This report was reviewed for medical and scientific accuracy by Joseph E. Eid, MD, Assistant Professor of Medicine, Division of Hematology, and Assistant Professor of Pathology & Laboratory Medicine, University of Medicine & Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey

Editorial

David Henry, MD, Clinical Associate Professor of Medicine, Pennsylvania Hospital, Joan Karnell Cancer Center, Philadelphia, Pennsylvania

Anemia is a common complication among patients with cancer, whether as a result of the disease itself, chemotherapy, or radiation therapy.¹ Anemia in cancer patients receiving chemotherapy is associated with a number of debilitating symptoms such as fatigue, dizziness, headache, chest pain, dyspnea, and depression, but also impairs cognitive function and the ability of patients to perform normal activities of daily living. For these reasons, anemia can have a profound influence on the quality of life (QOL) of patients with cancer.²

Blood transfusion was long considered the standard treatment for anemia. However, with recent concerns about transfusion-related complications, relatively limited supply of blood products, and the perceived risk of viral infection among patients, clinicians have sought alternative treatments for patients with anemia.¹

Recombinant human erythropoietin (epoetin alfa, Procrit®, Ortho Biotech Products, L.P., Bridgewater, NJ) stimulates red blood cell formation and is now an important component in the standard of care for chemotherapy-induced anemia.^3,4 A number of clinical studies conducted over the last decade have suggested that treatment of anemia using epoetin alfa increases hemoglobin levels, reduces the need for blood transfusions, and decreases anemia-related fatigue suggesting an improvement in QOL. Building upon that foundation, considerable recent evidence, including an analysis of data from more than 4300 patients enrolled in two large phase 4 clinical trials,⁵ indicates that epoetin alfa significantly improves the QOL among patients with chemotherapy-induced anemia.

Crawford and colleagues⁵ found that increases in hemoglobin levels were significantly correlated with improved patient scores on two standard QOL rating scales, the Linear Analog Scale Assessment (LASA) and the Functional Assessment of Cancer Therapy-Anemia (FACT-An). More importantly, investigators documented the maximum incremental gain seen in QOL scores occurred when patients' hemoglobin levels increased from 11 to 12 g/dL (range 11 to 13 g/dL). Similar findings, in terms of QOL improvement associated with incremental gains in hemoglobin level, have also been demonstrated by Cleeland et al⁶ and Shasha et al.⁷

The results of these studies suggest that the administration of epoetin alfa improves the QOL in anemic cancer patients receiving chemotherapy as a function of hemoglobin with the most significant increment in QOL improvement occurring as hemoglobin increases from 11 to 12 g/dL. Proactively taking these results one step further, recent clinical studies in cancer patients receiving chemotherapy have found that intervention with epoetin alfa at the beginning of chemotherapy can prevent declines in hemoglobin levels. Indeed, epoetin alfa significantly improves baseline hemoglobin levels, with corresponding maintenance or improvement in QOL.^8,9 Given this evidence, there appears support for early and aggressive treatment with epoetin alfa to prevent a decline in hemoglobin and associated QOL while receiving chemotherapy.

This Express Report will review the regulation of erythropoiesis by erythropoietin and discuss several clinical studies that have demonstrated a positive association between QOL improvement and higher hemoglobin levels.

Erythropoietin Regulation of Erythropoiesis

Erythropoietin, a glycoprotein hormone produced by the kidneys, increases the production of red blood cells from erythroid precursor cells. Erythropoietin is produced in response to diminished tissue oxygenation; whether as a result of decreased blood hemoglobin concentration, decreased oxygenation of hemoglobin, or increased affinity of hemoglobin-bound oxygen.¹⁰ There appear to be additional sensor mechanisms involved in signaling for increased production of erythropoietin and this possibility is supported by an important aspect of erythropoietin physiology; plasma levels of erythropoietin are remarkably constant over the range of normal hemoglobin levels. The production of erythropoietin is dramatically increased, and serum levels increase logarithmically, in response to hemoglobin levels falling below 12 g/dL¹¹ (Figure 1), which suggests that 12 g/dL may be a natural threshold below which the body responds. However, the feedback mechanism that stimulates an erythropoietin response often fails to function properly in patients with cancer-related anemia.¹²

Adapted from ^[10]

These observations provided the impetus for investigation of the multiple relationships (eg, fatigue, improvements in QOL) between the administration of epoetin alfa and incremental improvements in hemoglobin levels and are intriguing in light of the optimal biologic activity and efficacy of therapeutic epoetin alfa observed in patients when hemoglobin level reaches 12 g/dL.

