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Keywords:

  • anemia;
  • cancer;
  • erythropoietin;
  • hypoxia;
  • radiotherapy

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANEMIA IN CANCER PATIENTS
  5. THE RELATIONSHIP BETWEEN HYPOXIA AND ANEMIA
  6. TRANSFUSION
  7. ERYTHROPOIETIN
  8. CONCLUSION
  9. REFERENCES

Anemia is a deficiency in red blood cells or in the hemoglobin (Hb) levels that leads to a decrease in the transport capacity of oxygen in the blood, which can reduce tolerance in radiotherapy (RT) and chemotherapy. The relationship between anemia and hypoxia, however, is complex and influenced by multiple variables. Although the blood Hb values that might develop hypoxia in tumors were not described clearly, optimal oxygen pressure was accepted in patients with an Hb value of 12–14 g/dL. Erythropoietin is a glycoprotein, which acts via EPOR to stimulate the growth, to prevent apoptosis, and to induce differentiation of red blood cell precursors. RhuEPO-α and -β are classically administered subcutaneously three times per week at doses ranging from 150 to 300 IU/kg. Darbepoetin-α has been shown to exhibit a longer elimination half-life, thus allowing a once-weekly administration at the dose of 2.25 µg/kg. Side-effects related to rhuEPO include hypertension and thromboembolic events. RhuEPO can be used effectively in the treatment of anemia in patients with solid tumor being treated by RT or chemoradiotherapy. Furthermore, the use of rhuEPO has been demonstrated to have a sustained beneficial impact on quality of life in cancer patients. However, the role of combination of rhuEPO with external RT still remains inconclusive and several clinical trials have been pointed increased mortality in patients treated with rhuEPO. In this paper, the probable radiobiological effects of anemia in patients treated with RT, the beneficial and adverse effects of rhuEPO, and related studies are reviewed. Future directions for the use of rhuEPO are proposed.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANEMIA IN CANCER PATIENTS
  5. THE RELATIONSHIP BETWEEN HYPOXIA AND ANEMIA
  6. TRANSFUSION
  7. ERYTHROPOIETIN
  8. CONCLUSION
  9. REFERENCES

Anemia in patients with cancer is considered to lessen the efficacy of radiotherapy (RT) by increasing the tumor hypoxia.1,2 Historically, patients with serious anemia have been treated with blood transfusions; however, several side effects of this treatment in the short- and long-term period have been reported.3 Additionally, as the hemoglobin (Hb) level reached by transfusion is maintained for approximately 15 days, it might be necessary to give more than one blood transfusion during RT.4

Recombinant human erythropoietin (rhuEPO) received US Food and Drug Administration (FDA) approval for anemia of chronic renal failure in 1989, and the FDA expanded the approval for anemia of cancer chemotherapy in 1993. rhuEPOare The clinical efficacies of two rhuEPOs-α and -β are the same: rhuEPO-α (Procrit®, Johnson & Johnson and Epogen®, Amgen), approved in the US, and rhuEPO-β (NeoRecorman®, Roche), approved in Europe, share the same amino acid sequence but differ in carbohydrate content.5–7 Additionally, darbepoetin-α is a newly developed rhuEPO variant. Darbepoetin-α (Aranesp®, Amgen) differs from rhuEPO in that darbepoetin-α contains additional N-linked oligosaccharide chains that confer a three-fold longer terminal half-life and a five-fold lower affinity for EPO receptors (EPOR) relative to rhuEPO-α.8 Clinical trials have established rhuEPO's ability to increase Hb levels and reduce transfusion requirements.9 Many researchers have conducted studies to evaluate quality of life (QOL), local tumor control, and survival variation in anemic cancer patients treated with rhuEPO; however, the results have been inconsistent.10,11

In this paper, the probable radiobiological effects of anemia in patients treated with RT, the beneficial and adverse effects of rhuEPO, and related studies are reviewed. Future directions for the use of rhuEPO are proposed.

