Role of Iron in Optimizing Responses of Anemic Cancer Patients to Erythropoietin

Many patients with widespread cancer develop a hypoproliferative anemia,[1-3] which is often worsened by systemic cytotoxic chemotherapy. Some chemotherapeutic agents directly depress the capacity of bone marrow cells to proliferate, while other agents actually prevent the physiologic production or release of erythropoietin.[3,4] The latter effect is due to damage to kidney cells, where most of the erythropoietin is made in response to the relative tissue hypoxia associated with that anemia.

Cancer-Associated Anemia Does Not Equal Cancer-Associated Fatigue

Regardless of its specific cause, cancer-associated anemia is a common contributor to symptoms, such as fatigue, that markedly diminish the quality of life of a large proportion of cancer patients prior to their cure or death from cancer. This cancer fatigue is an important, near-universal clinical problem.[5] Glaspy and Cavill, as well as an increasing number of other researchers, have recently begun to equate cancer-associated fatigue with cancer-associated anemia. Although it is undeniable that both of these events occur in largely overlapping patient groups and are thereby associated with one another, we must be careful not to equate the two.

Fatigue associated with chronic disease, in general, and cancer, in particular, is without doubt the most disruptive of symptoms, one that is highly destructive of quality of life.[6] Anemia can and does cause fatigue. Severe acute blood loss is invariably associated with decreased tissue oxygenation, tachycardia, tachypnea, and an overwhelming feeling of fatigue. With cancer, all of these signs and symptoms can occur in patients with anemia. They also can and frequently do occur, however, with profound severity in cancer patients whose hemoglobin values lie well within the normal range and are no lower than they were when these individuals suffered neither cancer nor fatigue.

This ubiquitously recognized clinical fact clearly illustrates that, although fatigue can be caused by anemia, it can also be caused by cancer and many other chronic diseases per se, with or without anemia. While it is laudable to be able to correct anemia in some proportion of cancer patients, it is even more desirable to be able to improve quality of life by diminishing cancer-associated fatigue.

The authors review data clearly showing that, on average, recombinant human erythropoietin (rHuEPO, epoetin alfa [Epogen, Procrit]) increases both hemoglobin and quality of life. These data, although relevant, cannot demonstrate whether this concurrence is causal. For this, individual hemoglobin response and lack of response need to be assessed and associated with an independently measured, objective physiologic sign of fatigue. In fact, physicians with experience prescribing erythropoietin routinely note that fatigue seems to diminish before, sometimes long before, the hemoglobin concentration rises measurably. Observant patients and physicians also note that fatigue sometimes diminishes in the absence of apparent hemoglobin rise.

Cancer Fatigue Is More Than Anemia

These clinical observations suggest two important issues that need to be explored. First, cancer fatigue is more than anemia, and there may well be drugs that can address the fatigue associated with chronic diseases directly rather than by enhancing the oxygen-carrying capacity of the blood. Erythropoietin may, to some extent, be one of these drugs. Others are on the horizon, however. In any event, if enhancing the likelihood of individual responsiveness is a desired goal, data must be presented in a way that will permit careful assessment of individual, not average, responsiveness to EPO.

Objective, Physiologic Measurement of Fatigue Needed

Second, fatigue is unquestionably the major cause of the cancer-induced decline in quality of life. It is, therefore, well worth studying carefully.[5,6] In order to study fatigue properly, more than questionnaires are clearly required. A physiologic definition of fatigue must be agreed upon, and objective, physiologic measurements must be employed to quantify fatigue, as well as to quantify the efficacy of candidate agents developed to diminish it.

One approach that has been used to achieve the latter goal is the objective measurement of exercise capacity and efficiency of oxygen consumption.[7] Erythropoietin treatment, on average, improved both of these end points, but again, these data do not permit concurrent individual assessments of its effect on hemoglobin and fatigue.

In order to measure fatigue objectively and with ease, one might profitably take a page from sleep research protocols. The continuous electroencephalogram (EEG) and rapid eye movements characterizing sleep have given way to carefully validated, but much simpler, wristband-based monitoring of activity.[8] Using the same tools that time sleep and activity and quantifying each of them within the day have allowed for the noninvasive assessment of sleep latency, sleep onset, timing of awakening, and sleep quality. A similar quantitative approach should be used to objectify fatigue by using this device to measure the amount, duration, and timing of daily activity.

Once this kind of simple, noninvasive monitoring provides quantitatively reproducible, validated, physiologic signatures that measure fatigue, we can immediately embark upon clinical trials of a wide range of new peptides and small molecules designed to interrupt or short-circuit the fatigue signals sent by a range of chronic diseases, including cancer. Without such objective measurement, however, these new quality of life drugs will be hard to develop, and it will be unnecessarily difficult to gain their FDA approval.

