losartan-potassium and Lung-Neoplasms

Anemia is fairly common in lung neoplasms and adequate management can influence both the prognosis and the quality of life of patients. Anemia can stem from diverse mechanisms, and its management must include the search for correctable causes (iron deficiency, inflammation, disease- or treatment-related), and their subsequent treatment. Use of erythropoiesis stimulating agents, namely recombinant erythropoietin, results in hemoglobin increase, fewer blood transfusions, and better quality of life. However, there is also a significant increase in thromboembolic risk associated with this treatment, and their effect on overall survival is still debated. Thus, their use must be restricted to patients treated with palliative intent, receiving chemotherapy but no radiotherapy, with a baseline hemoglobin level under 100 g/L, and target hemoglobin level must not exceed 120 g/L.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Erythropoietin; Hematinics; Humans; Lung Neoplasms; Practice Guidelines as Topic

Anemia is common among patients with malignant tumors, due to the disease and chemotherapy. Active oncotherapy, combination chemotherapy of lung cancer is accompanied with many side effects which may impair the patient's quality of life and compromise the effectiveness of chemotherapy, the most frequent one of them being chemotherapy-induced anemia. Anemia decreases not only the patient's quality of life, but also worsens the dose-intensity of chemotherapy. One of the potential treatments of chemotherapy-induced anemia is erythropoietin-stimulating agents (ESAs) for the appropriate indications. Several national and international studies have shown that ESA therapy effectively increases hemoglobin level. However, more recently, contradictory results were published on ESA treatment in terms of survival and tumor progression. The reason for this may be that the tumor cells and endothelial cells may as well express erythropoietin receptor, the role of which has not yet been fully elucidated in tumor progression.. Daganatos betegek körében gyakori szövõdmény az anémia, amelyet maga a betegség vagy az onkológiai kezelés okozhat. A tüdõrák kezelése során az aktív kombinált kemoterápia mellett számos, a beteg életminõségét és az onkoterápia sikerességét rontó mellékhatással kell számolni, ezek közül az egyik leggyakoribb a kemoterápia indukálta anémia. A vérszegénység nemcsak a betegek életminõségét rontja, hanem a citotoxikus kezelés dóziscsökkentéséhez, illetve késleltetéséhez vezethet. A kemoterápia indukálta anémia kezelésének egyik lehetséges útja, az eritropoetin-stimuláló szerek (ESA) használata a megfelelõ indikációval. Számos nemzetközi és hazai tanulmány bizonyította, hogy az ESA-kezelés hatékonyan emeli a hemoglobinszintet. Az utóbbi idõben azonban ellentmondásos eredményeket olvashattunk az ESA-kezelésrõl a túlélés és a daganat progressziója tekintetében. Ennek a hátterében az állhat, hogy a tumorsejtek és az endothelsejtek is kifejezhetnek eritropoetinreceptort, amelynek a szerepe még nem teljesen tisztázott a daganatok progressziójában.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Disease Progression; Endothelial Cells; Erythrocyte Transfusion; Erythropoietin; Hematinics; Hemoglobins; Humans; Hypertension; Lung Neoplasms; Quality of Life; Receptors, Erythropoietin; Severity of Illness Index; Venous Thromboembolism

Complex intracellular signalling networks integrate extracellular signals and convert them into cellular responses. In cancer cells, the tightly regulated and fine-tuned dynamics of information processing in signalling networks is altered, leading to uncontrolled cell proliferation, survival and migration. Systems biology combines mathematical modelling with comprehensive, quantitative, time-resolved data and is most advanced in addressing dynamic properties of intracellular signalling networks. Here, we introduce different modelling approaches and their application to medical systems biology, focusing on the identifiability of parameters in ordinary differential equation models and their importance in network modelling to predict cellular decisions. Two related examples are given, which include processing of ligand-encoded information and dual feedback regulation in erythropoietin (Epo) receptor signalling. Finally, we review the current understanding of how systems biology could foster the development of new treatment strategies in the context of lung cancer and anaemia.

Topics: Anemia; Antineoplastic Agents; Cell Survival; Cytokines; Erythropoietin; Forecasting; Humans; Likelihood Functions; Lung Neoplasms; Mathematics; Models, Biological; Receptors, Erythropoietin; Recombinant Proteins; Risk Factors; Signal Transduction; Systems Biology; Transcription Factors

Topics: Anemia, Hypochromic; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Small Cell; Clinical Protocols; Darbepoetin alfa; Data Interpretation, Statistical; Erythropoietin; Female; Filgrastim; Follow-Up Studies; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Granulocytes; Hematinics; Hematologic Neoplasms; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulins, Intravenous; Lung Neoplasms; Lymphoma; Lymphoma, Non-Hodgkin; Male; Multicenter Studies as Topic; Neoplasms; Neutropenia; Platelet Aggregation Inhibitors; Polycythemia Vera; Polyethylene Glycols; Randomized Controlled Trials as Topic; Recombinant Proteins; Research Design; Survival Analysis; Thrombocythemia, Essential; Treatment Outcome

Erythopoietin (EPO) treatment of anemia during cancer has dramatically improved the tolerance of chemotherapy and quality of life of patients at all stages of the disease. Several surveys have demonstrated a high prevalence and a high incidence of anemia in lung cancer patients. The guidelines updates concerning EPO treatment for these patients are described. They take into account the debate concerning the potential harm of these molecules on the neoplastic disease and the possible role of EPO receptors expressed by several tumors, including non small cell lung cancer.

Topics: Anemia; Antineoplastic Agents; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Humans; Lung Neoplasms; Practice Guidelines as Topic; Quality of Life; Recombinant Proteins; Risk Factors

Lung cancer is a bad prognostic illness with a limited survival and many side effects related to treatment used. Supportive care in cancer attends to enhance patient care among cancer and treatments suffering. Opioids are one of the most important treatments in the management of dyspnoea and pain. Every new drug in supportive care is tested to diminish side effects of treatment like erythropoietin against anemia or aprepitant against emesis. Many trials are developed to enhance this supportive care especially in lung cancer management.

Topics: Algorithms; Analgesics, Opioid; Angiogenesis Inhibitors; Antiemetics; Antineoplastic Agents; Aprepitant; Carcinoma, Bronchogenic; Dyspnea; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Lung Neoplasms; Morphine; Morpholines; Pain; Palliative Care; Prognosis; Recombinant Proteins

Anemia is highly prevalent in patients with lung cancer, often occurring at baseline and frequently exacerbated as a result of treatment with platinum-based chemotherapy. Anemia has been shown to have a negative effect on quality of life in patients with lung cancer, and additional data indicate that decreases in hemoglobin in these patients are associated with impaired survival. Multiple clinical studies have demonstrated that treatment of anemia with erythropoietic agents in patients with lung cancer results in a significant increase in hemoglobin, decrease in transfusions, and improvement in quality of life. Ongoing research is evaluating whether erythropoietic therapy can reduce cognitive impairment associated with lung cancer, cytotoxic therapy, and anemia. Despite the known adverse effects of anemia and the established benefits of erythropoietic therapy in anemic patients with lung cancer, more than half of these patients do not receive any anemia treatment. The purpose of this review is to report results of the European Cancer Anaemia Survey that describe the prevalence of anemia in patients with lung cancer, to review the major studies evaluating the clinical outcomes of erythropoietic therapy in patients with lung cancer, to discuss the recent safety concerns regarding the use of erythropoietic agents in patients with cancer treated to high hemoglobin levels, and to describe various novel therapeutic applications of erythropoietic agents in lung cancer.

Topics: Anemia; Antineoplastic Agents; Cognition Disorders; Erythropoietin; Humans; Lung Neoplasms; Quality of Life; Survival Rate

Anemia and fatigue are frequent in lung cancer patients. Anemia is due to cancer and platinum-based chemotherapy. Anemia leads to a wide range of symptoms and affects health-related quality of life. Anemia also worsens outcome of therapy and prognosis. Efficient treatment exist: blood transfusion and recombinant erythropoietin. Early treatment of anemia is recommended as soon as diagnosis is made. But few patients receive optimal treatment. Its cost and unsolved question regarding therapeutic strategies may explain this phenomenon. This debate should not preclude correct treatment prescription. Clinical trials have to be preformed to clarify unsolved questions. As EPO administration can affect survival, this point should be of particular interest in future trials.

Topics: Anemia; Antineoplastic Agents; Blood Transfusion; Erythropoietin; Fatigue; Hemoglobin A; Humans; Lung Neoplasms; Prognosis; Recombinant Proteins

The purpose was to conduct an integrated analysis of the cumulative hematologic toxicity of topotecan in patients with relapsed ovarian cancer and small cell lung cancer (SCLC). Data were pooled from eight phase II and phase III clinical studies performed in patients with relapsed stage III/IV ovarian cancer or extensive SCLC treated with topotecan at a dose of 1.5 mg/m(2) per day on days 1-5 of a 21-day course. Quantitative hematologic toxicities were assessed using the National Cancer Institute Common Toxicity Criteria. A total of 4,124 courses of therapy was administered to the 879 patients in the pooled population. Grade 4 neutropenia was experienced by 78% of patients. The lowest nadirs for neutrophils and platelets generally occurred after the first course of therapy, followed by improvement or stabilization in subsequent courses. Neutropenia was noncumulative. During the first course, significant risk factors were identified: renal impairment and advanced age (grade 3/4 thrombocytopenia and grade 4 neutropenia) and prior radiotherapy; performance status score > or =2; SCLC; and exposure to both cisplatin (Platinol; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) and carboplatin (Paraplatin; Bristol-Myers Squibb) (grade 3/4 thrombocytopenia only). The most frequent interventions for hematologic toxicities were RBC transfusions, treatment delays, G-CSF support, and dose reductions. Analysis of neutrophil and platelet nadirs and dosing for each course of therapy showed no apparent evidence of cumulative neutropenia or thrombocytopenia. The risk of grade 3 or 4 anemia was higher during the first four courses of therapy and may need to be more aggressively managed with erythropoietin therapy.

Topics: Antineoplastic Agents; Bone Marrow; Carcinoma, Small Cell; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neutropenia; Ovarian Neoplasms; Topotecan

Despite therapeutic improvements and ongoing efforts to develop more efficacious therapies, the majority of lung cancer patients face a poor prognosis. Therefore, the primary goal of current treatment is palliation, improvement and maintenance of quality of life (QOL), and (modest) prolongation of survival. Anemia frequently occurs in lung cancer patients and has been associated with decreased QOL, impaired treatment outcomes, and shortened survival time. Furthermore, anemia is a causative factor of tumor hypoxia, which compromises the efficacy of chemotherapy and radiotherapy. Thus, correction of even mild anemia seems to have a beneficial effect on QOL and cancer treatment outcomes. The current article describes the basis and mechanism for the use of recombinant human erythropoietin (rHuEPO, epoetin alfa), a molecular targeted therapy, for the treatment of cancer-related anemia, with a focus on lung cancer. Epoetin alfa has proven efficacy and safety in correcting anemia and improving QOL based on numerous clinical studies and over a decade of clinical practice. In addition, emerging data show that epoetin alfa may offer potential benefits beyond treating anemia, specifically in terms of treatment outcomes and cognitive function. Future research needs to be conducted to explore the potential for epoetin alfa to improve survival time in lung cancer patients.

Topics: Anemia; Clinical Trials as Topic; Cognition; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Lung Neoplasms; Palliative Care; Quality of Life; Recombinant Proteins; Survival Analysis; Treatment Outcome

Anemia has a high prevalence in patients with lung cancer. Its frequency and severity depend on tumor stage, duration of disease, and previous and current treatment. Anemia affects the health-related quality of life and impacts prognosis and outcome of therapy. Despite this clinical relevance, anemia is often underrecognized and undertreated. Treatment options include the administration of hematopoietic growth factors and red blood cell transfusions. Blood transfusions result in rapid but often transient improvement of anemia. Administration of epoetin or darbepoetin alfa increases hemoglobin levels, decreases blood transfusions, and improves quality of life in patients with lung cancer. Trials determining the exact association of anemia with response to chemotherapy/radiation therapy and survival are ongoing. Oncologists must be aware of the clinical relevance of anemia and offer adequate treatment options to their patients.

Topics: Anemia; Erythrocyte Transfusion; Erythropoietin; Health Status; Humans; Lung Neoplasms; Prognosis; Quality of Life; Treatment Outcome

Anemia is common in patients with lung carcinoma, particularly among those undergoing platinum-based cytotoxic chemotherapy. Evidence is growing that anemia can have a profound impact on the patient's quality of life, often manifested as the patient's inability to function normally.. A literature review was conducted to provide a current picture of the incidence and impact of anemia in patients with lung carcinoma and the usage and limitations of current treatment.. The incidence of anemia (a hemoglobin [Hb] level < 11g/dL) in lung carcinoma patients is approximately 50-60%, varying according to treatment regimen. However, despite evidence supporting the treatment of anemia, many clinicians only intervene when Hb levels fall below 8 g/dL. This may be because of a lack of awareness of the incidence and impact of anemia on cancer patients, but most likely is because of limitations of current treatment options (blood transfusion and recombinant human erythropoietin [epoetin-alpha]). Darbepoetin-alpha represents a new generation of erythropoiesis-stimulating proteins. Biochemically distinct from epoetin-alpha, darbepoetin-alpha has a greater sialic acid content and biologic half-life than epoetin-alpha, but stimulates erythropoiesis in the same manner. Clinical trials involving patients with cancer-related anemia have shown that darbepoetin-alpha has a threefold longer half-life than epoetin-alpha, which may allow less frequent dosing. The results from an ongoing clinical trial dedicated to testing the clinical benefits of darbepoetin-alpha in treating anemia in lung carcinoma patients will provide a valuable insight into its full potential in this setting.. Anemia is common but is reported to be undertreated in patients with lung carcinoma. The introduction of darbepoetin-alpha into clinical practice may overcome some of the limitations of current treatments and facilitate improvement in the management of cancer-related anemia.

