title: 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.
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.
authors.affiliation: Department of Medical Oncology, 251 Airforce General Hospital, 11525 Athens, Greece.
authors.forename: Giannis
authors.initials: G
authors.lastname: Mountzios
authors.affiliation: Second Department of Medical Oncology, 'Agii Anargiri' Cancer Hospital, 14564 Athens, Greece.
authors.forename: Gerasimos
authors.initials: G
authors.lastname: Aravantinos
authors.affiliation: Health Data Specialists Ltd., 11526 Athens, Greece.
authors.forename: Zoi
authors.initials: Z
authors.lastname: Alexopoulou
authors.affiliation: Department of Medical Oncology, 'Papageorgiou' Hospital, Aristotle University of Thessaloniki School of Medicine, 56403 Thessaloniki, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Timotheadou
authors.affiliation: Oncology Unit, 'Hippokration' Hospital, 11527 Athens, Greece.
authors.forename: Fotini
authors.initials: F
authors.lastname: Matsiakou
authors.affiliation: Second Department of Medical Oncology, 'Metropolitan' Hospital, 18547 Piraeus, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Christodoulou
authors.affiliation: Second Department of Medical Oncology, 'Agii Anargiri' Cancer Hospital, 14564 Athens, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Laschos
authors.affiliation: Second Department of Medical Oncology, 'Metropolitan' Hospital, 18547 Piraeus, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Galani
authors.affiliation: Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, 26504 Patras, Greece.
authors.forename: Angelos
authors.initials: A
authors.lastname: Koutras
authors.affiliation: First Department of Medical Oncology, 'Metropolitan' Hospital, 18547 Piraeus, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Bafaloukos
authors.affiliation: First Department of Medical Oncology, 'Metropolitan' Hospital, 18547 Piraeus, Greece.
authors.forename: Helena
authors.initials: H
authors.lastname: Linardou
authors.affiliation: Oncology Section, Second Department of Internal Medicine, 'Hippokration' Hospital, 11527 Athens, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Pectasides
authors.affiliation: Oncology Department, General Hospital of Chania, 73300 Chania, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Varthalitis
authors.affiliation: Oncology Unit, 'Hippokration' Hospital, 11527 Athens, Greece.
authors.forename: Pavlos
authors.initials: P
authors.lastname: Papakostas
authors.affiliation: Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, 26504 Patras, Greece.
authors.forename: Haralambos P
authors.initials: HP
authors.lastname: Kalofonos
authors.affiliation: Department of Medical Oncology, 'Papageorgiou' Hospital, Aristotle University of Thessaloniki School of Medicine, 56403 Thessaloniki, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Fountzilas
keywords: chemotherapy-induced anemia; efficacy; erythropoietin; myocardial infarction; pulmonary embolism; safety; solid tumors; stroke; thrombosis; toxicity