Abstract:
The most common symptoms from anemia range from cold clammy skin, dizziness, palpitation, heart failure, depression, and the most overlooked yet the most debilitating symptom is fatigue. The worse the anemia the more fatigue a patient feels, particularly the ones suffering from cancer and undergoing chemotherapy. The term chemotherapy-induced anemia (CIA) is a condition that deteriorates the quality of life of cancer patients and to manage the condition, previously RBC transfusion and iron supplements were given. Epoetin beta is an erythropoiesis stimulating agents (ESA) that mimics the erythropoietin hormone to raise RBC level in CIA patients and reduces the need for RBC transfusion. A study on Epoetin beta revealed mixed data on its efficacy and adverse effects. Trials and studies enumerated the better quality of life after the use of epoetin beta but also demonstrated no change in survival rates and some thromboembolic events especially on patients with hemoglobin level of more than 11.5 gm/dL. Further evaluation of the safety of the drug is recommended.
Introduction:
Anemia is common in cancer patients, especially chemotherapy-induced anemia (CIA), which potentially impacts disease outcome negatively. Erythropoietin, produced mainly by the kidneys and some by liver, is the hormone that stimulate the production of RBCs from bone marrow.1 Chemotherapies are cytotoxic drugs which can directly impair red blood hcell (RBC) production and also cause renal tubular damage. Apart from CIA, cancer progression itself can disrupt erythropoietin synthesis in kidneys due to high levels of cytokines.
The management of CIA includes allogeneic RBC transfusion, and the combined use of intravenous iron supplementation, and erythropoiesis stimulating agents (ESAs). Epoetin beta is an ESA that has proven efficacy in raising hemoglobin levels in CIA patients that reduces the need for RBC transfusion. A study on Epoetin beta revealed mixed data and emphasizes on further evaluation of the drug safety in certain cancers.2
Survival of Cancer with Anemia:
According to the National Cancer Institute and the World Health Organization, severe and life-threatening anemia is when hemoglobin level is in the range of 6.5-7.9 g/dL and 6.5 g/dL respectively. The most debilitating symptom from anemia for cancer patients is fatigue. Although, overlooked by physicians, the patients complain that fatigue feels worse than any pain. It affects the quality of life and the survival of the patient. It increases the mortality risk by 65%. While on chemotherapy, if the patient develops anemia, then the survival is lower than non-anemic patients. The symptom that is most directly related to anemia is fatigue, the more the anemia the more the feeling of fatigue. Anemia is considered to be a standalone feature that has prognostic value to anticipate the outcome of treatment and survival of patients treated with chemotherapy or radiotherapy. The other symptoms of anemia are dizziness, palpitation, pulmonary oedema, heart failure, depression, cold skin and impairment of cognitive function.
Management of CIA:
CIA or anemia in cancer is a comorbid factor and it must be addressed for the patient’s survival.
The ESAs mimics the action of erythropoietin and activates the erythropoietin receptor on erythrocytic progenitor cells to enhance rapid production of RBCs in the bone marrow. It has shown to improve anemia, lower the fatigue and overall improve the quality of life in cancer patients3 until the late 1980s, RBC transfusion was the only management but currently the use of ESAs has reduced the number of RBC transfusions.
Risks Associated with ESAs:
Meta-analyses highlighted associated risks with the use of ESAs. Studies could not conclude the effects of ESAs on survival or disease progression. Increased risk of thromboembolic events was noted with the use of ESAs. This risk is hemoglobin level dependent. It is very important to not exceed hemoglobin levels since adverse events of ESAs was evident on patients having hemoglobin level of 13gm/dL. ESAs have no role in tumor progression.
Guidelines:
That the ESAs are effective in enhancing hemoglobin needs no justification, however the safety of ESAs require further studies, and more emphasis is needed to understand the causes of anemia in cancer patients with a hemoglobin level of 11gm/dL or 2gm/dL below the baseline. Except for small cell lung cancer, patients undergoing palliative treatment and having CIA (Hemoglobin level 10gm/dL) can be administered ESAs after a full evaluation along with patients’ agreement. Even asymptomatic patients with the same 10gm/dL of hemoglobin who need transfusions, can be given ESAs. For any ESA management, iron level monitoring is most essential.
Recommended doses of the three available ESAs- Epoetin Alfa, Epoetin Beta, & Darbepoetin:
- Epoetin Alfa and Beta- 10,000 IU three times weekly for epoetin alfa and beta
- Epoetin Beta- 30,000 IU once weekly
- Epoetin Alfa- 40,000 IU once weekly for epoetin alfa.
