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Prepublished online as a Blood First Edition Paper on August 29, 2002; DOI 10.1182/blood-2002-06-1767.
REVIEW ARTICLE
From the Medical College of Wisconsin, Milwaukee, WI;
Cleveland Clinic Foundation, Cleveland, OH; Virginia Commonwealth
University, Richmond, VA; Blue Cross and Blue Shield Association
Technology Evaluation Center, Chicago, IL; VA Chicago Health Care
System, Chicago, IL; Evanston Northwestern Healthcare, Evanston, IL; H. Lee Moffitt Cancer Center & Research Institute at the University of
South Florida, Tampa, FL; Mesa, AZ (patient representative); Memorial
Sloan-Kettering Cancer Center, New York, NY; Dana Farber Cancer
Institute, Boston, MA; Saint Agnes Hospital, Baltimore, MD; NW Kaiser
Permanente, Portland, OR; Northwest Cancer Specialists, Portland, OR;
Hamilton Regional Cancer Center, Hamilton, Ontario, Canada; and
University of Arizona Health Sciences Center, Phoenix, AZ.
Anemia resulting from cancer or its treatment is an important
clinical problem increasingly treated with the recombinant
hematopoietic growth factor erythropoietin. To address uncertainties
regarding indications and efficacy, the American Society of Clinical
Oncology and the American Society of Hematology developed an
evidence-based clinical practice guideline for the use of epoetin in
patients with cancer. The guideline panel found good evidence to
recommend use of epoetin as a treatment option for patients with
chemotherapy-associated anemia with a hemoglobin (Hgb)
concentration below 10 g/dL. Use of epoetin for patients with
less severe anemia (Hgb level below 12 g/dL but never below 10 g/dL)
should be determined by clinical circumstances. Good evidence from
clinical trials supports the use of subcutaneous epoetin thrice weekly
(150 U/kg) for a minimum of 4 weeks. Less strong evidence supports an
alternative weekly (40 000 U/wk) dosing regimen, based on common
clinical practice. With either administration schedule, dose escalation
should be considered for those not responding to the initial dose. In
the absence of response, continuing epoetin beyond 6-8 weeks does not
appear to be beneficial. Epoetin should be titrated once the hemoglobin
concentration reaches 12 g/dL. Evidence from one randomized controlled
trial supports use of epoetin for patients with anemia associated with
low-risk myelodysplasia not receiving chemotherapy; however, there are
no published high-quality studies to support its use for anemia in
other hematologic malignancies in the absence of chemotherapy.
Therefore, for anemic patients with hematologic malignancies it is
recommended that physicians initiate conventional therapy and observe
hematologic response before considering use of epoetin.
(Blood. 2002;100:2303-2320) Anemia secondary to a diagnosis of cancer or
resulting from its treatment is an important clinical problem for which
new therapeutic options have recently become available. The development
of chemotherapy-associated anemia is characteristically an insidious
and delayed complication of treatment. Transfusion was the traditional,
and the only, means of therapy for symptomatic anemia until the 1990s.
Newer chemotherapeutic agents and drug combinations have made anemia an
even more clinically significant problem. In some instances,
with improved cancer therapy treatment of malignancy has come to
resemble management of chronic illness. Evolution in the management of
anemia has accompanied these changes in cancer therapy. Growing concern
about infectious risks has led to decreased usage of red cell
transfusions. Likewise, the realization that transfusion products
represent a limited resource has led to strategies to optimize their use.
The identification and clinical development of the recombinant
hematopoietic growth factor erythropoietin triggered further evolution in the management of anemia in the 1990s. Anemia due to
malignancy may be related to either: (1) infiltration of marrow elements by cancer cells directly (bone marrow involvement), (2) an
impaired production process directly related to treatment (the effect
of cancer therapy), or (3) other nonspecific processes such as the
inhibitory effect of tumor necrosis factor that accounts for the
"anemia of chronic disorders," iron deficiency, or low endogenous
erythropoietin levels. The FDA approved epoetin, the human recombinant
form of erythropoietin, as a pharmaceutical in 1989 for anemia of
chronic renal failure. Since then, numerous studies have examined its
potential usefulness as an alternative to transfusion in the management
of anemia in the cancer population.
Initial studies explored the use of erythropoietin in a variety of
clinical oncology settings, testing various dosing and scheduling
regimens. These trials typically were small in size and used a variety
of regimens and schedules. Some failed to demonstrate significant
benefit, perhaps because of the patient populations enrolled, the study
design, or the limitations of the agent as a therapy. In addition,
issues that have subsequently been recognized as critical to successful
therapy such as iron repletion, baseline hemoglobin
concentration at entry, and dosing/schedule of epoetin were not
fully appreciated. These factors were increasingly considered in
subsequent, larger phase II and III trials. With greater clinical experience, trial designs have focused on fine-tuning the use of
epoetin to achieve clinical outcomes such as reduced transfusion requirements and improved quality of life.