Topics: Anemia; Blood Transfusion; Darbepoetin alfa; Erythropoietin; Hemoglobins; Humans; Lung Neoplasms; Platinum Compounds; Quality of Life

Topics: Anemia; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Erythropoietin; Forecasting; Humans; Lung Neoplasms; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Recombinant Proteins

Recent meta-analysis of patients with small cell lung cancer has confirmed the effectiveness of prophylactic cranial irradiation in reducing the cumulative incidence of brain metastases and contributing to a significant increase in 3-year survival. Likewise, with increased median survivals being documented in patients with stage IIIA/B non-small cell lung cancer, there is evidence that the brain is emerging as a significant metastatic target site. Although prophylactic cranial irradiation is a reasonable option to explore, the potential for long-term neuropsychologic adverse effects is of concern in both diagnostic groups. Radiation-induced reactive oxygen intermediates and reactive nitrogen intermediates appear to play a major role in mediating this toxicity. Hypoxic stress results in a significant increase in erythropoietin (EPO) mRNA in mouse brain and, in two models, the administration of EPO improves performance function and prevents cognitive impairment. With the demonstration of EPO receptors in astrocytes, neurons, and brain capillary endothelial cells as well as the ability of EPO to cross the blood-brain barrier, a potential for EPO-mediated central nervous system radioprotection is postulated. The rationale and preliminary design for a phase III study of EPO as a neurocognitive protectant in patients with lung cancer receiving prophylactic cranial irradiation is presented.

Topics: Animals; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cell Hypoxia; Clinical Trials, Phase III as Topic; Cognition; Cranial Irradiation; Cytoprotection; Drug Evaluation, Preclinical; Erythropoietin; Humans; Lung Neoplasms; Neuroprotective Agents; Reactive Nitrogen Species; Reactive Oxygen Species; Signal Transduction

Darbepoietin-alpha is a novel erythropoiesis-stimulating protein that may help address some of the unmet needs of anemia treatment in patients with cancer. Compared with recombinant human erythropoietin, darbepoietin-alpha has increased sialylated carbohydrate content, associated with a prolonged serum half-life and increased in vivo biologic activity. Data from trials in patients with cancer with a range of tumor types, whether receiving chemotherapy or not, indicate that darbepoietin-alpha is effective in alleviating anemia when dosed at intervals of once every 1, 2, or 3 weeks and may effect greater and more rapid responses than recombinant human erythropoietin. Health-related quality of life benefits have been observed with darbepoietin-alpha treatment, and in a study of patients with small-cell lung cancer, darbepoietin-alpha was associated with increased progression-free survival. Administration of darbepoietin-alpha at extended dosing intervals offers the possibility of enhanced patient convenience and compliance and a reduced burden on healthcare resources. Confirmation of improved response and response times with this novel therapy may enable patients with cancer to benefit more rapidly.

Topics: Carcinoma, Small Cell; Darbepoetin alfa; Disease-Free Survival; Erythropoiesis; Erythropoietin; Humans; Lung Neoplasms; Neoplasms

Cancer-related causes of anaemia include anaemia of chronic disorders, infections, autoimmune haemolysis associated with malignant conditions, bone marrow invasion by the tumour or clonogenic marrow dysfunction, iron, folate, or vitamin B 12 deficiency and bleeding from tumour erosion. Treatment-related anaemia results from chemotherapy, radiotherapy and bone marrow fibrosis. Severe anaemia increases the burden of treatment, contributes to fatigue, reduces the quality of life and may also delay or limit further treatment. Blood transfusion is currently the most common form of treatment and patients rarely require transfusion unless the haemoglobin is less than 8 g/l. It is often difficult to predict which patients will develop anaemia and require treatment, but the proportion of patients receiving transfusions increases markedly if the pre-treatment haemoglobin concentration is below 10 g/dl. Four studies have systematically evaluated the effects of erythropoietin on anaemia in lung cancer patients and each of these trials is likely to contribute information concerning the clinical benefit of erythropoietin in treating or preventing treatment-related or disease-related anaemia. Most of the improvements in quality of life observed with erythropoietin administration occurred with haemoglobin levels between 10 and 12 g/dl, and not with levels between 7 and 10 g/dl, with a plateau effect above 12 g/dl. Consequently, a 'functional' level of haemoglobin that appears to be more important is 12 g/dl, because it may be favourably associated with a significant improvement in fatigue compared with lower haemoglobin levels. This 'functional' level would be in keeping with the body's physiological erythropoietin response.

Topics: Anemia; Animals; Erythropoietin; Hematinics; Hematopoiesis; Humans; Lung Neoplasms; Quality of Life; Recombinant Proteins

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

Main mechanisms involved in the development of chemotherapy-induced anemia are the direct bone marrow damage and the renal impairment with a secondary deficient production of erythropoietin. The first mechanism is induced by almost all cytotoxic drugs whilst the second one has been demonstrated with cisplatin treatment. NSCLC patients are generally treated with platinum-based chemotherapy and then both mechanisms are involved in the development of anemia which can be, as a consequence, more frequent and more severe compared to other cancer patients. Chemotherapy regimens such as MVP (mitomycin, vindesine, platin), cisplatin-etoposide and cisplatin-teniposide induce grade > or = 2 anemia in 64%, 46% and 83% of patients, respectively, with grade 3-4 anemia occurring in 29%, 15% and 24% of patients. New chemotherapy regimens are also associated with a high incidence of anemia. Carboplatin-paclitaxel induces grade 3-4 anemia in 34% of patients and 30% of patients need blood transfusions. Similarly, 33% of patients treated with cisplatin-gemcitabine require blood transfusions. Erythropoietin is able to correct anemia in nearly 60%-80% of patients receiving platinum-based chemotherapy and in nearly 40% of patients treated with regimens without platinum compounds, leading to a reduction in blood transfusion requirement. Moreover, erythropoietin is able to prevent anemia development in cancer patients. Due to the high incidence of anemia, erythropoietin may represent an important tool in the supportive care of NSCLC patients. Erythropoietin use is mainly limited by the economic cost and then efforts should be made to identify the subset of patients in whom this supportive therapy is cost-effective. Patient and disease characteristics, factors predicting the probability to be transfused as well as factors predicting the response to erythropoietin can be useful in selecting patients likely to benefit from erythropoietin therapy.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Carcinoma, Non-Small-Cell Lung; Erythropoietin; Humans; Lung Neoplasms

Recombinant human erythropoietin (rHuEPO) improves chronic anemia of cancer, but the proportion of patients who respond favorably to the treatment varies depending on the type of neoplasia. Preliminary data of the two malignancies with the highest response rates, namely, multiple myeloma and squamous cell carcinoma, are reported. Twenty patients with multiple myeloma and 14 with squamous cell carcinoma, who had presented with hemoglobin levels < 11 g/dl, were treated with rHuEPO, 150 U/kg, three times/week. Response, defined as an increase of at least 2 g/dl hemoglobin within 12 weeks, was achieved by 15 myeloma patients (75%) and 11 patients with squamous cell carcinoma (79%). Tolerance of the treatment was excellent. The WHO performance status and quality of life improved in responders. The remarkably low levels of endogenous EPO in our patients with squamous cell carcinoma, most of whom had been treated with cisplatin-or carboplatin-containing regimens, suggest that anemia in these cases had been at least partly chemotherapy induced. In myeloma patients, the blunted EPO response to the anemic condition may have been partly caused by subclinical tubular insufficiency induced by toxic paraproteins. Future studies should aim to elucidate factors which are responsible for the inability of some patients to respond to rHuEPO treatment, even though in multiple myeloma and squamous cell carcinoma these non-responders are a small minority.

Topics: Anemia; Carcinoma, Squamous Cell; Erythropoietin; Esophageal Neoplasms; Head and Neck Neoplasms; Humans; Iron; Lung Neoplasms; Multiple Myeloma; Recombinant Proteins

Topics: Erythropoietin; Forecasting; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Lung Neoplasms

Tansplantability, growth, morphology, and function of xenotransplanted human tumors, such as carcinomas of the lung, liver, breast, choriocarcinoma, and blastomas of the liver, lung, kidney, and uterus, are described. From the tumor take rate, it is clear that xenotransplantation cannot be used for the study of every human tumor: slow-growing tumors are difficult to analyze, and functioning adenomas and low-grade malignant carcinomas are at present almost impossible to study by this approach. From the authors' transplantation experience, tumor antigenicity to nude mice with no T-cell function, either tumor specific or species specific, was suspected. Therefore, the growth in nude mice may not equate to that in the human body. The stroma of the transplanted tumor, which is most likely of mouse origin, might also alter the growth rate, as it did the histology of some tumors. Another possible hindrance that has not been described in the text is the mouse endogenous virus. Serially transplanted human tumors are often infected with C particles, which could well influence the tumor growth and character. In spite of the presence of some factors unfavorable for the study of human tumors through xenotransplantation, it has, nevertheless, been clearly shown that the nude mouse/human tumor system is a very useful tool for functional analysis of tumors in relation to growth, differentiation, and morphology, such as eutopic or ectopic production of various hormones, AFP, normal serum proteins, colony-stimulating factor, erythropoietin, and so on. This system can be employed to elucidate the production of many other biologically active and inactive substances by a variety of tumors and their effects on the host in the future and should provide better understanding of human cancers. Attempts to induce differentiation and to change the biologic behavior of xenotransplanted human malignant tumors have failed so far, except for induced dormancy of breast carcinoma under unfavorable hormonal conditions. This line of investigation may have particular import on cancer research, particularly in relation to the biology and treatment of human cancers.

Topics: alpha-Fetoproteins; Animals; Blood Proteins; Breast Neoplasms; Carcinoma; Carcinoma, Adenoid Cystic; Cell Division; Choriocarcinoma; Erythropoietin; Female; Graft Survival; Hormones, Ectopic; Humans; Kidney Neoplasms; Liver Neoplasms; Liver Neoplasms, Experimental; Lung Neoplasms; Male; Mesenchymoma; Mice; Mice, Nude; Middle Aged; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Neoplasms, Hormone-Dependent; Pregnancy; Transplantation, Heterologous

Topics: Adenocarcinoma; Adrenocorticotropic Hormone; Arginine; Biliary Tract Diseases; Bronchial Neoplasms; Carcinoma; Chorionic Gonadotropin; Colonic Neoplasms; Cushing Syndrome; Erythropoietin; Female; Follicle Stimulating Hormone; Growth Hormone; Gynecomastia; Hormones, Ectopic; Humans; Hypercalcemia; Lactation Disorders; Lung Neoplasms; Luteinizing Hormone; Models, Biological; Neoplasms; Paraganglioma; Paraneoplastic Endocrine Syndromes; Polycythemia; Pregnancy; Prolactin; Thyroid Neoplasms; Vasopressins

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Brain Neoplasms; Carcinoma; Carcinoma, Bronchogenic; Carcinoma, Hepatocellular; Carcinoma, Squamous Cell; Cerebellar Neoplasms; Child; Child, Preschool; Choriocarcinoma; Cushing Syndrome; Diagnosis, Differential; Erythropoietin; Female; Gonadotropins; Hemangiosarcoma; Hormones, Ectopic; Humans; Hypercalcemia; Hypoglycemia; Infant; Infant, Newborn; Insulin; Insulin Secretion; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Male; Neoplasms; Parathyroid Hormone; Pheochromocytoma; Polycythemia; Pregnancy; Teratoma; Testicular Neoplasms; Thymus Neoplasms

Topics: Adrenocorticotropic Hormone; Calcitonin; Chorionic Gonadotropin; Endocrine System Diseases; Erythropoietin; Gastrins; Hormones, Ectopic; Humans; Insulin; Lung Neoplasms; Neoplasms; Serotonin; Thyrotropin; Vasopressins

This study evaluated noninferiority of darbepoetin alfa versus placebo for overall survival (OS) and progression-free survival (PFS) in anemic patients with NSCLC treated to a 12.0-g/dL hemoglobin (Hb) ceiling.. Adults with stage IV NSCLC expected to receive two or more cycles of myelosuppressive chemotherapy and Hb less than or equal to 11.0 g/dL were randomized 2:1 to blinded 500 μg darbepoetin alfa or placebo every 3 weeks. The primary endpoint was OS; a stratified Cox proportional hazards model was used to evaluate noninferiority (upper confidence limit for hazard ratio [HR] < 1.15). Secondary endpoints were PFS and incidence of transfusions or Hb less than or equal to 8.0 g/dL from week 5 to end of the efficacy treatment period.. The primary analysis set included 2516 patients: 1680 were randomized to darbepoetin alfa; 836 to placebo. The study was stopped early per independent Data Monitoring Committee recommendation after the primary endpoint was met with no new safety concerns. Darbepoetin alfa was noninferior to placebo for OS (stratified HR = 0.92; 95% confidence interval [CI]: 0.83‒1.01) and PFS (stratified HR = 0.95; 95% CI: 0.87‒1.04). Darbepoetin alfa was superior to placebo for transfusion or Hb less than or equal to 8.0 g/dL from week 5 to end of the efficacy treatment period (stratified odds ratio = 0.70; 95% CI: 0.57‒0.86; p < 0.001). Objective tumor response was similar between the groups (darbepoetin alfa, 36.4%; placebo, 32.6%). Incidence of serious adverse events was 31.1% in both groups. No unexpected adverse events were observed.. Darbepoetin alfa dosed to a 12.0-g/dL Hb ceiling was noninferior to placebo for OS and PFS and significantly reduced odds of transfusion or Hb less than or equal to 8.0 g/dL in anemic patients with NSCLC receiving myelosuppressive chemotherapy.

