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Indian Journal of Cancer, Vol. 48, No. 1, January-March, 2011, pp. 1-10 Symposium Optimising management of cancer related anemia K Prabhash1, S Nag2, S Patil3, PM Parikh1 1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India Correspondence Address: Abstract This review article provides the current recommendations and evidence for the correct management of anemia in cancer patients. The various options available include transfusions, iron and erythropoiesis stimulation. The indications, pros and cons of each option are discussed.Keywords: Energy, erythropoietin, fatigue, iron, quality of life, survival, tumor Introduction Cancer related anemia (CRA) is a major healthcare problem. As many as three-fourths of cancer patients have anemia at some time during their illness (66% for solid tumors and 72% for hematological malignancies), 40% of them (36% of solid tumors and 47% of hematological malignancies) being severe enough to warrant red blood cell (RBC) transfusions. [1] This is true both during active treatment (62%) as well as during follow-up (38%). In the Indian context, these figures are likely to be higher due to the prevailing malnutrition in the general population. [2],[3],[4] It also varies with the underlying type of cancer, being highest for lung and ovarian cancer. [5] Factors that predict development of CRA include advancing age, baseline Hb levels, transfusions in the past 6 months and myelosuppressive therapy (chemotherapy or radiation therapy) [Table - 1], [Table - 2] and [Table - 3]. [6] There is a general consensus that Hb levels below 8 g/dl are considered severe. To label patients as having mild anemia, National Cancer Institute (NCI) uses the scale between 10 g/dl and normal value for that lab, whereas World Health Organization (WHO) uses the scale of between 9.5 and 11 g/dl. [7],[8] Causes of Cancer Related Anemia Physiological mechanisms to maintain adequate RBC production in our body are governed by the level of oxygenation as detected by the peritubular interstitial cells in the kidneys. These cells signal the secretion of erythropoietin (EPO) which in turn acts as an endocrine hormone and stimulates RBC precursors in the bone marrow. In cancer, anemia occurs due to several reasons, the common ones being nutritional deficiency, hemolysis, blood loss, infiltration of the bone marrow by tumor cells and myelosuppression due to therapy (chemo and radiation therapy) [Table - 2]. [9],[10] In addition, cancer per se is also an important cause of anemia of chronic diseases (others being infections, inflammatory disease and renal failure). The CRA of chronic disease is characterized by being proportional to the tumor burden and a relatively late manifestation of the malignancy. This is due to functional iron deficiency, shortened RBC lifespan and reduced production of EPO (mediated by inflammatory cytokines). [9] Consequences of Cancer Related Anemia If not corrected, this anemia leads to compromised quality of life (QoL; fatigue, poor performance status, impaired cognitive function, aggravation of existing co-morbidities like respiratory and cardiovascular illnesses) and even premature death (poor tolerance to chemotherapy, compromised dose intensity and tumor progression). [6] It is well documented that cancer patients with anemia (Hb < 10 g/dl) have more symptoms and poorer performance status, there being a linear correlation between Hb levels of 7 and 12 g/dl). [1],[2],[6] Investigations in Cancer Related Anemia For any cancer patient with Hb of less than 11 g/dl or below the lower limit of normal by ≥2 g/dl, the 2011 National Comprehensive Cancer Network (NCCN) guidelines recommend complete evaluation of its cause [Table - 4]. [9] Once CBC with indices, reticulocyte count and examination of peripheral blood smear are done for morphology, additional tests may be required to identify the cause (hemolysis, heredity, nutritional, renal, hemorrhage and therapy induced myelosuppression). If no cause is identified, the patient is presumed to have anemia of chronic illness/cancer. Functional Iron Deficiency In patients with anemia of chronic disease (including CRA), the liver produces hepcidin which reduces the absorption of iron from the upper gastrointestinal (GI) tract as well as impairs iron utilization. [11] This leads to functional iron deficiency. Patients with CRA should undergo evaluation for ferritin and transferrin saturation levels. If the ferritin is >800 ng/ml or transferrin saturation is >20%, the patient does not have iron deficiency. On the other hand, if ferritin is <800 ng/ml and transferrin saturation is <20%, the diagnosis of functional iron deficiency is established. [12] Therapy of Cancer Related Anemia Once CRA is diagnosed, the goals of therapy are to improve Hb levels, improve QoL and reduce the need for RBC transfusions. Several studies have elegantly shown that correct treatment of CRA leads to symptom control, improvement in QoL and even better overall outcomes. [2],[13],[14] In fact, even patients with mild anemia document significant improvement in fatigue when their Hb is restored [Table - 5]. Till as late as 