ANEMIA IN CANCER PATIENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANEMIA IN CANCER PATIENTS
  5. THE RELATIONSHIP BETWEEN HYPOXIA AND ANEMIA
  6. TRANSFUSION
  7. ERYTHROPOIETIN
  8. CONCLUSION
  9. REFERENCES

Anemia is a deficiency in red blood cells or in the Hb levels leading to a decrease in the transport capacity of oxygen in the blood.1 According to the World Health Organization and the US National Cancer Institute, anemia can be considered minor (10–11.9 g/dL), moderate (8–10 g/dL), or severe (6.5–7.9 g/dL), and life threatening below 6.5 g/dL.12 On average, 54% of cancer patients are diagnosed with anemia, and its incidence and severity vary depending on cancer type, tumor stage, treatment type, age of the patient, and bone marrow reserve.13,14 Ludwig et al. showed that according to cancer treatment status at enrollment, almost one-third (31.7%) of patients who were not receiving cancer treatment at enrollment were anaemic; for patients receiving cancer treatment, 50.5% of patients receiving chemotherapy, 43.5% of patients receiving chemoradiotherapy, and 28.7% of patients receiving RT were anaemic. According to its incidence, anemia is mostly seen in patients with lung cancer, followed by those with gynecologic cancer, genitourinary cancer, and lymphoma.13,14

The etiology of cancer-related anemia is shown in the Table 1. Anemia affects numerous functions of the organism. One is the alteration in QOL of patients with cancer. Weakness, vertigo, headache, pallor, dyspnea, angina pectoris, tachycardia, palpitation, depression, deficiency in cognitive functions, and loss of libido are among the primary symptoms.12 Moreover, a meta-analysis of 60 relevant studies found that anemia increased the relative risk of death by 19% in patients with lung cancer, 75% in patients with head and neck cancer, 47% in patients with prostate cancer, and 67% in patients with lymphoma.15 The severity of symptoms is affected by Hb value, the rapidity of anemia's onset, compensatory mechanisms, and concomitant diseases.16

Table 1.  The etiology of cancer-related anemia
  1. Abbreviations: ChT, chemotherapy; Epo, erythropoietin; RT, radiotherapy; TNF: tumor necrosis factor.

1.Myelosuppressive treatments (ChT, RT)
2.Infiltration of bone marrow by tumor cells
3.Epo deficiency
4.Inefficient response of the bone marrow to Epo
5.Iron deficiency
6.Bleeding
7.Inflammatory events caused by malignancy (TNF, Interferon-α and Interleukin-I)
8.Autoimmune hemolytic anemia

THE RELATIONSHIP BETWEEN HYPOXIA AND ANEMIA

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANEMIA IN CANCER PATIENTS
  5. THE RELATIONSHIP BETWEEN HYPOXIA AND ANEMIA
  6. TRANSFUSION
  7. ERYTHROPOIETIN
  8. CONCLUSION
  9. REFERENCES

It has long been recognized that oxygen plays an important role in the stabilization of genetic damage from ionizing radiation. In previous studies, cell death in the same radiation dose were reported to be three-fold more in a well-oxygenated environment than in a hypoxic environment, which was called the “oxygen enhancement ratio”.17,18

The relationship between anemia and hypoxia is complex and influenced by multiple variables. One of two main hypotheses is that decreased Hb levels may negatively influence intratumoral oxygen tension leading to radiation resistance. Clavo et al. concluded that Hb concentration affects tumor oxygenation in patients with head and neck cancer.19 In addition, previously anemic patients whose anemia was treated during RT were determined to have the similar outcomes as those who were spontaneously non-anemic.20,21 However, the other paradigm relating Hb levels on outcomes implies that low Hb levels are merely a symptom of a more aggressive and intrinsically radioresistant malignancy and correction would therefore have little chance at altering outcome. This theory gained momentum as animal and human data on hypoxia suggested that anemia correction itself may not completely reverse hypoxia in tumors.22–24

Although the blood Hb values that might develop hypoxia in tumors were not described clearly, optimal oxygen pressure was accepted in patients with an Hb value of 12–14 g/dL.25–27 Furthermore, it was also stated that increasing Hb levels above 14 g/dL could cause hyper-viscosity, and hence blood perfusion and tumor oxygenation could decline. Several authors have demonstrated that Hb levels during treatment are predictive of response to therapy to a greater extent than pretreatment levels.28–31 Dunst et al. reported that for patients with uterine cervix carcinoma, the mid-treatment Hb level was the most important prognostic factor for local control and survival.20

TRANSFUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANEMIA IN CANCER PATIENTS
  5. THE RELATIONSHIP BETWEEN HYPOXIA AND ANEMIA
  6. TRANSFUSION
  7. ERYTHROPOIETIN
  8. CONCLUSION
  9. REFERENCES

Although blood transfusions have been traditionally used to manage anemia in patients with cancer, each transfused blood product carries a small risk of an acute or late adverse effect. The most common immediate adverse reactions to transfusion are fever, chills, and urticaria. The most potentially significant reactions are acute and delayed hemolytic transfusion reactions and bacterial contamination of blood products.3 Additionally, a probable immunosuppressive side effect of blood transfusions may have some drawbacks in application in cancer patients.32–35 In a study evaluating patients with uterine cervical cancer although all disease characteristics were almost similar, in patients received blood transfusion had lower survival rates than those did not receive. The lower survival rates were thought to be caused by immunosuppression.36

ERYTHROPOIETIN

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANEMIA IN CANCER PATIENTS
  5. THE RELATIONSHIP BETWEEN HYPOXIA AND ANEMIA
  6. TRANSFUSION
  7. ERYTHROPOIETIN
  8. CONCLUSION
  9. REFERENCES

Erythropoietin is a glycoprotein, which acts via EPOR to stimulate the growth, to prevent apoptosis, and to induce differentiation of red blood cell precursors.37–39 Erythropoietin is produced endogenously in the human body and may be given exogenously in the human recombinant form to treat anemia. The main sites of EPO production are the kidneys and the fetal liver. Other sites such as the brain and the uterus also produce small quantities of EPO.37 Erythropoietin plasma levels generally range between 4 and 26 mU/mL. The biosynthesis of EPO is influenced by all factors that contribute to reduce the quantity of O2 delivered to tissues. There is a reciprocally regulation between the plasma EPO levels and the quantity of Hb. Measurement of endogenous EPO quantity could provide accurate information and data for any use of exogenous rhuEPO.40,41

Response to the erythropoietic agents varies depending on factors such as dose of the medication, duration of the epoetin treatment, and concomitant illness. Iron deficiency also plays a crucial role in the etiology of cancer-related anemia. The use of rhuEPO with iron preparations is known to increase the rates of response. RhuEPO -α and -β are classically administered subcutaneously three times per week at doses ranging from 150 to 300 IU/kg. However, recent studies suggest that a once-a-week subcutaneous injection of 30 000–40 000 rhuEPO units leads to equivalent results in terms of anemia correction.5 There are no clear pharmacological differences between -α and -β rhuEPO isoforms. More recently, darbepoetin-α has been shown to exhibit a longer elimination half-life, thus allowing a once-weekly administration at the dose of 2.25 µg/kg.8

The most common adverse effects of rhuEPO are grouped as hypertension, thromboembolic events (TVE), skin reactions, headache, flu-like symptoms, and pure red cell aplasia (PRCA) resulting from anti-EPO specified antibody production. Adverse effects except from PRCA are reported to be 10%; PRCA has never been reported in cancer patients.42,43

A relationship between the increase in TVE and the use of rhuEPO was shown in a few studies. A randomized trial assessing the impact of rhuEPO on Hb level and mood state in patients with metastatic breast cancer and mild anemia (Hb < 12 g/dL) was terminated prematurely due to an increased incidence of TVE in the rhuEPO arm.44 Furthermore, it should be taken into consideration that TVE were observed especially when the Hb level increased to over 12 g/dL. Despite these reports, the etiology of TVE remains elusive due to competing risks of TVE in cancer patients from other variables such as the release of procoagulants by tumor cells, comorbid predisposing conditions, and anti-cancer drugs.45,46 Moreover, a recent meta-analysis of 27 rhuEPO trials showed no statistically significant increase in TVE in the rhuEPO-treated patients (4%) compared with the untreated patients (2%).47

