Lessons from the past: Long-term safety and survival outcomes of a prematurely terminated randomized controlled trial on prophylactic vs. hemoglobin-based administration of erythropoiesis-stimulating agents in patients with chemotherapy-induced anemia

Mountzios,Giannis; Aravantinos,Gerasimos; Alexopoulou,Zoi; Timotheadou,Eleni; Matsiakou,Fotini; Christodoulou,Christos; Laschos,Konstantinos; Galani,Eleni; Koutras,Angelos; Bafaloukos,Dimitrios; Linardou,Helena; Pectasides,Dimitrios; Varthalitis,Ioannis; Papakostas,Pavlos; Kalofonos,Haralambos  P.; Fountzilas,George

doi:10.3892/mco.2015.693

February-2016 Volume 4 Issue 2

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

February-2016 Volume 4 Issue 2

Full Size Image

Article

Lessons from the past: Long-term safety and survival outcomes of a prematurely terminated randomized controlled trial on prophylactic vs. hemoglobin-based administration of erythropoiesis-stimulating agents in patients with chemotherapy-induced anemia

Authors:
- Giannis Mountzios
- Gerasimos Aravantinos
- Zoi Alexopoulou
- Eleni Timotheadou
- Fotini Matsiakou
- Christos Christodoulou
- Konstantinos Laschos
- Eleni Galani
- Angelos Koutras
- Dimitrios Bafaloukos
- Helena Linardou
- Dimitrios Pectasides
- Ioannis Varthalitis
- Pavlos Papakostas
- Haralambos P. Kalofonos
- George Fountzilas
View Affiliations / Copyright

Affiliations: Department of Medical Oncology, 251 Airforce General Hospital, 11525 Athens, Greece, Second Department of Medical Oncology, ‘Agii Anargiri’ Cancer Hospital, 14564 Athens, Greece, Health Data Specialists Ltd., 11526 Athens, Greece, Department of Medical Oncology, ‘Papageorgiou’ Hospital, Aristotle University of Thessaloniki School of Medicine, 56403 Thessaloniki, Greece, Oncology Unit, ‘Hippokration’ Hospital, 11527 Athens, Greece, Second Department of Medical Oncology, ‘Metropolitan’ Hospital, 18547 Piraeus, Greece, Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, 26504 Patras, Greece, First Department of Medical Oncology, ‘Metropolitan’ Hospital, 18547 Piraeus, Greece, Oncology Section, Second Department of Internal Medicine, ‘Hippokration’ Hospital, 11527 Athens, Greece, Oncology Department, General Hospital of Chania, 73300 Chania, Greece
Pages: 211-220
|
Published online on: December 4, 2015

https://doi.org/10.3892/mco.2015.693
Expand metrics +

Abstract

Prophylactic erythropoiesis-stimulating agent (ESA) administration for chemotherapy-induced anemia (CIA) is not supported by current guidelines. Long‑term follow‑up of patients who had been treated with ESA for CIA in the past may provide useful information. In 2002, we undertook a prospective, randomized phase III trial of prophylactic vs. hemoglobin (Hb)‑based (threshold: 11 mg/dl) ESA administration in patients with solid tumors and CIA. ESA administration for CIA was permanently suspended in 2007 in view of published data at that time, while patient surveillance continued. Among 630 evaluable patients, 38.6% were male, 50.9% had advanced cancer at diagnosis, 40.6% had Hb levels <12 mg/dl at baseline and 47.9% received ESA prophylactically (1:1 randomization). The major tumor types included colorectal (36.0%), breast (20.6%), non‑prostate genitourinary (11.0%) and lung cancer (8.4%). After a median follow‑up of 85.4 months, 358 patients had relapsed and 380 had succumbed to the disease. Patients in the prophylactic ESA group (group A; experimental arm), as compared with those in the Hb‑based group (group B; iron supplementation alone), exhibited a significantly more prominent increase in median Hb levels, particularly in the subset of patients with non‑metastatic disease (two‑sided P<0.01) Among patients receiving chemotherapy for advanced cancer, those who received ESAs prophylactically exhibited a lower incidence of CIA (all grades: P=0.014, grades 3‑4: P=0.034) and fatigue (all grades: P<0.001, grades 3‑4: P=0.055), but a higher rate of a composite outcome encompassing all thrombosis‑related events (all grades: P=0.043, grades 3‑4: P=0.099). These differences were less prominent in the group of patients who received adjuvant treatment. There were no significant differences in overall mortality and relapse/progression rates between the two groups. Therefore, prophylactic, compared with Hb‑based, administration of ESAs for CIA in patients with solid tumors, was found to be associated with a significantly lower incidence of anemia and fatigue, but with a marginally higher rate of thrombosis-related adverse events, particularly in patients receiving first-line chemotherapy for advanced cancer.