1991, the only management option was use of blood transfusions. Then, erythropoietin stimulating agents (ESAs) became available. However, the focus still remained on the treatment of only severe anemia. The current era of emphasis on QoL began in 1998. Additional data and new therapies now (after 2004) have expanded the treatment options to include oral iron therapy, parenteral iron therapy, RBC transfusions and ESAs. [2],[3],[15] Iron Therapy If the patient has iron deficiency, it needs to be corrected by using iron supplementation. [16] This is usually recommended when the transferrin saturation is <20%. A recent study suggested that improvement in hemoglobin and QoL may be better with intravenous iron. [17] Traditionally, iron therapy has been given orally as ferrous gluconate, ferrous sulfate or ferrous fumarate at a daily dose of 325 mg three times daily. Though the total dose given is the same, these preparations vary in the amount of elemental iron available in them, with the amounts being 35, 65 and 108 mg, respectively. The other options include different salts of iron and drug delivery systems. An advantage of oral iron is its convenience of administration. Disadvantages are delay in response, no response in patients with functional iron deficiency, GI symptoms (diarrhea, constipation, cramps, dysphagia), altered taste, and discoloration of teeth (with liquid preparations). Up to 20% of patients discontinue oral iron due to such side effects. [18] Strategies to reduce these side effects include initiating oral iron at half the recommended dose for the first 2 weeks, taking the medication with meals (risk is reduction in iron absorption to 50%), dividing the daily dose, simultaneous use of stool softeners and changing to a different formulation as required. [16],[18] Parenteral iron is available as iron dextran, iron sucrose and ferric gluconate [Table - 6]. The latter two are preferred since they have the advantages of easier administration, lesser side effects and better Hb response. [17] In the last few years, the usage of iron dextran has reduced significantly, and currently, iron sucrose is the most commonly used parenteral iron preparation. Red Blood Cell Transfusions Transfusions have been traditionally reserved for the treatment of more severe anemia (Hb < 8 g/dl), especially if it has developed rapidly or if the patient is hemodynamically compromised/has significant co-morbidities that aggravate symptoms. [15] For asymptomatic cases, the objective is to maintain Hb at or near 9 g/dl. For symptomatic patients or patients with significant comorbidities (acute hemorrhage, acute coronary syndrome, acute myocardial infarction), the aim is to ensure that the patient becomes hemodynamically stable and relieved of symptoms, irrespective of Hb levels (usually the Hb will need to be increased to at least 10 g/dl). [15] The usual mode is to use packed RBC transfusions. Recently, practice management guidelines for red blood cell transfusion in adults were developed by a joint taskforce of Eastern Association for Surgery of Trauma (EAST) and the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM). [19],[20] They found a lack of level 1 evidence for several critical issues. Hence, the majority of their recommendations fall under level 2. They clearly state that RBC transfusion is associated with the risk of increased nosocomial infections, multiorgan failure (MOF), systemic inflammatory response syndrome (SIRS), longer ICU and hospital length of stay, increased complications and increased mortality. Other than ESAs, there are no established alternatives to RBC transfusions. They also recommend important steps for reducing RBC transfusions (e.g. use of low-volume adult or pediatric blood sampling tubes, blood conservation devices for reinfusion of waste blood, intraoperative and postoperative blood salvage and reduction in diagnostic laboratory testing). Unfortunately, most of them are not applicable in the oncology setting. Erythropoietin Stimulating Agents Commonly available ESAs are broadly divided into recombinant human EPO and prolonged acting versions (Darbepoetin). [13],[14],[21] For the management of CRA, patients may receive one or more of the above agents for variable durations. Typically, EPO is recommended at a dose of 150 units/kg three times a week or 40,000 units weekly subcutaneously [Table - 7]. Darbepoetin is usually given at a dose of 2.25 μg/kg weekly or 500 μg once in 3 weeks subcutaneously. Littlewood and colleagues showed in 2001 that as compared to placebo, use of ESAs led to rise in Hb levels after 2 weeks, reached about 12 g/dl by week 10 and maintained the benefit till the end of study (week 28). [24] Appropriate use of ESA improves fatigue and energy rating score consistently. Vadhan-Raj and colleagues have shown this elegantly in the report on the Successful Outcomes in Anemia Research (SOAR) trial that evaluated Functional Assessment of Cancer Therapy (FACT)-Fatigue and the Linear Analogue Scale covering more than 1000 patients. After 8 weeks of ESA therapy, the improvement documented was 4.6 points on the FACT-Fatigue score and 7.3 points in energy score, benefits that