Erythropoietin is usually started 7 to 14 days before the beginning of RT in patients treated with a combination of rhuEPO and RT (Table 2). Lavey et al. reported the first phase I trial in which 40 non-metastatic patients with different types of localized supradiaphragmatic cancers were presented. In 20 patients with an Hb level <13.5 g/dL, rhuEPO-α was administered. An increase of 6% in Hb levels during RT was demonstrated and rhuEPO was well tolerated.48 Dusenbery et al. evaluated the efficacy of rhuEPO-α in patients with uterine cervical carcinoma and Hb < 12.5 g/dL. The researchers observed an increase of 30% in Hb levels during RT in the rhuEPO group.49 Henke et al. randomized 50 patients with head and neck or uterine cervical carcinoma to one of four different rhuEPO dosing regimens. Hemoglobin levels increased 0.7 g/dL a week with this treatment. Moreover, a significant increase to be independent of doses was observed not only in Hb values but also in local control rates.50 In addition, Vijayakumar et al. carried out a randomized phase II study in 26 patients with various solid tumors. The first group received chemoradiotherapy alone, and the second group received rhuEPO-α. Treatment of rhuEPO was planned to start 15 days before initiation of RT; however, patients and referring physicians were often reluctant to allow such a delay in starting RT. Only 4 of the 26 patients were started the rhuEPO one or more weeks in advance and Hb levels increased by 0.43 g/dL per week. The authors recommend of administering rhuEPO several weeks before starting radiotherapy.51

Table 2.  Phase I/II clinical trials combination of RT and Epo
StudyTumor site (n = number of patients treated with Epo)Treatment typeTreatment of Epo ProtocolBaseline Hb (g/dL)Final Hb or rise (g/dL)TVETumor outcomeComment
  1. ChT, chemotherapy; Epo, erythropoietin; Hb, hemoglobin; HNSCC, Head and neck squamous cell carcinoma; LRC, Locoregional control; LRF, loco-regional failure; LRPFS, loco-regional progression free survival; NA, not available; OS, overall survival; PFS, progression free survival; RT, radiotherapy; TVE, tromboembolic events.

LaveySupradiafragmatic malignancy (n = 20)RT150–300 IU/kg, SC, three times a week, 0–10 days before RT, with iron sulfate(11.9)(15.1)NoNArhuEPO was well tolerated. It increased the Hb levels. The study was not designed to detect for disease control, the overall sample size was relatively small and the group was heterogenous
VijayakumarLung (n = 5), prostat (n = 7) or breast carcinoma (n = 2)RT+/−ChT200 IU/kg/day, SC, five times a week, after 10 injections three times a week, 2 weeks before RT, with iron sulfate11.414.2NoNArhuEPO was well tolerated. It increased the Hb levels. The study was not designed to detect for disease control, the overall sample size was relatively small and the group was heterogenous
DusenberyUterine cervical carcinoma (n = 15)RT+/−ChT200 IU/kg/day, SC, five times a week, 5–10 days before RT, with iron sulfate10.313.213.3%Pelvic failure; 2/15 (13.3%)rhuEPO was well tolerated. It increased the Hb levels. Follow-up is limited for evaluating disease control
HenkeHead and neck (n = 32), the others (uterine cervix, uterus or colorectal carcinoma n = 7)RT150 IU/kg/day IV, 300 IU/kg/day IV, or 150 IU/kg/day SC, three times a week, 10–14 days before RT, with iron sulfate10.9, 11.4, 11.53.2 (rise) 3.5 3.9NoLRC improved in HNSCC patients who experienced a rapid rise of Hb (not significant)rhuEPO was well tolerated. A rise to be independent of doses was attained in Hb values The study was not designed to detect for disease control, the overall sample size was relatively small and the group was heterogenous.
SWOGUterine cervical carcinoma (n = 53)RT+ChT400 IU/kg/day, SC, three times a week, 9–14 days before RT10.411.813%Two year PFS and OS were significantly associated with final Hb levelPFS and OS rates were lower than previous trials, the negative effect of rhuEPO on tumor control couldn't be excluded.
RTOGSquomous cell carcinoma of the head and neck (n = 72)RT+/−ChT40 000 U once weekly throughout RT, SC, an initial dose 7–10 days before RT12.0Rose by an average of 1.661 death by a pulmonary embolismLRF rate, LRPFS, patterns of failure, overall survival were similarA clinically relevant detrimental effect of rhuEPO couldn't be excluded. The study was not designed to detect a potential detrimental effect, and the overall sample size was relatively small

