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EORTC updates guidelines for the use of erythropoietic proteins in anemic patients with cancer

Background: The European Organization for Research and Treatment of Cancer (EORTC) conducted a systematic literature review (1996-2003) to produce evidence-based guidelines for the use of erythropoietic proteins in anemic patients with cancer. These guidelines were updated using literature published through November 2005.

Objectives: In addition to previous objectives, the update includes the new question of whether oral or intravenous (IV) iron supplementation increases the response rate to erythropoietin treatment.

Results: The update is based on the addition of 43 published studies and 78 relevant abstracts. Level I evidence supports the use of erythropoietic proteins for chemotherapy-induced anemia, anemia of chronic disease, cancer anemia, and patients undergoing cancer surgery. In cancer patients receiving chemotherapy and/or radiotherapy, erythropoietin treatment should be initiated at hemoglobin (Hb) = 9-11 g/dl, based on anemia-related symptoms, not a fixed Hb concentration. Early correction of anemia may be considered in asymptomatic patients with Hb levels <12 g/dl, if individual factors are considered. Level I evidence supports the dosing of erythropoietic proteins less frequently than three times per week when used to treat chemotherapy-induced anemia or prevent cancer anemia.

Level I evidence suggests that hypertension and thromboembolic events are slightly elevated in patients with chemotherapy-induced anemia receiving erythropoietin treatment.

No evidence was found that oral iron supplementation increased erythropoietin response. However level II evidence found that IV iron supplementation improved response to erythropoietic proteins. The update confirms prior evidence that transfusion requirements were reduced following treatment with erythropoietic proteins, and quality-of-life was significantly improved in patients with chemotherapy-induced anemia and anemia of chronic disease.

There is only indirect evidence that elevated doses will lead to a response to erythropoietin treatment in patients who did not initially respond to standard doses. Data is insufficient to determine the effect of erythropoietin therapy on survival in conjunction with chemotherapy or radiotherapy. Similarly, there were no clear links between erythropoietin therapy and other endpoints such as local tumor control, time to progression, and progression-free survival. No evidence was found to support concerns that red cell aplasia occurs in cancer patients following erythropoietin treatment.

NAAC Expert Commentary:
Bokemeyer et al. should be commended for this exhaustive update of their previous review of the literature on the use of erythropoietic proteins in anemic cancer patients. Most of their recommendations remain valid, even though these recommendations were published over one year after the completion of the literature search used for this review. The major concern is the recommended Hb target goal of 12 to 13 g/dL. The results of the recently published CREATE and CHOIR trials (1, 2), involving over 2000 patients with chronic kidney disease, suggest serious adverse outcomes when the target hemoglobin was greater than 11.5 g/dL (CREATE) or 11.3 g/dL (CHOIR).

As the authors of the EORTC guidelines have noted, several previous studies had raised concerns about increased risks of hypertension and thromboembolic events in subjects treated with erythropoietic proteins. I believe these concerns cannot be discounted any longer. Events in this rapidly evolving field, once again, underscore the importance of monitoring multiple outcomes over a prolonged period of time, when conducting clinical trials.

While the stated goal was to improve quality of life and decrease blood transfusions by using erythropoietic proteins in managing anemia in cancer patients, the more widespread and prolonged use of these products is revealing complications, which did not manifest in earlier studies.

For additional information on this research, please reference the source article:
Bokemeyer, C., M. S. Aapro, et al. (2007). "EORTC guidelines for the use of erythropoietic proteins in anemic patients with cancer: 2006 update." Eur J Cancer 43(2): 258-70.

Anemia after kidney transplantation is not completely explained by kidney function

Background: Anemia is typical in patients with decreased kidney function. Although kidney transplantation may be associated with complete correction of anemia, recent studies document the persistence of anemia in approximately one-third of patients with transplants.

Objectives: To determine whether kidney function completely accounts for anemia post-transplantation.

Methods: The prevalence of anemia in a cohort of 851 kidney transplant recipients was compared to anemia in a cohort of 732 subjects matched for kidney function from the AusDiab survey (a survey of the general population, undertaken in 1999 to 2000).

Results: The mean hemoglobin (Hb) concentration for the kidney transplant recipients was 13.1 g/dl. The prevalence of anemia in this cohort was 30.8% and was observed in significantly more women than men (P < 0.01). The prevalence of anemia in the general population matched for kidney function was 3.4% and the prevalence of anemia was 4.5-fold greater in women, compared to men (P < 0.01).

