epoetin-alfa and Colorectal-Neoplasms

Anemia is a common complication of myelosuppressive chemotherapy that results in a decreased functional capacity and quality of life (QOL) for cancer patients. Severe anemia is treated with red blood cell transfusions, but mild-to-moderate anemia in patients receiving chemotherapy has traditionally been managed conservatively on the basis of the perception that it was clinically unimportant. This practice has been reflected in the relative inattention to standardized and complete reporting of all degrees of chemotherapy-induced anemia. We undertook a comprehensive review of published chemotherapy trials of the most common single agents and combination chemotherapy regimens, including the new generation of chemotherapeutic agents, used in the treatment of the major nonmyeloid malignancies in adults to characterize and to document the incidence and severity of chemotherapy-induced anemia. Despite identified limitations in the grading and reporting of treatment-related anemia, the results confirm a relatively high incidence of mild-to-moderate anemia. Recent advances in assessing the relationships of anemia, fatigue, and QOL in cancer patients are providing new insights into these closely related factors. Clinical data are emerging that suggest that mild-to-moderate chemotherapy-induced anemia results in a perceptible reduction in a patient's energy level and QOL. Future research may lead to new classifications of chemotherapy-induced anemia that can guide therapeutic interventions on the basis of outcomes and hemoglobin levels. Perceptions by oncologists and patients that lesser degrees of anemia must be endured without treatment may be overcome as greater emphasis is placed on the QOL of the oncology patient and as research provides further insights into the relationships between hemoglobin levels, patient well-being, and symptoms.

Topics: Adult; Aged; Anemia; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Colorectal Neoplasms; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Female; Head and Neck Neoplasms; Hematinics; Humans; Incidence; Lung Neoplasms; Lymphoma; Middle Aged; Neoplasms; Ovarian Neoplasms; Recombinant Proteins; Severity of Illness Index; Treatment Outcome

Patients undergoing cancer surgery frequently require blood, and the transfusion of allogeneic blood in these patients has been controversially linked to an increased risk of tumor recurrence. This patient population may therefore benefit from preoperative autologous blood donation (ABD) with or without epoetin alfa therapy, although the precise impact of autologous blood transfusion has not been fully explored. In some trials, preoperative ABD reduced allogeneic blood exposure by 50% in patients undergoing surgery for cancer resection, while, in another study, perioperative treatment with epoetin alfa significantly increased hematocrit (Hct) levels preoperatively and led to a reduction in postoperative allogeneic blood exposure. A combination of epoetin alfa and preoperative ABD seems a reasonable approach to reducing allogeneic blood exposure in patients undergoing cancer surgery.

Topics: Anemia; Blood Transfusion; Blood Transfusion, Autologous; Colorectal Neoplasms; Disease-Free Survival; Epoetin Alfa; Erythropoiesis; Erythropoietin; Gastrointestinal Neoplasms; Humans; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms; Premedication; Prospective Studies; Recombinant Proteins; Survival Rate; Transfusion Reaction; Treatment Outcome

Colorectal cancer patients are often anemic before surgery, and this leads to an increased requirement for allogeneic blood transfusion. This may result in transfusion-induced immunosuppression, which in turn leads to increased morbidity and possibly an increased rate of tumor relapse. We investigated the possible benefits of perioperative epoetin alfa administration in anemic patients to correct hemoglobin levels and reduce transfusion needs.. A total of 223 colorectal cancer patients with anemia scheduled for surgery were randomized to a group that received epoetin alfa 150 or 300 IU/kg/day subcutaneously for 12 days (day -10 to +1) or to a control group. All received iron (200 mg/day by mouth) for 10 days before surgery. Hemoglobin levels, hematocrit, and the number of blood units transfused were recorded.. A total of 204 patients were eligible for analysis. Mean hemoglobin levels and hematocrit were significantly higher in the 300 IU/kg group than in the control group, both 1 day before surgery (hemoglobin, P = .008; hematocrit, P = .0005) and 1 day after surgery (hemoglobin, P = .011; hematocrit, P = .0008). Blood loss during and after surgery was similar in all groups. Patients who received epoetin alfa 300 IU/kg required significantly fewer perioperative transfusion units than control patients (.81 vs. 1.32; P = .016) and significantly fewer postoperative units (.87 vs. 1.33; P = .023). There were no significant differences in the number of units in the 150 IU/kg group.. Preoperative epoetin alfa (300 IU/day) increases hemoglobin levels and hematocrit in colorectal surgery patients. These effects are associated with a reduced need for perioperative and postoperative transfusions.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Blood Transfusion; Colectomy; Colorectal Neoplasms; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hematologic Tests; Humans; Male; Middle Aged; Preoperative Care; Recombinant Proteins

Patients undergoing cancer surgery frequently require blood, and the transfusion of allogeneic blood in these patients has been controversially linked to an increased risk of tumor recurrence. This patient population may therefore benefit from preoperative autologous blood donation (ABD) with or without epoetin alfa therapy, although the precise impact of autologous blood transfusion has not been fully explored. In some trials, preoperative ABD reduced allogeneic blood exposure by 50% in patients undergoing surgery for cancer resection, while, in another study, perioperative treatment with epoetin alfa significantly increased hematocrit (Hct) levels preoperatively and led to a reduction in postoperative allogeneic blood exposure. A combination of epoetin alfa and preoperative ABD seems a reasonable approach to reducing allogeneic blood exposure in patients undergoing cancer surgery.