Epoetin Alfa and Quality of Life in Anemic Cancer Patients Receiving Chemotherapy

An extensive body of literature supports a direct and positive relationship between hemoglobin and QOL in patients with cancer. Two clinical trials in anemic cancer patients receiving chemotherapy demonstrated the efficacy of epoetin alfa in improving hemoglobin levels and QOL.^13,14 These studies enrolled 4,382 anemic cancer patients with baseline hemoglobin levels that ranged from 8 to 14 g/dL and used comprehensive statistical methods in examining the relationship between hemoglobin and QOL. A recent analysis of these studies⁵ further evaluated the relationship between: 1) changes in hemoglobin levels and change in QOL; and 2) incremental changes in hemoglobin levels and incremental change in QOL.

To evaluate the impact of epoetin alfa on QOL, patients in both studies rated their energy levels, abilities to perform daily activities, and overall QOL at baseline and Month 4 using the 100 mm LASA. However, in one study, an additional LASA was administered at Month 2 along with the more detailed FACT-An questionnaire. The FACT-An was used to evaluate four general domains of day-to-day functioning (physical, emotional/mental, social/family, and functional well-being). The results from that study showed that QOL changes derived from the FACT-An questionnaire correlated well (r = 0.72) with those derived from the LASA.¹³

Based on data obtained at baseline (mean hemoglobin level 9.3 g/dL; mean LASA overall QOL 45 mm; mean FACT-An 113 points), Month 2 and Month 4, direct correlations between hemoglobin levels and LASA overall QOL scores in each study were modest but statistically significant (r = 0.25 and 0.29, respectively; P<.01). Furthermore, the direct correlation between hemoglobin levels and FACT-An scores (r = 0.27) was also significant (P<.01) and followed a pattern similar to that observed with LASA overall QOL scores.

Longitudinal analysis revealed that successively positive changes (improvements) in LASA overall QOL scores continued with increases in hemoglobin levels to 14 g/dL, where the estimated QOL was 15.2 mm higher than at a hemoglobin level below 7.5 g/dL (P<.01) (Figure 2). The relationship between the change in hemoglobin level and change in LASA overall QOL scores was direct and significant (P<.01).

Adapted from ^[5]

Based on the results of the longitudinal analysis, it was possible to identify the incremental effect of increases in hemoglobin levels on overall QOL, as measured by LASA. In fact, the findings revealed that incremental increases in hemoglobin had differing effects on patients' QOL response depending on the level of hemoglobin from which that incremental increase was achieved.

Incremental increases in QOL resulting from increases in hemoglobin were evident from 7 to 14 g/dL. The overall LASA scores indicated that the 1 g/dL rise in hemoglobin from 11 g/dL to 12 g/dL yielded the greatest incremental gain in QOL. Beyond a hemoglobin level of 12 g/dL, subsequent incremental increase in hemoglobin continued to yield additional gains in QOL, albeit of a decreasing magnitude. These results are compelling since the physiological response to epoetin alfa appears (manifested here by QOL) to mimic the natural threshold for feedback mechanism of erythropoietin production (ie, the 12 g/dL threshold seen regarding endogenous erythropoietin secretion; Figure 1).

Appropriately, increasing emphasis has been placed on using the patient's perception of QOL to guide therapeutic decision-making. The current analysis suggests that it would be optimal to incorporate not only the monitoring of hemoglobin levels but also the presence and severity of anemia-related symptoms and patient QOL. Additionally, the findings indicate that hemoglobin levels ≤12 g/dL are associated with suboptimal (and potentially correctible) levels of functional ability and overall QOL in patients with cancer.

Looking to confirm these findings in a carefully designed, randomized, double-blind, placebo-controlled study, Littlewood et al¹⁵ demonstrated that intervention with epoetin alfa resulted in significant improvements in QOL (measured by either LASA or FACT-An) while patients receiving placebo showed a decline in QOL. The investigators noted statistically significant correlations between the changes in hemoglobin values from baseline and final scores on the FACT-An (r = 0.2899), the LASA energy scale (r = 0.3062), LASA activity (r = 0.3422) and LASA overall QOL ratings (r = 0.3285; all P = .02). In epoetin alfa-treated patients, mean hemoglobin levels (baseline 9.9 g/dL) increased gradually to reach approximately 12 g/dL compared to 10.2 g/dL in placebo-treated patients (baseline 9.7 g/dL). The mean increase in hemoglobin level from baseline was significantly greater in epoetin alfa-treated patients than in placebo-treated patients (2.2 g/dL vs 0.5 g/dL, P<.001). Although the study was not powered with respect to survival, a trend in survival favoring epoetin alfa was also identified (P = .13). These findings suggest that the administration of epoetin alfa safely and effectively increases hemoglobin levels thereby ameliorating anemia and significantly improving QOL in cancer patients receiving chemotherapy. A subsequent multivariate analysis, accounting for the effects of disease progression and confounding variables on QOL, confirmed these results.¹⁶