In the combined cohort of kidney transplant recipients and general-population subjects, the following clinical factors had an independent association with Hb concentration: transplant status, sex, CrCl, and age (in order of strength of relationship; (P < 0.01).

Among the kidney transplant recipients, a decrease in CrCl of 10 mL/min was associated with a decrease in Hb concentration of 0.23 g/dl. The use of the immunosuppressive agent, azathioprine may have contributed to higher Hb concentrations in kidney transplant recipients receiving this agent. Cyclosporine and tacrolimus use were associated with lower Hb concentrations, and MMF had no affect on Hb concentration in kidney transplant recipients.

Authors Conclusions: CrCl was related directly to Hb concentration within both groups. However, because the two cohorts were matched for CrCl, other factors must contribute to the 10-fold excess of anemia observed in kidney transplant recipients.

NAAC Expert Commentary:
Several factors have hampered the understanding of anemia in patients following kidney transplantation: no standard definition of anemia is used in the literature; there is limited data on the prevalence of anemia in post-transplant patients; the prevalence data that is available shows that the likelihood on anemia varies by time after transplantation and degree of graft function; and the relationship between Hb level and estimated glomerular filtration rate may not be the same as in other patients with CKD. The latter point is the focus of the current paper which quite clearly showed that although the severity of anemia correlated with the level of GFR in both post-transplant and control patients, the severity of anemia was much greater for any level of GFR in post-transplant patients.

The causes and correction of anemia in post-transplant patients is important clinically, since such anemia is associated with poorer survival, higher rates of death from cardiovascular disease, and higher rates of hospitalization. The contributors to anemia following kidney transplantation, in addition to the presence of a decreased GFR, include acute rejection; induction therapy; immunosuppressive medications; antiviral and antimicrobial medications; medications and malignancies; hemolytic uremic syndrome, and rarely, thrombocytopenic thrombotic purpura. Vigilance in identifying anemia in post-transplant patients and initiating appropriate therapy will most likely improve outcomes.

For additional information on this research, please reference the source article: Chadban, S. J., L. Baines, et al. (2007). "Anemia after kidney transplantation is not completely explained by reduced kidney function." Am J Kidney Dis 49(2): 301-9.

IV ferric gluconate provides greater increases in hemoglobin and hemoglobin response

Background: Recombinant human erythropoietin (rHuEPO) is an effective treatment for anemia caused by cancer or chemotherapy. However, rHuEPO fails to achieve clinically meaningful response in 30-50% of patients treated for chemotherapy-related anemia. Studies have demonstrated the efficacy of sodium ferric gluconate complex (FG) for optimizing response to rHuEPO therapy in hemodialysis patients. However, FG has not been well studied in patients with chemotherapy-related anemia.

Objectives: To evaluate the safety and efficacy of intravenous (IV) FG, oral iron, or no iron in cancer patients receiving epoetin therapy for chemotherapy-related anemia.

Methods: This was an open-label, randomized, and controlled, multicenter, prospective trial in 187 patients with chemotherapy-related anemia. Patients receiving chemotherapy and epoetin alfa (40,000 U subcutaneously weekly) were randomized to either 8 weeks of 125 mg of IV FG weekly, 325 mg of oral ferrous sulfate three times daily, or no iron. Patients were assessed weekly during the 8-week treatment period, and again during the 4-week follow-up period, at weeks 10 and 12. Patients were not allowed to take vitamin, mineral, or herbal supplements containing >27 mg/day of iron or >100 mg/day of vitamin C. Epoetin alfa dose was increased in patients that did not experience a sufficient hemoglobin increase or response. Likewise, dosages were reduced for patients in which the response to epoetin treatment was too robust.

Results: The hemoglobin (Hb) increases from baseline to endpoint in evaluable patients was 2.4 g/dl (95% CI, 2.1-2.7) for FG treatment, 1.6 g/dl (95% CI, 1.1-2.1) for oral iron treatment, and 1.5/dl (95% CI, 1.1-1.9) for no iron treatment. The Hb response rate was 73% for FG treatment, 45% for oral iron treatment, and 41% for no iron treatment.