Topics: Adult; Anemia; Antineoplastic Agents; Darbepoetin alfa; Double-Blind Method; Erythropoietin; Hemoglobins; Humans; Lung Neoplasms; Treatment Outcome

Induction chemotherapy is associated with anemia in non-small cell lung cancer (NSCLC) patients undergoing radiotherapy. This randomized, open-label study compared the effect of sequential radiochemotherapy (RCHT) versus RCHT + epoetin alfa (RCHT + EPO), with respect to 2-year overall survival (OS).. Patients ⩾18 years received sequential RCHT; one arm also received EPO (chemotherapy day 1, when Hb<12 g/dL). Kaplan-Meier analysis with log-rank test, and Cox-regression methods were performed.. Of the 385 patients randomized (RCHT + EPO: n = 195; RCHT: n = 190), 78 (RCTH + EPO: 46 [23.6%]; RCHT: 32 [16.8%]) were anemic at baseline. Two-year OS was higher in RCHT + EPO-treated versus RCHT-treated (28.5% [95% CI: 22.2-35.1%] versus 20.6% [95% CI: 15.1-26.8%] [p = 0.2278]), and requirement for RBC transfusion was lower (24/195 [12.3%] versus 61/190 [32.1%]). In anemic (baseline) patients (post hoc analysis), median survival was shorter in RCTH-treated (212 days) versus RCHT + EPO-treated (343 days) (Hazard ratio = 1.62 [95% CI: 0.99-2.63], p = 0.0525). Adverse events were documented in 72.7% (RCHT + EPO: 75.0%; RCHT: 70.5%) patients, and thrombovascular events (TVEs) in 45 patients (RCHT + EPO: 16.7%; RCHT: 7.9%; p = 0.0099).. A statistically non-significant trend for 2-year OS was observed in a sub-group of EPO-treated NSCLC-patients with baseline anemia, although this trend was not maintained in the overall population with inoperable NSCLC.

Topics: Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Cisplatin; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Prospective Studies; Recombinant Proteins; Vinblastine; Vinorelbine

We retrospectively analyzed hematologic parameters in 22 patients with advanced, nonsquamous, NSCLC undergoing VEGF inhibition on a phase II clinical trial of bevacizumab, carboplatin, and gemcitabine. We also examined TTP in relation to hemoglobin changes. Median hemoglobin increased significantly from a 12.9 g/dL pretreatment to 13.8 g/dL (p =.01) after the second cycle of maintenance bevacizumab until the first off cycle measurement. There was no difference in TTP in patients who achieved a rise in hemoglobin compared with patients who did not (median 238 days vs. 268 days, p =.38.) Maintenance bevacizumab is associated with increased hemoglobin in advanced, nonsquamous, NSCLC patients.

Topics: Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Erythropoietin; Female; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Retrospective Studies; Vascular Endothelial Growth Factor A

Darbepoetin alfa, an erythropoiesis-stimulating agent (ESA), is used in cancer patients as a supportive care for anemia. For small-cell lung cancer (SCLC), several studies have shown that the administration of ESAs does not affect survival but decreases the need for blood transfusions and improves the quality of life (QOL) of patients receiving chemotherapy. The present randomized phase II study assessed the feasibility, efficacy, and safety of the administration of darbepoetin alfa to patients with SCLC receiving dose-dense (every 2 weeks) standard chemotherapy consisting of carboplatin plus etoposide, pegfilgrastim prophylactically. Seventy-four chemotherapy-naive patients with limited or extensive SCLC received combination chemotherapy for 6 cycles, and half of the patients additionally received darbepoetin to achieve a target hemoglobin concentration of 12-13 g/dL. The primary study outcome, progression-free survival, showed no difference between the 2 arms of the study. Among the secondary endpoints, objective response was similar in the presence and absence of darbepoetin (best response rates = 75.0% vs. 77.8%). Likewise, 1-year survival rates were not different between the 2 treatment arms (40.1% vs. 45.9%). There were no significant differences in grade 3/4 toxicities. As expected, the need for blood transfusions differed significantly: 19.4% of patients in the darbepoetin arm received transfusions versus 38.9% in the control arm. Analysis of European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) scales at different time points showed that the darbepoetin group's QOL was significantly better for certain readouts and never significantly worse than that of the control group. Thus, the combination of darbepoetin alfa with dose-dense carboplatin plus etoposide was feasible and well tolerated. Addition of darbepoetin alfa to chemotherapy lowered the need for blood transfusions and did not affect measures of survival and objective response.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Carboplatin; Darbepoetin alfa; Disease-Free Survival; Erythropoietin; Etoposide; Female; Hematinics; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Quality of Life; Small Cell Lung Carcinoma

Erythropoietin-stimulating agents (ESAs) effectively decrease the transfusion requirements of patients with chemotherapy-induced anaemia (CIA). Recent studies indicate that ESAs increase mortality and accelerate tumour progression. The studies also identify a 1.6-fold increased risk of venous thromboembolism. The ESA labelling was thus revised in Europe and the United States in 2008. This is the first randomised, phase III trial evaluating the efficacy and safety of epoetin-β (EPO), an ESA, dosed in accordance with the revised labelling, which specifies that ESAs should be administered to CIA patients with a haemoglobin level of ≤ 10 g dl⁻¹ and that a sustained haemoglobin level of > 12 g dl⁻¹ should be avoided.. A total of 186 CIA patients (8.0 g dl⁻¹ ≤ haemoglobin ≤ 10.0 g dl⁻¹) with lung or gynaecological cancer were randomised to receive EPO 36,000 IU or placebo weekly for 12 weeks.. The proportion of patients receiving transfusions or with haemoglobin < 8.0 g dl⁻¹ between week 5 and the end of the treatment period as the primary end point was significantly lower in the EPO group (n=89) than in the placebo group (n=92; 10.0% vs 56.4%, P < 0.001). The proportion receiving transfusions was significantly lower in the EPO group (4.5% vs 19.6%, P=0.002). Changes in quality of life were not different. No significant differences in adverse events - for example, the incidence of thromboembolic events was 1.1% for each group - or the 1-year overall survival were observed between groups.. Weekly EPO administered according to the revised labelling approved by the European Medicines Agency is effective and well tolerated for CIA treatment. Further investigations are needed on the effect of ESAs on mortality.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Erythropoietin; Female; Genital Neoplasms, Female; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Placebos; Quality of Life; Recombinant Proteins

Continuous erythropoietin receptor activator (CERA; methoxy polyethylene glycol-epoetin beta) is a new erythropoiesis-stimulating agent with a prolonged half-life. The objective of this study was to select a starting dose of CERA for the treatment of anemia in non-small-cell lung cancer (NSCLC) patients.. The study was an open-label randomized phase II trial containing four treatment groups of patients with anemia and stage IIIB or IV NSCLC. The fourth treatment group was a reference group of patients treated with darbepoetin alfa administered at either 6.75 μg/kg s.c. every 3 weeks or 2.25 μg/kg weekly. Due to observed imbalances in death across treatment arms, this study was prematurely terminated.. The primary efficacy parameter of the mean hemoglobin (Hb) change from baseline during weeks 5-13 was +0.03 g/dl, +0.50 g/dl, and -0.02 g/dl in the CERA 6.3, 9, and 12 μg/kg dose groups, respectively, and +0.26 g/dl in the darbepoetin alfa dose group (P value not significant for all three study arms). Eight (21%), 12 (32%), 9 (24%), and 4 (10%) patients in the CERA 6.3, 9, and 12 μg/kg and darbepoetin groups, respectively, died.. In this phase II study in patients with stage IIIB or IV NSCLC receiving chemotherapy, none of the four treatment arms showed an adequate increase in mean Hb level.

Topics: Adenocarcinoma; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Erythropoietin; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Survival Rate; Treatment Outcome

This is the first clinical trial for Japanese to evaluate the dose-response and determine the clinically effective dose of darbepoetin alpha by weekly subcutaneously administration in anemic patients with lung cancer or ovarian cancer receiving chemotherapy.. Eligible patients were required to have anemia (hemoglobin level of 15.0 g/dl (for men) or 14.0 g/dl (for women), and reinstated at 50% of the previous weekly dose when the hemoglobin level decreased to

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Ovarian Neoplasms; Platinum Compounds; Quality of Life

The purpose of the current study was to investigate the role of amifostine and epoetin-alpha in reducing severe toxicities during concurrent chemo-hyperfractionated radiotherapy (CCRT) for limited disease small cell lung cancer (LD-SCLC).. Seventy-six patients with LD-SCLC were enrolled. The treatment schedule was consisted of two 28-day cycles of cisplatin at a dose of 30 mg/m2 (Days 1 and 8) and irinotecan at a dose of 60 mg/m2 (Days 1, 8, and 15) followed by two 21-day cycles of cisplatin at a dose of 60 mg/m2 (Day 1) and etoposide at a dose of 100 mg/m2 (Days 1-3) with concurrent twice-daily thoracic radiotherapy for a total of 45 grays. Patients were randomly assigned at registration to either amifostine at a dose of 500 mg or epoetin-alpha at a dose of 10,000 IU subcutaneously 3 times weekly (n = 36 patients and 40 patients, respectively). Fifteen of 36 patients assigned to the amifostine arm did not receive amifostine because of a lack of supply.. Amifostine treatment was associated with higher febrile neutropenia (P = .003) and grade 2 or 3 nausea (according to the National Cancer Institute Common Toxicity Criteria [version 3.0]) (P = .03). It also demonstrated a trend toward higher grade 4 leukopenia (P = .05). Grade 3 esophagitis was reported in 30% of patients treated with amifostine and 9% of patients treated with epoetin-alpha (P = .059). Epoetin-alpha treatment was associated with less grade 2 or 3 anemia (P = .031) and lower decreases in hemoglobin level during CCRT (P = .016). The median survival times for both treatment arms were comparable (22.6 months in the amifostine arm vs 25.6 months in the epoetin-alpha arm; P = .447).. Although amifostine administered 3 times weekly during CCRT did not significantly reduce severe toxicities, epoetin-alpha was effective in preventing severe anemia during CCRT in patients with LD-SCLC. Other radioprotective strategies to minimize severe toxicities should be investigated.

Topics: Aged; Amifostine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Combined Modality Therapy; Dose Fractionation, Radiation; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Humans; Injections, Subcutaneous; Lung Neoplasms; Male; Middle Aged; Radiation-Protective Agents; Recombinant Proteins; Survival Analysis

We investigated dose-dense docetaxel and cisplatin in patients with measurable non-small cell lung cancer in a randomized phase II study without [A] or with [B] a putative chemoprotective agent, BNP7787.. Chemotherapy-naive patients with stage IIIB (effusion) or IV, performance status 0 to 1, and adequate organ function were eligible. Treatment with docetaxel 75 mg/m followed by cisplatin 75 mg/m over 1 hour day 1 with darbepoetin 200 mug day 1 and pegfilgrastim 6 mg day 2 without/with BNP7787 before cisplatin was repeated every other week for up to 6 cycles. The primary end point was to differentiate between grade >/=2 neurotoxicity rates of 30% on [A] and 10% on [B]. Feasibility was prospectively defined as febrile neutropenia in <10% of patients and /=2 occurred in 32% on [A] and 29% on [B]. The incidence of febrile neutropenia was 4% on [A] and 3% on [B]. Treatment delays occurred in 13% and 20% of patients on [A] and [B], respectively. Completion rates for 3/6 cycles were 84%/51% on [A] and 84%/53% on [B]. Objective response rates were 55% on [A] and 51% on [B]. Median progression-free/overall survival times were 5.5/10.7 on [A] and 6.5/14.1 month on [B].. This dose-dense treatment regimen is active, feasible, and tolerable. Its further investigation in the curative setting in non-small cell lung cancer should be considered. BNP7787 did not result in significant protection from neurotoxicity.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cisplatin; Darbepoetin alfa; Docetaxel; Dose-Response Relationship, Drug; Drug Therapy, Combination; Erythropoietin; Feasibility Studies; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Mesna; Middle Aged; Neoplasm Staging; Neutropenia; Polyethylene Glycols; Prognosis; Recombinant Proteins; Survival Rate; Taxoids

The NeoPrevent study showed that early intervention with epoetin beta could prevent severe anaemia in patients with solid tumours receiving platinum-based chemotherapy. An early intervention strategy may be particularly warranted in patients with lung cancer, as anaemia is very common in these patients and can be severe. The purpose of this study was to examine the efficacy and safety of epoetin beta in the subpopulation of patients with lung cancer included in the NeoPrevent study. Patients were enrolled if baseline haemoglobin (Hb) levels were 1g/dl) plus the proportion whose Hb was maintained at +/-1g/dl of baseline. Quality of life (QoL) was measured using the linear analogue scale assessment. The NeoPrevent study included 255 patients in total, and the results for the 102 patients with lung cancer (non-small-cell lung cancer 64%; small-cell lung cancer 36%) are presented here. The overall anaemia prevention response was 90%, with Hb response in 60% of patients and maintenance of baseline Hb level in 30%. Only 9% of patients required transfusions. QoL improved significantly in patients with Hb response (p<0.01) and was maintained in non-responders (p>or=0.578). Epoetin beta was effective in preventing severe anaemia in lung cancer patients receiving platinum-based chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Disease Progression; Dose-Response Relationship, Drug; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Injections, Subcutaneous; Lung Neoplasms; Male; Middle Aged; Platinum Compounds; Recombinant Proteins; Severity of Illness Index; Time Factors; Treatment Outcome

