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In Reply

Medical College of Wisconsin, Milwuakee, WI

Mark R. Somerfield, Karen L. Hagerty

American Society of Clinical Oncology, Alexandria, VA

Jerome Seidenfeld

Blue Cross and Blue Shield Association, Chicago, IL

Julia Bohlius

University of Cologne, Cologne, Germany

Charles L. Bennett, David F. Cella

Northwestern University, Evanston Northwestern Healthcare, Evanston, IL

Benjamin Djulbegovic

H. Lee Moffitt Cancer Center, Tampa, FL

Matthew J. Goode

Patient Representative, Mesa, AZ

Ann A. Jakubowski

Memorial Sloan-Kettering Cancer Center, New York, NY

Carole B. Miller

St Agnes Healthcare, Baltimore, MD

Mark U. Rarick

NW Kaiser Permanente, Portland, OR

David H. Regan

US Oncology, Houston TX

Alan E. Lichtin

Cleveland Clinic Foundation, Cleveland, OH

We agree with many points made by Drs Murray and Klasa, and by Dr Arcasoy, in their letters concerning the December 2007 American Society of Clinical Oncology/American Society of Hematology (ASCO/ASH) Clinical Practice Guideline Update on erythropoiesis-stimulating agents (ESAs).¹ We also are grateful for the opportunity to clarify certain aspects of the Update Committee's recommendations raised in these letters, to clarify the process that led to the Update Committee's consensus on recommendations, and to correct an important misstatement in Dr Arcasoy's letter. It should also be noted that data continue to emerge regarding use of ESAs for chemotherapy-induced anemia. These data include additional meta-analyses,^2,3 publication of recently analyzed clinical trials,⁴ and deliberations of the US Food and Drug Administration's (FDA) Oncology Drug Advisory Committee. Although it is not possible to address these emerging data in a Correspondence, the Update Committee is following the changing situation and will issue new recommendations as warranted.

Dr Arcasoy incorrectly states that the Update Committee "... broadly..." recommends initiating "... ESA therapy at Hb less than 12 g/dL... ." In contrast, Drs Murray and Klasa correctly note the December 2007 Guideline Update recommendation that ESA therapy for most patients should be considered as "... hemoglobin approaches or falls below 10 g/dL... ." However, neither letter mentions that recommendations IIIa (considering ESA therapy for most patients as Hb approaches or falls below 10 g/dL) and IIIb (considering ESA therapy at Hb between 10 and 12 g/dL if individual circumstances and clinical judgment warrant) include the following alternative to ESA therapy: managing the anemia with RBC transfusions as needed.

The Update Committee intentionally included this statement, in both the original guideline⁵ and in the update, to clarify that monitoring of Hb concentration and transfusion when it falls below an acceptable threshold based on symptoms or institutional standards is a reasonable alternative to ESA treatment. It is also stated by Dr Arcasoy that "there is no conclusive evidence that ESA initiation at Hb levels above 10 g/dL... improves quality of life." In fact, based on available quality-of-life studies and other data available at the time of the guideline update, the best clinical opinion of the Committee was that a trial of ESA therapy may be warranted for patients with a hemoglobin between 10 g/dL and 12 g/dL with impaired physical functioning due to decreased energy or exercise capacity.

Both letters agree with systematic reviews reported before December 2007^6-8 and the updated guideline¹ that the literature is not uniform with respect to study participants’ tumor types (homogeneous v heterogeneous), baseline hemoglobin concentrations and target thresholds, thresholds for transfusions, monitoring for adverse events, or monitoring for poststudy survival. Literature-based meta-analyses have attempted to draw inferences from the published studies, but have been unable to control for the many confounding differences in study design and treatment protocols, and have also been hampered by generally inadequate reporting, particularly on adverse events.

We agree with Dr Arcasoy that it seems arbitrary to initiate ESA therapy at a prespecified Hb level. It is also true that an otherwise healthy 30-year-old cancer patient would be approached differently from a 75-year-old person with coronary artery disease, chronic obstructive pulmonary disease, obesity, or other comorbid conditions. Similarly, use of an ESA may vary by cancer indication and type of cancer therapy. Clinical judgment guides whether one would manage such different patients (whether the Hb concentration was 9.9 or 10.1 g/dL) using ESA therapy or observation and transfusion as necessary. However, as Dr Arcasoy acknowledges, evidence available at the time of our December 2007 guideline update was insufficient to support specific recommendations for all but the most general individual circumstances. Consequently, the guideline Update Committee recommended clinically prudent Hb levels at which to initiate an ESA, and at the same time indicated that future updates would be disseminated as new data regarding safety and effectiveness became available.

We recognize that readers might be confused by changes in the updated guideline recommendations, given the numerous reports on ESA safety in the last 2 years. The Update Committee agreed with conclusions of the Agency for Healthcare Research and Quality comparative effectiveness review, based on clinical trials reported before March 2005, that the evidence at that time did not show any initial dose or dosing regimen to be superior to any other in efficacy (except for suboptimal doses well below those recommended in package inserts) or safety. Consequently, the Update Committee viewed adherence to initial doses and dose modification regimens recommended in FDA-approved labeling as the most prudent course of action. Shortly after the final update manuscript was accepted for publication, the FDA approved new black box warnings and certain changes to dosing and administration. The Update Committee believed it served the interests of readers to add information on these changes, which reflected in large part the numerous trials reported from mid-2005 through 2007, while the Update Committee deliberated, then drafted, submitted, and finalized the updated guideline. To minimize delay of the targeted publication date, the information was added as an additional Appendix table, rather than replacing the table originally published online. FDA-approved labeling on ESA use, dosage, and administration will likely change yet again after the March 13, 2008, Oncologic Drugs Advisory Committee (ODAC) meeting, where other related safety notifications that have been published since the ASCO/ASH guideline was disseminated in December 2007, were discussed. The Update Committee continues to support adherence to FDA-approved labeling on dosage and administration through all these changes as the most prudent course of action at the current time. Most importantly, it should be noted that practice guidelines must deal with moving targets as new findings appear, often requiring modifications as the article goes to press to incorporate the new data into updates.