For example, it has already been noted that rheumatoid arthritis patients receiving the tumor necrosis factor (TNF)–receptor blocker etanercept (Enbrel) have diminished fatigue, seemingly out of proportion to their joint responses.[9] The need to objectify fatigue is demanded by the universal importance of this most disruptive and destructive of all cancer symptoms and by the potential ease with which this goal can be accomplished.

Functional Iron Insufficiency and EPO Responsiveness

The article by Glaspy and Cavill does not address the objective measurement of fatigue, but rather, explores the equally important observation that EPO does not always elevate the hemoglobin concentrations of cancer patients.[10,11] Glaspy and Cavill try to explain why high, frequent, subcutaneous doses of EPO fail to diminish anemias associated with metastatic cancer and/or its systemic treatment in approximately half of the patients so treated.

The authors make a reasonably compelling case for the existence of a functional iron insufficiency in these patients, analogous to the iron insufficiency more carefully described in patients with chronic renal failure.[12-14] They use the clinical experience with intravenous iron in chronic renal failure to argue persuasively for treating this functional iron insufficiency in the face of apparently “adequate iron stores.” They also cite reasonable data demonstrating the utility of this approach in patients with renal failure. They further argue convincingly that oral iron supplementation is unlikely to achieve the desired goal and that intravenous iron loading may well be essential to the efficacy of this therapeutic approach.

All of the authors’ suggestions and recommendations are reasonable and, to some extent, logical. To make their case, they cite data demonstrating that average hemoglobin values can be improved by such an approach. This, however, fails to address the question at hand; namely, why EPO fails to work in more than half of specific individual cancer patients to whom it is given.

It is clear that, while intravenous iron loading enhances average response to EPO, this strategy, like all others, fails to achieve gratifying EPO responses in all but a small minority of nonresponders. While iron is important, it obviously is not the sole determinant of response to large doses of EPO. Other non–iron-based approaches to improve response to EPO include the addition of anti-inflammatory agents and effective anticancer therapy.[7,15] Clearly, cancer control is the most desirable way to improve both anemia and fatigue.[3]

It is important to directly test the author’s hypothesis that functional iron insufficiency lies at the heart of the inability of at least half of the cancer patients treated with EPO to respond to that treatment. It is heartening to learn from the authors that such a clinical trial will soon underway.

It is likely that some cancer EPO nonresponders will be converted to responders by adding intravenous iron to their therapy. What proportion of the more than half of such patients given the drug will ultimately respond is, however, critical information that will determine whether this additional intravenous therapy should be given to all EPO nonresponders. Iron is, of course, not without chronic, as well as acute, toxicities.[16]

Other Physiologic Sources of Variation in EPO Responsiveness

There are other prominent physiologic sources of variation in responsiveness to EPO that the authors have not considered, sources which have been shown in mice to enhance the likelihood, as well as the degree, of EPO response. The circadian organization of bone marrow cell proliferation and the erythron’s responsiveness to erythropoietin are responsible for regular, up to 15-fold, time-of-day–dependent differences in relative EPO refractoriness and responsiveness.[17] Relevant to this EPO chronobiology in human beings, both Smaaland et al recently and Mauer et al previously have demonstrated the tight rhythmic circadian control of human bone marrow cell proliferation.[18,19]

We have demonstrated repeatedly and recently that the circadian coordination of cell proliferation in both normal and cancerous tissues is well maintained in patients with metastatic cancer.[20] In fact, in a murine model, both DNA synthesis and baseline erythron clonogenicity are organized tightly within the day, and the time of day of subcutaneous EPO administration determines, up to 15-fold, the degree to which it stimulates colony-forming units–erythroid (CFU-E) and burst-forming units–erythroid (BFU-E), as compared with an identical EPO dose given at other specific times of day.[17]

These clinical and preclinical data argue strongly for the concurrent consideration of the circadian phase of EPO administration when trying to enhance an individual’s likelihood of EPO response. Such a strategy would be without both risk and additional cost.

Finally, these provocative circadian data may ultimately be connected to the strategy of enhancing iron availability as posed by Glaspy and Cavill. Substantial, venerable literature has already documented that both plasma iron and erythropoietin concentrations are rhythmically available during the day. Perhaps the concordance of circadian rhythm of iron availability and EPO availability is necessary for the optimization of EPO responsiveness (see Figure 1).[21,22]

Summary

In summary, cancer-associated fatigue is clearly more than cancer-associated anemia. It is an important, virtually universal cancer symptom that has a strong negative impact on quality of life and, therefore, needs to be studied objectively, if possible, and in its own right.