The results of the studies to evaluate combining RT and rhuEPO differed greatly. Several clinical trials showed that use of rhuEPO has a sustained beneficial impact on patient QOL as well as treatment outcomes. However, others have shown an increased risk of recurrence, a shorter disease-free survival (DFS), and decreased overall survival (OS). Glaser et al. conducted a study of 60 patients with T2-4 N0-2 oral cavity tumor and Hb < 12.5 g/dL. This study was designed to administer a neoadjuvant combination of external RT and chemotherapy followed by surgery at week 10. The first arm was administered 150 IU/kg/week rhuEPO-α; however, the dose was increased to 300 IU/kg as the increase in weekly Hb level was lower than 0.3 g/dL. Complete response rates were 68% in rhuEPO arm and 27% in the control arm. Average survival rates (90 vs 60%, P = 0.03) and loco-regional control rates (90 vs 63% P = 0.03) at 2 years were found to be significantly increased in the rhuEPO arm.52

Rades et al. evaluated the effectiveness of rhuEPO-α (150 IU/kg, three times a week) in maintaining Hb levels at 12 to 14 g/dL during chemoradiation for Stage III esophageal carcinoma, which was started at Hb < 13 g/dL and stopped at 14 g/dL or higher. Iron was administered if the ferritin < 100 ng/mL or the ferritin saturation was below 20%. The median change in Hb levels was +0.3 g/dL/week with rhuEPO, −0.5 g/dL/week without rhuEPO. Patients who received rhuEPO-α had better local control and OS (P = 0.001 and P = 0.009, respectively) at 2 years.53

A study reported by Blohmer et al. investigated the impact of rhuEPO on high-risk patients with uterine cervical cancer. The patients underwent hysterectomy followed by chemoradiotherapy combined with rhuEPO-α (3 × 10 000 IU/week) versus standard care and transfusions as needed. RhuEPO treatment kept Hb levels above 12 g/dL despite the negative effect of chemoradiotherapy. The relapse rate was lower in the rhuEPO arm (17 vs 25%, P < 0.07) than in the control arm at 2 years.54

Henke et al. designed a phase III trial that involved 351 patients with oral cavity, oropharynx, and hypopharynx or larynx cancer. The target Hb level was 12 g/dL for female patients and 13 g/dL for male patients. The first group was administered 300 IU/kg rhuEPO-β three times a week, which started 10 to 14 days before RT, while the second group received placebo treatment. All patients were administered iron preparations, but none of them was applied chemotherapy. The primary objective of the study was to determine loco-regional control and, secondarily, loco-regional progression time and OS. However, they showed that statistically significant poor results for all end points with rhuEPO.11

This study has raised a number of critiques. Treatment protocol was not completed by 34.4% of the patients in the placebo arm, and 56% of the patients in the rhuEPO arm. When the patients who completed the treatment in the planned form were analyzed, loco-regional control and survival rates were similar in both groups. Additionally, TNM classification and performance status, which were known to be the main factors in determining the prognosis in the head and neck region, were not reported by the authors. Moreover, both groups were considered to have imbalanced distributions of patients in terms of their characteristics, which could have affected the results. There was a higher percentage of patients who continued smoking during the treatment, had stage IV disease and with hypopharyngeal cancer, which was known to be associated with a worse prognosis than other head and neck cancers, in the rhuEPO group. They reported that the results of the study did not support the fact that rhuEPO had a radiosensitizer effect and also added that it was necessary to conduct other studies to determine the importance of using rhuEPO in cancer patients.55–57