This study was aimed at investigating the effectiveness and safety of once-weekly epoetin beta for anaemic cancer patients receiving chemotherapy.. A total of 104 patients with a haemoglobin level of /=2.0 g/dL; the haemoglobin response rate. Quality of life (QOL) was assessed using the Functional Assessment of Cancer Therapy-Anaemia (FACT-An) questionnaire.. The haemoglobin response rate was 66.3% among the 98 patients (breast cancer: n = 25; malignant lymphoma: n = 21; ovarian cancer: n = 20; lung cancer: n = 15; other cancers: n = 17) assessable for a haemoglobin response. Thirty-nine patients (39.8%) required a dose escalation to 54 000 IU. At the end of the study, QOL assessable patients (n = 96) showed a mean improvement in the FACT-An total fatigue subscale score (FSS) of 0.3 points from baseline. Patients with a haemoglobin response had a mean change in the total FSS of +3.2, compared with -3.4 for patients without a haemoglobin response. No serious adverse event of epoetin beta was observed.. Epoetin beta administered at an initial dose of 36 000 IU once-weekly was well tolerated, with increased haemoglobin levels and improved QOL in anaemic cancer patients receiving myelosuppressive chemotherapy.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Administration Schedule; Erythrocyte Transfusion; Erythropoietin; Female; Hemoglobins; Humans; Lung Neoplasms; Lymphoma; Male; Middle Aged; Ovarian Neoplasms; Patient Compliance; Quality of Life; Recombinant Proteins

A placebo-controlled, double-blind, randomized, phase III study was conducted in patients with extensive-stage small-cell lung cancer receiving first-line platinum-containing chemotherapy to determine if increasing or maintaining hemoglobin concentration with darbepoetin alpha could increase patient survival.. Darbepoetin alpha (300 microg) or placebo was administered once per week for 4 weeks then every 3 weeks for up to six cycles of chemotherapy (carboplatin plus etoposide or cisplatin plus etoposide) plus 3 weeks after the last dose of chemotherapy. Patients with disease progression were observed until death or until all patients completed their end-of-study visit and 496 deaths had occurred. The two coprimary end points were change in hemoglobin concentration from baseline to the end of the chemotherapy period and overall survival; statistical testing of survival was done if change in hemoglobin was significant at P < .05.. The study enrolled 600 patients. Patients' hemoglobin levels dropped due to the myelosuppressive chemotherapy; however, treatment with darbepoetin alpha maintained hemoglobin levels significantly higher than placebo (P < .001). There was no statistically significant difference in overall survival between the treatment groups (hazard ratio [HR], 0.93; 95% CI, 0.78 to 1.11; P = .431). As expected, darbepoetin alpha was associated with a higher incidence of thromboembolic events (darbepoetin alpha, 9%; placebo, 5%). The transfusion risk was lower in the darbepoetin versus placebo group (HR, 0.40; 95% CI, 0.29 to 0.55).. The results of this study did not demonstrate improved survival after treatment with darbepoetin alpha; however, they reinforce the benefit of erythropoiesis-stimulating agents in reducing transfusions and their neutral impact on survival in patients with chemotherapy-induced anemia.

Topics: Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Small Cell; Cisplatin; Darbepoetin alfa; Double-Blind Method; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Survival Rate

Previous trials have suggested a quality-of-life (QOL) improvement for anemic cancer patients treated with erythropoietin, but few used QOL as the primary outcome. We designed a trial to investigate the effects of epoetin alfa therapy on the QOL of anemic patients with advanced non-small-cell carcinoma of the lung (NSCLC).. A multicenter, randomized, double-blind, placebo-controlled trial was conducted. The proposed sample size was 300 patients. Eligible patients were required to have NSCLC unsuitable for curative therapy and baseline hemoglobin (Hgb) levels less than 121 g/L. Patients were assigned to 12 weekly injections of subcutaneous epoetin alpha or placebo, targeting Hgb levels between 120 and 140 g/L. The primary outcome was the difference in the change in Functional Assessment of Cancer Therapy-Anemia scores between baseline and 12 weeks.. Reports of thrombotic events in other epoetin trials prompted an unplanned safety analysis after 70 patients had been randomly assigned (33 to the active arm and 37 to the placebo arm). This revealed a significant difference in the median survival in favor of the patients on the placebo arm of the trial (63 v 129 days; hazard ratio, 1.84; P = .04). The Steering Committee closed the trial. Patient numbers compromised the interpretation of the QOL analysis, but a positive Hgb response was noted with epoetin alfa treatment.. An unplanned safety analysis suggested decreased overall survival in patients with advanced NSCLC treated with epoetin alfa. Although infrequent, other similar reports highlight the need for ongoing trials evaluating erythropoietin receptor agonists to ensure that overall survival is monitored closely.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Canada; Carcinoma, Non-Small-Cell Lung; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Proportional Hazards Models; Quality of Life; Recombinant Proteins; Thrombosis; Time Factors; Treatment Outcome

The combination of interferon-alpha2a (IFN-alpha2a) and interleukin-2 (IL-2) induces objective responses in patients with metastatic renal cell carcinoma (MRCC). Anaemia is associated with poor cancer control and reduced quality of life. The aim of the study was to investigate response rate and quality of life in patients with MRCC receiving the combination of Erythropoetin, IFN-alpha2a and IL-2.. Patients with MRCC received epoetin beta (150 IU/kg and haemoglobin <130 g/l or 75 IU/kg and haemoglobin >or=130 g/l) three times weekly, from 14 days before and continuing throughout immunotherapy. In weeks 3-6 the patients received IFN-alpha2a 6 x 10(6) IU/m2 and IL-2 4.5 x 10(6) IU/m2 three times weekly on days 1, 3 and 5. The treatment was repeated two times and in the case of success a third cycle was added. The quality of life was assessed with the FACT questionnaire for fatigue, before, during and after therapy.. A total of 21 patients were treated, 19 of whom could be evaluated concerning response, toxicity and quality of life. We observed 1 complete remission, 2 partial remissions, 5 cases of stable disease and 11 with progressive disease. The overall response rate was 16%. Toxicity was mild to moderate; there were no WHO grade III or IV toxicity. The quality of life increased in ten patients, nine of whom exhibited an increase in their haemoglobin during therapy. Five of the nine patients with decreased quality of life also experienced a decrease in their haemoglobin. The correlation of increased haemoglobin and quality of life was significant (p<0.05).. The combination of IFN-alpha2a, IL-2 and epoetin beta resulted in objective remissions with mild to moderate toxicity. The quality of life correlates significantly with increasing haemoglobin.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Follow-Up Studies; Hemoglobinometry; Humans; Injections, Subcutaneous; Interferon alpha-2; Interferon-alpha; Interleukin-2; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Nephrectomy; Quality of Life; Recombinant Proteins

This study evaluated the safety/efficacy of once-weekly (QW) epoetin alfa measured by quality of life (QOL), hemoglobin (Hb), transfusion incidence, tumor response, and survival in patients with chemotherapy-naïve, advanced non-small cell lung cancer (NSCLC).. Stage IIIB/IV NSCLC patients with Hb > or = 11 to < 15 g/dl scheduled for at least 8 weeks of first-line chemotherapy were randomized to subcutaneously receive 40,000 U of epoetin alfa QW at chemotherapy initiation (immediate) or no epoetin alfa unless Hb decreased to < or = 10 g/dl (delayed). The primary efficacy variable was change in QOL for immediate versus delayed intervention. Target accrual was 320 patients.. The study was terminated early because of slow accrual; of 216 patients enrolled, 211 were evaluable for efficacy. Hb was maintained in the immediate group, but it decreased in the delayed group (12.9 versus 11.6 g/dl final values, respectively). Numerically, fewer immediate patients required transfusions versus delayed patients. Mean QOL scores, modestly declining in both groups from baseline to final measurement, were not significantly different between groups. Tumor response and median overall survival were similar between groups. Epoetin alfa was well tolerated, with a similar thrombovascular event rate between groups.. Epoetin alfa in subcutaneous doses of 40,000 U QW, given immediately at chemotherapy initiation for advanced NSCLC, was well tolerated, and it effectively maintained Hb, leading to a reduced transfusion incidence versus delayed epoetin alfa. Overall QOL scores were higher than typical in this population, decreasing slightly during treatment in both groups. Overall survival was similar between groups, with no evidence of a negative effect by early epoetin alfa intervention.

Topics: Aged; Anemia; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Recombinant Proteins; Survival Analysis; Time Factors

Anaemia seriously threatens the quality of life (QOL) in cancer patients receiving chemotherapy. In this article results are presented on the lung cancer population from a Dutch observational study. This study addressed the real-life situation of recombinant human erythropoietin (r-Hu-EPO or epoetin alfa) treatment in anaemic cancer patients receiving chemotherapy, with a focus on efficacy. In total 781 patients were enrolled in the observational study, including 382 patients with lung cancer. At enrolment patients were receiving epoetin alfa treatment and/or patients had a haemoglobin (Hb) level 11.3g/dl) was especially effective for NSCLC patients where it resulted in a stabilization of Hb at baseline level. For SCLC patients this strategy was less effective. Furthermore, early intervention seemed to diminish the need for a blood transfusion, i.e., the higher the Hb at epoetin initiation the more patients did not receive any blood transfusion. Results from this observational study demonstrate that epoetin alfa treatment corrects chemotherapy-related anaemia in both NSCLC as well as SCLC patients. Early epoetin alfa intervention seems advantageous for lung cancer patients both in terms of maintaining adequate Hb levels during che

Topics: Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Carcinoma, Non-Small-Cell Lung; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Netherlands; Quality of Life; Recombinant Proteins

To assess the pharmacokinetic profile and time-course of trough concentrations and hemoglobin levels associated with subcutaneous weekly administration of epoetin beta in lung cancer patients with chemotherapy-induced anemia.. Epoetin beta was subcutaneously administered to 15 anemic lung cancer patients once weekly for 8 weeks at doses of 9000, 18,000 and 36,000 IU. Pharmacokinetic parameters (C(max), AUC(inf) and T(1/2)) were determined after the first single dose administration on a model-independent basis, and the relationship between the dose and these parameters was examined for linearity.. Weekly administration of epoetin beta at 9000, 18,000 and 36,000 IU produced C(max) values of 308 +/- 117 (mean +/- standard deviation), 678 +/- 86.7 and 1316 +/- 766 mIU/ml, and AUC(inf) values of 15,300 +/- 9524, 54,574 +/- 16,265 and 88,501 +/- 55,687 hr mIU/ml, respectively, showing dose-proportional increases. Trough concentrations tended to increase in the presence of severe bone marrow suppression induced by chemotherapy or other factors. Extremely high values were seen in three patients, but there was no apparent trend toward an increase with repeated doses. After 8 weeks' administration at 9000, 18,000 and 36,000 IU, hemoglobin levels were changed by -0.37 +/- 1.26, 2.15 +/- 1.36 and 2.82 +/- 2.17 g/dl, respectively.. Epoetin beta exhibited linear pharmacokinetics when administered to anemic cancer patients at weekly doses of 9000-36,000 IU and did not cause drug accumulation. Hemoglobin levels increased with weekly doses of 18,000 or 36,000 IU.

Topics: Adenocarcinoma; Adult; Aged; Anemia; Antineoplastic Agents; Carcinoma, Large Cell; Carcinoma, Squamous Cell; Drug Administration Schedule; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Recombinant Proteins

To assess the therapeutic activity of accelerated cisplatin and high-dose epirubicin with erythropoietin and G-CSF support as induction therapy for patients with stage IIIa-N2 non-small-cell lung cancer (NSCLC). Patients with stage IIIa-N2 NSCLC were enrolled in a phase II trial. They received cisplatin 60 mg m(-2) and epirubicin 135 mg m(-2) every 2 weeks for three courses combined with erythropoietin and G-CSF. Depending on results of clinical response to induction therapy and restaging, patients were treated with surgery or radiotherapy. In total, 61 patients entered from March 2001 to April 2004. During 169 courses of induction chemotherapy, National Cancer Institute of Canada (NCI-C) grade III/IV leucocytopenia was reported in 35 courses (20.7%), NCI-C grade III/IV thrombocytopenia in 26 courses (15.4%) and NCI-C grade III/IV anaemia in six courses (3.6%). Main cause of cisplatin dose reduction was nephrotoxicity (12 courses). Most patients received three courses. There were no chemotherapy-related deaths. Three patients were not evaluable for clinical response. Twenty-eight patients had a partial response (48.3%, 95% CI: 36-61.1%), 24 stable disease and six progressive disease. After induction therapy, 30 patients underwent surgery; complete resection was achieved in 19 procedures (31.1%). Radical radiotherapy was delivered to 25 patients (41%). Six patients were considered unfit for further treatment. Median survival for all patients was 18 months. Response rate of accelerated cisplatin and high-dose epirubicin as induction chemotherapy for stage IIIa-N2 NSCLC patients is not different from more commonly used cisplatin-based regimen.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Epirubicin; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Lung Neoplasms; Lymphatic Metastasis; Male; Mediastinum; Middle Aged; Pneumonectomy; Survival Analysis

To determine a recommended dose of once-weekly epoetin-beta administration for anemic cancer patients receiving myelosuppressive chemotherapy, we conducted a multicenter, randomized, double-blind trial.. A total of 86 patients with malignant lymphoma or lung cancer who received chemotherapy containing platinum, taxanes or anthracyclines were enrolled in the study. Patients were randomly assigned into groups that received three dose levels of epoetin-beta (9000, 18,000 or 36,000 IU) administered subcutaneously once a week for 12 weeks. The primary endpoint was change in hemoglobin, while the secondary endpoints were quality of life (QOL) assessed by Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire and transfusion requirements.. Among the 69 patients (per protocol set population) assessable for efficacy, hemoglobin level change in the 36,000 IU group was significantly greater than that in the 9000 IU group (1.75 +/- 2.15 versus 0.04 +/- 1.98 g/dl; P = 0.009), and a significant dose-response relationship was observed for the change in hemoglobin level (P = 0.003). Although changes in FACT-An Total Fatigue subscale (Fatigue subscale) scores were similar for the three dosage groups, there was a statistically significant correlation (r = 0.435, P < 0.001) between the change in hemoglobin levels and the change in Fatigue subscale scores. The proportion of transfused patients was significantly smaller in the 36 000 IU group compared with that in the 9000 IU group (P = 0.022, not adjusted for pre-study transfusions). The incidence of adverse events was similar in the three dosage groups.. Once-weekly epoetin-beta 36,000 IU for 12 weeks was well tolerated and significantly increased hemoglobin levels in anemic cancer patients receiving chemotherapy.