Topics: Anemia; Blood Transfusion; Blood Transfusion, Autologous; Colorectal Neoplasms; Disease-Free Survival; Epoetin Alfa; Erythropoiesis; Erythropoietin; Gastrointestinal Neoplasms; Humans; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms; Premedication; Prospective Studies; Recombinant Proteins; Survival Rate; Transfusion Reaction; Treatment Outcome

The US Food and Drug Administration (FDA) has approved epoetin and darbepoetin for chemotherapy-induced anemia (CIA). Approved epoetin and darbepoetin dosing schedules were three times per week and weekly, respectively, although off-label, less frequent scheduling was common. In 2004, 2007, and 2008, a US Food and Drug Administration Advisory Committees warned of risks associated with erythropoiesis-stimulating agents. During this period, lawsuits alleging illegal darbepoetin marketing practices have concluded, resulting in $1.1 billion in fines and settlements and one criminal conviction. No prior study, to our knowledge, has reported on the use of darbepoetin versus epoetin for CIA.. We evaluated the dosing, utilization, and costs of erythropoiesis-stimulating agents among 3,761 South Carolina Medicaid patients with CIA.. Epoetin and darbepoetin utilization rates were 22% and 28% in 2003, 10% and 33% in 2007, and 3% and 7% in 2010, respectively. Mean per-patient per-administration epoetin and darbepoetin doses were 40,983 IU and 191 µg, respectively, in 2003 and 47,753 IU and 369 µg, respectively, in 2010. Mean monthly patient costs for epoetin and darbepoetin were $1,030 and $981, respectively, in 2003 and $932 and $1,352, respectively, in 2010. Epoetin use decreased steadily between 2002 and 2010; darbepoetin use increased steadily between 2003 and 2007 and then decreased steadily thereafter. Per-patient dosing of darbepoetin, but not epoetin, increased steadily between 2003 and 2010, and monthly per-patient epoetin costs decreased 3% while the per-patients costs of darbepoetin increased 30% between 2003 and 2010.. To our knowledge, our findings are the first data reporting on epoetin versus darbepoetin use for CIA and support recently concluded lawsuits involving allegations of illegal marketing practices of the manufacturer of darbepoetin.

Topics: Adolescent; Adult; Anemia; Antineoplastic Agents; Breast Neoplasms; Colorectal Neoplasms; Darbepoetin alfa; Drug Utilization; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Logistic Models; Lung Neoplasms; Male; Medicaid; Middle Aged; Recombinant Proteins; South Carolina; United States; Young Adult

Several clinical trials in oncology have reported increased mortality or disease progression associated with erythropoiesis-stimulating agents. One hypothesis proposes that erythropoiesis-stimulating agents directly stimulate tumor proliferation and/or survival through cell-surface receptors. To test this hypothesis and examine if human tumors utilize the erythropoietin receptor pathway, the response of tumor cells to human recombinant erythropoietin was investigated in disaggregated tumor cells obtained from 186 patients with colorectal, breast, lung, ovarian, head and neck, and other tumors. A cocktail of well characterized tumor growth factors (EGF, HGF, and IGF-1) were analyzed in parallel as a positive control to determine whether freshly-isolated tumor cells were able to respond to growth factor activation ex vivo. Exposing tumor cells to the growth factor cocktail resulted in stimulation of survival and proliferation pathways as measured by an increase in phosphorylation of the downstream signaling proteins AKT and ERK. In contrast, no activation by human recombinant erythropoietin was observed in isolated tumor cells. Though tumor samples exhibited a broad range of cell-surface expression of EGFR, c-Met, and IGF-1R, no cell-surface erythropoietin receptor was detected in tumor cells from the 186 tumors examined (by flow cytometry or Western blot). Erythropoiesis-stimulating agents did not act directly upon isolated tumor cells to stimulate pathways known to promote proliferation or survival of human tumor cells isolated from primary and metastatic tumor tissues.