Overall, there was no association between (1) baseline TSAT and mean Hb change from baseline (p = 0.2224); (2) baseline reticulocyte Hb content and mean Hb change from baseline; (3) baseline ferritin and Hb response.

The mean change from baseline to endpoint in serum ferritin was +343.7 ng/ml for patients receiving FG, -13.9 ng/ml for patients receiving oral iron, and -95.8 ng/ml for patients receiving no iron.

The number of patients requiring transfusions did not differ according to iron treatment; however, the study was not powered to detect a statistical difference in this parameter. Most adverse events were mild in severity and only six patients discontinued the study due to drug-related adverse events (FG= 2; oral iron= 4).

Authors Conclusions: Compared to oral iron, or no iron, FG produced a significantly greater increase in Hb and Hb response in cancer patients receiving epoetin alfa treatment for chemotherapy-related anemia.

NAAC Expert Commentary:
Henry and colleagues evaluated the Hb response for chemotherapy-induced anemia treated with epoetin alfa, comparing supplemental intravenous iron sodium ferric gluconate complex, oral iron, or no iron therapy. Eligibility required Hb < 11 g/dL and adequate iron stores defined as a ferritin > 100 ng/ml or iron saturation > 15%.

The improved Hb response employing adjunctive IV iron was expected as similar data have been shown in anemia of renal failure. IV iron can be considered to enhance the erythropoietic response to epoetin for chemotherapy-induced anemia, even in patients having adequate iron stores. However, larger studies will be required that evaluate toxicity, costs, and long-term outcome before routinely using adjunctive IV iron for epoetin treatment of chemotherapy-induced anemia.

For additional information on this research, please reference the source article: Henry, D. H., N. V. Dahl, et al. (2007). "Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy." Oncologist 12(2): 231-42.

Hemoglobin level predicts one-year-survival and hospitalization in hemodialysis patients: The MAR Study

Background: Retrospective studies have shown that level of anemia is associated with morbidity and mortality in kidney disease and the onset and progression of left ventricular hypertrophy. In addition, almost half of all deaths in patients on hemodialysis (HD) are of cardiovascular origin. However, because mortality among patients on HD is the result of multiple factors, is difficult to isolate each factor's specific contribution.

Objectives: The Morbidity-and-mortality anemia renal (MAR) study was designed to determine the impact of anemia on morbidity and mortality in patients with chronic kidney disease (CKD).

Methods: This was a 1-year prospective, observational, multicenter cohort study in patients with CKD on HD to isolate the burden of anemia, by controlling for other risk factors. Patients entering the study were at least 18 years old and started HD between January 1999 and March 2001. A total of 119 centers (65 hospital units and 54 dialysis centers) provided the initial sample of 1,710 cases, of which, 1,428 completed follow-up. At the start of the study, 94.8% of patients were being treated with rHuEPO at a mean dose of 111.6 U/kg per week. Most patients were receiving intravenous iron supplementation.

Results: Almost half of the patients (45.0%) were hospitalized at least once and the cumulative mortality was 12%. Patients who died were older, had greater comorbidity, lower albumin levels, and had more severe anemia than patients who did not die. The relative risk and confidence interval (CI) for hospitalization was 0.86 (0.81-0.91) per 1 g/dl increase in initial Hb after adjustment for comorbidity, vintage, etiology, access type, albumin, and Kt/V. The probability of remaining free from hospitalization (CI) was 0.34 (0.27-0.41) for initial Hb <10 g/dl, 0.47 (0.41-0.53) for Hb 10-11 g/dl, 0.54 (0.49-0.59) for Hb 11-12 g/dl, and 0.63 (0.59-0.67) for Hb >12 g/dl.

The relative risk and CI for death was 0.82 (0.73-0.91) per 1 g/dl increase in initial Hb, after adjustment for additional risk factors. The probability for patient survival (CI) was 0.77 (0.71-0.83) for initial Hb <10 g/dl, 0.82 (0.77-0.87) for Hb 10-11 g/dl, 0.89 (0.86-0.92) for Hb 11-12 g/dl, and 0.92 (0.90-0.94) for Hb >12 g/dl, P < 0.001.

Authors Conclusions: The study demonstrated that the severity of anemia is associated with the likelihood of hospitalization and death, even after adjusting for comorbidity and other risk factors.