Erythropoietin and other agents may modulate cancer-associated fatigue by enhancing hemoglobin and tissue oxygenation, but these agents may also act through other means. A noninvasive, objective measure of fatigue will be essential to the development of such agents. Such a measure is readily at hand.

Inadequate iron availability is one of many reasons that cancer patients do not respond to EPO. Circadian coordination of marrow EPO stimulability may also explain the up to 15-fold, time-of-day–dependent differences in EPO responsiveness. Physiologically, both serum EPO and serum iron have distinct, mirror-image circadian rhythms, further supporting and, perhaps, partly explaining the profound circadian coordination of hematopoiesis. It will be terribly unfortunate for cancer patients, and unnecessarily expensive for third-party payors, should this prominent circadian erythropoietic chronobiology continue to be ignored therapeutically.

References:

1. Miller CB, Jones RJ, Piantadosi S, et al: Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med 322:1689-1692, 1990.

2. Henry D, Nelson R, Brooks B, et al: Prospective evaluation of transfusion (Tx) requirements for anemic cancer patients +/- chemorx. Blood 78:152a, 1991.

3. Wood PA, Hrushesky WJML: Cisplatin-associated anemia: An erythropoietin deficiency syndrome. J Clin Invest 95:1650-1659, 1995.

4. Barton CH, Pahl M, Vaziri ND, et al: Renal magnesium wasting associated with amphotericin B therapy. Ann Intern Med 77:471-474, 1984.

5. Miaskowski C, Portenoy R: Update on the assessment and management of cancer-related fatigue. Principles and Practice of Supportive Oncology Updates 1(2):1-10, 1998.

6. Glaspy J: Fatigue may be most under-recognized, undertreated cancer-related symptom. Oncology News International 6(3):3,38, 1997.

7. Daneryd P, Svanberg E, Korner U, et al: Protection of metabolic and exercise capacity in unselected weight-losing cancer patients following treatment with recombinant erythropoietin: A randomized prospective study. Cancer Res 58:5374-5379, 1998.

8. Mormont M, Claustrat B, Waterhouse J, et al: Clinical relevance of circadian rhythm assessment in cancer patients, in Touitou Y (ed): Biological Clocks: Mechanisms and Applications, pp 497-505. Berlin, Elsevier Science, 1998.

9. Weinblatt M, Kremer J, Bankhurst A, et al: A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 340(4):253-259, 1999.

10. MacDougall I: Poor response to erythropoietin should be fully investigated and treated. Br Med J 310:1424-1424, 1995.

11. Ludwig H, Fritz E, Leitgeb C, et al: Prediction of response to erythropoietin treatment in chronic anemia of cancer. Blood 84:1056-1063, 1994.

12. Cavill I: r-HuEPO: The iron dimension. Presented at a meeting held at The Royal Society of Medicine, 1995.

13. Cavill I, Macdougall I, Gokal R, et al: Iron management in patients on rHuEPO. Br J Renal Med 2:6-8, 1997.

14. MacDougall I, Cavill I, Hulme B, et al: Detection of functional iron deficiency during erythropoietin treatment: A new approach. Br Med J 304:225-226, 1992.

15. Lundholm K, Gelin J, Hyltander A, et al: Anti-inflammatory treatment may prolong survival in undernourished patients with metastatic solid tumors. Cancer Res 54:5602-5606, 1994.

16. Salonen J, Nyyssonen K, Korpela H, et al: High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation 86:802-811, 1992.

17. Wood P, Hrushesky W, Klevecz R: Distinct circadian time structures characterize myeloid and erythroid progenitor and multipotential cell clonogenicity as well as marrow precursor proliferation dynamics. Exp Hematol 26:523-533, 1998.

18. Smaaland R, Laerum O, Sothern R, et al: Colony-forming unit-granulocyte-macrophage and DNA synthesis of human bone marrow are circadian stage dependent and show covariation. Blood 79:2281-2287, 1992.

19. Mauer AM: Diurnal variation of proliferative activity in the human bone marrow. Blood 26:1-7, 1965.

20. Hrushesky W, Lannin D, Haus E: Evidence for an ontogenetic basis for circadian coordination of cancer cell proliferation. J Natl Cancer Inst 90(19):1480-1484, 1998.

21. Wide L, Bengtsson C, Birgegard G: Circadian rhythm of erythropoietin in human serum. Br J Haematol 72:85-90, 1989.

22. Hamilton LD, Gubler CJ, Carwright GE, et al: Diurnal variation in plasma iron level of man. Proc Soc Exp Biol Med 75:65-68, 1950.