| HOME | HELP | CONTACT US | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
a Memorial Sloan-Kettering Cancer Center, New York, New York, USA; b University Hospital Ghent, Ghent, Belgium
Correspondence: Clifford A. Hudis, M.D., Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. Telephone: 212-639-5449; Fax: 212-639-6483; e-mail: hudis{at}mskcc.org
Key Words. Anemia • Cancer • Erythropoietin • Epoetin alfa • Fatigue • Hemoglobin • Outcomes • Quality of life • rHuEPO • Treatment • Tumor hypoxia
Over the past decade, there has been a growing appreciation of anemia as the source of a wide range of symptoms, most notably fatigue, that diminish cancer patients’ physical, mental, and functional capacities, and thus impair their quality of life (QOL). Moreover, emerging data suggest that cancer-related anemia can induce or exacerbate tumor hypoxia, which compromises cancer therapy. Additionally, tumor hypoxia may lead to changes in the tumor cells that promote malignant progression, resulting in poorer outcomes, including shorter survival times.
Clinical studies have shown that administration of recombinant human erythropoietin (rHuEPO, epoetin alfa) can increase hemoglobin (Hb) levels and thus prevent or correct anemia in patients undergoing cancer therapy, with subsequent improvements in QOL.
In May 2002, a 2-day conference entitled "Workshop on the Potential Impact of rHuEPO on Prognosis: Modes of Action, Clinical Evidence" was held in New York, New York, USA. This workshop convened a group of leading international clinical investigators in the field of oncology to discuss two issues: whether there was sufficient preclinical and clinical evidence regarding a potential role for rHuEPO in improving treatment outcomes in anemic cancer patients and whether there was sufficient interest in the oncology community to conduct future investigations in this area. Other objectives of the workshop were to hypothesize how rHuEPO might affect survival and to generate ideas for future preclinical and clinical studies of the potential benefits of epoetin alfa with respect to survival, treatment outcomes, and QOL. The presentations from the workshop are summarized in this supplement to The Oncologist.
On day 1, the discussions focused on the science of hypoxia, erythropoietin, and the erythropoietin receptor, as well as on the role of hypoxia in malignant progression and impaired therapeutic response, and on the relationship between hypoxia and anemia; also, the preclinical experience with epoetin alfa was briefly reviewed. On day 2, the clinical experience relevant to anemia and its treatment with epoetin alfa was addressed. Particular attention was given to the results of studies that evaluated the prognostic and predictive significance of anemia and Hb levels and the impact of increasing Hb levels on patient outcomes and QOL. New treatment schedules aimed at optimizing epoetin alfa therapy and elements to be considered in planning future trials of this agent with respect to survival and QOL end points were also discussed.
In this supplement, Peter Vaupel and Louis Harrison [1] provide an overview of tumor hypoxia, including its causes, measurement, and apparent relationship to Hb levels. They also discuss several mechanisms by which hypoxia can reduce tumor sensitivity to treatment and lead ultimately to poorer outcomes. Importantly, tumor tissue appears to be more sensitive to low Hb levels than normal tissue, suggesting that correcting low Hb levels may provide increased tumor oxygenation and improved treatment outcomes.
In a follow-up article, Peter Vaupel [2] details some of the important hypoxia-driven processes that promote malignant progression, including induction of genomic instability and chromosomal abnormalities and increased expression of genes involved in the physiologic adaptation of tumor cells to hypoxia. Among these are the genes that encode vascular endothelial growth factor, which induces angiogenesis, and glycolytic enzymes, which are involved in the energy-preserving switch of tumor cells from aerobic to anaerobic metabolism. Transcription of these and other adaptation-facilitating genes that promote tumor cell survival and metastasis is stimulated by hypoxia-inducible factor 1 alpha (HIF-1
), a transcription factor that is expressed under hypoxic conditions. The negative role of hypoxia in malignant progression suggests that it may be an important target in developing strategies for the treatment of cancer patients.
Francis Farrell and his co-authors [3] review the chemical structure of erythropoietin and its receptor and the signaling pathways established by the binding of erythropoietin to the receptor. Also, they discuss hypoxia-induced upregulation of erythropoietin and the erythropoietin receptor in nonhematopoietic cells and tissues (e.g., vascular endothelial cells, neurons, and renal and breast carcinomas) and the therapeutic implications of administering rHuEPO to patients who express the erythropoietin receptor at these sites. Erythropoietin has been shown to have angiogenic potential, and this has raised concern that administration of rHuEPO to patients with breast or other cancer cells expressing the erythropoietin receptor may promote tumor growth through induction of angiogenesis. The authors note, however, that evidence supporting a tumor-growth-promoting effect of rHuEPO has been equivocal, and any angiogenic activity of rHuEPO may be counterbalanced by its antihypoxia activity and subsequent downregulation of HIF-1. Farrell and his co-authors [3] also discuss the interesting results obtained regarding potential therapeutic benefits following epoetin alfa administration to ischemic stroke patients and breast cancer patients with chemotherapy-related cognitive deficits—a reflection of the presence of the erythropoietin receptor in central nervous system tissue and the ability of epoetin alfa to cross the blood-brain barrier.