Currently, the field of hematopoietic support for anemia of cancer
continues to evolve. The investigation of the "next generation" of
erythropoietin products indicates that this area will continue to
change over the next several years. Nonetheless, physicians making use
of current evidence confront difficult questions about the proper
indications for administering epoetin in anemic patients with cancer
and confront uncertainties regarding the efficacy of this agent and the
quality of the trials on which current claims of efficacy are based.
Furthermore, the use of epoetin is in the context of the availability
of an effective alternative form of traditional therapy, namely, blood transfusion.
To address these uncertainties, the American Society of Clinical
Oncology (ASCO) and the American Society of Hematology (ASH) began
discussions in 1997 to develop an evidence-based clinical practice
guideline on the use of epoetin in cancer patients. At that time, the
Agency for Healthcare Research and Quality (AHRQ) solicited topic
nominations for evidence reviews that were to be based on systematic,
rigorous and unbiased methods for selecting the literature and
synthesizing the data through its network of 12 Evidence-Based Practice
Centers (EPCs).1 The evidence reviews can serve as a
scientific foundation for developing and implementing clinical practice
guidelines and related products. ASH and ASCO submitted to AHRQ a
formal proposal for an EPC review on the use of epoetin in cancer patients.
AHRQ selected erythropoietin as one of the topics to be reviewed. The
undertaking was awarded to the Blue Cross and Blue Shield Association
Technology Evaluation Center (TEC) in Chicago, Illinois.2 ASH and ASCO established an independent panel of experts in clinical medicine, clinical research, health services research, and related disciplines to develop an evidence-based guideline from the evidence review. A draft of the TEC report was made available to the panel in
late 2000, and the final report was released publicly in May 2001. The
full-text TEC evidence report, Use of Epoetin for Anemia in
Oncology,3 and the executive summary can be obtained
in print form from the AHRQ Publications Clearinghouse (800-358-9295) or online at www.ahrq.gov/clinic/epcix.htm. This report should be
consulted by those interested in a more detailed treatment of the state
of the evidence supporting the use of epoetin in clinical oncology
practice than the information provided in this guideline.
This document is the evidence-based clinical practice guideline
developed by ASH and ASCO that is based on the review. The guideline is
a blend of evidence, the opinions of experienced practitioners, and
their interpretation of the evidence. ASH and ASCO acknowledge that
guidelines cannot always account for individual variations
among patients. Guidelines are not intended to supplant physician
judgment with respect to particular patients or special clinical
situations and cannot be considered inclusive of all proper methods of
care or exclusive of other treatments reasonably directed at obtaining
the same results. Accordingly, ASCO and ASH consider adherence to these
guidelines to be voluntary, with the ultimate determination regarding
their application to be made by the physician in light of each
patient's individual circumstances. In addition, these guidelines
describe administration of therapies in clinical practice; they cannot
be assumed to apply to interventions performed in the context of
clinical trials, given that clinical studies are designed to test
innovative and novel therapies in a clinical situation where better
therapy is needed. In that guideline development involves a review and
synthesis of the latest literature, a practice guideline also serves to
identify important questions for further research and those settings in
which investigational therapy could be considered as an option.
The following sections detail the methods used by the panel to develop
its recommendations, the recommendations and the findings of the TEC
report that influenced the panel's conclusions, and suggestions for
future research. A summary of the guideline recommendations can be
found in Table 1.