NAAC Expert Commentary:
This well-designed observational study adds to the large body of literature showing an association between important outcomes in patients with CKD and the severity of anemia. These data, consistent with other observational studies, show that the greater severity of the anemia, the greater the likelihood of hospitalization or death. However, the fundamental question is whether correcting the Hb level in these patients would mitigate these adverse outcomes.

The results of recent randomized controlled trials in patients with CKD not yet on dialysis suggest that such an approach might in fact be harmful, if using a normal Hb target. Whether a somewhat lower Hb target would be beneficial and safe remains to be determined. The value of this study and other such observational trials is to generate hypotheses. The most obvious hypothesis that would derive from the current study is that maintaining a higher hemoglobin in this patient population would decrease hospitalizations and improve survival. Only carefully performed randomized controlled trials to test this hypothesis will be sufficient to guide clinical practice in this difficult, but important area.

For additional information on this research, please reference the source article: Portoles, J., J. M. Lopez-Gomez, et al. (2007). "A prospective multicentre study of the role of anaemia as a risk factor in haemodialysis patients: the MAR Study." Nephrol Dial Transplant 22(2): 500-7.

Diabetic kidney disease is associated with lower hemoglobin, especially at GFR less than 60 ml/min.

Background: In the western world, diabetes remains the most common cause of end-stage renal disease, while patients with diabetic kidney disease continue to have very poor prognoses. It is commonly believed that anemia associated with diabetic kidney disease is typically more severe compared to anemia in patients with other causes of renal disease. However, studies have not substantiated this belief conclusively. Definitive evidence in this matter is especially desirable, since erythropoietin therapy is an effective and readily available treatment.

Objectives: To determine if renal failure secondary to diabetes is independently associated with more severe anemia, by controlling for other contributing factors, such as ACE inhibitors, secondary hypothyroidism, and iron deficiency that are commonly associated with anemia.

Methods: This was a retrospective review of information from the PROTON database for patients under active follow-up by the Richard Bright renal unit at Bristol, UK, between January 1, 2004 and June 31, 2004. Patients with diabetic nephropathy were identified, by either renal histology or clinical features, and grouped according to stage of chronic kidney disease (CKD; 1-5), as outlined by the National Kidney Federation/Diseases Outcomes Quality Initiative. Glomerular filtration rate (GFR) was estimated using the modified four variable Modification of Diet in Renal Diseases formula.

Results: Linear regression analysis of hemoglobin (Hb) plotted against GFR showed that Hb was significantly lower in patients with diabetic kidney disease, especially below GFR < 60 ml/min (p<0.01). At CKD stages 3, 4 and 5, the mean Hb levels in patients with diabetic kidney disease compared with those in patients with non-diabetic kidney disease were 129.5 vs 136.9 g/l (p<0.001), 120.5 vs 126.9 g/l (p<0.001) and 107.1 vs 115.9 g/l (p<0.01), respectively. At CKD stage 4 and 5 (GFR <30 ml/min) there were no significant differences between the two groups for ferritin, plasma intact parathyroid hormone levels, ACE inhibitor use, and length of follow-up by a nephrologist.

Authors Conclusions: The study concluded that after controlling for common factors known to contribute to anemia, patients with diabetic kidney disease had significantly lower Hb levels than in patients with non-diabetic kidney disease, implicating diabetes as an independent risk factor for anemia.

NAAC Expert Commentary:
For the first time, this study demonstrates that patients with moderate CKD (grade 2-4), whose disease was due to diabetes mellitus, have lower Hb levels. The authors are aware of the limitations of the study-that this was a retrospective study conducted in a British chronic kidney disease unit. While it is not clear whether the differences found in this study are clinically meaningful, these results are definitely intriguing and require an explanation. Further studies should explore the following potential explanations: Is comorbidity more common and severe in diabetic patients? Is polypharmacy more common in diabetic patients? Are levels of erythopoietin lower in diabetic patients? This last explanation has support from a previous study showing that erythopoietin production was reduced in patients with postural hypotension, which is a common complication of diabetic neuropathy.

For additional information on this research, please reference the source article: Ravanan, R., J. R. Spiro, et al. (2007). "Impact of diabetes on haemoglobin levels in renal disease." Diabetologia 50(1): 26-31.