continued till the end of the study. [25] The improvement in fatigue was related to the hemoglobin rise (no increase vs. 1-2 g/dl rise vs. rise by >2 g/dl). Another study also showed that there is a linear correlation up to Hb level of 12 g/dl, after which the curve tends to flatten. This also correlated with diminished requirements of blood transfusions. [26] Side effects of ESA are well documented. [27],[28],[29],[30],[31] The US Food and Drug Administration (US FDA) black box warnings include increased mortality, cardiovascular, thromboembolic events and tumor progression. The controversy surrounding this is mentioned later in this article. There are ways by which such eventualities may be anticipated. For instance, Henry et al, have shown that for patients on ESAs whose platelet count increases to >350,000/ml, the risk of developing thromboembolism was increased by 2.9 times (P = 0.036). [32] How to optimize the use of ESA is shown in [Table - 8]. Auerbach et al, studied 157 patients with CIA on ESAs.[33] They were randomly assigned to additional therapy as follows: arm 1: no iron; arm 2: oral iron 325 mg twice daily; arm 3: bolus parenteral iron 100 mg intravenous; or arm 4: infusional parenteral iron total dose. At 6 weeks, the change in Hb from baseline was highest for the arms receiving parenteral iron (2.4-2.5 g/dl) as compared to no iron (0.9 g/dl) and oral iron (1.5 g/dl). In both instances, the P value was <0.05 (statistically significant). This improvement in Hb was independent of baseline transferring saturation though the statistical significance was higher for those with TS of <15% (P = 0.0002 vs. P = 0.006 for those with baseline TS of ≥15%). Patients on ESA therapy also have lower requirement of RBC transfusion irrespective of baseline Hb level, as shown by Witzig and others. [34] [Table - 9] summarizes the advantages and disadvantages of these two important modes of managing CRA. Controversy Three years ago, the US FDA warned of safety issues with the use of ESAs. [27],[31] This was based on studies that were interpreted to show increased risk of death, blood clot, stroke, and heart attack in patients with chronic renal failure (CRF) receiving ESAs, more rapid tumor growth in patients with head and neck cancers as well as increased risk of death among patients with cancer receiving ESAs. [13],[14] Attention was not paid to the fact that the first two were in patients continuing to receive ESAs in higher doses and for longer than is recommended, whereas the third study was in patients not receiving chemotherapy. This is a classic example of going overboard on the basis of overinterpretation as a measure of "abundant precaution", an initiative that actually has the potential to deny effective therapy to a significant number of patients with CRA and ultimately leading to the adverse outcome, the very same problem that it was intended to prevent. [21],[29],[30] Better sense prevailed on the other side of the Atlantic Ocean. Clinical experts from Europe, medical societies like European Organisation for the Research and Treatment of Cancer (EORTC) as well as the European Medicines Agency (EMEA; the European medical authority) reviewed the new and available data only to reaffirm their original conclusion - that when ESAs are used according to approved indications and guidelines recommended by EORTC, they remain safe and benefits outweigh risks. [22],[28] ESAs are indicated for cancer patients receiving chemotherapy (either alone or concomitant with radiotherapy), whose Hb is less than 10 g/dl or who have symptoms related to anemia that compromise their QoL. [9] They should also be evaluated for other causes that may attribute to anemia and, if found, should be managed simultaneously. Such patients should be given the recommended dose of ESAs, monitored regularly and as soon as their Hb reaches 12 g/dl, should be discontinued from further ESAs. [9],[13],[14] On follow-up, if such patients show a drop in Hb to below 10 g/dl, ESA can be restarted using the same precautions. Clearly, for patients with normal Hb, prophylactic use of ESAs is not recommended. The gray area is asymptomatic patients whose Hb is between 10 and 12 g/dl. Decision whether to start ESA or not needs to be taken on a case to case basis. As far back as in 2004, EORTC recommended that ESAs are to be used only when cancer patients have an Hb that is <11 g/dl and have symptoms. [22] The use of ESAs in the USA has often been for asymptomatic patients or in the prophylactic setting. This overenthusiasm has been associated with some indication of adverse outcomes, though data are neither robust nor consistent. In short, there is no increase in ESA risks if cancer patients are treated within the framework of existing guidelines, label and recommendations. [35],[36] What is the hypothesis that explains the mechanism by which ESAs lead to poorer outcome in cancer? It is said that tumor cells may overexpress erythropoietin receptors (EPO-R) that can stimulate their growth when using ESAs. [37],[38],[39],[40] In one study, more than 1000 tumors were evaluated for the level of EPO-R expression. It concluded that malignant tumors rarely express