- Darbepoetin- 150 µg per week or 500 µg every 3 weeks.
- ESAs increase the level of erythropoietin which results in RBC production at a speed that exceeds the iron mobilization from body stores, hence it is important to monitor iron level and administer iron a per demand as well.
European Medicines Agency’s Committee recommends the use of ESAs in approved indications (hemoglobin target range of 10–12 g/dL in CIA) as it outweighs the associated risks.
Epoetin Beta:
Epoetin beta is a human recombinant erythropoietin molecule with identical amino acid structure to the human endogenous hormone. It is a glycoprotein composed of an amino acid chain of 156 residues and four carbohydrate side chains that represent approximately 40% of the molecular weight. Epoetin beta was given license in Europe in 1990 for the treatment of symptomatic anemia associated with chronic kidney disease and to treat CIA in cancer patients.
The mechanism of action is of epoetin beta is the same as endogenous erythropoietin. It binds to EpoR on erythroid progenitor cells in the bone marrow and stimulates erythropoiesis. However, in certain malignancies, EpoR is also expressed on the surface of endothelial cells and ESAs can then lead to increased angiogenesis, thus promoting tumor cell proliferation, augmenting metastasis and even drug resistance (e.g., breast cancer) as ESA can activate pathways that was targeted to be deactivated by anti-cancer therapies. ESAs bioavailability and clearance are reduced in cancer patients, but half-life of 12-28 hours remains same for healthy volunteers and patients. ESAs are degraded after EpoR-mediated cellular uptake.
Clinical Efficacy:
| Trials | ESA Type | Type of Cancer | Patient Number | Dose | Outcome |
| Multicenter Randomized | Epoetin Beta | Low-grade non-Hodgkin’s lymphoma, Chronic lymphocytic leukemia, or Multiple Myeloma | 349 (Hb Level 10gm/dL) | 150 IU/kg, subcutaneously, 3 times a week for 16 weeks | 67% showed an increase in hemoglobin levels by 2 g/dL, while only 27% of patients in the placebo group. Quality of life better. |
| NOW | Epoetin Beta | Lymphoid malignancies (multiple myeloma, low-grade non-Hodgkin’s lymphoma, chronic lymphocytic leukemia) | 241 (Hb Level 9–11 gm/dL) | Compared the regimen of 30,000 IU once a week with that of the established dose of 10,000 IU three times a week, for 16 weeks. | Weekly vs three times per week regimen response similar (72% versus 75%, respectively). 90% of patients treated with 30,000 IU epoetin beta once weekly remained transfusion-free throughout the study. |
| Randomized Trial | Epoetin Beta | Head and neck cancer | 100 patients (Hb-10gm/dL) | Compared the regimen of 30,000 IU once a week with that of the established dose of 10,000 IU three times a week. | Improved hemoglobin levels, energy levels, and quality of life. Similar on both regimens, along with comparable 2-year survival. |
| Pirker et al. – Observational and Prospective Study | Epoetin Beta was needed after the second chemotherapy | Lung cancer patients (n=40, 72.5% with non-small cell lung cancer and 27.5% with small cell lung cancer) receiving chemotherapy | 40 patients (Hb-12gm/dL) | 30,000 IU once weekly | Hb level increased by 1.3gm/dL by week 4. 95% patients did not require RBC transfusion. |
| Multicenter, Open label, Prospective NAUTICA trial | Epoetin Beta | Solid and Non-myeloid hematological malignancies undergoing chemotherapy | 691 patients | 30,000 IU once weekly | Hemoglobin response observed in 60.4% of all patients and in 61.2% of those with baseline hemoglobin 11 g/dL. Solid and non-myeloid tumor response was 60.5% versus 60.2% consecutively. |
Clinical Safety:
Clinical safety of epoetin beta has been a focus of study since the conflicting data regarding the adverse effects and reduced survival in ESA treatment for CIA countered the benefit of the drug.