A ferritin cutoff of 100 ng/mL may help identify at-risk men with unexplained anemia for colonoscopy

Background: Whereas studies have shown that patients with iron deficiency anemia have a high prevalence of colonic neoplasia and should undergo prompt colonoscopy, the prevalence of colonic neoplasia in patients with anemia without iron deficiency remains unknown. Understandably, guidelines for diagnostic colonoscopy in these patients have not been established.

Objectives: To compare the prevalence of colonic neoplasia between patients with (1) ferritin =50 ng/mL, (2) ferritin 51-100 ng/mL, and (3) ferritin >100 ng/mL, and compare these to the prevalence in asymptomatic, nonanemic persons, undergoing colonoscopy.

Methods: Medical records from the colonoscopy database at the Minneapolis Veterans Affairs Medical Center were searched from 1997 to 2004 to identify patients referred for colonoscopy for anemia or cancer screening. Patients with anemia were stratified into three groups and compared to each other and to a control group consisting of asymptomatic, nonanemic individuals, undergoing colonoscopy for average-risk colon cancer screening. The prevalence of advanced colonic neoplasia in each group was compared.

Results: During the study period, 6,885 patients underwent colonoscopy. The inclusion criteria were met by 414 patients who were undergoing anemia evaluation and 323 nonanemic individuals undergoing cancer screening. Study subjects were mostly men. Persons in the nonanemic control group were younger on average compared to those in the other groups (P = 0.0001).

The prevalence of advanced colonic neoplasia in patients with ferritin 51-100 ng/mL was similar to that of patients with ferritin =50 ng/mL (7.9% vs. 7.2%, P = 0.9), and was significantly higher than individuals in the nonanemic control group (7.2% vs. 1.2%, P = 0.0001).

The prevalence of advanced colonic neoplasia in patients with ferritin 51-100 ng/dL was also higher than those patients with ferritin >100 ng/dL (7.2% vs. 1.7%), although the difference was not significant (P =0.08). After adjusting for age, patients with ferritin =50 ng/mL and 51-100 ng/mL were almost 5 times more likely to have advanced colonic neoplasia than the other groups.

Authors Conclusions: The study found that the prevalence of advanced colonic neoplasia was similar among anemic patients with ferritin 51-100 ng/mL (7.2%) and ferritin =50 ng/mL (7.9%). The prevalence of colonic neoplasia in anemic patients with ferritin >100 ng/mL was low (1.7%) and similar to the prevalence in asymptomatic nonanemic subjects (1.2%). Therefore, a ferritin cutoff of 100 ng/mL can be used to determine the need for colonoscopy in men with anemia.

NAAC Expert Commentary:
For practicing physicians and other healthcare providers, this is a very useful contribution. Unexplained anemia is increasingly recognized, particularly with advancing age, accounting for approximately 1/3 of those with anemia in the 65 year and older age group. For those in this group with ferritin levels below 100 ng/dL, even in the absence of other evidence for iron deficiency, colonoscopy is clearly warranted, based upon the current data. Yet, the corollary may be somewhat controversial. Does a ferritin level of greater than 100 ng/dL indicate absence of iron deficiency? And, if so, is it sufficient to exclude colonoscopy in the diagnostic workup for anemia? Although ferritin, itself, is the single most reliable marker of iron deficiency, its level in the presence of inflammatory disease may be elevated by inflammatory processes, reflecting non-useable iron that results from the action of inflammatory mediators and hepcidin on iron trafficking between the gut, bone marrow, and extra-marrow stores. Some investigators have found the assessment of soluble transferrin receptor to be useful in defining iron deficiency in those with coexistent inflammation.

Furthermore, for those older people with anemia but without evidence for iron deficiency, colonoscopy has a significantly higher (five-fold) risk for discovery of a colonic neoplasm, compared with those without anemia.

Thus, older people with anemia have a higher likelihood of colon cancer. Such individuals with ferritin levels <100 ng/dL are likely to have anemia secondary to blood loss and subsequent iron deficiency. However, the presence of unexplained anemia, alone, is of sufficient importance to warrant colonoscopy. Of course, all adults over the age of 50 should engage in routine screening colonoscopy.

For additional information on this research, please reference the source article: Sawhney, M. S., T. Lipato, et al. (2007). "Should patients with anemia and low normal or normal serum ferritin undergo colonoscopy?" Am J Gastroenterol 102(1): 82-8.