In developing strategies to optimize cancer treatment, it is important to understand how hypoxia influences the effectiveness of radiation therapy and chemotherapy. Louis Harrison and Kim Blackwell [4] describe mechanisms by which hypoxia can contribute to treatment resistance and review the results of several clinical studies that examined the prognostic significance of low pretreatment tumor oxygenation levels for response to radiation therapy. Also, they review the results of several experimental and clinical studies that evaluated rHuEPO administration as a possible means for reducing tumor hypoxia and subsequently increasing the effectiveness of radiation therapy and chemotherapy.
In addition to the mechanisms by which hypoxia influences sensitivity to cancer treatment, the mechanisms by which rHuEPO therapy may improve treatment outcomes have been explored. In their paper, Kim Blackwell and coauthors [5] discuss these proposed mechanisms. Several mechanisms, including correction of hypoxia, increasing the sensitivity of tumor cells to radiation therapy and chemotherapy, and correction of anemia and its symptoms (especially fatigue), are almost intuitive. However, another mechanism, suggested by the work of Mittelman et al. [6], is both surprising and somewhat controversial—namely, induction of an immune-mediated antitumor effect. In their study, Mittelman and his colleagues [6] found that administration of epoetin alfa in a mouse myeloma model resulted in tumor-specific, T-cell-mediated tumor regression. Clearly, these intriguing findings suggest another direction for future investigation.
Heinz Ludwig [7] summarizes the results of several preclinical studies that examined the impact of anemia prevention or correction on tumor sensitivity to radiation therapy or chemotherapy. Overall, these studies demonstrated improved sensitivity to treatment, which appeared to be associated with increased tumor oxygenation subsequent to correction of anemia. Additionally, data from the Mittelman et al. [6] study mentioned above suggested that epoetin alfa may exert an immunomodulatory effect in multiple myeloma.
In the final paper, Hudis and co-authors [8] provide an overview of a large number of clinical studies, mainly retrospective, that evaluated the significance of anemia, or low Hb levels, as a prognostic and predictive factor for outcome in patients with a variety of solid tumors or hematologic malignancies. Those authors also discuss the findings of several double-blind, placebo-controlled clinical trials and large, open-label, single-arm, community-based studies that examined the impact of the treatment of anemia on outcomes in anemic patients undergoing cancer treatment. The results of these studies variously suggested that epoetin alfa has the potential to improve locoregional tumor control, recurrence rates, response rates, and treatment outcomes in such patients, and that it additionally may increase patients’ energy levels, ability to perform daily activities, and overall QOL. The authors also discuss very recent data on new and presumably more convenient dosing schedules for epoetin alfa and the potential benefits of this agent with regard to cognitive function—indicating activity of epoetin alfa beyond its hematopoietic effects.
Subsequent to the workshop, results of a recently completed randomized, double-blind, placebo-controlled trial of epoetin alfa as an adjunct to chemotherapy in metastatic breast cancer patients with initially normal Hb levels (Hb >13 g/dl) to evaluate the effects of epoetin alfa on survival have become available. The results, which show a survival benefit at 12 months in the placebo group (76%) versus the epoetin alfa group (70%) (p = 0.0117), are in contrast with the numerous other studies in anemic cancer patients suggesting a survival benefit with epoetin alfa. A discussion of this study and an analysis of these results in relation to the other reports have been added to the final paper.
The results of the experimental and clinical studies performed to date suggest the need for earlier and more extensive treatment of anemia in cancer patients, the conduct of additional studies of epoetin alfa to further determine its potential for improving treatment outcome in cancer patients, and the exploration of other possible clinical applications of this agent. This supplement will provide the reader with an analysis of new data regarding the basic science underlying the potential clinical effects of epoetin alfa, which should be considered in the design of future investigations in this important area of experimental and clinical research.
 |
REFERENCES |
|---|
 Top References |
|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | CONTACT US | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| THE ONCOLOGIST | STEM CELLS | CME | ALPHAMED PRESS JOURNALS |