its messenger RNA. This study using stringent methodology also failed to demonstrate any significant presence of EPO-R on the surface of tumor cells. It is important to note that previous studies were flawed since they used monoclonal antibodies that crosslink with other proteins such as the ubiquitous chaperone protein - heat shock protein 70. [38] The study by Henke et al, is a classic example. [39] It is said to show that head and neck cancer patients enrolled in a phase III trial (epoietin beta vs. placebo) had a significant decrease in locoregional progression-free survival for overexpressing patients treated on the erythropoietin arm (vs. placebo; P = 0.003). Fortunately, Blau et al, [40] did a review to confirm this by looking at EPO-R mRNA levels in 101 of the archived tissue samples from the Henke study. It was not surprising that they found no correlation between EPO-R mRNA levels and EPO-R protein levels reported in the study by Henke et al. [39] Coupled with the fact that the study patients treated with radiation therapy and EPO were often found to have Hb levels of 15 or 16 g/dl, evidence leads to the logical conclusion that the adverse outcome in these patients is due to not stopping ESA when Hb reached 12 g/dl but is rather due to stimulation of EPO-R on tumor cells. A recent meta-analysis of 27 trials (including more than 10,000 patients) and four large prospective randomized trials (totaling 7000 patients) draws the same conclusion. [41],[42] Now, let us address the recommendation of EMEA Committee for Medicinal Products that for patients treated with curative intent, RBC transfusion (as compared to ESAs) is the lesser evil. Is this based on "eminence" based medicine or is there robust evidence to back this up? [43],[44] In the pre-ESA era, transfusions were considered as the only option and have never been subject to systematic evaluation. The potential disadvantages of using RBC transfusions are well established - febrile reactions, sensitization, transmission of infectious diseases, immunesuppression, to name a few. In 2008, Khorana et al, published data on 504,208 hospitalizations of patients with cancer, between 1995 and 2003, at 60 US medical centers. Their data showed that RBC transfusions are associated with 7.2% incidence of venous thromboembolism (vs. 3.8% for those not getting transfusions), 5.2% incidence of arterial thromboembolism (vs. 3.1% for those not getting transfusions) and a higher risk of inpatient mortality. [19] Studies have even cast a doubt that stored blood is even more associated with some of these effects (leading to increased complications and even poorer survival). [44] Even among patients being given potentially curative therapy, meta-analysis shows that RBC transfusions are associated with adverse outcome, some of the same parameters used against advocating use of ESAs. [43] Why then is there no impetus to advocate well-designed prospective randomized studies to establish clearly the risks and benefits of RBC transfusions in cancer? Now, let us examine the incidence of venous thrombosis. [19],[45],[47],[48],[49],[50],[51] Cancer patients are known to have a higher risk of such episodes even without any therapy, the incidence varying from 4 to 20%. The risk of venous thrombosis is 4.1 times higher as compared to a patient without cancer and it increases to 6.5 times if the patient is on chemotherapy. These episodes are also known to reduce survival. This is because a patient with venous thrombosis has a 25% risk of developing pulmonary embolism and that, in turn, results in a 20% risk of death.[47],[49] But this is not due to a single factor. Known causes and risk factors can be divided into three broad groups - patient related, cancer related and therapy related. [50],[51] Patient related factors include comorbidities, increasing age, elevated platelet count and previous history of venous thrombosis. Cancer related factors include the presence of metastasis, primary tumors in pancreas, gastrointestinal tract and brain tumors. Thrombosis is also higher within the first 6 months of diagnosis. Causes related to therapy have been associated with several factors including hospitalization, central venous access devices, major surgeries and systemic chemotherapy, hormonal therapy, ESAs and anti-angiogenic therapy. The common underlying mechanism is that cancer patients have a hypercoagulable state involving interleukin 1 (IL-1) and tumor necrosis factor (inducing expression of tissue factor on monocytes/endothelial cells and activating factor VIIa), tissue factor and cancer procoagulants (activating the extrinsic pathway) as well as thrombin (leading to platelet aggregation).