Panel composition
Conflict of interest Potential conflicts of interest were handled through full disclosure and according to the policies of ASH and ASCO (Appendix 2). As part of the conflicts of interest consideration, the relationship of TEC to the Blue Cross and Blue Shield Association was addressed.Definition of topic At its first meeting, the panel determined that the guideline would focus on the role of epoetin in the treatment of anemia caused by chemotherapy or radiation therapy, anemia associated with cancer, and anemia with bone marrow failure (myelodysplasia and aplastic anemia). The objective of the guideline was to delineate, according to the best available evidence, which patients should receive epoetin, the appropriate dosages and routes of administration, and the duration of treatment. Predictors of response and evaluation of response were also included when possible.The outcomes of interest in evaluating the effectiveness of epoetin were to include requirements for transfused red blood cells, changes in hemoglobin level or hematocrit concentration, and quality of life. Although recommendations were not to be based on economic considerations, the panel did consider it important to review existing literature on the costs and cost-effectiveness of epoetin. Review of evidence The review of evidence upon which this guideline is based consists largely of the rigorous systematic review of the literature conducted by the Technology Evaluation Center, whose process and procedures have been reviewed in detail by the AHRQ. Details of this review can be found in the full report to AHRQ available in print3 and at www.ahrq.gov/clinic/epcix.htm, or in the condensed summary published in a journal article.4In summary, the TEC searched the MEDLINE, Cancerlit, and Embase databases for all relevant articles published since 1985. The TEC supplemented the above strategy by searching issues of Current Contents on Diskette and Medscape Oncology5 through October 30, 1999, to identify recently published articles that had not yet been indexed by the online databases. The reviewers also examined abstracts presented at the 1999 meeting of the American Society of Clinical Oncology, bibliographic information and reprints of clinical studies provided by Ortho Biotech, Inc, and reference lists from relevant review articles, editorials, and letters published after 1994. Subsequently, the panel also reviewed emerging evidence on a new agent, darbepoetin, and kept abreast of other important emerging evidence that is cited in this document. Admissible evidence included controlled trials (randomized and nonrandomized) that compared the outcomes of managing anemia with and without the use of epoetin. All trials that met study selection criteria compared epoetin plus red blood cell transfusion as necessary with red blood cell transfusion alone. Studies had to include at least 10 similarly treated evaluable patients in each arm, relevant strata, and relevant epoetin dose level. Studies that used nonrandomized concurrent or historical controls were included only if the reviewers were satisfied that patients in the treatment and control groups were comparable at baseline and that obvious selection bias was absent; however, it is acknowledged that the nature of such designs cannot completely protect against such biases. Two reviewers independently conducted each step in the review process. Disagreements were resolved by consensus. The TEC also conducted a pooled statistical analysis (meta-analysis) of the effect of epoetin on the odds of transfusion for patients with anemia or at risk of anemia due primarily to cancer therapy. The guideline panel relied mainly on the evidence review performed by
TEC in developing the guideline. However, the panel, with
acknowledgment of their design limitations, also included large
community studies excluded by TEC because of methodological concerns. A
summary and critical appraisal of the studies reviewed for this
guideline can be found in Tables
2-5
(chemotherapy-induced anemia) and Appendix 1.
Process overview The cochairs and a planning committee of ASH and ASCO representatives developed a joint operating structure for coordinating the work of the panel under the auspices of both organizations. Coordinated procedures were developed for defining the role of the cochairs, for panel selection, for addressing conflicts of interest, and for peer review and final approval of the document.The panel considered it essential to use a systematic review of the
evidence as its foundation for making recommendations. This process
includes a systematic weighting of the level of evidence and a
systematic grading of the evidence for making a
recommendation.6,7 The hierarchical grading system gives
greater weight to well-designed randomized controlled trials and
meta-analyses and progressively less weight to studies
with weaker internal validity. When evidence was lacking, the panel
determined that it was appropriate to reach conclusions based on expert
opinion as long as it was acknowledged explicitly. The panel
determined that consensus would be reached by majority vote. The
strength of evidence and grade of recommendations were assigned
according to the coding scheme in use by ASCO (Table 6).8 However, for clarity
these are supplemented by narrative descriptions of the state of
the evidence.
The panel met on several occasions. After developing procedures and reviewing the evidence as presented by the TEC report, draft recommendations were prepared and discussed in a face-to-face meeting before the completion of a full draft report. All panel members reviewed all iterations of the guideline, contributing feedback to the levels of evidence and the systematic grading of the data supporting the recommendations. Independent review from 3 external experts was obtained. The final content of the guidelines and the manuscript were reviewed and approved by the ASCO Health Services Research Committee and Board of Directors, and the ASH Executive Committee.
General recommendation As in any medical situation, it is essential to give consideration to other correctable causes of anemia before proceeding to therapy with stimulants of erythropoiesis. Therefore, it is advisable to conduct an appropriate history and physical, and consider relevant diagnostic testing aimed at identifying causes of anemia aside from chemotherapy or underlying hematopoietic malignancy. At a minimum, one should take a thorough drug exposure history; carefully review the peripheral blood smear (and in some cases the bone marrow); consider iron, folate, or B12 deficiency where indicated; and assess for occult blood loss. Coombs testing may be appropriate for patients with chronic lymphocytic leukemia; endogenous erythropoietin levels may predict response in patients with myelodysplasia.Chemotherapy-induced anemia Recommendation. The use of epoetin is recommended as a treatment option for patients with chemotherapy-associated anemia and a hemoglobin concentration that has declined to a level less than or equal to 10 g/dL. Red blood cell transfusion is also a treatment option depending upon the severity of anemia or clinical circumstances. Level of evidence (status of evidence): II (several small and one larger [n = 375] placebo-controlled randomized trials, and nonblind trials with generally consistent results favoring the use of epoetin). Grade of recommendation: B.Rationale. Improvement in hemoglobin concentration.
