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rHuEPO and Treatment Outcomes: The Preclinical Experience

Department of Medicine and Medical Oncology, Wilhelminenspital, Vienna, Austria

Correspondence: Heinz Ludwig, M.D., Department of Medicine and Medical Oncology, 1st Medical Department/Oncology, Wilhelminenspital, Montleartstrasse 37, A-1171 Vienna, Austria. Telephone: 43-1-49-150-2101; Fax: 43-1-49-150-2109; e-mail: Heinz.Ludwig{at}weinkav.at

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction rHuEPO and Radiation Therapy... Epoetin Alfa and Chemotherapy... Epoetin Alfa: An... Summary References

 
After completing this course, the reader will be able to:

1. Discuss some of the animal model systems that have been used to understand the effects of erythropoietin on cancer treatment.
   
2. Describe the effects of hypoxia on treatment end points in animal model systems.
   
3. Discuss our evolving understanding of the effects of erythropoietin on the immune system.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction rHuEPO and Radiation Therapy... Epoetin Alfa and Chemotherapy... Epoetin Alfa: An... Summary References

 
The presence of hypoxic areas is a common feature of solid tumors and has been associated with decreased sensitivity of the tumors to radiation therapy and oxygen-dependent chemotherapeutic agents, as well as worsened outcomes, including survival. Anemia is also common in cancer patients and is believed to contribute to tumor hypoxia. Thus, the rationale exists for administering recombinant human erythropoietin (rHuEPO, epoetin alfa) in an effort to increase hemoglobin levels, correct anemia, and thereby possibly increase the sensitivity of tumors to standard cancer treatment and improve patient outcomes. The results of several preclinical studies that examined the impact of anemia prevention by rHuEPO on tumor sensitivity to radiation therapy in rodent models of cancer showed that induction of anemia increased hypoxia in tumor cells and that correction of anemia with rHuEPO could improve tumor oxygenation. Further studies in rodent models showed significantly delayed tumor growth in both irradiated mice and irradiated rats treated with rHuEPO. In those studies, the increased radiosensitivity observed was believed to be due to improved tumor oxygenation following the correction of anemia. Similarly, enhancements in chemosensitivity were found in rHuEPO-treated rodent models. In the chemosensitivity studies, as in the radiosensitivity studies, the therapeutic benefit obtained was believed to reflect improved tumor oxygenation subsequent to an rHuEPO-related increase in oxygen availability. One study evaluated the potential biologic effects of epoetin alfa on tumor progression using murine myeloma models (MOPC-315 and 5T33 MM). Treatment of MOPC-315 tumor-bearing mice with epoetin alfa induced complete tumor regression in 30%–60% of mice. Regression was found to be tumor specific, and the effect of epoetin alfa was shown to be T-cell mediated. Additionally, epoetin alfa administration prolonged survival and reduced morbidity and mortality in the 5T33 MM tumor model. Those investigators suggested that epoetin alfa may have antitumor activity in addition to its hematopoietic effects. Overall, these preclinical findings suggest that correction of anemia by rHuEPO can increase tumor sensitivity to both radiation therapy and chemotherapy and that epoetin alfa may exert an immunomodulatory effect in multiple myeloma.

Key Words. Anemia • Cancer • Epoetin alfa • Hemoglobin • Outcomes • Preclinical • rHuEPO • Tumor hypoxia • Survival

	INTRODUCTION

Top Learning Objectives Abstract Introduction rHuEPO and Radiation Therapy... Epoetin Alfa and Chemotherapy... Epoetin Alfa: An... Summary References

 
The adverse influence of tumor hypoxia on the outcome of radiation therapy has been well established for many years, and data from more recent studies have led to the growing recognition of hypoxia as a negative factor in the outcomes of some forms of chemotherapy [1, 2]. Anemia is commonly present in cancer patients at the time of diagnosis, and its incidence tends to increase with standard cancer treatment, including both radiation therapy and chemotherapy. Because anemia can contribute to the development of tumor hypoxia (possibly via the reduced oxygen-carrying capacity of the blood), it has been suggested that early correction of anemia may enhance the effectiveness and improve the outcomes of both radiation therapy and chemotherapy by correcting tumor hypoxia [3].