The expression of EPOR has been documented in breast adenocarcinoma,58 embryonal,59 and hepatocellular carcinomas,60 neuroblastoma cell lines,61 and in squamous cell carcinoma of the cervix.62 Furthermore, rhuEPO may bind to EPOR; ultimately, increased cancer cell proliferation, migration, and clonogenicity will evolve.62 Henke et al. concluded that EPOR is variably expressed on head and neck cancer cells and is associated with a detrimental effect of rhuEPO-β administration. They also stated that a possible mechanism is that stimulation with rhuEPO protects the residual tumor from radiation treatment. It might reassure that rhuEPO-β did not affect the clinical course of patients with EPOR-negative cancer. This study drew attention to a potential risk for tumor progression under rhuEPO treatment, but more controlled trials are needed to more firmly conclude this potentially important aspect of the deleterious effects brought on by rhuEPO treatment in cancer.63

The Southwest Oncology Group (SWOG) determined the rhuEPO activity in stages IIB-IVA uterine cervical carcinoma patients treated with concurrent chemoradiotherapy. The 2-year progression-free survival (PFS) and OS rates were lower than those in previous trials, and the authors noted that the possibility of the negative effect of rhuEPO administration on tumor control couldn't be excluded.64

The interim analysis of the DAHANCA 10 trial of darbepoetin-α in which 522 patients with head and neck cancer treated with RT, showed small but significant poor results for loco-regional control and OS rates in the patients were given darbapoetin-α. Therefore, the DAHANCA group decided to terminate the study.65

Temkin et al. reported a retrospective review of locally advanced uterine cervical carcinoma treated with concurrent chemoradiotherapy. They evaluated whether the administration of rhuEPO (40 000 IU/weekly) affects recurrence rates, DFS, and OS. It was shown that rhuEPO administration was significantly associated with both disease recurrence and death related to disease (P = 0.014, P = 0.045, respectively).66

More recently, RTOG designed a study to determine whether the addition of rhuEPO could improve the outcomes of anemic patients receiving definitive RT for squamous cell carcinoma of the head and neck. The 3-year loco-regional PFS rate was 52% for the control group and 47% for the rhuEPO group. The 3-year loco-regional failure rate was 36% for the control group and 44% for the rhuEPO group. The OS rates were 57% and 56%, respectively at 3 years. There was also no significant difference in loco-regional control, PFS, patterns of failure, OS, or toxicity. The authors reported that a clinically relevant detrimental effect of rhuEPO couldn't be excluded because the study was not designed to detect a potential detrimental effect, and the overall sample size was relatively small.67

The European Organization for Research and Treatment of Cancer proposed guidelines for treating patients with anemia. They suggested that the two major goals of erythropoetic protein therapy should be to improve QOL and prevent transfusion. For an Hb level between 10 and 12 g/dL, it is possible to give an rhuEPO supplementation or to wait until the Hb level reaches a value below 10 g/dL. The target Hb concentration should be 12–13 g/dL. There is no indication for prophylactic use of rhuEPO to prevent anemia in patients undergoing RT who have normal Hb values at the start of therapy. rhuEPO is not recommended to improve survival or as response to treatment as there is no evidence to support this.68

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANEMIA IN CANCER PATIENTS
  5. THE RELATIONSHIP BETWEEN HYPOXIA AND ANEMIA
  6. TRANSFUSION
  7. ERYTHROPOIETIN
  8. CONCLUSION
  9. REFERENCES

The occurrence of anemia is frequently observed in cancer patients and may markedly alter the QOL. The presence of anemia may also have detrimental effects on disease progression. The administration of rhuEPO has a corrective impact on Hb levels and reduces transfusional needs in anemic cancer patients. Patients should be followed up regularly in terms of HT and TVE, which are the most common side effects. There are numerous reports showing the presence of functional EPOR in human tumors. Adequate trials are needed to further evaluate the effects of rhuEPO on certain types of cancers. In view of the current uncertainties, patients should be involved in the risk-benefit decisions that accompany this well-established but incompletely understood therapy.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ANEMIA IN CANCER PATIENTS
  5. THE RELATIONSHIP BETWEEN HYPOXIA AND ANEMIA
  6. TRANSFUSION
  7. ERYTHROPOIETIN
  8. CONCLUSION
  9. REFERENCES