| Trials | ESA Type | Type of Cancer | Patient Number | Dose | Outcome |
| ENHANCE Trial | Epoetin Beta | Head and neck cancer patients undergoing radiotherapy | 351 (placebo 171 & epoetin beta treatment 180) patients | 300 IU/kg three weekly | Anemia was corrected in epoetin beta versus placebo (82% versus 15%) group. However, epoetin beta group experienced increased locoregional progression, decreased survival from cardiac and general disorders. |
| Study of 154 patients from EVIDENCE Trial | Epoetin Beta | Head and neck cancer patients, observe expression of EpoR | 154 | Correlations between patients positive for EpoR and epoetin beta. Patients had poorer locoregional progression-free survival compared with those given placebo. Epoetin had no effect on the outcome in EpoR-negative patients. | |
| BRAVE Study | Epoetin Beta | Metastatic breast cancer and hemoglobin levels 12.9 gm/dL undergoing chemotherapy. | No effect of epoetin beta on overall survival or progression-free survival. Hemoglobin levels increased by 1.6 g/dL, but thromboembolic events also increased. | ||
| Fujisaka et al | Epoetin beta was administered only when hemoglobin level was 10 gm/dL and not exceeded 12 gm/dL | Lung or gynecological cancer | 186 | Reduced RBC transfusion. No difference in quality of life. |
Meta Analysis:
| Trials | ESA Type | Type of Cancer | Patient Number | Outcome |
| Boogaerts et al | Epoetin Beta | Solid tumors receiving different chemotherapy regimens | Epoetin beta group 255. Standard care 199. | Rapid increase in hemoglobin level, reduced transfusion requirement, transfusion-free survival was improved in the epoetin beta group, with no risk for tumor progression or overall survival. |
| Study based on 12 randomized controlled studies. | Epoetin Beta | 65% with solid tumors, and 35% with non-myeloid hematological malignancies | 2,297 | Treated and untreated individuals had a similar risk of progression, a trend for a reduction of such risk was seen overall. On epoetin beta, the time to thromboembolic events was shorter and their frequency higher However, the frequency of thromboembolic event-related deaths was only 1% in both treated and control patients. |
| Aapro et al | Epoetin beta had no negative effect on survival or disease progression when therapy was initiated with hemoglobin levels 10 gm/dL. When treatment was started with hemoglobin 11 gm/dL, a negative effect on survival was observed | |||
| Cochrane Collaboration, systemic review of 91 randomized control trials. | Erythropoietin and darbe poetin. | 20,102 | ESA patients had a decreased risk of RBC transfusions, improved quality of life. During study period, ESAs increased mortality, decreased overall survival, increased thromboembolic events | |
| Meta-analysis of three randomized placebo-controlled trials | Epoetin beta or Darbepoetin alfa; n=273 | Solid tumors or lymphoma | 511 Japanese patients. ESA group 273, placebo 238 | ESAs reduced the risk of transfusion, no significant impact on overall survival, mortality rate, or frequency of thromboembolic events. |
Conclusion
CIA affects most cancer patients. The current guidelines for treatment of CIA indicates Epoetin Beta is safe to use for patients with hemoglobin level from 10 gm/dL to 11.5 gm/dL to avoid thromboembolic events. There is also a hypothesis that erythropoietin might impair disease control in patients undergoing radiotherapy. Low hemoglobin cause intense fatigue among patients getting chemotherapy and epoetin beta has proven effective in raising hemoglobin and reducing RBC transfusion. However, there is still safety issues- in certain tumor condition, the ESAs may increase EpoR expression in endothelial cells which may lead to angiogenesis resulting in tumor proliferation and metastasis, and also, they may activate pathways that were deactivated by the anticancer drugs and ultimately develop drug resistance. Even though ESAs increase the RBC level and provide better quality of life, long-term large, randomized trials are recommended to record survival rates from ESA use and safety of the drug.
Author of this article
- Dr. Maliha Mannan Ahmed has an MBBS (BMC), MBA (ULAB) and Masters in Healthcare Leadership (Brown University) and is the Executive Editor of The Coronal.
Reference
1. Erythropoietin: Production, Purpose, Test & Levels. Cleveland Clinic. Accessed February 24, 2025. https://my.clevelandclinic.org/health/articles/14573-erythropoietin
2. Galli L, Ricci C, Egan CG. Epoetin beta for the treatment of chemotherapy-induced anemia: an update. OncoTargets Ther. 2015;8:583-591. doi:10.2147/OTT.S77497
3. Recombinant Human Erythropoietin (rhEPO) in Clinical Oncology: Scientific and Clinical Aspects of Anemia in Cancer | SpringerLink. Accessed February 24, 2025. https://link.springer.com/book/10.1007/978-3-211-69459-6