One approach currently used to treat disease- and treatment-related anemia in cancer patients is the administration of recombinant human erythropoietin (rHuEPO, epoetin alfa). Epoetin alfa has been shown in numerous clinical and community-based trials to increase hemoglobin (Hb) levels and thereby correct anemia and improve quality of life [4–8]. However, despite the use of epoetin alfa in the oncology setting for more than a decade, questions regarding this agent remain: Does epoetin alfa indeed increase sensitivity to radiation therapy and chemotherapy? Does this agent affect clinical outcomes, including survival, or does it only play a supportive role? and Are the benefits of epoetin alfa due to the correction of anemia alone or are other biologic actions of this agent, such as immunomodulation, coming into play? In an effort to answer some of these questions, experimental studies have been conducted in animal models of cancer to examine the effects of anemia prevention or correction with epoetin alfa on tumor sensitivity to standard cancer treatment and to explore other effects of epoetin alfa possibly related to tumor progression. Results of several of these studies are summarized below.

	RHUEPO AND RADIATION THERAPY OUTCOMES

Top Learning Objectives Abstract Introduction rHuEPO and Radiation Therapy... Epoetin Alfa and Chemotherapy... Epoetin Alfa: An... Summary References

 
In 1996, Kelleher et al. [9] investigated the growth, blood flow, and oxygenation of experimental Dawley Sprague (DS)-sarcomas in nonanemic (control) rats, rats in which anemia had been induced, and rats in which the development of anemia had been prevented by administration of rHuEPO. Those investigators found a significant slowing of tumor growth in the anemic animals. Further, induction of moderate anemia resulted in a worsening of tumor oxygenation, as reflected by a marked decrease in the median oxygen tension (pO₂) and a marked increase (from 21% to 76%) in the fraction of hypoxic pO₂ values, that is, values between 0 mmHg and 2.5 mmHg. Administration of rHuEPO to anemic animals, compared with anemic animals that did not receive rHuEPO, resulted in a significantly (p < 0.01) greater median pO₂ value and a significantly (p < 0.01) lower hypoxic fraction (55%) in tumors less than 1.4 ml, although the high hypoxic fraction was not fully corrected by rHuEPO treatment.

In a subsequent study, Thews et al. [10] compared the radiosensitivity of s.c. implanted DS-sarcomas in rats with anemia induced by carboplatin (Paraplatin^®; Bristol-Myers Squibb; Princeton, NJ) with those of nonanemic (control) rats and rats in which the development of anemia had been prevented by administration of rHuEPO. rHuEPO had been administered at a dosage of 1,000 IU/kg three times weekly starting 6 days before carboplatin administration. Neither carboplatin nor rHuEPO treatment influenced the rate of tumor growth. Five days after implantation, all animals were subjected to a noncurative dose of radiation, and the subsequent regrowth of the tumors was assessed. In the rHuEPO treatment group, the tumor growth delay was significantly longer than in the anemic group (9.5 days versus 4.5 days; range: p < 0.05 to p < 0.01), but was somewhat shorter than in the nonanemic control group (12.0 days).

