iron sequestration. Erythropoiesis is suboptimal due to the relative iron deficiency. Supplemental iron administration can partially overcome this trapping effect by providing transient surges in mineral availability in the circulation that can be used briefly for hematopoiesis before the iron is sequestered away. Few published investigations directly address the question. In one study, patients given iron dextran either as total dose infusion or as smaller intermittent boluses had substantially better hemoglobin increments in response to ESA treatment than did control patients who received either no iron supplementation or iron as an oral preparation. 44 Assuming that corroborating data are forthcoming, the study suggests that iron bioavailability for erythropoiesis in cancer patients is a dynamic process. Boluses of parenteral iron create a brief crack in the wall of iron impris- onment created by high levels of hepcidin. During this wrinkle in time, the erythropoietic machinery has the opportunity to use some of this iron for new red cell production. CHAPTER 5 CANCER AND ANEMIA 71 Iron supplementation in anemic cancer patients is not without risk. Since these patients usually are not deficient in total body iron, supplementation opens the possibility of iron overload as a complication. Careful monitoring along with the administration of the smallest quantity of parenteral iron that will temporarily perturb the block in hemoglobin synthesis should provide an adequate safety margin. A less well-defined risk is the possibility of tumor progression in response to supplemental iron. Although iron deficit can blunt tumor proliferation, little data support the contention that iron surfeit promotes tumor growth. Nonetheless, any study that assesses iron supplementation should address this issue. The conceptually related idea that excess iron could create an infection risk (a hypothesis with considerably more supporting data) also deserves exploration. Malignancies that involve the primary blood-forming elements of the bone marrow are generally excluded from ESA treatment. Acute leukemia in particular is not eligible for this form of therapy. Lymphoma and multiple myeloma are malignancies that derive from the lymphoid branch of the hematopoietic system. Both commonly produce substantial anemia and both respond well to treatment with ESAs. Among the solid tumors, the incidence of anemia varies greatly, as noted above. The rate of response to ESA treatment does not appear to vary across the spectrum of cancer subtypes. 45 Irrespective of tumor type or other obvious distinctions, ESA treatment produces poor responses in some patients and brisk responses in others. A rapid rise in the hemoglobin level, for instance an increase of more than 2 g/dL over 2 weeks, places patients at risk for complications, such as dangerous rises in blood pressure. Con- sequently, careful monitoring of the rate of hemoglobin rise and the blood pressure status is essential to the safe use of ESAs in the treatment of cancer-related anemia. Similarly, the magnitude of the hemoglobin response can be a source of concern. Early studies of ESAs in the setting of cancer anemia often permitted the hemoglobin value to rise into the high normal range, namely 14–15 g/dL. However, patients with cancer are not normal. Reports of serious thrombovascular complications including strokes, myocardial infarctions, and deep venous thromboses prompted the imposi- tion of a 13 g/dL ceiling on hemoglobin values deemed acceptable in this treatment setting (see below). For patients who exceed that value, ESA therapy is held until the hemoglobin value declines to an acceptable range. Treatment is restarted at a lower dose if continued therapy is necessary. Although no existing test predicts patient response to ESAs, careful early monitoring provides guidance into the possible magnitude of the hemoglobin rise. About three-quarters of patients for whom hemoglobin values rise by 1 g/dL or more during the first 4 weeks of therapy eventually have a positive therapeutic response. 