Reviewed studies were grouped into 3 categories based on subjects'
mean baseline hemoglobin concentration at study entry
( Transfusion requirements. The difference in the percent of adult patients requiring any transfusions between epoetin and control arms in the various trials ranged from 9% to 45% in favor of epoetin (Table 4). In 4 trials the difference was reported as statistically significant10,13,14,16; however, many of these trials did not use intention-to-treat analysis. Some trials reported that patients receiving epoetin required fewer units of transfused red blood cells compared with control; adults in the control groups of the trials required 0.6-2 units of red blood cells per 4-week period, compared with 0.1-2 units for those randomized to epoetin, representing an absolute difference range of 0 to 0.7 units of red blood cells. The differences in transfused units were statistically significant in 2 trials.10,14 Meta-analysis confirmed a reduction in the relative odds of transfusion for those randomized to epoetin. The meta-analysis conducted by the TEC (Appendix 1), when applied to those randomized controlled studies that used subcutaneous epoetin and reported numbers of patients transfused, yielded a cumulative odds ratio of 0.38 (95% CI, 0.28-0.51), suggesting that use of epoetin decreases the relative odds of receiving a red blood cell transfusion by an average of 62% (Table 7). When the meta-analysis was restricted to data from studies meeting TEC criteria for higher quality, the odds ratio remained significant at 0.45 (95% CI, 0.33-0.62).
Symptomatic improvement. Whether improvement in hemoglobin and reduction in transfusions with epoetin therapy translate into clinically meaningful symptomatic improvement requires further study. Some studies that have examined functional status or overall quality of life have produced inconsistent results or rely on data of variable methodological quality (Table 5). Threats to validity of these trials include higher than usual dropout rates; among the trials that include quality of life as an outcome, 10%-40% of the patients were not evaluable at the end of the study. Quality-of-life studies can be difficult to conduct and, unlike transfusion or hemoglobin outcomes, depend upon respondents completing surveys at distant time points. Therefore, missing data in quality-of-life studies do not necessarily represent neglect on the part of investigators. The largest randomized trial to date (n = 375), though supporting a significant improvement in quality of life in the epoetin arm, does suffer from the problem of missing data, thus threatening the validity of the inferences that can be made.16 It is unclear whether this missing data had any significant effect on the distribution of quality-of-life (QOL) outcomes between the treatment arms.17 Ideally, randomized studies of quality of life would be analyzed using intention-to-treat principles; however, research to identify proper methods for handling nonrandom missing data in QOL studies is ongoing.17 Many studies used quality-of-life instruments that have only recently been introduced.18 Since the experience with these instruments is limited, research defining minimum clinically meaningful changes in QOL scores is ongoing. In particular, psychometric research is underway to quantify the clinical impact associated with changes in the QOL measured by one popular instrument, the Functional Assessment of Cancer Therapy general version (FACT-G).19 Because the trials on which these conclusions are based are only of fair quality regarding QOL outcomes (due to limitations in reporting and conduct of the investigations), the probability of false-positive and false-negative results cannot be assumed to be low (level II evidence; see Table 6). In making recommendations for use of epoetin, the evidence for improvements in hemoglobin and transfusion outcomes was considerably stronger then that for quality-of-life outcomes. Replication of quality-of-life improvements that are demonstrated to be clinically meaningful in other well-designed clinical trials would improve the strength of evidence and further support this recommendation. Dose and dose schedule of epoetin. Please refer to discussion below regarding optimal dose and dose schedule for administering epoetin. Recommendation. For patients with declining 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 circumstances. Red blood cell transfusion is also a therapeutic option when warranted by severe clinical conditions. Level of evidence (status of evidence): II (several small [n < 100], randomized and nonrandomized, mostly nonblind studies consistently favoring epoetin but with inconsistent statistical significance for reported outcomes across the studies). Grade of recommendation: C.Rationale. Improvement in hemoglobin concentration. Among trials that enrolled patients with this concentration of hemoglobin at baseline, there is mixed evidence that epoetin achieves a statistically significant improvement in hemoglobin concentrations (Table 3). Seven trials20-26 involving patients with a starting hemoglobin level of 10-12 g/dL reported that the difference in the percentage of patients achieving a designated hematologic response to epoetin versus control ranged from 48% to 75%, with a mean difference in changes in hemoglobin of 1.0-3.7 g/dL. The