Darbepoetin alfa and epoetin alfa achieved similar rates of transfusion independence in critically ill patientsBackground: A "transfusion trigger" refers to a threshold when transfusions are begun. For many years, clinicians used the "30/10 rule," which indicates the initiation of transfusion at a hematocrit (Ht) below 30% or a hemoglobin (Hb) concentration below 10 g/dl. Although in use for several years, the restrictive practice has recently come under scrutiny due to a large study conducted in critically ill patients. Investigators found that transfusion requirements showed no difference in mortality rates for patients treated with either a restrictive or liberal policy for blood transfusion. As a result, research has focused on therapies to decrease the number of red blood cell (RBC) transfusions. Recombinant human erythropoietin (rHuEPO) is one such therapy. Whereas rHuEPO has the identical amino acid sequence as endogenous erythropoietin, darbepoetin alfa contains additional carbohydrate content, which confers an approximately 3-fold increase to the terminal half-life of darbepoetin alfa vs. rHuEPO.

Objectives: To compare the effectiveness of darbepoetin alfa with rHuEPO (equivalent doses) for achieving transfusion independence and increasing hemoglobin concentrations in critically ill patients.

Methods: This was a retrospective, descriptive study of 72 patients who spent at least three days in a level 1 trauma center intensive care unit (ICU) between January 1, 2003, and June 30, 2005. After the initial review of 773 patients, 72 patients met the inclusion criteria. Patients were excluded if they received epoetin treatment for other indications, such as anemia of chronic renal failure. Patients received at least one weekly dose of rHuEPO 40,000 units (33 patients) or darbepoetin alfa 100 µg (39 patients).

The number of rHuEPO and darbepoetin alfa doses, Hb concentrations, and cumulative number of transfusions were recorded for up to 28 days after the first dose was given. Beginning a median of 10 days after the patients were admitted to the ICU, they received a median of 3.5 doses of darbepoetin alfa or 4 doses of rHuEPO. Mean Hb concentrations at which treatment with darbepoetin alfa and rHuEPO were started were 8 and 8.2 g/dl, respectively (p=0.41). The institution changed its formulary for erythropoietic treatment, on September 1, 2004, such that patients received rHuEPO before this date and darbepoetin alfa after this date. According to institutional practice, all patients received ferrous sulfate 325 mg/day given orally or nasogastrically. The need for RBC transfusion was determined by each patient's physician using a general guideline-there was no "transfusion trigger."

Results: Transfusion independence was achieved in 44% of patients in the darbepoetin alfa group compared with 36% of patients in the rHuEPO group (p=0.63). Differences in transfusion independence between groups was not affected by age, baseline Hb level, or APACHE II scores. The mean change in hemoglobin levels from baseline over time did not significantly differ between groups (p=0.75). Patients in both groups received a mean of 2.7 units of packed red blood cells during the 28-day study period. Five patients in each group experienced thrombotic events that included deep vein thrombosis, pulmonary embolism, cerebrovascular accident, and acute coronary syndrome.

Authors Conclusions: Patients receiving equivalent doses of darbepoetin alfa and rHuEPO for anemia of critical illness achieved similar rates of transfusion independence and increases in hemoglobin concentrations during the 28-day study.

NAAC Expert Commentary:
This retrospective trial had some significant limitations regarding the equivalency of the two erythroid stimulating agents. Although all available recombinant erythroid stimulants share the effect of the endogenous hormone, they may not be equivalent in potency. In addition, a small sample size can result in skewed results as mentioned by the authors. Other parameters should also be considered: According to the severity of illness (APACHE) scores, the rHuEPO group was 'sicker'. Also, the overall length of stay of both groups was very long, suggesting a higher acuity or more complex morbidity among the patients. The absence of a transfusion trigger could lead to the administration of transfusions according to the institutional 'culture' rather than the need for blood.

A prospective, randomized, and well-powered study could better demonstrate the equivalency (or non-equivalency) of these agents, but would probably be limited to a subgroup of patients with a long length of ICU stay. Many ICU patients are discharged within the first few days or first week, making a 28-day analysis difficult, and thus, resulting in the selection of patients with higher acuity and longer length of stay.