We also agree with Drs Murray and Klasa and with Dr Arcasoy that current evidence is insufficient to determine the mechanism(s) responsible for adverse events (decreased survival, increased tumor progression, and/or increased rates of thromboemboli) in some patients treated with an ESA. Certainly, relevant mechanisms may differ among specific malignancies or disease stages, different chemotherapy regimens, and the different adverse events themselves. The Update Committee found that evidence was insufficiently conclusive to attribute all such adverse events to any study variable related to Hb concentrations: baseline, target, peak, or average Hb across the study period. As Drs Murray and Klasa hypothesize, there may be an ESA cumulative dose or dose-density issue contributing to one or more of the adverse outcomes, but testing this requires more definitive research, as does the hypothesis that, as in the chronic kidney disease setting, adverse outcomes are more frequent among patients who do not immediately respond with an increase in Hb concentrations and then have their ESA dose increased or even doubled. We certainly agree with Drs Murray and Klasa that data on ESA doses administered to study participants would be useful and should have been included in published reports. However, those who conduct literature-based systematic reviews and meta-analyses and use them to develop clinical practice guidelines have little influence over the specific data that are collected and reported from clinical trials. The Update Committee is hopeful that such data will be made available to the Cochrane group presently conducting an individual patient data meta-analysis on outcomes of ESA use.

Drs Murray and Klasa advocated suspending the use of ESAs in the adjuvant chemotherapy setting. Although the guideline Update Committee did not recommend such a suspension, ODAC voted on March 13, 2008, to recommend that the FDA approve labeling stating that ESAs are not indicated in patients undergoing potentially curative treatment, and also are not indicated for patients with metastatic breast or head and neck cancers. It remains unknown whether the FDA will follow these and other ODAC recommendations. As before, the Update Committee will continue to monitor changes to FDA-approved labeling and reporting of new evidence, and will inform ASCO and ASH members and readers as new information emerges.

As a final note, the Update Committee, like Dr Arcasoy, regrets the fact that "... more than a decade after the FDA approval of epoetin-alfa for cancer patients with CIA [chemotherapy-induced anemia], the optimal administration of this useful drug and its analogs in supportive cancer care is not settled." It seems likely that the lack of necessary evidence is at least partly attributable to the way most drug trials are presently funded in the United States. Commercial interests cautiously consider which studies to fund and are disinclined to fund those that are unlikely to expand the patient population for which their drug is indicated. For similar reasons, trials seeking evidence on comparative effectiveness and safety of marketed products (drugs or devices) almost never find commercial sponsors. Unless the clinical research enterprise is adequately motivated and funded to conduct such studies, systematic reviewers, meta-analysts, guideline panels, clinicians, and patients will continue to seek in vain some of the evidence they need to make decisions informed by high-quality clinical evidence.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Alan E. Lichtin, Amgen (U) Stock Ownership: None Honoraria: Carole B. Miller, Orthobiotech Research Funding: David F. Cella, Amgen; Alan E. Lichtin, Amgen Expert Testimony: None Other Remuneration: None

REFERENCES

1. Rizzo JD, Somerfield MR, Hagerty KL, et al: Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update. J Clin Oncol 26:132-149, 2008[Abstract/Free Full Text]

2. Bennett CL, Silver SM, Djulbegovic B, et al: Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 299:914-924, 2008[Abstract/Free Full Text]

3. Minton O, Stone P, Richardson A, et al: Drug therapy for the management of cancer related fatigue. Cochrane Database Syst Rev 1:CD006704, 2008[Medline]

4. Smith RE Jr, Aapro MS, Ludwig H, et al: Darbepoetin alpha for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy: Results of a phase III, multicenter, randomized, double-blind, placebo-controlled study. J Clin Oncol 26:1040-1050, 2008[Abstract/Free Full Text]

5. 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. J Clin Oncol 20:4083-4107, 2002[Abstract/Free Full Text]

6. Bohlius J, Wilson J, Seidendfelf J, et al: Erythropoietin or darbepetin for patients with cancer. Cochrane Database Syst Rev 3:CD003407, 2006[Medline]

7. Seidenfeld J, Piper M, Bohlius J, et al: Comparative Effectiveness of Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment. Comparative Effectiveness Review No. 3 (Prepared by Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. 290-02-0026). Agency for Healthcare Research and Quality, www.effectivehealthcare.ahrq.gov/reports/final.cfm2006

8. Wilson J, Yao GL, Raftery J, et al: A systematic review and economic evaluation of epoetin alfa, epoetin beta and darbepoetin alfa in anaemia associated with cancer, especially that attributable to cancer treatment. Health Technol Assess 11:1-220, 2007[Medline]

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