difference in response rate, or change in mean hemoglobin, all favoring epoetin, was statistically significant in 4 out of 7 trials.20-23 None of these 4 trials met the TEC criteria for higher quality (Appendix 1). In the only trial meeting these criteria,24 there was no statistically significant difference reported for change in hemoglobin level. Transfusion requirements. Of the 5 trials that used as an outcome the percentage of patients requiring transfusion,21,22,24-26 the range of the difference in percentage transfused was 7%-47%, all favoring epoetin (Table 4). The difference in the proportion of patients requiring transfusion was statistically significant in 1 of the 5 trials.25 Of the 3 studies that reported the number of units transfused, the differences between epoetin and control groups over a 4-week period ranged between 0.1 and 1.3 units per patient, all favoring epoetin. One trial24 reported that the reduction in transfused units was statistically significant, but the other 2 did not discuss statistical significance.25,26 In this trial24 the dose of epoetin was among the highest used, 1200 U/kg/wk. The meta-analysis performed by the TEC, which pooled randomized trials for patients with all levels of hemoglobin at entry, did show a reduction in the relative odds of receiving a transfusion for those treated with epoetin. However, because study quality may confound the effect of baseline hemoglobin on the odds of transfusion and because all of the studies considered to be of "higher quality" by the TEC enrolled patients with baseline hemoglobin no higher than 10 g/dL, the meta-analysis was unable to test for a specific effect of baseline hemoglobin on the odds of transfusion.Symptomatic improvement. No trials reported data to evaluate whether epoetin improves symptoms or quality of life specifically among patients with baseline hemoglobin levels of 10-12 g/dL (Table 5). Although one randomized trial reporting significant quality-of-life improvement with epoetin included patients with baseline hemoglobin levels of 10-12 g/dL, this group represented only 16% of all patients studied and outcomes were not presented for QOL stratified by hemoglobin level.16 The panel's ability to support a definitive recommendation is limited by the heterogeneity of the statistical significance of response outcomes. This heterogeneity may, in fact, be due to the small size of these trials. It is noteworthy, however, that the relative improvement in outcomes observed in these studies, although often not statistically significant, is consistent with the relative rates seen for patients with more severe anemia (baseline hemoglobin < 10 g/dL), and in all studies, including those that were placebo-controlled, the direction of the effect always favored epoetin. Unfortunately, the meta-analysis accounts for small sample sizes by pooling the data from many trials but could not be used to isolate the effect of epoetin on transfusion outcomes for specific baseline hemoglobin levels. The lower absolute risk for transfusions among patients with a baseline hemoglobin level of 10-12 g/dL limits the absolute probability of benefit (and the statistical power of published trials to demonstrate such a benefit) in this population. The recommendation for use of epoetin in patients with baseline hemoglobin levels of 10-12 g/dL based on clinical judgment is premised on the assumption that patients with specific comorbid conditions face a higher absolute probability of anemia or a higher risk of adverse events related to this degree of anemia than do other patients with this hemoglobin concentration. Examples of patients at this higher degree of absolute risk, who may be considered reasonable candidates for this agent, based upon clinical judgment, include but are not limited to elderly individuals with limited cardiopulmonary reserve or patients with underlying coronary artery disease and symptomatic angina.Recommendation. The recommendations are based on evidence from trials in which epoetin was administered subcutaneously thrice weekly. The recommended starting dose is 150 U/kg thrice weekly for a minimum of 4 weeks, with consideration given for dose escalation to 300 U/kg thrice weekly for an additional 4-8 weeks in those who do not respond to the initial dose. Although supported by less strong evidence, an alternative weekly dosing regimen (40 000 U/wk), based on common clinical practice, can be considered (see discussion below). Dose escalation of weekly regimens should be under similar circumstances to thrice- weekly regimens. Level of evidence (status of evidence): II (Nineteen comparative, controlled trials involving a total of 1618 patients, of which 15 trials were randomized and 6 were either blind or placebo-controlled. Epoetin was administered 3 times weekly in the treatment arm for all controlled trials reviewed except 1, where it was administered daily.) Grade of recommendation: B.Rationale. Dosing interval. Most trials were parallel group designs comparing subcutaneous epoetin with transfusion alone. Two nonblind, randomized trials used 3-arm designs to compare 2 different doses of subcutaneous epoetin to transfusion alone. Three studies used intravenous epoetin.10,13,23 Of the 17 two-arm subcutaneous epoetin trials, 13 were randomized and 6 were either blind or placebo-controlled. In studies using