Topics: Adult; Aged; Anemia; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Erythrocyte Transfusion; Erythropoietin; Female; Hemoglobins; Humans; Leukopenia; Lung Neoplasms; Lymphoma; Male; Middle Aged; Platinum Compounds; Quality of Life; Recombinant Proteins; Taxoids

To determine whether weekly epoetin alfa could improve hemoglobin (HgB) levels, reduce RBC transfusions, and improve quality of life (QOL) in patients with advanced cancer and with anemia after receiving myelosuppressive chemotherapy.. This double-blind, placebo-controlled study randomly assigned patients to placebo or epoetin alfa (Ortho Biotech, Bridgewater, NJ) 40,000 U subcutaneous weekly for 16 weeks. QOL, HgB, and RBC transfusions were measured pretreatment and monthly.. The study accrued 344 patients; 330 were assessable for efficacy and 305 were assessable for QOL. Placebo-treated patients had a mean increase in HgB of 0.9 g/dL (range, -3.8 to +5.3) compared with 2.8 g/dL (range, -2.2 to +7.5) for epoetin-treated patients (P < .0001). During the study, 31.7% of placebo-treated patients achieved a > or = 2 g/dL HgB increase compared with 72.7% of epoetin-treated patients (P < .0001). The incidence of RBC transfusion for placebo and epoetin treatment arms was 39.6% and 25.3% (P = .005), respectively. The placebo group received 256 units of RBCs compared with 127 units in the epoetin group (P < .0001). The incidence of toxicity in the groups was similar. Changes in the average QOL scores from baseline to the end of the study were similar in the two groups (P = not significant). The HgB responders (irrespective of treatment arm) had a mean change in Functional Assessment of Cancer Therapy (FACT) fatigue score from a baseline of +5.1 compared with -2.1 for the nonresponders (P = .006).. Epoetin alfa significantly improved HgB and reduced transfusions in this patient population. These results support the use of weekly epoetin alfa as an ameliorative agent for cancer-related anemia.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Breast Neoplasms; Double-Blind Method; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Humans; Injections, Subcutaneous; Lung Neoplasms; Male; Middle Aged; Neoplasms; Placebos; Quality of Life; Recombinant Proteins; Treatment Outcome

To determine the effect of darbepoetin alfa (DA) on progression-free survival (PFS) and overall survival (OS) in patients with chemotherapy-induced anemia (CIA).. Two 16-week randomized, double-blind, placebo-controlled phase III studies of weekly DA in anemic patients with lung cancer (n = 314) or lymphoproliferative malignancies (LPMs; n = 344) undergoing chemotherapy were analyzed with prospectively defined long-term PFS and OS end points. Short-term effects of DA on PFS and OS were analyzed by including two additional 16-week dose-finding, double-blind, placebo-controlled studies in anemic patients with multiple tumor types (n = 405) and LPMs (n = 66).. Median follow-up is 15.8 months (lung cancer) and 32.6 months (LPM). Median duration of PFS was comparable between DA and placebo: 5.1 months (95% CI, 4.1 to 6.9 months) versus 4.4 months (95% CI, 3.7 to 5.3 months) for lung cancer and 14.2 months (95% CI, 12.2 to 17.5 months) versus 15.9 months (95% CI, 13.1 to 19.0 months) for LPMs. The estimated hazard ratio (HR) of death related to DA use for lung cancer was 0.77 (95% CI, 0.59 to 1.01) and 1.26 (95% CI, 0.92 to 1.71) for LPMs. In the pooled analyses of all four studies (n = 1,129), no differences in PFS or OS were observed between DA and placebo (HR = 0.92; 95% CI, 0.78 to 1.07; and HR = 0.95; 95% CI, 0.78 to 1.16, respectively).. Treatment with DA does not seem to influence PFS or OS in patients with CIA. Prospective, randomized clinical trials will provide additional insights into the effects of DA on PFS and OS in specific tumor types.

Topics: Anemia; Darbepoetin alfa; Disease Progression; Disease-Free Survival; Double-Blind Method; Erythropoietin; Female; Humans; Lung Neoplasms; Lymphoma; Male; Placebos; Survival Analysis; Treatment Outcome

This randomized, double-blind, placebo-controlled trial (N93-004) evaluated the effects of epoetin alfa on tumor response to chemotherapy and survival in patients with small-cell lung cancer (SCLC).. Adult patients with hemoglobin < or = 14.5 g/dL starting chemotherapy received epoetin alfa 150 U/kg or placebo subcutaneously 3 times weekly until 3 weeks after completion of chemotherapy. Survival was assessed for 3 years. The primary end point was the proportion of patients with complete or partial response after three chemotherapy cycles.. The trial was terminated prematurely after 224 of a projected 400 patients were accrued. Baseline characteristics were similar between groups. Epoetin alfa and placebo patients (n = 109 and n = 115, respectively) had mean baseline hemoglobin of 12.8 g/dL and 13.0 g/dL, respectively. Overall tumor response was similar between the epoetin alfa and placebo groups after three chemotherapy cycles (72% and 67%, respectively; 95% CI of difference, -6% to 18%) and after completion of chemotherapy (60% and 56%, respectively; 95% CI of difference, -9% to 17%). Epoetin alfa and placebo groups had similar median overall survival (10.5 and 10.4 months, respectively) and overall mortality (91.7% and 87.8%, respectively; hazard ratio, 1.172; 95% CI, 0.887 to 1.549; P = .264). Hemoglobin was maintained in the prechemotherapy range in epoetin alfa patients, but decreased substantially in placebo patients. Fewer epoetin alfa patients than placebo patients required transfusion.. These results suggest that in newly diagnosed patients with SCLC epoetin alfa does not affect tumor response to chemotherapy or survival. However, the early trial closure makes these conclusions preliminary.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Lung Neoplasms; Middle Aged; Placebos; Recombinant Proteins; Survival Analysis

Currently, there is some debate concerning the haemoglobin level at which treatment of anaemia with erythropoiesis-stimulating agents should be initiated in cancer patients on chemotherapy. We report several analyses of data from a phase III trial of darbepoetin alfa versus placebo, comparing outcomes for patients with mild and moderate-to-severe anaemia.. Data were obtained from a phase III trial of darbepoetin alfa versus placebo in anaemic patients with lung cancer receiving chemotherapy ( n=314). Outcomes were compared for patients with baseline haemoglobin > or =10-11 g/dl and <10 g/dl.. Darbepoetin alfa significantly reduced transfusions compared with placebo, irrespective of haemoglobin level at treatment initiation. For patients with baseline haemoglobin <10 g/dl, 31% and 59% of those receiving darbepoetin alfa and placebo, respectively, required a transfusion from week 5 to the end of the treatment phase ( P<0.038). For patients with baseline haemoglobin > or =10 g/dl, the proportions were 15% and 41%, respectively ( P<0.001). Darbepoetin alfa also improved fatigue compared with placebo in both haemoglobin categories.. These findings show that initiating treatment at haemoglobin levels both <10 g/dl and > or =10-11 g/dl results in substantial clinical benefits, supporting the use of erythropoietic therapy also in patients with mild anaemia.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Chi-Square Distribution; Darbepoetin alfa; Erythrocyte Transfusion; Erythropoietin; Fatigue; Female; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Placebos; Retrospective Studies; Treatment Outcome

Non-small cell lung cancer (NSCLC) treatment with new drugs in combination with platinum salts induce anemia G1/2 and G3/4 WHO in about 35 and 10-20% of patients, respectively, with a chemotherapy (CT) dose intensity decrease in 20% of cases. Epoetin alfa, administered at standard dosages has been shown to significantly increase hemoglobin (Hb) levels, decrease transfusion requirements, and improve quality-of-life parameters in patients undergoing chemotherapy.. This open-label, non-randomized study was conducted to evaluate the efficacy and safety of an induction dose of epoetin alfa 40.000 IU in lung cancer patients with moderate or severe anemia who were receiving CT.. Twenty-four patients (8 SCLC and 16 NSCLC) were enrolled in the study to receive single subcutaneous (s.c.) injections of epoetin alfa 40.000 IU on days 1, 4, 7, 10, and 13, followed by standard treatment (10.000 IU t.i.w.) for the further 2 weeks. Nine patients had been previously treated with epoetin alfa 10.000 IU t.i.w. Twenty-two patients were receiving first-line CT and two patients were receiving docetaxel as second-line CT.. After 15 days of treatment, in 21 evaluable patients, Hb was 10.5 +/- 1.3 g/dL (mean +/- S.D.), with a mean increase from baseline of 2.0 g/dL (95%CI: 1.3-2.7). Hb increase was > or =2g/dL in 11 patients, 1-1.9 g/dL in 5 patients, and <1g/dL in 5 patients. After 30 days of treatment, Hb was 11.5 +/- 0.8 g/dL (mean +/- S.D.), with a mean increase from baseline of 2.9 g/dL (95%CI: 2.4-3.4) in 20 evaluable patients. No adverse events possibly related to epoetin alfa treatment were observed.. An induction therapy with epoetin alfa 40.000 IU for 2 weeks followed by standard treatment allows an Hb increase of 2.9 g/dL even in advanced lung cancer patients with a moderate/severe anemia, without RBC transfusion requirements. A randomized study of the proposed induction dose of epoetin alfa 40.000 IU is actually ongoing.

Topics: Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Injections, Intravenous; Lung Neoplasms; Male; Middle Aged; Recombinant Proteins; Treatment Outcome

An important clinical question is the relative efficacy of the most common dosages of darbepoetin alfa (Aranesp; Amgen Inc.; Thousand Oaks, CA) 200 microg every 2 weeks (Q2W) and epoetin alfa (Procrit; Ortho Biotech Products, LP; Raritan, NJ) 40,000 U weekly (QW) for the treatment of chemotherapy-induced anemia. We designed three concurrent randomized, open-label, multicenter, identical trials (with the exception of tumor type criteria of breast, gynecologic, or lung cancer) of darbepoetin alfa and epoetin alfa in patients with chemotherapy-induced anemia to validate the Patient Satisfaction Questionnaire for Anemia (PSQ-An) treatment tool and to compare the efficacies and safety profiles of these two agents. In each trial, patients were randomized 1:1 to receive either darbepoetin alfa at a dose of 200 microg Q2W or epoetin alfa at a dose of 40,000 U QW for up to 16 weeks. The PSQ-An was assessed for validity, feasibility, and reliability. Secondary clinical endpoints were analyzed using the primary analysis set. Both individual trial analyses and a protocol-specified combined analysis of data from all three trials were conducted. Overall, 312 patients (157 darbepoetin alfa; 155 epoetin alfa) were randomized and received study drug. Baseline characteristics were similar in both treatment groups in each trial and overall. The PSQ-An was valid, feasible, and reliable. In general, no difference between treatment groups was observed for hemoglobin- and transfusion-based endpoints in each individual trial or in the combined analysis. From exploratory analyses, achievement and maintenance of a hemoglobin target range (11-13 g/dl) were similar in both groups. No differences in safety were observed. With the PSQ-An, formal comparisons of the impact of anemia therapies on patients and caregivers can be made in future prospective studies. Further, darbepoetin alfa (200 microg Q2W) and epoetin alfa (40,000 U QW) appear to achieve comparable clinical and hematologic outcomes.