Two murine studies have shown that anemia reduced the efficacy of radiotherapy and that rHuEPO administered to anemic mice restored radiosensitivity of experimental human tumors [11, 12]. Another study conducted by Stüben et al. [13] compared the effects of epoetin alfa on the radiosensitivity of human glioblastoma xenografts implanted in nude mice with radiation-induced anemia, in nonanemic nude mice (controls), and in nude mice in which the development of anemia had been prevented by administration of rHuEPO at a dose of 1,000 IU/kg three times weekly starting 2 weeks before irradiation. Treatment with rHuEPO did not influence the growth rate of the tumors, as evidenced by the nearly identical growth curves of nonirradiated tumors in the rHuEPO group, the nonanemic controls, and the group with irradiation-induced anemia. Assessment of the radiation response revealed that prevention of anemia by rHuEPO resulted in greater sensitivity of tumors to radiation therapy than was seen in the anemic mice (36 ± 3 days to reach four times the initial tumor volume versus 23 ± 3 days, respectively) (Fig. 1). However, as in the Thews et al. study [10], the radiosensitivity of the tumors in mice in which anemia development was prevented by rHuEPO did not reach the level found in nonanemic animals (42 ± 3 days to four times initial volume). In concluding, the investigators noted that the results of their study confirmed those of the earlier study [10], indicating a beneficial effect of rHuEPO on radiosensitivity, and that they demonstrated the ability of rHuEPO to increase radiosensitivity: A) in a different species; B) following a different mode of anemia induction; and C) in a human tumor cell line. In both studies the increase in tumor radiosensitivity was presumed to be due to an improvement in tumor oxygenation following anemia correction. Importantly, the results of both studies also provided evidence that rHuEPO per se does not influence the growth rate of tumors, confirming the earlier study of Kelleher et al. [9].

View larger version (21K): [in this window] [in a new window]   Figure 1. Relative volume growth of tumors treated with single-dose radiation (12 Gy). Reprinted with permission from Stüben et al. [13].

	EPOETIN ALFA AND CHEMOTHERAPY OUTCOMES

Top Learning Objectives Abstract Introduction rHuEPO and Radiation Therapy... Epoetin Alfa and Chemotherapy... Epoetin Alfa: An... Summary References

 
Anemia may significantly influence the pharmacokinetics of certain cytostatics and significantly reduce their bioavailability, since red blood cells and Hb function as important carriers for several drugs [15]. Thus, increasing Hb levels in anemic cancer patients may enhance the cytotoxicity of some antitumor drugs simply by increasing tumor exposure to these drugs.

Data suggest that hypoxic tumor cells are more resistant to the cytotoxic effects of cisplatin than are well-oxygenated cells [16, 17]. This is similar to the lower radiosensitivity of hypoxic tumor cells compared with normoxic cells [2, 18]. Results of in vitro studies have demonstrated that the cytotoxic effects of platinum compounds, like those of radiation therapy, are related to the oxygen content of the tumor cells [16, 17, 19, 20]. Therefore, Silver and Piver [21] conducted an in vivo study to determine whether increasing the oxygen-carrying capacity of blood in an experimental animal model via administration of epoetin alfa could enhance the antitumor response to cisplatin.

In that study, female severe combined immunodeficient (SCID) mice with either small s.c. human ovarian cancer xenografts or large human ovarian cancer xenografts implanted in the gonadal fat pad were treated with epoetin alfa (20 IU three times weekly from day –15 to day +13), with cisplatin (5 mg/kg weekly on days 0 and 7), with epoetin alfa plus cisplatin as described, or with a buffered saline solution (control). In the mice bearing small s.c. tumors, tumor regression (as indicated by a lower tumor volume) was significantly (p < 0.05) greater in the epoetin alfa/cisplatin-treated group than in the group treated with cisplatin only (Fig. 2). However, there was no difference in tumor regression between the epoetin alfa-treated and control groups, indicating that epoetin alfa alone had no antitumor effect in this model. The beneficial effect of epoetin alfa was associated with a 25%–35% increase in hematocrit, which was significantly (p < 0.01) different from the decreases in hematocrit noted in mice not treated with epoetin alfa (2% decrease in the control group and 20% decrease in the group treated with cisplatin only).