subcutaneous epoetin, the most common initial dose was 150 U/kg administered 3 times weekly (the most common higher starting dose was 300 U/kg 3 times weekly). The dose range was 300-450 U/kg per week in 12 trials and 700-1000 U/kg per week in 5 trials. The 2 three-arm trials compared initial doses of 450 and 900 U/kg per week with controls.25,27 Four of the 6 trials designated as higher quality by the TEC used 450 U/kg per week as the starting dose of epoetin. All of these trials administered epoetin 3 times weekly. One study administered 5000 U daily, regardless of weight or body size.14 Because the multiple-arm studies detecting improvements in hemoglobin and transfusion outcomes favoring epoetin have based dosing on a 3 times weekly regimen, the most compelling evidence for use of epoetin supports a thrice-weekly regimen. However, for convenience of patients, common clinical practice has evolved to once weekly dosing. Pharmacokinetic studies suggest that once weekly dosing intervals with higher doses of epoetin achieves similar rises in reticulocyte counts when compared with thrice- weekly intervals.28,29 Although both are randomized, controlled trials, they are small (< 40 persons), involve healthy volunteers, and are descriptive in nature (not powered to detect statistical significance). A large, nonrandomized, community-based study employing once-weekly dosing has reported similar improvements in hemoglobin and quality of life to thrice weekly dosing.30 In addition to lacking a concurrent control comparison, the study has been criticized for lack of adjustment for potential baseline confounding variables and for its handling of the relatively large dropout rate.31 No randomized controlled trials have yet been reported to substantiate or contradict the outcome of once-weekly epoetin versus thrice-weekly treatment. A randomized trial comparing once-weekly epoetin dosing with a placebo control arm has completed accrual and was presented as an abstract in May 2002.32 The preliminary results suggest that weekly epoetin increases hemoglobin concentrations and decreases transfusion rates compared with placebo among patients receiving chemotherapy. Another pharmaceutical erythropoiesis-stimulating protein that requires less frequent dosing (darbepoetin alfa) is also being tested in randomized trials to confirm the data from dose finding studies,33 which suggest it can be administered effectively as infrequently as once per chemotherapy cycle. Comparative studies are in progress to evaluate darbepoetin in patients with cancer. Table 8 lists the ongoing studies and preliminary reports available to the panel at the time of this writing, regarding darbepoetin.34-38
Dose escalation and duration. In studies using subcutaneous epoetin, the most common initial dose was 150 U/kg administered 3 times weekly. The most common higher starting dose was 300 U/kg 3 times weekly. Among studies using subcutaneous epoetin at these lower-dose ranges (300-450 U/kg/wk), 4 trials increased the dose for nonresponders after a fixed period of time, 4 decreased the dose for responders, and 4 used a fixed and continuous dose throughout treatment. The criteria for dose escalation were typically a combination of failure to achieve at least a 1 g/dL rise over baseline hemoglobin and a reticulocyte count below 40 000/µL by the fourth week of treatment. Treatment duration was longer than 20 weeks in 6 trials, 12-16 weeks in 8 trials, and no longer than 10 weeks in 5 trials. Heterogeneity of dosing limits comparability among trials. Weight-based versus uniform dosing. Most trials reviewed by the TEC utilized weight-based epoetin dosing regimens (Table 2). Recently, some single-arm studies have shifted to uniform dosing (10 000 U 3 times weekly, 40 000 U once weekly).30,39 No randomized trials have directly compared weight-based dosing with uniform dosing. Subcutaneous versus intravenous administration. Virtually all studies evaluating the effectiveness of epoetin have employed subcutaneous administration. Intravenous administration has been used in only 3 studies (98 patients),23,24,40 limiting the ability to make a specific recommendation. No study included in this report compared intravenous adminstration with subcutaneous administration. Evidence from hemodialysis patients suggests that subcutaneous administration is 30%-50% more efficient than the intravenous route.41,42 Recommendation. Continuing epoetin treatment beyond 6-8 weeks in the absence of response (eg, < 1-2 g/dL rise in hemoglobin level), assuming appropriate dose increase has been attempted in nonresponders, does not appear to be beneficial. Patients who do not respond should be investigated for underlying tumor progression or iron deficiency. As with other failed individual therapeutic trials, consideration should be given to discontinuing the medication. Level of evidence (status of evidence): N/A (expert opinion based on indirect evidence and biological inference). Grade of recommendation: Panel consensus.Rationale. A number of weeks may be required to observe a response to treatment with epoetin, but available studies suggest a low probability of response if hemoglobin/hematocrit concentrations have not risen significantly by 6-8 weeks. In the best trials that have consistently reported hemoglobin response criteria, response has been defined as