Topics: Anemia; Antineoplastic Agents; Breast Neoplasms; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Female; Genital Neoplasms, Female; Hematinics; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Prospective Studies; Quality of Life; Recombinant Proteins; Reproducibility of Results; Surveys and Questionnaires

A prospective Phase II trial was carried out to evaluate the effectiveness of erythropoietin in improving or maintaining performance status as determined by the Karnofsky performance status (KPS) score and hemoglobin (Hb) levels in lung cancer patients treated with concurrent chemoradiation (CH-RT).. A total of 51 patients with lung cancer (11 with small-cell, limited stage and 40 with non-small-cell disease, 17 with Stage IIIA and 23 with Stage IIIB), who underwent three different concurrent CH-RT protocols were enrolled. Baseline Hb and KPS values were recorded, as were the nadir Hb and KPS values before concurrent CH-RT. The final Hb and KPS values were recorded the last week of concurrent CH-RT. An Hb level of

Topics: Adult; Aged; Combined Modality Therapy; Erythropoietin; Female; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Prospective Studies; Quality of Life; Recombinant Proteins; Survival Rate

Patients receiving chemotherapy often develop anemia. Darbepoetin alfa (Aranesp(TM)) is an erythropoiesis-stimulating glycoprotein that has been shown, in dose-finding studies, to be safe and clinically active when administered to patients with cancer every 1, 2, or 3 weeks. This phase III study compared the safety and efficacy of darbepoetin alfa with placebo in patients with lung cancer receiving chemotherapy.. In this multicenter, double-blind, placebo-controlled study, 320 anemic patients (hemoglobin or=25% improvement; mean difference = 13%; 95% CI = 2% to 23%, P =.019) than patients receiving placebo. Patients receiving darbepoetin alfa did not appear to have any untoward effect in disease outcome and did not develop antibodies to the drug. Adverse events were similar between the groups.. Patients with chemotherapy-associated anemia can safely and effectively be treated with weekly darbepoetin alfa therapy. Darbepoetin alfa decreased blood transfusion requirements, increased hemoglobin concentration, and decreased fatigue. Although no conclusions can be drawn about survival from this study, the potential salutary effect on disease outcome warrants further investigation in a prospectively designed study.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Darbepoetin alfa; Disease Progression; Double-Blind Method; Erythrocyte Transfusion; Erythropoiesis; Erythropoietin; Fatigue; Female; Humans; Length of Stay; Lung Neoplasms; Male; Middle Aged; Patient Admission; Platinum Compounds; Surveys and Questionnaires; Survival Analysis; Treatment Outcome

Paclitaxel and vinorelbine combination in previous untreated patients with stage IIIb-IV non-small cell lung cancer (NSCLC) as a phase II study.. Thirty-four patients (4 patients with stage IIIb, 30 patients in stage IV), with median age 66 and performance status 0-1, were administered paclitaxel, 175 mg/m(2) in a 3-h infusion rate on day 1 and vinorelbine, 25 mg/m(2) in a 10-min infusion rate on days 1, and 8 with G-CSF and EPO support.. Among our 33 evaluable patients for toxicity 16 patients (48.4%) presented leukopenia and 15 patients (45.4%) presented anemia despite G-CSF and EPO administration. Two patients (6%) presented Grade III-IV peripheral neuropathy. The overall response rate was 67.7%; 5 patients (16.1%) showed complete response (2 patients stage IIIb) and 16 patients (51.6%) showed partial response (1 patient stage IIIb). The overall median survival time was 10 months (range 3-18 months) and the median disease-free survival was 9 months (range 3-15 months) with an 1-year survival time of 45.1% (14 patients).. The results of the combination as 1st line treatment for patients with non-operable NSCLC are promising and should be further investigated.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Infusions, Intravenous; Leukopenia; Lung Neoplasms; Male; Middle Aged; Paclitaxel; Treatment Outcome; Vinblastine; Vinorelbine

The objectives of this study were to assess the safety and efficacy of darbepoetin alfa (Aranesp) administered every 2 weeks in anemic patients with solid tumors receiving chemotherapy. This was an open-label, randomized, active-controlled, multicenter dose-finding study evaluating a range of every-2-week darbepoetin alfa doses. The active control arm received epoetin alfa (Epogen, Procrit) at 40,000 U weekly with a dose increase to 60,000 U weekly for subjects with an inadequate response. The lowest clinically effective doses of darbepoetin alfa in this study were 3.0 and 5.0 microg/kg every 2 weeks, with no additional benefit observed at higher doses. The percentage of patients who achieved a hematopoietic response in the 3.0- and 5.0-microg/kg groups was 66% (95% confidence interval [CI] = 46%-86%) and 84% (95% CI = 67%-100%), respectively, compared with 63% (95% CI = 46%-81%) in the epoetin alfa group. Darbepoetin alfa administered at a dose of 3.0 microg/kg every 2 weeks is safe and effective for treating anemia in patients with solid tumors on chemotherapy, and is comparable to epoetin alfa. A dose increase to 5.0 microg/kg of darbepoetin alfa administered every 2 weeks may be appropriate in patients with an inadequate initial response.

Topics: Anemia; Breast Neoplasms; Darbepoetin alfa; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Gastrointestinal Neoplasms; Genital Neoplasms, Female; Genital Neoplasms, Male; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Recombinant Proteins; Treatment Outcome

Our objective was to evaluate the effects of darbepoetin alfa (Aranesp) on hemoglobin and transfusions in anemic patients with cancer undergoing chemotherapy, and the impact of age, sex, baseline hemoglobin, chemotherapy type, and tumor type. Patients were randomized to one of three darbepoetin alfa groups based on average weekly dose (< 1.5 microg/kg, 1.5 to 2.25 microg/kg, and > 2.25 microg/kg) or to placebo. Dose response was evaluated for change in hemoglobin, hemoglobin and hematopoietic responses, and red blood cell transfusion rates. Hazard ratios for the incidence of hemoglobin response and transfusions were calculated. Adverse events and antibody formation were assessed. Treatment effects were observedfor all hemoglobin end points and incidence of transfusion. The incidence of hematopoietic response among the darbepoetin alfa dose groups ranged from 46% (95% confidence interval [CI] = 33%-60%) to 74% (95% CI = 66%-81%) and increased with higher darbepoetin alfa dose. Patients receiving darbepoetin alfa were more likely to exhibit a hemoglobin response and less likely to require a transfusion, compared with placebo, irrespective of the patient characteristics examined. No increased risk of adverse events and no development of neutralizing antibodies were observed with darbepoetin alfa use. Darbepoetin alfa increased the likelihood of a hemoglobin response and decreased the need for transfusions in cancer patients with chemotherapy-induced anemia.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Double-Blind Method; Drug Administration Schedule; Erythrocyte Transfusion; Erythropoietin; Female; Hemoglobins; Humans; Lung Neoplasms; Lymphoproliferative Disorders; Male; Middle Aged; Platinum; Population Surveillance; Sex Factors; Treatment Outcome

We studied the clinical effect of recombinant human erythropoietin (r-huEPO) on anemia induced by two courses of cisplatin-based chemotherapy in patients with non-small cell lung cancer (NSCLC).. Seventy-two patients with NSCLC were randomized into three groups, receiving 100, or 200 IU/kg of r-huEPO, or placebo. The r-huEPO and placebo were administered subcutaneously three times a week for 6 weeks, starting 2 weeks after the initiation of chemotherapy.. In the 53 evaluable patients, hemoglobin (Hb) levels at the nadir after the second cycle of chemotherapy were significantly elevated compared with the nadir after the first cycle in both r-huEPO treated groups, while this level was decreased in the placebo group. Hb levels at the end of the second course of chemotherapy (week 8) in both r-huEPO groups were higher than that in the placebo groups. No adverse drug reaction attributable to r-huEPO was observed. Serum erythropoietin levels after the administration of r-huEPO were higher than those after placebo administration.. r-huEPO had an effect in preventing anemia in patients with NSCLC who had cisplatin-based chemotherapy.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Carcinoma, Non-Small-Cell Lung; Cisplatin; Double-Blind Method; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Mitomycin; Recombinant Proteins; Treatment Outcome; Vindesine

Anaemia commonly occurs in cancer patients receiving chemotherapy, often necessitating blood transfusion. This multicentre study was designed to evaluate the efficacy and safety of epoetin alpha in preventing the decline in haemoglobin (Hb) level, and to determine whether the transfusion requirement could be reduced, in patients receiving 4-6 cycles of primarily platinum-based combination cyclic chemotherapy for small cell lung cancer (SCLC). A total of 130 non-anaemic SCLC patients were randomized to receive no additional treatment (n = 44), epoetin alpha 150 IU kg(-1) subcutaneously (s.c.) three times a week (n = 42) or 300 IU kg(-1) s.c. three times a week (n = 44). Reductions in epoetin alpha dosage were made during the study if Hb level increased to >15 g dl(-1). The mean weekly dosage was 335 and 612 IU kg(-1), respectively, in the two active treatment groups. Significantly fewer (P < 0.05) epoetin alpha-treated patients experienced anaemia (Hb < 10 g dl(-1)) during the course of chemotherapy (300 IU kg(-1), 39%; 150 IU kg(-1), 48%; untreated, 66%). This was reflected in the significantly lower number of treated patients transfused [300 IU kg(-1), 20% (P< 0.001); 150 IU kg(-1), 45% (P< 0.05); untreated, 59%]. Epoetin alpha was well-tolerated, and there was no evidence of sustained, clinically significant, hypertension. In summary, epoetin alpha is effective and well-tolerated in maintaining Hb level and reducing transfusion requirement in patients undergoing cyclic chemotherapy for SCLC.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Small Cell; Cisplatin; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Quality of Life; Recombinant Proteins

Anemia has been reported to develop during preoperative chemotherapy with paclitaxel and carboplatin. The use of recombinant human erythropoietin (EPO) has been shown to reduce anemia and subsequent packed red blood cell transfusions. The current study is a report of a Phase III, prospective, randomized trial with or without EPO that confirms the original observations of less anemia and fewer transfusions in those patients randomized to receive EPO concurrently with paclitaxel and carboplatin.. Thirty patients with advanced head and neck or lung carcinoma were treated with 2 courses of paclitaxel, 230 mg/m(2), and carboplatin, 7.5 mg/mL/minute, repeated every 21 days. The treatment group was comprised of 15 patients randomized to receive concurrent EPO, 150 U/kg, 3 times per week; in patients deemed nonresponsive the dose was increased to 300 U/kg and 450 U/kg in subsequent courses. The control group was comprised of 15 patients randomized not to receive EPO.. Twenty-seven patients were evaluable. After 2 courses of chemotherapy the mean hemoglobin decrease was 1.2 g/dL in the EPO group versus 2.8 g/dL in the control group (P = 0.037). There was a highly significant decrease in hemoglobin over time in patients who did not receive EPO (P = 0.008). After 4 courses of chemotherapy, fewer patients were transfused in the EPO arm: 2 of 13 (15%) in the EPO treatment group versus 5 of 14 (36%) in the control group.. There was significantly less anemia and transfusions were reduced by 50% in patients randomized to receive EPO during chemotherapy with paclitaxel and carboplatin.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Carboplatin; Erythropoietin; Female; Head and Neck Neoplasms; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Paclitaxel; Prospective Studies

Carboplatin is one of the most common drugs used for radiochemotherapy of cancer. However, the best way to combine the drug with fractionated radiotherapy has not been established. In the present study the authors investigated which maximum tolerated daily bolus dose of carboplatin would allow safe radiopotentiation for 10 consecutive radiotherapy days, the scheme being repeated twice during the 6 weeks that a conventional radiotherapy scheme lasts. Seventy-two patients with lung or pelvis malignancies were included in a dose escalation study. Twenty-four patients comprised the first baseline cohort and were treated with radiotherapy alone. The daily dose of carboplatin was escalated starting from 38 mg/m2 daily (for 10 days) and increasing by 7 mg/m2 per day. Six patients were to be included in each cohort. All 12 patients treated at the 38 mg/m2 and 45 mg/m2 dose level completed two cycles of 10-day carboplatin treatment with no grade III-IV toxicity. Granulocyte colony-stimulating factor effectively averted the incidence of neutropenia and allowed the administration of the second carboplatin 10-day cycle in five of six patients at the 52 mg/m2 daily dose level. Platelet grade III-IV toxicity was observed in all 12 patients (six supported with granulocyte colony-stimulating factor and six with granulocyte colony-stimulating factor and recombinant human erythropoietin) treated at the 59 mg/m2 daily dose level and none of them received the second cycle of chemotherapy. Twelve patients were treated at the same dose level using amifostine 500 mg before carboplatin infusion. Two patients interrupted chemotherapy because of severe nausea and vomiting. Nine of 10 who accomplished the 10-day treatment had platelet levels more than 90,000/microl on day 28 and completed the second 10-day cycle without severe toxicity. Acute radiation toxicity did not increase in the carboplatin cohorts. In this study the authors established a high-dose fractionated carboplatin schedule that can be safely administered during radical radiotherapy.

Topics: Adult; Aged; Amifostine; Antineoplastic Agents; Carboplatin; Combined Modality Therapy; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Lung Neoplasms; Male; Middle Aged; Pelvic Neoplasms; Radiation-Protective Agents; Radiation-Sensitizing Agents; Recombinant Proteins

Recombinant human erythropoietin (r-Hu-EPO) is known to be effective in untreated cancer patients. Here we assess the possibility that r-Hu-EPO may also prevent or reduce anemia in patients who receive cytotoxic chemotherapy.. Thirty-six patients with small-cell lung carcinoma (SCLC) were enrolled onto a three-arm, randomized trial to investigate the effect of r-Hu-EPO on hemoglobin (Hb) levels and RBC and platelet (Plt) transfusions during chemotherapy. Bone marrow progenitors were studied before and after treatment. Two groups of patients received r-Hu-EPO at a dose of either 150 IU/kg (group 150) or 300 IU/kg (group 300) three times per week for the duration of chemotherapy. A control group did not receive r-Hu-EPO (group O). A maximum of six cycles of a chemotherapy regimen that consisted of vincristine, ifosfamide, carboplatin, and etoposide (VICE) were given to all patients. Hematologic parameters were measured weekly, and RBC or Plt transfusions were given for Hb levels less than 9 g/dL and Plt counts less than 20 x 10(9)/L.. Hb levels decreased in all patients, but onset of anemia was delayed in groups that received r-Hu-EPO (P = .002). A total of 116 U RBC were transfused in group 0, 54 in group 150, and 52 in group 300 (P = .017). In addition, there was a nonsignificant trend toward higher Plt counts and fewer Plt transfusions in patients who received r-Hu-EPO.. r-Hu-EPO at a dose of either 150 or 300 IU/kg three times weekly delays the onset of anemia and reduces RBC transfusion requirements in patients who undergo intensive chemotherapy for SCLC. A possible effect of r-Hu-EPO on platelet numbers deserves further study.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Small Cell; Colony-Forming Units Assay; Drug Administration Schedule; Erythrocyte Transfusion; Erythropoietin; Etoposide; Female; Granulocytes; Hemoglobin A; Humans; Ifosfamide; Iron; Leukocyte Count; Lung Neoplasms; Macrophages; Male; Mesna; Middle Aged; Platelet Count; Platelet Transfusion; Recombinant Proteins; Vincristine