[52] It is important to remember that the upregulation of tissue factor is also associated with an increase in vascular endothelial growth factor (VEGF) implicated in tumor progression and metastasis. In one study on colorectal cancers, association between tissue factor (TF) and VEGF was confirmed. Elevated VEGF levels were seen in the majority of tumors (80%) with high expression of TF as compared to only 40% of the tumors with low TF expression (P = 0.0015). [46],[52],[53],[54] Chemotherapy drugs (e.g. doxorubicin and epirubicin) are known to downregulate expression of endothelial protein C receptor, compromising the activated protein C (APC) pathway and resulting in an environment identical to factor V Leiden. [55] A quarter of patients treated with anthracyclines have a low APC level, leading to thrombophilia. Similarly, in multiple myeloma, a study showed 23% had APC resistance at baseline and 50% of these patients developed a venous thromboembolism (VTE), the incidence being the highest among those treated with thalidomide. [56],[57] Do similar changes and risk factors exist with ESA therapy? In a study on breast cancer and anemia by Aapro et al, patients on chemotherapy were randomized between epoetin beta and control.[58] Patients receiving epoetin beta did have more thromboembolic events (13% vs. 6% among the controls; P = 0.012). However, there was no significant difference in serious thrombotic episodes or related deaths. There was also no significant difference in terms of overall survival or progression-free survival. Studies with standard dose and labeled indication for ESAs have shown that the odds of death were identical to that in the control group. (Overall relative risk is 1.0003 and relative risk is 0.965 for those getting less frequent higher doses.) In fact, it is the Hb level at which treatment with ESAs is stopped that shows important correlation with increased risk of thrombotic events, [45] with the relative risk being 0.70 for Hb of 13 g/dl and increasing to 1.71 for higher target Hb levels. Keeping in mind the fact that recommended target Hb is only 12 g/dl, the fear of increased risk in unfounded. The 2006 Cochrane meta-analysis involving 35 clinical trials and almost 7000 cancer patients receiving ESAs showed significant benefit (reduced risk for RBC transfusions and improved hematologic response). This report also showed that [59] higher incidence of thromboembolic episodes (TEEs) was seen in patients treated off-label, especially when Hb levels targeted were higher or when using ESA for patients not receiving chemotherapy. In summary, the hazard ratio of 1.09 for thrombotic incidence from meta-analysis of ESA trials shows it to be within the range of 1.02-4.34 for the same complication among cancer patients without ESA therapy. In addition, the incidence of such thrombotic episodes does not seem to be influenced by the ESA dose. [45],[48],[60] In fact, Gascon reported a meta-analysis of 12 studies that showed an incidence of death of 16.8% (231/1372) in the placebo arm versus 16.7% (290/1732) in the ESA arm (HR 1.13 with CI of 0.95-1.34). [61] So, let us see if RESPOND (an EORTC online system that helps and increases compliance with anemia management guidelines) makes a difference. Initial data clearly indicate that its benefit is consistent and stands validated. [62],[63] [For instance, congruence (CSs; 0-10) with EORTC RESPOND guidelines shows that a one-point increase in CS was associated with 0.60 g/dl increase in Hb at month 4 and each one-point increase in CS increased the odds of reaching Hb 11 g/dl by 3.14] [Table - 10]. [62] Conclusions The NCCN Trend′s survey of 2009 shows the consequences of this controversy. Almost half of the 1589 clinicians polled showed that their use of ESAs had reduced, whereas 27% actually reported a significant increase in their use during the same 2-year period. The Atlantic divide was clearly obvious in the results; the majority of the former were from USA, whereas those who increased their use were international oncologists. The reduction in the use of ESAs within USA was also associated with increase in the use of outpatient RBC transfusions. Interestingly, the US FDA requires oncologists (but not nephrologists) to consent, register and counsel patients receiving ESAs at each follow-up. What motivates the US FDA′s singular concern with ESAs remains an enigma. In fact, use of ESAs is associated with a favorable benefit-risk ratio as long as it is used within the globally accepted and labeled indications. Trend to increased mortality is seen only when its use is beyond Hb levels of 12 g/dl, for patients not on chemotherapy or when used prophylactically. The risk of tumor progression because of ESA receptors is conjectural and flawed due to cross-reactivity of the antibody used. Isn′t this the classical example of subjecting patients to potential hazards of transfusions (whose safety among cancer patients has never been studied systematically) due to the fear of potential side effects of ESAs that have been seen only when they are used inappropriately? What is the consequence of such an approach? Isn′t it the denial of ESAs to patients who could benefit most from their judicious use?[64] We therefore conclude with this take-home message for the optimal management of CRA: Cancer related anemia
Iron
References
Copyright 2011 - Indian Journal of Cancer The following images related to this document are available:Photo images[cn11001t7.jpg] [cn11001t9.jpg] [cn11001t8.jpg] [cn11001t2.jpg] [cn11001t10.jpg] [cn11001t4.jpg] [cn11001t5.jpg] [cn11001t3.jpg] [cn11001t1.jpg] [cn11001t6.jpg] |
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