View larger version (18K): [in this window] [in a new window]   Figure 2. Tumor growth curves for mice with small s.c. tumors. Tumors in mice treated with epoetin alfa/cisplatin demonstrated significantly more tumor regression than tumors in mice treated with cisplatin alone. *Difference in tumor growth curve for the cisplatin group versus the control group (p < 0.01). Difference in tumor growth curve for the epoetin alfa/cisplatin group versus the control group (p < 0.01) and the cisplatin group (p < 0.05). Cisplatin administered on days 0 and 7, and epoetin alfa administered from day –15 to day +13. NS = not significant. Reprinted with permission from Silver et al. [21].

In another study, Thews et al. [22] showed a similar effect of epoetin alfa on cyclophosphamide-based chemotherapy. Those investigators evaluated the effects of epoetin alfa on cyclophosphamide cytotoxicity in male Sprague-Dawley rats injected with DS-sarcoma cells in the hind-foot dorsum. Anemia was either induced by carboplatin or prevented by s.c. injection of epoetin alfa at a dose of 1,000 IU/kg three times weekly 7 days before carboplatin administration. The tumors were treated with cyclophosphamide 5 days after implantation. Growth delays with subsequent regrowth were observed in both groups. However, the delay was significantly shorter in the anemic group than in the group in which anemia had been reversed by epoetin alfa, as well as in a control group in which anemia had not been induced (8.6 days versus 13.3 days for both the epoetin alfa-treated group and nonanemic controls). Hemoglobin levels on the day of cyclophosphamide administration were 9.8 g/dl for the anemic group, 13.7 g/dl for the epoetin alfa-treated group, and 14.1 g/dl for the nonanemic control group. The results suggest that chemotherapy-induced anemia decreases the cytotoxicity of cyclophosphamide, but that this lower sensitivity can be reversed by correction of anemia with epoetin alfa. As in the Silver and Piver study [21], the investigators believed that the increased sensitivity to chemotherapy probably reflected improved oxygenation of the hypoxic tumor tissue as a result of the increase in oxygen availability by epoetin alfa.

	EPOETIN ALFA: AN IMMUNOMODULATORY EFFECT IN MULTIPLE MYELOMA?

Top Learning Objectives Abstract Introduction rHuEPO and Radiation Therapy... Epoetin Alfa and Chemotherapy... Epoetin Alfa: An... Summary References

 
Multiple myeloma is a malignant plasma cell neoplasm with a median survival time of 30–60 months [23]. This disease mainly affects the elderly and causes osteolytic bone lesions, renal failure, and hypercalcemia [24]. Anemia is another prominent symptom, occurring in up to 90% of patients [25–28]. The main cause of the anemia is blunted production of erythropoietin [29, 30]; however, bone marrow infiltration by the malignant plasma cells, hemodilution due to hypervolemia, reduced survival of red blood cells, renal failure, anemia of chronic disease, and chemotherapy-induced bone marrow suppression are also contributing factors [30, 31]. Recently, a direct cytotoxic activity of myeloma cells on erythroid precursors was identified in patients with rapidly progressive disease. Myeloma cells were shown to overexpress Fas ligand (FAS) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which interact with FAS and TRAIL receptors on erythroblasts and induce apoptosis, which, in turn, may eventually lead to exhaustion of erythropoietic progenitors [32].

Epoetin alfa has been shown to be effective in the treatment of multiple-myeloma-associated anemia, resulting in response rates of 70%–85% [28, 30, 31, 33]. In a clinical trial conducted by Mittelman et al. [28, 34], several multiple myeloma patients experienced stabilization of their disease and lived beyond their estimated survival time. Those patients had received epoetin alfa for 42–74 months, and this was the only therapy administered for most of the follow-up period. Based on these observations, Mittelman and his colleagues theorized that epoetin alfa, in addition to its red blood cell-stimulating activity, had other potentially beneficial effects on the disease, although the underlying mode of action was unknown. Those investigators, therefore, undertook a study in two murine models of multiple myeloma (MOPC-315 and 5T33 MM tumors) to investigate the biologic effects of epoetin alfa on tumor progression [34].