Chronic anemia is a common complication in patients with cancer, especially in those with advanced disease or who are under intensive chemotherapy. Because homologous blood transfusions involve some hazards, the safety and efficacy of recombinant human erythropoietin (r-HuEPO) in the treatment of anemic patients with cancer with and without concomitant chemotherapy were studied.. One-hundred two cancer patients with hemoglobin less than 11 g/dl, ferritin greater than 30 micrograms/l, and creatinine < 220 mumol/l were enrolled in the study, 94 were eligible for efficacy evaluation. Sixty-eight patients received chemotherapy (CT group) and 26 had no cytotoxic cancer treatment (NT group). Recombinant human erythropoietin was administered subcutaneously at a dose of 150 U/kg three times per week for 6 weeks; in nonresponders the dose was doubled for the subsequent 6 weeks. Response was defined as the achievement of a hemoglobin increase of 2g/dl. Clinical and laboratory parameters, including serum erythropoietin (EPO) levels, performance status, and quality of life, were investigated at baseline and monitored at regular intervals thereafter.. Response was achieved by 52% and 62% of CT and NT patients, respectively. The highest response rates were observed in patients with lung cancer or with a histology of squamous cell carcinoma (both 80%). In responding patients, the symptoms of anemia subsided. They no longer needed blood transfusions after 4 weeks of therapy; and both their performance status and quality of life improved significantly. The NT patients achieved slightly more favorable results on lower weekly doses: 450 U/kg/week in NT versus 570 U/kg/week in CT patients. Serum EPO levels were higher in nonresponders at baseline and further increased during the course of treatment. Recombinant human erythropoietin was well tolerated by all patients.. This multicenter study in a large patient collective shows that r-HuEPO treatment represents a safe and effective means to increase the red cell mass and eliminate the need for blood transfusions in approximately 50% of the patients with chronic anemia of cancer. Responding patients not only have increased levels of hemoglobin, but their performance status also improves significantly, and they enjoy a significantly enhanced quality of life.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Agents; Blood Transfusion; Carcinoma, Squamous Cell; Chronic Disease; Creatinine; Erythrocyte Volume; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Injections, Subcutaneous; Lung Neoplasms; Male; Middle Aged; Neoplasms; Quality of Life; Recombinant Proteins; Remission Induction

To determine the efficacy and safety of subcutaneous administration of recombinant human erythropoietin (r-HuEPO) at a dose of 200 units/kg/day to cancer patients undergoing radiotherapy.. This is a randomized, open-labeled, Phase II study. Only patients receiving radiotherapy +/- chemotherapy are included. Eligibility is restricted to patients with lung cancer, carcinoma of the uterine cervix, prostatic adenocarcinoma, or adenocarcinoma of the breast. Patients in the control and treatment arms receive radiotherapy with similar policies, and their doses of radiotherapy and treatment volumes are determined by the site and stage of the disease. Patients in the "treatment arm" receive 200 units/kg/day of r-HuEPO, subcutaneously, five times a week with iron (Fe SO4, 325 mg. p.o., t.i.d.) supplements. Complete blood counts are obtained weekly. Quality of life is assessed weekly by the patients themselves by a few simple entries on an analog scale.. Twenty-six patients have been entered in the study so far. Twelve patients were placed in the control arm and 14 in the treatment arm. Pre-randomization demographic and laboratory mean values in both arms were comparable, with none of 16 parameters compared reaching statistical significance. Our results can be summarized as follows: (a) Mean hemoglobin, hematocrit, and red blood cell values increased gradually in the treatment arm patients. Week-by-week comparison showed that mean values for these three parameters were significantly higher in the treatment arm than in the control arm. For example, the p values for the differences in hemoglobin mean values for weeks 1-6 were 0.015, 0.002, 0.003, 0.0002, 0.0006, and 0.007, respectively. Similar trends were observed for red blood cells and the hematocrit values. (b) No significant toxicity has been encountered. (c) No significant differences in the mean values of white blood cells and platelet counts were seen between the two arms. The values of these two parameters declined over the course of radiotherapy. (d) The mean weekly increase in hemoglobin levels in the treatment arm was 0.43 gm/dl.. (a) The safety and efficacy of r-HuEPO, with 200 units/kg/day of subcutaneous administration, have been confirmed in our study group. (b) However, the rate of increase in hemoglobin levels is not very rapid with the doses used. (c) Dose escalation studies are needed for determination of the feasibility of improving hemoglobin levels by about 1 gm/dl/week. (d) The question whether improvement in hemoglobin with r-HuEPO therapy can improve outcome by improving tumor oxygenation needs to be studied in carcinoma of the uterine cervix and squamous cell carcinoma of the head and neck.

Topics: Adenocarcinoma; Anemia; Breast Neoplasms; Combined Modality Therapy; Erythropoietin; Female; Humans; Injections, Subcutaneous; Lung Neoplasms; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms; Recombinant Proteins

Chemoresistance is the crux of clinical treatment failure of small-cell lung cancer (SCLC). Cancer stem cells play a critical role in therapeutic resistance of malignant tumors. Studies have shown that the role of erythropoietin-producing hepatocellular A2 (EphA2) in tumors is complex. This study aimed to test the hypothesis that ligand-independent activation of EphA2 modulates chemoresistance by enhancing stemness in SCLC. We verified that EphA2 was activated in chemoresistance sublines in a ligand-independent manner rather than a ligand-dependent manner. Ligand-independent EphA2 enhanced the expression of stemness-associated biomarkers (CD44, Myc, and SOX2), accelerated epithelial-mesenchymal transition (EMT) and reinforced self-renewal to drive the chemoresistance of SCLC, while the P817H mutant EphA2 neutralized intrinsic function. Co-immunoprecipitation (co-IP) and GST-pull down experiments were conducted to verify that EphA2 directly interacted with PRMT1. Moreover, EphA2 increased the expression and activity of PRMT1. Whereafter, PRMT1 interacted with and methylated SOX2 to induce stemness and chemoresistance in SCLC. Pharmacological inhibition of EphA2 showed a synergistic anti-tumor effect with chemotherapy in preclinical models, including patient-derived xenograft (PDX) models. These findings highlight, for the first time, that the EphA2/PRMT1/SOX2 pathway induces chemoresistance in SCLC by promoting stemness. EphA2 is a potential therapeutic target in SCLC treatment.

Topics: Cell Line, Tumor; Drug Resistance, Neoplasm; Erythropoietin; Humans; Ligands; Lung Neoplasms; Methylation; Protein-Arginine N-Methyltransferases; Repressor Proteins; Small Cell Lung Carcinoma; SOXB1 Transcription Factors

Topics: Age Factors; Antineoplastic Combined Chemotherapy Protocols; Asian People; Carcinoma, Non-Small-Cell Lung; Cisplatin; Erythropoietin; Female; Genotype; Hematologic Diseases; Humans; Lung Neoplasms; Male; Middle Aged; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Severity of Illness Index; Sex Factors; Treatment Outcome

Topics: Aged; Carcinoma, Renal Cell; Diagnosis, Differential; Dizziness; Erythropoietin; Fatigue; Humans; Kidney Neoplasms; Lung Neoplasms; Male; Nephrectomy; Polycythemia; Tomography, X-Ray Computed; Treatment Outcome

Tissue-resident macrophages can be educated to tumor-associated macrophages (TAMs) by the tumor microenvironment and many types of macrophages express erythropoietic receptor (EPOR); However, little is known about the expression of EPOR on TAMs and the identity of EPOR. EPOR-eGFPcre mice were used to determine the expression of EPOR on lung tissue-resident macrophages. Flow cytometry, RT-PCR, and Western blot were examined to define the identity of EPOR. We found that a subpopulation of mouse lung tissue-resident macrophages express EPOR and EPO enhances the proliferation of EPOR. We have characterized TAMs expressing EPOR and CD163

Topics: Adolescent; Adult; Animals; Biomarkers, Tumor; Cell Proliferation; Child; Cytokines; Disease Models, Animal; Erythropoietin; Female; Gene Expression; Genes, Reporter; Humans; Immunophenotyping; Lung Neoplasms; Male; Mice; Mice, Knockout; Osteosarcoma; Prognosis; Receptors, Erythropoietin; Tumor Microenvironment; Tumor-Associated Macrophages; Young Adult

Several studies have documented that blood biomarkers can improve basic prognostic models in radiotherapy and radio-chemotherapy for non-small cell lung cancer. The current study evaluated the prognostic impact of six markers focusing on their utility in homogenous subsets, compared to the significance in a large heterogeneous group.. Blood samples of 337 patients who were referred for curative or palliative external beam thoracic radiotherapy for non-small cell lung cancer were collected. The concentration of osteopontin (OPN), vascular endothelial growth factor (VEGF), erythropoetin (EPO), high mobility group box 1 protein (HMGB1), insulin-like growth factor 1 (IGF-1) and platelet-derived growth factor (PDGF) in serum were measured by ELISA assay and the prognostic potential was assessed using univariable and multivariable survival models.. Multivariable analysis revealed that out of several variables studied six dichotomized features: namely: cigarette smoking, lack of chemotherapy, palliative doses of radiotherapy, high OPN concentration, advanced T stage and high VEGF concentration had a highly significant (p < 0.005) and independent influence on overall survival in the group of 337 patients. In a subset of patients treated with curative radio-chemotherapy or radiotherapy (N = 148) tumor pathology, EPO concentration and VEGF concentration, significantly and independently influenced overall survival. In a subset of patients with squamous cell cancer (N = 206) OPN had a highly significant impact on overall survival. In contrast, in a subset of patients with nonsquamous histology (N = 131) only VEGF had a significant influence on survival.. Blood serum proteins appear to be clinically useful prognosticators of overall survival in radio-chemotherapy and radiotherapy for non-small cell lung cancer. In unselected heterogeneous groups, dichotomized concentrations of OPN and VEGF emerged among the strongest independent prognosticators of overall survival. VEGF and EPO concentration (dichotomized) were found to be independent prognostic factors among the patients treated with curative doses of radiotherapy. The utility of OPN as a prognostic marker appeared restricted to the patients with squamous histology.

Topics: Aged; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Disease-Free Survival; Erythropoietin; Female; Follow-Up Studies; Humans; Lung; Lung Neoplasms; Male; Middle Aged; Osteopontin; Prognosis; Prospective Studies; Risk Assessment; Survival Analysis; Vascular Endothelial Growth Factor A

Lung cancer patients have the highest incidence of anemia among patients with solid tumors. The use of recombinant human erythropoietin (Epo) has consistently been shown to reduce the need for blood transfusions and to increase hemoglobin levels in lung cancer patients with chemotherapy-induced anemia. However, clinical and preclinical studies have prompted concerns that Epo and the presence of its receptor, EpoR, in tumor cells may be responsible for adverse effects and, eventually, death. The question has been raised whether Epo promotes tumor growth and inhibits the death of cancer cells. In this study, we investigated the presence and functionality of EpoR, as well as the implications of Epo upon the proliferation and survival of lung cancer cells. Since the protein expression of both Epo and EpoR is induced by hypoxia, which is frequently present in lung cancer, the cells were treated with Epo under both normoxic and hypoxic conditions (1% O2). By using quantitative (real-time) PCR, western blot analysis, and immunocytochemical staining, three non-small cell lung cancer (NSCLC) cell lines (A427, A549 and NCI-H358) were analyzed for the expression of EpoR and its specific downstream signaling pathways [Janus kinase 2 (Jak2)-signal transducer and activator of transcription 5 (STAT5), phosphatidylinositol-3-kinase (PI3K)-Akt, mitogen-activated protein (MAP) kinase]. The effects of 100 U/ml Epo on cell proliferation and cisplatin-induced apoptosis were assessed. All NSCLC cell lines expressed EpoR mRNA and protein, while these levels differed considerably between the cell lines. We found the constitutive phosphorylation of EpoR and most of its downstream signaling pathways (STAT5, Akt and ERK1/2) independently of Epo administration. While Epo markedly enhanced the proliferation and reduced apoptosis of Epo-dependent UT-7/Epo leukemia cells, it did not affect tumor cell proliferation or the cisplatin-induced apoptosis of NSCLC cells. Thus, this in vitro study suggests that there are no tumor-promoting effects of Epo in the NSCLC cell lines studied, neither under normoxic nor under hypoxic conditions.

