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Do Erythropoietin Receptors on Cancer Cells Explain Unexpected Clinical Findings?

Department of Radiation Oncology, Research Unit of the Dr Negrin University Hospital, Las Palmas, Spain; Canary Islands Institute for Cancer Research, Las Palmas, Spain; and Grupo de Investigación Clínica en Oncología Radioterápica (GICOR), Madrid, Spain

To the Editor:

The recent article by Henke et al¹ in the Journal of Clinical Oncology addresses the question of whether erythropoietin (EPO) receptor expression on cancer cells may be responsible for their unexpected observation in their previous study. This study showed poorer prognosis for patients receiving EPO in conjunction with their scheduled oncology therapy.² Many subsequent articles have highlighted the limitations of the study and have also been published in The Lancet^3-11 as well as other journals.¹² In the original study, 39% of patients from different enrollment centers were not available for per-protocol analysis. This was an important criticism. The current article by Henke et al¹ evaluating patients from the Freiburg Center pre-empted this criticism by correctly following an appropriate protocol. I congratulate the investigators on their highly relevant data. However, I would like to highlight a few irregularities in their data presentation and some clinical aspects of the receptor positive group of patients.

The results were adjusted for stratification because of the imbalance in resection status (37% v 27%). In addition, although not statistically significant (P = .101), the treatment group also had higher percentage of ganglionar stage IV (73% v 56%). However, the quartile of low-dose radiotherapy (RT) was 4 Gy lower in this group than in the placebo group, and the median dose of RT was similar in both groups (64 Gy), which suggests that the EPO group may have contained a greater number of patients receiving an inadequate RT dose. The median time taken to administer this dose was 3 days longer (49 v 46) in the treatment group, which is a well-documented factor for decreased effectiveness of RT.

Age is related to lower performance status, tolerance to the treatment, more comorbidities, and susceptibility to vascular events. Data presented on range and quartiles of age were higher (5 to 6 years older) in the EPO treatment group. However, this point may be an error since we note that the mean age was similar between the receptor positive groups and that the range and quartiles for age were the same as that for the range and quartiles for weight in the next row of the Table; a data transcription error, perhaps?

The authors presented the hemoglobin (Hb) concentrations at study commencement. It would be interesting to know, as well, the Hb levels during RT, at the end of RT, and, particularly, the highest levels achieved by the patients. The last aspect could be highly relevant for a correct interpretation of the results since the difference was probably statistically significant. Nonstandard doses of EPO were administered (60,000 U/week), and the target was supraphysiological Hb levels higher than 15 g/dL, which was reached in more than 80% of the patients.² This factor can, indeed, explain the poorer prognosis if the treatment group reached significantly higher levels of Hb. For example, when Hb and hematocrit increase, blood viscosity and peripheral resistance also increase and, as a consequence, blood flow decreases following Poiseuille's law. Higher than a certain Hb level, the increased oxygen transport associated with increased Hb will not compensate for the decrease in blood flow, and this leads to tissue and tumor hypoxia and less effectiveness of RT and/or chemotherapy. This effect is well documented in cyanotic heavy smokers with hyperglobulinemia, and has been described in theoretical and experimental tumor models.¹³ Animal studies have demonstrated the effects of Hb on the outcomes of RT. In a mouse model, using EPO under conditions of mild anemia to increase hematocrit values of up to 65% did not increase the effect of RT.¹⁴ However, studies using EPO in animals to correct severe anemia to levels of 12.7 to 14.3 g/dL showed a significant increase in tumor oxygenation and effectiveness of RT.^15-17 In human gynecologic tumors, a range of 12 to 14 g/dL has been described as the optimal Hb level.¹⁸ In that study, Hb level higher than 14 g/dL were associated with decreased tumor oxygenation.

It is necessary to highlight that American Society of Clinical Oncology guidelines¹⁹ for the use of EPO in patients with cancer have not changed, and adverse findings in studies using high-dose EPO, or in nonanemic patients, did not follow these guidelines. Several years ago, EPO was used quite regularly, but recently many oncologists are reluctant under any circumstances to use EPO in cancer patients during RT. If clinical trials in head and neck cancer were to be conducted using doses of RT of 140 Gy (twice that of standard dose) or using doses of chemotherapy twice what was recommended, and should adverse events result, would the usefulness of appropriate RT or chemotherapy be questioned by any oncologists?

The work from Henke et al reminds us that the administration of EPO, like any drug, needs to be performed with caution. In their concluding paragraph the authors state, "Erythropoietin might adversely affect prognosis of head and neck cancer patients if cancer cells express erythropoietin receptors."¹ However, this statement would be more accurate if modified to read, "Nonstandard elevated doses of erythropoietin might adversely affect... ." Some studies have suggested that to elicit a response in tumor EPO receptors requires higher local concentrations of EPO than the plasma levels obtained after standard clinical dose administration.²⁰ We believe that, in a similar manner to blood flow and oxygenation, the adverse results of EPO administration in patients with tumors expressing EPO receptors could be secondary to the high dose and protracted period of EPO administration, such as that employed by Henke et al. The effect of using standard doses of EPO to correct anemia (Hb levels no higher than 13 to 14 g/dL) would be very different. Further investigation is required to resolve this issue.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: Bernardino Clavo, Roche, Janssen-Cilag Research Funds: N/A Testimony: N/A Other: N/A

REFERENCES

1. Henke M, Mattern D, Pepe M, et al: Do erythropoietin receptors on cancer cells explain unexpected clinical findings? J Clin Oncol 24:4708-4713, 2006[Abstract/Free Full Text]

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13. Fyles AW, Milosevic M, Pintilie M, et al: Anemia, hypoxia and transfusion in patients with cervix cancer: A review. Radiother Oncol 57:13-19, 2000[CrossRef][Medline]

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15. Thews O, Koenig R, Kelleher DK, et al: Enhanced radiosensitivity in experimental tumours following erythropoietin treatment of chemotherapy-induced anaemia. Br J Cancer 78:752-756, 1998[Medline]

16. Kelleher DK, Thews O, Vaupel P: Modulation of tumor oxygenation and radiosensitivity by erythropoietin, in Vaupel P, Kelleher DK (eds): Tumor Hypoxia. Stuttgart, Wissenschaftliche Verlagsgesellschaft, 1999, pp 83-90

17. Stuben G, Thews O, Pottgen C, et al: Recombinant human erythropoietin increases the radiosensitivity of xenografted human tumours in anaemic nude mice. J Cancer Res Clin Oncol 127:346-350, 2001[CrossRef][Medline]

18. Vaupel P, Thews O, Mayer A, et al: Oxygenation status of gynecologic tumors: What is the optimal hemoglobin level? Strahlenther Onkol 178:727-731, 2002[CrossRef][Medline]

19. 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 20:4082-4107, 2002

20. Batra S, Perelman N, Luck LR, et al: Pediatric tumor cells express erythropoietin and a functional erythropoietin receptor that promotes angiogenesis and tumor cell survival. Lab Invest 83:1477-1487, 2003[CrossRef][Medline]

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