Topics: Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Epidermal Growth Factor; Epoetin Alfa; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; Female; Hepatocyte Growth Factor; HT29 Cells; Humans; Insulin-Like Growth Factor I; Male; Ovarian Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; Receptor, IGF Type 1; Receptors, Erythropoietin; Signal Transduction

In a large, 16-week, prospective study of 2,964 anemic patients with various cancers undergoing chemotherapy, once-weekly subcutaneous administration of 40,000 U of epoetin alfa,with potential escalation to 60,000 U, increased hemoglobin (Hgb) levels, decreased transfusion requirements, and improved quality of life (QOL) as assessed using the Linear Analog Scale Assessment (LASA) for energy, activity, and overall QOL and the Functional Assessment in Cancer Therapy-Anemia (FACT-An) QOL instrument. A retrospective subset analysis conducted in 244 colorectal cancer patients enrolled in the study showed statistically significant improvements from baseline to final readings in LASA energy, activity, and overall QOL and FACT-An Anemia Symptoms and Fatigue subscale scores (P < 0.02). Moreover, patients who achieved larger improvements in Hgb levels also demonstrated greater percentage improvements in QOL over baseline measurements. Mean Hgb levels increased by 1.2 g/dL after 4 weeks of treatment and by 1.6 g/dL by study end, independent of red blood cell transfusion within 28 days prior to the Hgb assessment. Hematopoietic response (Hgb level > or = 12 g/dL and/or increase in Hgb level > or = 2 g/dL, independent of transfusion) was observed in 61% of patients (139/229). Additionally, the proportion of patients receiving transfusions decreased from 17% at baseline to 4% during the final month of therapy. Epoetin alfa was well tolerated, with no evidence of unexpected adverse events. Except for significantly higher QOL scores at baseline, results for the cohort of colorectal cancer patients were similar to those for patients with other cancer types in the main study population.

Topics: Adenocarcinoma; Adult; Anemia; Antineoplastic Agents; Clinical Trials as Topic; Colorectal Neoplasms; Epoetin Alfa; Erythropoietin; Fatigue; Hemoglobins; Humans; Quality of Life; Recombinant Proteins; Retrospective Studies

Consorcial projects focused on 5 cancer types, breast-, colorectal-, head and neck- and pediatric cancers, and malignant melanoma. Breast cancer studies revealed unique splicing mechanisms concerning BRCA1. In sporadic breast cancers the involvement of DNA-repair genes was proved to be dependent on the histological type. Bone-metastatic tumors have been characterized by decreased NM23 and increased c-met and p53 expressions. C-erbB2 genotype of the primary tumor was not maintained frequently in bone metastases. Application of DNA-microarray and quantitative PCR technologies improved the prediction of therapeutic sensitivity of breast cancers. Colorectal cancer studies revealed regional inhomogenities (clusters) in various geographical regions of Hungary, which were distinct in the case of colonic and rectal cancers. To increase the sensitivity of fecal blood test of colorectal cancer screening, a new double-antibody test was developed and tested in a large cohort of patients. Genetic analysis revealed that hypermethylation is a significant factor in microsatellite instability which, and plays a role in silencing of APC and E-cadherin genes as well. The Hungarian pattern of TS polymorphism was also determined and was correlated not only with the efficacy of 5-FU treatment but with the progression of the disease as well. Population-based studies have been carried out in head and neck cancer patients (HNC) and smokers as well to reveal the genetic background of increasing tumor incidence. These studies revealed polymorphism in XRCC1/3 methylation enzyme gene which has preventive role. Other studies found frequent local immunosuppression in HNC patients. Studies indicated that the success of irradiation in this cancer type is dependent on the anti-vascular effects. Pediatric cancer studies determined the parameters of neuroblastoma screening based on VMA measurements. New splice variants of the WT1 gene involved in the monitoring of MRD of ALL patients was also described this year. We also obtained positive experimental data for the retinoic acid therapy of ALL. Melanoma studies extensively used DNA-microarray technology which identified 4 melanoma-specific and 2 melanoma progression-specific genes. In experimental human melanoma xenograft models we have identified 3 anti-metastatic agents: low molecular weight heparin, 2-methoxyestradiol and erythropoietin-alpha, where the later was characterized by specific effects on tumor vasculature.

Topics: 2-Methoxyestradiol; Adult; Animals; Antineoplastic Agents; Biomarkers, Tumor; Biomedical Research; Bone Neoplasms; Breast Neoplasms; Child; Colorectal Neoplasms; Disease Models, Animal; Disease Progression; DNA Methylation; Epoetin Alfa; Erythropoietin; Estradiol; Female; Gene Expression Regulation, Neoplastic; Gene Silencing; Genetic Markers; Head and Neck Neoplasms; Heparin, Low-Molecular-Weight; Humans; Hungary; Incidence; Male; Melanoma; Microsatellite Repeats; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Polymorphism, Genetic; Predictive Value of Tests; Recombinant Proteins; Transplantation, Heterologous