For that study, BALB/c female mice aged 6–8 weeks were injected s.c. with 10⁴ MOPC-315 cells in the abdomen. Treatment with epoetin alfa was initiated once a small, palpable tumor (2–5 mm diameter) was detectable, that is, approximately 10–13 days after inoculation of the tumor cells. The epoetin alfa dosage used was 30 IU daily for 10 consecutive days, followed by thrice-weekly dosing for the next 2–3 weeks (30 IU in mice correlates roughly with 60,000 IU in men). Additional mice were injected with the epoetin alfa diluent (sterile water) and served as controls. Tumor growth rate was monitored twice weekly during study treatment.

The rate of tumor growth for the first 14–18 days following tumor-cell inoculation was similar in all mice. After this period, mice responding to epoetin alfa experienced a decrease in tumor size, with permanent and complete tumor regression occurring in 30%–60% of the mice (n = 150), compared with 0%–10% of diluent-treated mice (n = 100) (Fig. 3). Once regression was established, further administration of epoetin alfa was not required to maintain this effect. No binding of ¹²⁵I-epoetin alfa to cell-surface receptors on the MOPC-315 cells was detected, suggesting that the effect of epoetin alfa on tumor regression involved an indirect mechanism.

View larger version (14K): [in this window] [in a new window]   Figure 3. Survival of MOPC-315 tumor-cell-inoculated mice treated with epoetin alfa or epoetin alfa diluent (control); pooled results of five independent experiments. Complete regression was observed in 51% (31/61) of mice treated with epoetin alfa, compared with 5.4% (3/55) of diluent-treated mice (p < 0.05). Adapted with permission from Mittelman et al. [34].

View larger version (17K): [in this window] [in a new window]   Figure 4. Survival of normal BALB/c mice and mice with monoclonal antibody (mAb)-depleted CD4+ or CD8+ cells injected with 104 MOPC-315 tumor cells. Postinoculation treatment with epoetin alfa resulted in tumor regression in 50% of mice in the epoetin alfa-treated control group, whereas 90%–100% of epoetin alfa-treated mice with depleted CD4+ or CD8+ cells showed experimental tumor growth. Adapted with permission from Mittelman et al. [34].

View larger version (16K): [in this window] [in a new window]   Figure 5. Survival of C57BL/KaLwRij mice with experimental bone disease; pooled results for four experimental groups. Mice were inoculated with 5 x 104 5T33 MM cells and treated with epoetin alfa or epoetin alfa diluent (control) 7 days later. Epoetin alfa treatment significantly (p < 0.0001) prolonged survival of the treated mice. Adapted with permission from Mittelman et al. [34].

	SUMMARY

Top Learning Objectives Abstract Introduction rHuEPO and Radiation Therapy... Epoetin Alfa and Chemotherapy... Epoetin Alfa: An... Summary References

 
The efficacy of both radiation therapy and several chemotherapeutic agents (e.g., cyclophosphamide) appears to depend on adequate tumor oxygenation. This being the case, the presence of anemia and tumor hypoxia would reduce the efficacy of radiation therapy and chemotherapy, and improvement in tumor oxygenation would be expected to restore tumor sensitivity to these treatment modalities. Results of several preclinical studies that evaluated the impact of preventing or correcting anemia have demonstrated that administration of rHuEPO can increase the sensitivity of tumor cells to radiation therapy and chemotherapy in animal models of cancer. Moreover, data from a study using a murine myeloma model suggest that epoetin alfa, a recombinant human erythropoietin, may exert an immunomodulatory effect in multiple myeloma. Further study of the mechanism(s) of action of epoetin alfa is clearly warranted, as corroboration of these preclinical findings may have significant implications for the treatment and therapeutic outcome of cancer patients.

	REFERENCES

Top Learning Objectives Abstract Introduction rHuEPO and Radiation Therapy... Epoetin Alfa and Chemotherapy... Epoetin Alfa: An... Summary References

 

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This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ludwig, H. Search for Related Content PubMed PubMed Citation Articles by Ludwig, H.