View Figures

View References

1	Knight K, Wade S and Balducci L: Prevalence and outcomes of anemia in cancer, A systematic review of the literature. Am J Med. 116(Suppl 7A): 11S–26S. 2004. View Article : Google Scholar : PubMed/NCBI
2	Smith RE Jr, Aapro MS, Ludwig H, Pintér T, Smakal M, Ciuleanu TE, Chen L, Lillie T and Glaspy JA: Darbepoetin alpha for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy, Results of a phase III, multicenter, randomized, double-blind, placebo-controlled study. J Clin Oncol. 26:1040–1050. 2008. View Article : Google Scholar : PubMed/NCBI
3	Clark O, Adams JR, Bennett CL and Djulbegovic B: Erythropoietin, uncertainty principle and cancer related anaemia. BMC Cancer. 2:232002. View Article : Google Scholar : PubMed/NCBI
4	Bohlius J, Langensiepen S, Schwarzer G, Seidenfeld J, Piper M, Bennett C and Engert A: Recombinant human erythropoietin and overall survival in cancer patients, Results of a comprehensive meta-analysis. J Natl Cancer Inst. 97:489–498. 2005. View Article : Google Scholar : PubMed/NCBI
5	Littlewood TJ, Bajetta E, Nortier JW, Vercammen E and Rapoport B: Epoetin Alfa Study Group: Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum, chemotherapy. Results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 19:2865–2874. 2001.PubMed/NCBI
6	Hedenus M, Adriansson M, Miguel San J, Kramer MH, Schipperus MR, Juvonen E, Taylor K, Belch A, Altés A, Martinelli G, et al: Darbepoetin Alfa 20000161 Study Group: Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: A randomized, double-blind, placebo-controlled study. Br J Haematol. 122:394–403. 2003. View Article : Google Scholar : PubMed/NCBI
7	Henke M, Laszig R, Rübe C, Schäfer U, Haase KD, Schilcher B, Mose S, Beer KT, Burger U, Dougherty C, et al: Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: Randomised, double-blind, placebo-controlled trial. Lancet. 362:1255–1260. 2003. View Article : Google Scholar : PubMed/NCBI
8	Leyland-Jones B, Semiglazov V, Pawlicki M, Pienkowski T, Tjulandin S, Manikhas G, Makhson A, Roth A, Dodwell D, Baselga J, et al: Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: A survival study. J Clin Oncol. 23:5960–5972. 2005. View Article : Google Scholar : PubMed/NCBI
9	Thomas G, Ali S, Hoebers FJ, Darcy KM, Rodgers WH, Patel M, Abulafia O, Lucci JA III and Begg AC: Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dl with erythropoietin vs above 10.0 g/dl without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer. Gynecol Oncol. 108:317–325. 2008. View Article : Google Scholar : PubMed/NCBI
10	Wright JR, Ung YC, Julian JA, Pritchard KI, Whelan TJ, Smith C, Szechtman B, Roa W, Mulroy L, Rudinskas L, et al: Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol. 25:1027–1032. 2007. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Lessons from the past: Long-term safety and survival outcomes of a prematurely terminated randomized controlled trial on prophylactic vs. hemoglobin-based administration of erythropoiesis-stimulating agents in patients with chemotherapy-induced anemia

This article is mentioned in:

Abstract

Figure 1

Figure 2

Figure 3

Figure 4

Related Articles