a rise in hemoglobin of at least 2g/dL at study end. It is reasonable to suggest that responders would achieve a hemoglobin level improvement of at least 1 g/dL by 8 weeks from initiation of epoetin. For patients not responding it is advisable to investigate for tumor progression. In patients with myelodysplasia, it is reasonable to repeat the bone marrow analysis if patients respond initially to epoetin and then develop worsening anemia to ensure that the myelodysplasia is not evolving toward a more malignant state. Likewise, the clinician should consider iron deficiency, intercurrent infection, blood loss, and hemolysis as other causes of anemia. Similarly, a recent report suggests that antibodies directed against erythropoietin causing pure red cell aplasia can develop in patients with anemia of chronic renal failure treated with epoetin.43 Whether this phenomenon will be observed in cancer patients on chemotherapy or in patients with hematologic malignancies receiving epoetin for shorter duration is not known. There is no empirical evidence to support these suggestions, but it can be reasoned that obtaining this information would be useful in recognizing the need to discontinue epoetin therapy and to revise the patient's treatment plan. Recommendation. Hemoglobin levels can be raised to (or near) a concentration of 12 g/dL, at which time the dosage of epoetin should be titrated to maintain that level or restarted when the level falls to near 10 g/dL. Insufficient evidence to date supports the "normalization" of hemoglobin levels to above 12 g/dL. Level of evidence (status of evidence): N/A (expert opinion based on indirect evidence and biological inferences). Grade of recommendation: Panel consensus.Rationale. All of the trials conducted to date have focused on raising the hemoglobin level to a maximum of 12 g/dL. Clinical trials have generally mandated that the dosing of epoetin be suspended until the hemoglobin has fallen to a level indicative of the need to restart therapy. While there are some observational data to suggest that the benefits of epoetin continue to improve with rising hemoglobin levels,39,44 no randomized controlled studies in cancer have been conducted to validate the additional benefit of routinely improving hemoglobin above the level of 12 g/dL. It should also be considered that, in a large (n = 1233) prospective clinical trial of patients with chronic renal failure and concurrent cardiac disease treated with epoetin, patients randomized to achieve a target hematocrit of 42% were shown to have higher mortality than those randomized to a target of 30%.45 The trial was designed with 90% power to detect a 20% difference (2-sided) in survival or time to first nonfatal myocardial infarction between the 2 groups using intention to treat analysis. It was discontinued at its third interim analysis when patients in the normal hematocrit group were found to have a higher event rate (relative risk of 1.3; 95% confidence interval, 0.9-1.8) than patients in the low-hematocrit target group. Although this result was not statistically significant, the study monitors believed that it was very unlikely continued accrual to the study would reveal a benefit for the normal hematocrit group. As well, in post hoc analysis it was shown that those in the normal hematocrit group had less adequate dialysis and greater iron chelation therapy than the control group, which may have contributed to the higher mortality rates. A substantial proportion of patients that receive epoetin report adverse events. Of the 10 studies reporting "any adverse event" among the 1155 patients, the rate was 46% among the controls and 56% among the epoetin-treated groups.3 These complications, however, are often reasonably ascribable to concurrent treatments or to the underlying disease. Most of the trials examined for this guideline evaluated relatively few patients. Trials powered to detect specified differences in main outcomes may not have sufficient power to detect adverse events that are less frequent. With relatively few patients in each study arm, differences in adverse events in these trials are unlikely to achieve statistical significance.Recommendation. Baseline and periodic monitoring of iron, total iron-binding capacity (TIBC), transferrin saturation, or ferritin levels and instituting iron repletion when indicated may be valuable in limiting the need for epoetin, maximizing symptomatic improvement for patients, and determining the reason for failure to respond adequately to epoetin. There is inadequate evidence to specify the optimal timing, periodicity, or testing regimen for such monitoring. Level of evidence (status of evidence): N/A (expert opinion based on indirect evidence and biological inferences). Grade of recommendation: Panel consensus.Rationale. Clinical experience and informal reports suggest that correcting iron deficiency can obviate the need for epoetin, enhance its effectiveness, and explain the emergence of non-response over time. These assumptions have not been tested in controlled trials, nor have studies formally tested which monitoring protocols maximize sensitivity, specificity, and cost-effectiveness. No data exist to support the use of endogenous erythropoietin levels to guide therapy outside of myelodysplastic syndrome. Myelodysplasia, multiple myeloma, non-Hodgkin