Supplemental iron in many ICU patients is given parenterally, since absorption via the gut is impaired in the critically ill. The oral administration of iron in this study could also reduce the effectiveness of both drugs, increasing the likelihood of transfusions and reducing transfusion independence.

For additional information on this research, please reference the source article: Voils, S. A., S. H. Harpe, et al. (2007). "Comparison of Darbepoetin alfa and Epoetin alfa in the Management of Anemia of Critical Illness." Pharmacotherapy 27(4): 535-41.

Epoetin alfa study of quality of life outcomes in lung cancer patients with disease-related anemia halted after unplanned safety analysis: Highlights the need to monitor overall survival

Background: Anemia is common in cancer patients both as a consequence of cancer treatments such as chemotherapy and as a result of the underlying disease. Up to 34% of patients with lung cancer may present with hemoglobin (Hb) levels less than or equal to 12.5 g/dL.

Objective: To determine whether epoetin alfa therapy improved the quality of life of anemic patients with unresectable locally advanced non-small cell lung cancer (NSCLC) who were not candidates for high dose thoracic radiation and were not treated with chemotherapy during or within two months prior to entering the trial.

Methods: This was a multicenter, randomized, double-blind, placebo-controlled trial with a twelve-week treatment period. Patients were randomly assigned to receive either 12 weekly subcutaneous injections of 40,000 U of rHuEPO or 1.0 ml of an identical-appearing placebo with dose escalation to 60,000 U (active arm) or 1.5 ml (placebo arm) if Hb increased less than 1.0 g/dL from baseline at the 4 week assessment. Random assignment was stratified by center, entry Hb level (less than 10.0 g/dL vs. 10.0-12.0 g/dL), and concurrent or planned palliative radiotherapy (no/yes). Dose/injection volume decreased by 25% if the hemoglobin increased by 2.0 g/dL over 4 weeks. Treatment was withheld with an Hb of 14.0 g/dL or above and restarted at 75% of the initial dose/volume when the Hb was below 12.0 g/dL. Iron was supplemented at the discretion of the attending physician.

Because of low accrual, the eligibility criteria were modified during the study to allow inclusion of subjects receiving palliative chemotherapy with the exception of platinum-based regimens. Seventy patients were randomized (33 receiving epoetin alfa and 37 receiving placebo). The primary outcome of change in quality of life (QOL) on the Functional Assessment of Cancer Therapy-Anemia (FACT-An) score was evaluated as change from baseline to the 12 week assessment. Secondary outcomes included change in Hb and need for blood transfusions. QOL data were collected through 16 weeks with Hb assessed at 26 weeks and only overall survival was followed after 26 weeks.

Results: The Steering Committee suspended the trial following a review by the study's independent Data Safety and Monitoring Committee (DSMC) requested by Ortho Biotech. The request for the review was prompted by concern about higher than expected rates of thrombotic events found in other studies. The DSMC review of the first 66 patients found low rates of thrombotic events with no difference between study arms, but revealed differences in median time to death (63 days in the epoetin alfa arm and 129 days in the placebo arm; HR 1.84, 95% CI 1.01 to 3.35, p = .04).

NAAC Expert Commentary:
This study was designed to examine the effects of epoetin alfa on QOL in a previously unstudied population: anemic patients with advanced NSCLC who had disease-related rather than chemotherapy-related anemia. Additional contextual differences from the majority of previously reported epoetin alfa trials were the use of a Hb level of 12 g/dL for defining anemia and the continuation of treatment to a Hb level of 14.0 g/dL. As noted by the authors, the data presented raise a number of questions ranging from whether or not erythropoietic stimulating agents interact with unknown biologic factors to influence the rate of disease progression in subsets of people with cancer to the possibility that there were factors associated with prognosis that were not adequately controlled, or that the variables used to represent prognostic factors lacked the sensitivity required to detect real differences between the groups.

The authors present a thoughtful discussion of several strengths and weaknesses of the trial and emphasize the need to include survival outcomes in current and future trials of erythropoietic agents. Given the lack of data on possible biologic explanations for discrepant findings in some studies, it is important to begin including measures of variables that assess potential mechanisms of thrombosis and disease progression to examine these hypotheses in clinical populations.

For additional information on this research, please reference the source article: Wright, J. R., Y. C. Ung, et al. (2007). "Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia." J Clin Oncol 25(9): 1027-32.