Although epoetin alfa has been extensively studied in cancer- and chemotherapy-related anemia, the use of epoetin alfa in cancer patients receiving curative-intent concomitant or sequential chemoradiation and its effect on QOL is less well-studied. An analysis of data from 442 patients undergoing treatment for solid tumors with baseline hemoglobin values ≤11 g/dL found that higher hemoglobin values were significantly correlated with higher LASA scores for activity (r = .33), energy (r = .32), and overall QOL (r = .29; all P<.05).⁷ A similar incremental analysis to that of Cleeland et al,⁶ identified that the largest improvements in QOL were observed when hemoglobin values increased from 11 to 12 g/dL and are consistent with those of Cleeland⁶ and Crawford.⁵

With evidence indicating an optimal QOL response to epoetin alfa with hemoglobin levels in the range of 11 to 12 g/dL, investigators have explored the effect of epoetin alfa administration in preventing a decline in hemoglobin level and QOL parameters during chemotherapy. Hudis and colleagues studied the effects of epoetin alfa (40,000 U QW) in 721 female patients with breast cancer (stage I-III) who were receiving concurrent adjuvant anthracycline chemotherapy either with or without a taxane.⁸ An analysis of the QOL data described significant improvement in scores on the LASA energy rating scale (mean improvement of 4.9 mm from baseline; P<.05) and activity (mean improvement of 4.4 mm; P<.05). Investigators noted that hemoglobin values increased from a baseline average of 12.3 g/dL to a final value of 13.2 g/dL during the course of the study. These data from Hudis and colleagues suggested a compelling new paradigm regarding the treatment of anemia. Rather than waiting for a patient's hemoglobin level to fall when receiving chemotherapy, their data support the administration of epoetin alfa to prevent a patient's hemoglobin and associated QOL from declining.

Practice Guidelines Support Use of Epoetin alfa

Recent practice guidelines developed by the National Comprehensive Cancer Network (NCCN)³ and the American Society of Clinical Oncology/American Society of Hematology (ASCO/ASH)⁴ characterize epoetin alfa as an important part of the standard of care for chemotherapy-related anemia based upon evidence demonstrating its associated improvements in symptoms of anemia, reduction of the need for transfusion, improvements in QOL, and possibly improved overall survival.

According to the NCCN guidelines, epoetin alfa should be considered for patients with hemoglobin levels of 10 to 11 g/dL who are asymptomatic but who have risk factors for anemia (eg, recent transfusion, current or recently completed myelosuppressive treatment) or have symptoms of anemia (eg, fatigue, impaired performance status). The NCCN guidelines further state that epoetin alfa should be strongly considered if the hemoglobin level is less than 10 g/dL. The ASCO/ASH guidelines differ on this point, in that their guidelines definitely recommend the use of epoetin alfa if hemoglobin level falls below 10 g/dL. Both guidelines indicate that the administration of epoetin alfa should be titrated to maintain an optimal hemoglobin level of 12 g/dL. A second erythropoietic agent, darbepoetin alfa (Aranesp®, Amgen Inc., Thousand Oaks, CA) has recently been made available for the treatment of anemia. Although structurally and physiologically similar to epoetin alfa, darbepoetin alfa has been modified to provide a longer half life.¹⁷ Recent evidence suggests that darbepoetin alfa is also safe and effective and can correct the anemia occurring in cancer patients receiving chemotherapy.^18,19 Both guidelines cite preliminary positive data on darbepoetin alfa, but defer clinical recommendations pending further evaluation and final publication of current darbepoetin alfa clinical studies.

Conclusion

The traditional approach to managing chemotherapy-related anemia has been to wait until hemoglobin levels drop to ≤10 g/dL before initiating epoetin alfa therapy. These new data from Crawford et al, Shasha et al, and Hudis et al support a paradigm change, in an effort to maintain and/or maximize a cancer patient's QOL. New data may even support earlier intervention with epoetin alfa and the importance of maintaining hemoglobin levels ≥12 g/dL.