46 By contrast, only one-quarter of patients who fail to meet this milestone will have a positive response to continued ESA treatment. The 1-g/dL threshold augurs fa- vorably for response to ESAs both in patients on chemotherapy and those who are treatment na¨ıve. 47 An algorithm that combines a greater than 1 g/dL ESA response at 4 weeks, baseline transfusion independence and a favorable erythropoietin level predicts a favorable ESA response 85% of the time. 72 OVERVIEW OF ANEMIA SECTION I Baseline erythropoietin levels indicate the extent to which renal production of the hormone has risen in response to anemia. High erythropoietin levels at the start of treatment means that bone marrow erythroid precursor cells have substantial expo- sure to the hormone. Pharmacological intervention with an ESA consequently faces a serious challenge in the quest to further accelerate erythropoiesis. In contrast, the combination of a low baseline erythropoietin level (<100 mIU/mL) and a rise in hemoglobin of >0.5 g/dL at 2 weeks gives a 95% prediction of a positive erythropoietic response. 48 ANEMIA SEVERITY AND ESA TREATMENT The issue of effective ESA use in cancer-related anemia is a broadly important question in medicine. The problem has implications of both medical and economic importance. The former reflects the impact of ESAs on patient well-being. The latter reflects the impact of ESAs on health-care costs. The point of inflection between a net positive and a net negative scenario is an issue involving complex considerations. Additional careful consideration of the subject is warranted. A plethora of studies address the issue of medical use of ESAs in cancer-related anemia. The quality of these studies varies greatly, along with the design and objec- tives of the work. At the behest of the Agency for Healthcare Research and Quality, the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) convened an expert panel to review the data and make recom- mendations. Over the course of several years, the panel evaluated the literature published between 1985 and 1999, and issued an evidence-based clinical practice guideline. 49 These voluntary guidelines recommended use of epoetin for cancer patients with anemia where the hemoglobin value was ≤10 g/dL. For cancer patients “with declin- ing hemoglobin levels but less severe anemia (those with hemoglobin concentration below 12 g/dL but who never have fallen below 10 g/dL), the decision of whether to use epoetin immediately or to wait until hemoglobin levels fall closer to 10 g/dL should be determined by clinical circumstance.” The latter recommendation reflected the fact that while existing data on the whole favored the use of epoetin in this setting, the studies were small and mainly unblinded. That along with inconsistent statisti- cal treatments across the spectrum made impossible any definitive statement on the matter. The initial large studies of ESAs in cancer anemia not surprisingly focused on patients with more severe degrees of anemia. Additional reports involving patients with milder anemia appeared after the ASCO/ASH panel disbanded. One review evaluated 69 publications from between 1999 and 2004, deeming 11 worthy of detailed analysis based on size, design, and completeness. 50 The composite data strongly supported the benefit of ESA therapy in patients with hemoglobin values exceeding 10 g/dL. The recommendation, which dovetailed with that of the National Comprehensive Cancer Network, was that clinicians consider ESA intervention for patients with hemoglobin values ≤11 g/dL. The European Organisation for Research and Treatment of Cancer Guidelines set a hemoglobin target range of 11–13 g/dL. CHAPTER 5 CANCER AND ANEMIA 73 The key studies involving ESA use in cancer anemia have addressed patients un- dergoing chemotherapy. The role of ESAs in the management of the 30% of cancer patients who are anemic in the absence of myelosuppressive chemotherapy is un- known. The growing use of biological agents, such as monoclonal antibodies and hormones, along with directed therapies, such as drugs aimed at tyrosine kinase enzymes, means that the fraction of cancer patients who do not fit the vetted profile for ESA use will grow. Also outside the circle of defined use are the large number of people who receive myelosuppressive agents as part of adjuvant treatment regimens. Only additional investigation will provide the needed answers. ᭿ IMPACT OF ANEMIA IN CANCER In the context of a pernicious and potentially fatal illness, anemia sometimes receives little attention from health-care providers. Recently, however, the increased weight given to issues of QoL in circumstances where cancer cure is not possible has brought greater attention to the impact of anemia. 51 Fatigue and dyspnea are the key manifes- tations in people with anemia of any cause, and this holds for anemia in the setting of cancer. 