lymphoma, and chronic lymphocytic leukemia (anemia primarily related to hematologic malignancy) Recommendation. There is evidence from one well-designed, placebo-controlled randomized trial that supports the use of epoetin in patients with anemia associated with low-risk myelodysplasia, but there are no published high-quality studies to support its use in anemic myeloma, non-Hodgkin lymphoma, or chronic lymphocytic leukemia patients in the absence of chemotherapy. Treatment with epoetin for myeloma, non-Hodgkin lymphoma, or chronic lymphocytic leukemia patients experiencing chemotherapy-associated anemia should follow the recommendations outlined in the previous section. Level of evidence (status of evidence): II (one placebo-controlled randomized trial in myelodysplasia involving 87 patients and using a credible clinical outcome measure; 5 randomized trials with important design or reporting flaws for patients with lymphatic malignancy and/or myeloma not necessarily receiving chemotherapy at enrollment). Grade of recommendation: B.Rationale. In order to provide a recommendation for patients who would be anemic whether or not they were receiving chemotherapy for their malignancy, the TEC reviewed 6 trials that reported patients with hematologic malignancies enrolled regardless of whether or not chemotherapy was given. Trials of epoetin for patients with these diseases requiring treatment with chemotherapy at enrollment were reviewed in the sections pertaining to chemotherapy-associated anemia. Two additional randomized, double-blind, placebo-controlled trials for patients with multiple myeloma and/or hematologic malignancies receiving chemotherapy have been published since the TEC review.46,47 These trials appear to show similar results to those reviewed by the TEC for chemotherapy-associated anemia. Of the 6 trials in patients with hematologic malignancies where chemotherapy was not required for enrollment, only the trial for patients with MDS48 restricted enrollment to patients where no chemotherapy was given. The other 5 trials for patients with myeloma, non-Hodgkin lymphoma (NHL), or chronic lymphocytic leukemia (CLL) all include patients receiving concurrent or recent chemotherapy for their disease.49-53 Three of these trials specify that between 79% and 88% of the patients received concurrent chemotherapy.50,51,53 No trials have been reported for patients with anemia related to these diseases in the absence of chemotherapy. Patients with myeloid malignancies have typically been excluded from epoetin trials; consequently no evidence is available to make a recommendation in this area. Myelodysplasia. The effectiveness of epoetin has been examined in one randomized, double-blind, placebo-controlled trial involving 87 patients with myelodysplasia.48 Significantly more patients who were treated with epoetin achieved a hematologic response than those treated with placebo controls (37% versus 11%; P = .007). Patients received a fixed epoetin dose of 1050 U/kg/wk. Nearly 50% of patients in both groups had refractory anemia (RA). In a subgroup analysis, 50% of the patients with RA in the epoetin group experienced a response, whereas only 6% of patients with RA in the control group responded (P = .007). A partial response was defined as a 1-2 g/dL rise in hemoglobin. Surprisingly, for patients with RARS (refractory anemia with ring sideroblasts) in the respective arms, the response rates were 38 versus 18% (P = .6), and for RAEB (refractory anemia with excess blasts) they were 17 versus 11% (P = 1.0). Neither transfusion requirements nor quality-of-life outcomes were reported. Baseline serum erythropoietin levels above 200 mU/L predicted for nonresponse. The results of this study are limited in terms of generalizability because the study included patients with low-risk myelodysplasia (mostly refractory anemia) and the definition of hematologic response was not standard. In addition, there was inadequate information on baseline vitamin B12, iron status, or use of iron supplements, which may be more important in this disease than cancer chemotherapy. On the basis of the evidence, a reasonable approach in low-risk myelodysplasia (refractory anemia) patients with a low endogenous erythropoietin level (eg, < 200 mU/L) involves an 8-week trial of epoetin. No randomized trials have evaluated alternate dosing regimens of epoetin for patients with myelodysplasia. Myeloma, lymphoma, and chronic lymphocytic leukemia. The TEC review identified 2 randomized controlled trials that examined the use of epoetin in myeloma only,49,50 a randomized study of patients with chronic lymphocytic leukemia that is available only as an abstract,51 and 2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Abstract
Historical background
12 g/dL, > 10 g/dL but < 12 g/dL, or
10 g/dL). This categorization was performed in order to provide
recommendations regarding the appropriate starting threshold for
epoetin and to account for different population/gender norms. Seven
trials (5 placebo-controlled) enrolled adult patients with baseline
hemoglobin concentration no higher than 10 g/dL (Table
control %) ranged from 28% to 80%, with an absolute difference in
change of mean hemoglobin level ranging between 1.6 g/dL and 3.1 g/dL.
In 5 of these 7 trials, the difference in hematologic outcomes achieved
statistical significance.