References

1. Gordon MS. Managing anemia in the cancer patient: old problems, future solutions. The Oncologist. 2002;7:331-341.
2. Gabrilove J. Overview: erythropoiesis, anemia, and the impact of erythropoietin. Semin Hematol. 2000;37(suppl 6):1-3.
3. NCCN Practice Guidelines in Oncology-Version 1.2002. Cancer and treatment-related anemia. National Comprehensive Cancer Network, Inc. Available at http://www.nccn.org. Accessed January 25, 2002.
4. Rizzo JD, Lichtin AE, Woolf SH, et al. Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. Blood. 2002;100:2303-2320.
5. Crawford J, Cella D, Cleeland CS, et al. Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Cancer. 2002;95:888-895.
6. Cleeland C, Demetri G, Glaspy J, et al. Identifying hemoglobin level for optimal quality of life: results of an incremental analysis. Proc Am Soc Clin Oncol. 1999;18:547a. Abstract 2215.
7. Shasha D, George MJ, Harrison LB. Relationship between hemoglobin (Hb) levels and quality of life (QOL) during chemoradiation: findings from an incremental analysis of a 442-patient, prospective, community-based epoetin alfa study. Int J Radiat Oncol Biol Phys. 2002;54(Number 2, Supplement):48.
8. Hudis CA, Williams D, Gralow JR. Final report: epoetin alfa maintains hemoglobin levels and quality of life in breast cancer patients during conventional adjuvant chemotherapy. Breast Cancer Res Treat. 2002;76(suppl 1):S135. Abstract 539.
9. O'Shaughnessy J, Vukelja S, Savin M, et al. Impact of epoetin alfa on cognitive function, asthenia, and quality of life in women with breast cancer receiving adjuvant or neoadjuvant chemotherapy: analysis of 6-month follow-up data. Breast Cancer Res Treat. 2002;76(suppl 1):S138. Abstract 550.
10. Hillman RS, Finch CA (eds): Red Cell Manual (ed 7). Philadelphia, PA, Davis, 1996.
11. Finch CA. Erythropoiesis, erythropoietin, and iron. Blood. 1982;60:1241-1246.
12. Miller CB, Jones RJ, Piantadosi S, Abeloff MD, Spivak JL. Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med. 1990; 322:1689-1692.
13. Demetri GD, Kris M, Wade J, Degos L, Cella D. Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: results from a prospective community oncology study. Procrit Study Group. J Clin Oncol. 1998;16:3412-3425.
14. Glaspy J, Bukowski R, Steinberg D, Taylor C, Tchekmedyian S, Vadhan-Raj S. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. J Clin Oncol. 1997;15:1218-1234.
15. Littlewood TJ, Bajetta E, Nortier JWR, Vercammen E, Rapoport B for the Epoetin Alfa Study Group. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2001;19:2865-2874.
16. Fallowfield L, Gagnon D, Zagari M, et al. Multivariate regression analyses of data from a randomized, double-blind, placebo-controlled study confirm quality of life benefit of epoetin alfa in patients receiving non-platinum chemotherapy. Br J Cancer. 2002;87:1341-1353.
17. Valley AW. Overview of cancer-related anemia: focus on the potential role of darbepoetin alfa. Pharmacotherapy. 2002;22:150S-159S.
18. Pirker R, Vansteenkiste J, Gateley J, Yates P, Colowick A, Musil J for the NESP 980297 Study Group. A phase 3, double-blind, placebo-controlled, randomized study of novel erythropoiesis stimulating protein (NESP) in patients undergoing platinum treatment for lung cancer. Proc Am Soc Clin Oncol. 2001;20. Abstract 1572.
19. Kotasek D, Albertsson M, Mackey J for the Darbepoetin alfa 980291 Study Group. Randomized, double-blind, placebo-controlled, dose-finding study of darbepoetin alfa administered once every 3 (Q3W) or 4 (Q4W) weeks in patients with solid tumors. Proc Am Soc Clin Oncol. 2002;21. Abstract 1421.

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Disclosure

David Henry, MD: Grant/Research Support-Amgen, Inc., Ortho Biotech Products, L.P.; Speakers Bureau-Amgen, Inc., Ortho Biotech Products, L.P.

Joseph E. Eid, MD: Has no significant relationships to disclose.

This report is supported by an educational grant from Ortho Biotech Products, L.P., Bridgewater, New Jersey

This monograph has been planned and implemented in accordance with the Standards of Commercial Support of the Accreditation Council for Continuing Medical Education (ACCME) through a joint sponsorship with UMDNJ-Center for Continuing and Outreach Education and Millennium Medical Communications, Inc. UMDNJ-Center for Continuing and Outreach Education is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Oncology Express Report™ does include discussion of treatment and indications outside of current approved labeling. Procrit is not approved for once-weekly dosing or for improvements in quality of life. This Oncology Express Report™ was made possible through an educational grant from Ortho Biotech Products, L.P., Bridgewater, New Jersey. Release date February 2003.

© 2003 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education