52 The impact of fatigue on the well-being of patients with cancer is often substantial. No objective measure for fatigue exists, making its assessment difficult. The development of an objective scoring system for the problem has made possible the sys- tematic investigation of the impact of fatigue on the well-being of patients in general and cancer patients in particular. A commonly used questionnaire is the Functional Assessment of Cancer Therapy (FACT). 53 The version of this instrument that assesses anemia (FACT-An) entails a series of questions that describe anemia along with related fatigue and assesses their effect on well-being relative to other problems commonly faced by cancer patients, including nausea, pain, and depression. 54,55 In addition, patients estimate the impact of fatigue on other aspects of their lives such as social functioning, ability to work, and dependence on the person(s) providing them with primary help and support. Open-ended questions allow patients to fill in other important aspects of their clinical experience. Another tool used to determine the impact of fatigue is the Linear Analogue Scale Assessment (LASA). 56 Here, a 100-mm line represents the patient’s sense of well-being, with one end indicating “worst” and the other “best.” The line is segmented by nine small bars spaced 10 mm apart. At the start of the study, the patient marks the point along the line that best corresponds to his or her sense of well-being. Subsequent evaluations involve the patient placing indicators on new line with no previous assessment marking that the patient might use as a reference. Investigators can compare the scales at the end of the study, thereby gaining a feel for changes in the patient’s sense of well-being over the interval. Pooled patient LASA data provides a window into the benefit of the treatment intervention. LASA data are easier to collect than that from FACT-An surveys. The penalty for the tool’s simplicity is greater variability of outcome. Consequently, LASA instruments perform best when used in the setting of large study cohorts. 57 74 OVERVIEW OF ANEMIA SECTION I ESA THERAPY AND PATIENT QUALITY OF LIFE A key observation is that cancer patients with mild anemia, i.e., hemoglobin values in the 10–11 g/dL range, have significant symptoms and debility. Two studies of cancer patients in community treatment settings reviewed over 4000 patients and recorded responses to interventions designed to correct the anemia. 58,59 Substantial improvements in the QoL measures paralleled rises in hemoglobin values. Inter- estingly, the most marked improvement occurred with a hemoglobin rise from 11 to 12 g/dL, supporting the practice of intervening before severe anemia develops. 60 Hemoglobin values in this mild range commonly drew little notice in the past. A 1-g rise in hemoglobin values from 11 to 12 g/dL often would have been dismissed as an insignificant change. However, this degree of rise in hemoglobin level improved QoL measures even in patients whose underlying cancer progressed. This observation indicates that hemoglobin rise is not simply a surrogate for cancer treatment response with respect to enhanced patient well-being. Over half of patients in one large study reported that fatigue had a significant negative impact on their lives. 61 Despite the clinical impact of fatigue, more than half of the patients never discussed the issue with their health-care providers. A sense of resignation existed among many of the patients in whom they assumed that chronic debilitating fatigue was a reality they simply had to live with. Interestingly, only 14% of patients who experienced fatigue reported that an intervention was prescribed or recommended for the problem. The most common recommendation was for the patient to “have a rest.” Fatigue produces significant difficulties for patients, including diminished energy levels, a need to slow down from a normal pace of living, and a general sense of sluggishness or tiredness. Ninety percent of patients in one study reported that fatigue prevented them from leading a normal life and forced an alteration in their normal daily routine. 62 Sixty percent of these patients reported that fatigue exceeded nausea, pain, and depression as a negative factor in their lives. Other problems associated with fatigue were decreased motivation or interest, difficulty concentrating, and difficulty remembering dates and “keeping things straight.” Ordinary activities such as walking or house cleaning become new challenges as a result of fatigue. Three-quarters of patients are forced to change their employment status and one-quarter discontinued work altogether due to fatigue. The caregivers for these individuals also suffer, with one in five taking more time off from work or accepting fewer responsibilities. Fatigue can reach such distressing proportions that 1 in 10 patients report an urge to die in the face of this problem. 63 Fatigue resulting from anemia clearly is a major problem in cancer. Another trial failed to identify an optimal hemoglobin level for improvement of QoL. 64 Nonetheless, an increase in hemoglobin of at least 2 g/dL from baseline (without transfusion) correlated significantly with improvements in QoL. These results are in accord with another study in which increases in hemoglobin concentration (as opposed to reaching a predefined target hemoglobin level) produced the greatest improvement in QoL. 65 A study of over 300 patients in the Netherlands showed that ESA therapy for patients with hemoglobin values below 12 g/dL reduced the need CHAPTER 5 CANCER AND ANEMIA 75 for transfusion, increased aggregate hemoglobin levels, and improved QoL. 66 The lesson of these trials is that treatment intervention before severe anemia develops (Hb ≤10g/dL) averts side effects that greatly hamper patients with anemia. ESA THERAPY AND TRANSFUSION REQUIREMENT Elimination of the need for transfusion is a key goal in the use of ESAs in cancer- related anemia. Although complete abolition of transfusions often is not possible, trials with blood transfusion as a study end point generally show reductions that range between 10% and 50%. 67,68 Since as many as 40% of patients treated with ESAs fail to respond to the drugs, the benefit in transfusion avoidance is substantial for the group of people who do respond to these agents. Chemotherapy regimes that use agents in the platinum family of drugs (e.g., cisplatinum) are mainstays in the treatment of many of the common solid tumors, including malignancies of lung, GI, and ovarian origin. These agents also have powerful myelosuppressive qualities, with severe anemia as a common sequel. In an investigation involving over 300 such patients, 36% of the ESA-treated group required transfusion, compared with 65% of controls. 69 Furthermore, the ESA group required only 1.5 units of blood on average, while the value was 3.1 for the controls. Finally, the ESA-treated patients had higher aggregate hemoglobin values during treatment and better QoL scores. The net result is strong support for the use of ESAs in these patients. IMPACT OF ESA THERAPY ON SURVIVAL The question of whether ESA therapy alters the survival of patients with cancer-related anemia has drawn great scrutiny and engendered intense debate. From a theoretical standpoint, arguments exist for ESAs prolonging or shortening survival. Correction of anemia might improve perfusion and oxygenation of tumors, making them more susceptible to anticancer treatments. Hypoxic tumors are more resistant to radiation therapy since the effect of this intervention depends in part on the generation of ROS. 70,71 ROS are important to the action of some chemotherapy agents, such as doxorubicin. 72 In addition, the improved sense of well-being associated with ESA therapy might allow some patients to adhere more closely to debilitating chemotherapy regimens. On the other side of the equation lies the fact that erythropoietin is a growth promoting hormone. 73,74 Although erythropoietic precursors are the primary site of erythropoietin receptors, other tissues also express functional receptors. 75 Data suggesting possible erythropoietin receptor expression by tumor cells give pause for contemplation. 76 However, two studies in particular raised serious questions about the impact of ESAs on the survival of patients with cancer. One investigation with over 900 patients involved epoetin alfa treatment of women with metastatic breast cancer, most of whom were not anemic. 77 The investigation used a randomized, placebo-controlled, double-blind design. Higher mortality among the patients receiving epoetin alfa prompted early termination of the trial. No clear cause for the difference existed, although a larger number of deaths from thrombovascular events in the treated group contributed to some of the excess mortality. [...]... haemoglobin S and beta-thalassaemia traits Ann Trop Med Parasitol 77: 239 –246 Modiano D, Luoni G, Sirima BS, et al 2001 Haemoglobin C protects against clinical Plasmodium falciparum malaria Nature 414 :30 5 30 8 Mockenhaupt FP, Ehrhardt S, Cramer JP, et al 2004 Hemoglobin C and resistance to severe malaria in Ghanaian children J Infect Dis 190:1006–1009 92 OVERVIEW OF ANEMIA 29 30 31 32 33 34 35 36 37 38 39 40... 1992 Basis of unique red cell membrane properties in hereditary ovalocytosis J Mol Biol 2 23: 949–958 93 REFERENCES 48 49 50 51 52 53 54 55 56 57 Schofield AE, Reardon DM, Tanner MJ 1992 Defective anion transport activity of the abnormal band 3 in hereditary ovalocytic red blood cells Nature 35 5: 836 – 838 Sarabia VE, Casey JR, Reithmeier RA 19 93 Molecular characterization of the band 3 protein from Southeast... of red cell invasion and multiplication Red cells are constantly created and then destroyed as they age and senesce A mutation that somehow destroys both the infected red cells and the parasite could eliminate the malaria parasite Newly 86 OVERVIEW OF ANEMIA SECTION I produced healthy cells would replace the infected cells destroyed by the defense response ᭿ MALARIA AND THE RED CELL The morbidity and. .. membrane oxidation by hemichromes and the reactive oxygen species they generate.29 ,30 These reactive oxygen species also injure and kill malaria parasites .31 Cells containing hemoglobin H (β-globin tetramers) provide the best in vitro evidence of malaria toxicity produced by thalassemic red cells .32 ,33 Hemoglobin H occurs most often in people with three-gene-deletion α-thalassemia (see Chapter 14) The... condition of two-gene-deletion α-thalassemia and hemoglobin Constant Spring also produces erythrocytes that contain hemoglobin H .34 Two-gene-deletion α-thalassemia alone also protects the host from malaria, apparently by retarding parasite growth in erythrocytes .35 α-Thalassemia might provide additional protection against malaria in part by altering the immune response to parasitized red cells .36 In any... of hemolysis and resistance to malaria Blood 67 :33 1 33 3 Roth EF, Jr, Raventos-Suarez C, Rinaldi A, Nagel RL 19 83 Glucose-6-phosphate dehydrogenase deficiency inhibits in vitro growth of Plasmodium falciparum Proc Natl Acad Sci U S A 80:298–299 Usanga EA, Luzzatto L 1985 Adaptation of Plasmodium falciparum to glucose 6phosphate dehydrogenase-deficient host red cells by production of parasite-encoded enzyme... Skillings JR, Sridhar FG, Wong C, et al 19 93 The frequency of red cell transfusion for anemia in patients receiving chemotherapy: A retrospective cohort study Am J Clin Oncol 16:22–25 78 OVERVIEW OF ANEMIA 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 SECTION I Rizzo JD, Lichtin AE, Woolf SH, et al 2002 Use of epoetin in patients with cancer: Evidence-based clinical practice guidelines of... 34 35 36 37 38 39 40 41 42 43 44 45 46 47 SECTION I Grinberg LN, Rachmilewitz EA, Kitrossky N, Chevion M 1995 Hydroxyl radical generation in beta-thalassemic red blood cells Free Radic Biol Med 18:611–615 Sorensen S, Rubin E, Polster H, Mohandas N, Schrier S 1990 The role of membrane skeletal-associated alpha-globin in the pathophysiology of beta-thalassemia Blood 75: 133 3– 133 6 Clark IA, Chaudhri G, Cowden... 48 :39 0 39 7 Carlson J, Nash GB, Gabutti V, al-Yaman F, Wahlgren M 1994 Natural protection against severe Plasmodium falciparum malaria due to impaired rosette formation Blood 84 :39 09– 38 14 Udomsangpetch R, Sueblinvong T, Pattanapanyasat K, Dharmkrong-at A, Kittikalayawong A, Webster HK 19 93 Alteration in cytoadherence and rosetting of Plasmodium falciparuminfected thalassemic red blood cells Blood 82 :37 52 37 59... MALARIA AND THE RED CELL 83 FIGURE 6–1 Leading causes of death in children from developing countries (in 2002) (Source: World Health Organization The World Health Report 20 03. ) cells, enter the blood stream, and penetrate red cells Here the parasites begin their second phase of growth and maturation Parasites in the trophozoite or ring stage are the usual form seen in the peripheral blood (Figure 6 -3 ) The . phase of red cell invasion and multiplication. Red cells are constantly created and then destroyed as they age and senesce. A mutation that somehow destroys both the infected red cells and the. with chemotherapy-related anemia: A multicenter, open-label, randomized trial. J Clin Oncol 22 :30 1 30 1. 45 Gabrilove JL, Cleeland CS, Livingston RB, et al. 2001. Clinical evaluation of once-weekly dosing. meta-analysis of 57 studies including 935 3 patients. J Natl Cancer Inst 98:708–714. CHAPTER 6 MALARIA AND THE RED CELL ᭿ MALARIA 82 ᭿ MALARIA DEFENSES 84 ᭿ MALARIA AND THE RED CELL 86 Malaria has had a greater

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