Topics: Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Erythropoietin; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Phosphorylation; Receptors, Erythropoietin; Tumor Hypoxia

With growing use of nivolumab, rare but serious side effects have surfaced in some patients. We present a case of autoimmune haemolytic anaemia that developed after 39 cycles of nivolumab. A 78-year-old man with metastatic lung adenocarcinoma, refractory to multiple lines of chemotherapy was switched to nivolumab. After around 2 years of stable course on nivolumab, he developed transfusion-dependent anaemia with haemoglobin of 8.6 g/dL. Nivolumab was held immediately. Bone marrow biopsy findings were inconclusive of myelodysplastic syndrome. Further testing was suggestive of haemolysis with haptoglobin <10 mg/dL, elevated reticulocyte count and identification of immunoglobulin G antibody. Haemoglobin improved significantly with initiation of 1 mg/kg prednisone in addition to rituximab weekly × four doses. The development of transfusion-dependent anaemia with the exposure to cytotoxic chemotherapy usually raises the question for myelodysplastic syndrome. In contradiction, our patient was diagnosed to have a haematological autoimmune complication related to immunotherapy.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Aged; Anemia, Hemolytic, Autoimmune; Antibodies, Monoclonal; Antineoplastic Agents; Blood Transfusion; Erythropoietin; Hemoglobin A; Humans; Lung Neoplasms; Male; Nivolumab; 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

Recombinant human erythropoietin (rhuEpo) is used clinically to treat anaemia. However, rhuEpo-treated cancer patients show decreased survival rates and erythropoietin receptor (EpoR) expression has been found in patient tumour tissue. Thus, rhuEpo application might promote EpoR(+) tumour progression. We therefore developed the positron emission tomography (PET)-probe (68)Ga-DOTA-rhuEpo and evaluated its performance in EpoR(+) A549 non-small-cell lung cancer (NSCLC) xenografts.. (68)Ga-DOTA-rhuEpo was generated by coupling DOTA-hydrazide to carbohydrate side-chains of rhuEpo. Biodistribution was determined in tumour-bearing mice 0.5, 3, 6, and 9 h after probe injection. Competition experiments were performed by co-injecting (68)Ga-DOTA-rhuEpo and rhuEpo in five-fold excess. Probe specificity was further evaluated histologically using Epo-Cy5.5 stainings.. The blood half-life of (68)Ga-DOTA-rhuEpo was 2.6 h and the unbound fraction was cleared by the liver and kidney. After 6 h, the highest tumour to muscle ratio was reached. The highest (68)Ga-DOTA-rhuEpo accumulation was found in liver (10.06 ± 6.26%ID/ml), followed by bone marrow (1.87 ± 0.53%ID/ml), kidney (1.58 ± 0.39%ID/ml), and tumour (0.99 ± 0.16%ID/ml). EpoR presence in these organs was histologically confirmed. Competition experiments showed significantly (p < 0.05) lower PET-signals in tumour and bone marrow at 3 and 6 h.. (68)Ga-DOTA-rhuEpo shows favourable pharmacokinetic properties and detects EpoR specifically. Therefore, it might become a valuable radiotracer to monitor EpoR status in tumours and support decision-making in anaemia therapy.. • PET-probe (68) Ga-DOTA-rhuEpo was administered to assess the EpoR status in vivo • (68) Ga-DOTA-rhuEpo binds specifically to EpoR positive organs in vivo • Tumour EpoR status determination might enable decision-making in anaemia therapy with rhuEpo.

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Epoetin Alfa; Erythropoietin; Female; Heterografts; Humans; Lung Neoplasms; Mice; Mice, Nude; Neoplasms; Neoplasms, Experimental; Positron-Emission Tomography; Receptors, Erythropoietin; Recombinant Proteins; Tissue Distribution

Recombinant human erythropoietin (rhEPO), a glycoprotein hormone regulating red blood cell (RBC) formation, is used for the treatment of cancer-related anemia. The effect of rhEPO on tumor growth, however, remains controversial. Here, we report the construction and characterization of the recombinant vaccinia virus (VACV) GLV-1h210, expressing hEPO. GLV-1h210 was shown to replicate in and kill A549 lung cancer cells in culture efficiently. In mice bearing A549 lung cancer xenografts, treatment with a single intravenous dose of GLV-1h210 resulted in tumor-specific production and secretion of functional hEPO, which exerted an effect on RBC progenitors and precursors in the mouse bone marrow, leading to a significant increase in the number of RBCs and in the level of hemoglobin. Furthermore, virally expressed hEPO, but not exogenously added rhEPO, enhanced virus-mediated green fluorescent protein (GFP) expression in tumors and subsequently accelerated tumor regression when compared with the treatment with the parental virus GLV-1h68 or GLV-1h209 that expressed a nonfunctional hEPO protein. Moreover, intratumorally expressed hEPO caused enlarged tumoral microvessels, likely facilitating virus spreading. Taken together, VACV-mediated intratumorally expressed hEPO not only enhanced oncolytic virotherapy but also simultaneously alleviated cancer-related anemia.

Topics: Anemia; Animals; Cell Line, Tumor; Chlorocebus aethiops; Erythropoietin; Green Fluorescent Proteins; Humans; Liver Neoplasms, Experimental; Lung Neoplasms; Male; Mice; Mice, Nude; Microvessels; Oncolytic Virotherapy; Oncolytic Viruses; Recombinant Proteins; Vaccinia virus; Virus Replication; Xenograft Model Antitumor Assays

The putative presence of the erythropoietin receptor (EpoR) on human cancer cells has given rise to controversial discussion about the use of recombinant human erythropoietin (rhuEpo) for treatment of patients with chemotherapy-induced anemia. In vivo analysis of the EpoR status in tumors could help in elucidating the role of erythropoietin in cancer. Thus, the aim of this study was to develop a targeted EpoR probe for the investigation of EpoR expression in human lung cancer xenografts by fluorescence-mediated tomography.. Epo-Cy5.5 was generated by coupling Cy5.5 to rhuEpo. In vitro binding assays were performed using the EpoR-positive non-small cell lung cancer (NSCLC) cell lines A549 (lower EpoR expression) and H838 (higher EpoR expression), the EpoR-negative cell line H2030, and EpoR/EGFP-overexpressing HeLa cells. In vivo specificity of Epo-Cy5.5 was confirmed by competition analyses using micro-CT/fluorescence-mediated tomography fusion imaging. Biodistribution was analyzed over 50 h after injection. Binding of Epo-Cy5.5 was validated on tumor cryosections.. After intravenous injection, the probe was rapidly cleared from the circulation. An accumulation was observed in liver and kidneys, with a maximum at 7 h after injection followed by a decline, indicating renal excretion. Almost constant accumulation of Epo-Cy5.5 was found in bone marrow and tumors, indicating specific receptor binding. The probe allowed the discrimination between H838 with higher EpoR expression (89.54 ± 15.91 nM at 25 h) and A549 tumors with lower EpoR expression (60.45 ± 14.59 nM at 25 h, P < 0.05). Tumor accumulation of Epo-Cy5.5 could be significantly reduced by adding unlabeled rhuEpo (P < 0.05 at 4, 7, and 24 h). In vitro validation confirmed specific binding of Epo-Cy5.5 to the tumor cells, and this binding correlated with the EpoR expression level. Binding was also observed on endothelial cells. Vessel density and Epo-Cy5.5 binding on endothelial cells were comparable.. Epo-Cy5.5 allows the longitudinal analysis of EpoR expression in tumors and thereby can investigate the influence of erythropoietin on EpoR expression, tumor growth, and angiogenesis.

Topics: Animals; Bone Marrow; Carbocyanines; Cell Line, Tumor; Cell Transformation, Neoplastic; Endothelial Cells; Erythropoietin; Female; Gene Expression Regulation, Neoplastic; Humans; Infrared Rays; Lung Neoplasms; Mice; Molecular Imaging; Molecular Probes; Receptors, Erythropoietin; Substrate Specificity

The CHOICE study was a prospective, multicentre, observational study designed to assess levels of adherence in current clinical practice to the European product label and EORTC guidelines for the treatment of chemotherapy-induced anaemia (CIA) with darbepoetin alfa (DA). Here we present data split by tumour types: breast, colorectal, ovarian and lung.. Haemoglobin (Hb) levels and red blood cell transfusion requirements were evaluated among patients with solid tumours in 11 European countries. The primary outcome measure was the proportion of patients with a target Hb level of ≥10-≤12 g/dL.. The full analysis set included 1887 patients (mean ± SD 62.4 ± 11.4 years); 1585 (84%) had a current disease stage of ≥3. Common chemotherapy regimens were non-platinum + non-taxane based (n = 696 [37%]) or platinum + non-taxane based (n = 660 [35%]). Breast cancer (n = 575): The mean ± SD Hb level at baseline was 9.9 ± 0.8 g/dL (n = 568). Target Hb level was reached by 187 (55%) patients. Colorectal cancer (n = 310): At baseline the mean ± SD Hb level was 9.8 ± 0.8 g/dL (n = 306). Target Hb level was reached by 107 patients (56%). Ovarian cancer (n = 301): The mean ± SD Hb level at baseline was 9.7 ± 0.8 g/dL (n = 294). Target Hb level was reached by 81 patients (44%). Lung cancer (n = 701): At baseline the mean ± SD Hb level was 9.8 ± 0.9 g/dL (n = 692). Target Hb level was reached by 142 patients (39%).. Five severe or life-threatening adverse drug reactions were seen (three patients with breast cancer, one patient with colorectal cancer and one patient with ovarian cancer).. Potential bias could not be excluded due to the study's observational nature.. This study demonstrates that the recommendations are adhered to in clinical practice, with the mean starting Hb level <10 g/dL irrespective of tumour type. Furthermore, DA is likely to be effective and well tolerated for the treatment of CIA in patients with breast, colorectal, ovarian or lung cancer.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Breast Neoplasms; Colorectal Neoplasms; Darbepoetin alfa; Erythropoietin; Europe; Female; Hematinics; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Ovarian Neoplasms; Prospective Studies

The CHOICE study was a prospective, multicentre, observational study designed to assess the level of adherence in current clinical practice to the European product label and the EORTC guidelines for the treatment of chemotherapy-induced anaemia with darbepoetin alfa (DA).. Hb levels and red blood cell (RBC) transfusion requirements were evaluated among 1900 patients with solid tumours in 11 European countries. The primary outcome measure was the proportion of patients with a target Hb level of ≥10-≤12 g/dL after 9 weeks' DA treatment.. The full analysis set (FAS) comprised 1887 patients (mean ± SD age 62.4 ± 11.4 years) divided into categories by baseline Hb < 9 g/dL (n = 281); 9-<10 g/dL (n = 770); 10-<11 g/dL (n = 695); ≥11 g/dL (n = 114). The proportion of patients who remained on the study at week 9 achieving the target Hb level was 37% (n = 60), 48% (n = 217), 54% (n = 210) and 38% (n = 23) in the subgroups with a baseline Hb level of <9 g/dL, 9-<10 g/dL, 10-<11 g/dL and ≥11 g/dL, respectively. In the <9 g/dL, 9-<10 g/dL, 10-<11 g/dL and ≥11 g/dL subgroups of the FAS, the number of patients maintaining Hb levels ≥10 g/dL after their first achievement of an Hb value of 10 g/dL was 95 (34%), 372 (48%), 476 (68%) and 87 (76%), respectively. The Kaplan-Meier percentages of patients who required an RBC transfusion from week 5 until end of treatment period were: 29%, 20%, 12% and 17% in the <9 g/dL, 9-<10 g/dL, 10-<11 g/dL and ≥11 g/dL subgroups, respectively. Kaplan-Meier percentages of patients reaching an Hb level of >13 g/dL were 10%, 9%, 21% and 29%, respectively. Potential bias could not be excluded due to the study's observational nature.. DA initiation and target Hb ranges adhered to current guidelines in the majority of patients. Furthermore, this study demonstrates faster achievement of the target range and reduced transfusion requirements are associated with initiation of DA at Hb levels of 9-<10 g/dL and 10-<11 g/dL rather than <9 g/dL.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Breast Neoplasms; Colorectal Neoplasms; Darbepoetin alfa; Erythropoietin; Europe; Female; Guideline Adherence; Hematinics; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Ovarian Neoplasms; Practice Guidelines as Topic; Prospective Studies

Erythropoietin and erythropoietin receptor (EPO-R) are expressed in many kinds of tumors. The EPO/EPO-R signaling is involved in tumor cell proliferation, invasion and angiogenesis. The aim of this study was to detect the expression of EPO-R in non-small cell lung cancer (NSCLC), and explore its correlation with angiogenesis.. The expression patterns of EPO and EPO-R in 31 cases of NSCLC tissues were detected by immunohistochemistry, and that in benign lung lesions of 21 patients as control. To analyze the correlation of EPO/EPO-R expression patterns and clinicopathological factors. CD34 was used to label the vascular endothelial cells and calculate the microvessel density (MVD).. The positive rates of EPO and EPO-R expression in NSCLC were 67.7% and 96.8%, respectively, significantly higher than those in the control ones. The positive rates of EPO and EPO-R expression in adjacent tissues were 19.4% and 35.5%, and in benign lesions were 9.5% and 19.0%, respectively (P < 0.001). The expression patterns of EPO/EPO-R were not related with pTNM stage, histological type, histological grade and lymph node metastasis (P > 0.05). Increased MVD was correlated with poor differentiation, lymph node metastasis, and advanced stage.. High expression of EPO/EPO-R in NSCLC patients suggest that they may be involved in tumorigenesis. EPO/EPO-R expression and MVD are closely related, and they might be an endogenous stimulant of angiogenesis during the progression of non-small cell lung cancer. It may provide evidence for clinical diagnosis.

Topics: Antigens, CD34; Carcinoma, Non-Small-Cell Lung; Erythropoietin; Humans; Lung Neoplasms; Lymphatic Metastasis; Microvessels; Neoplasm Staging; Neovascularization, Pathologic; Receptors, Erythropoietin

Prognostic factors can guide the physician in selecting the optimal treatment for an individual patient. This study investigates the prognostic value of erythropoietin (EPO) and EPO receptor (EPO-R) expression of tumor cells for locoregional control and survival in non-small-cell lung cancer (NSCLC) patients.. Fourteen factors were investigated in 62 patients irradiated for stage II/III NSCLC, as follows: age, gender, Karnofsky performance score (KPS), histology, grading, TNM/American Joint Committee on Cancer (AJCC) stage, surgery, chemotherapy, pack years (average number of packages of cigarettes smoked per day multiplied by the number of years smoked), smoking during radiotherapy, hemoglobin levels during radiotherapy, EPO expression, and EPO-R expression. Additionally, patients with tumors expressing both EPO and EPO-R were compared to those expressing either EPO or EPO-R and to those expressing neither EPO nor EPO-R.. On univariate analysis, improved locoregional control was associated with AJCC stage II cancer (p < 0.048), surgery (p < 0.042), no smoking during radiotherapy (p = 0.024), and no EPO expression (p = 0.001). A trend was observed for a KPS of >70 (p = 0.08), an N stage of 0 to 1 (p = 0.07), and no EPO-R expression (p = 0.10). On multivariate analysis, AJCC stage II and no EPO expression remained significant. No smoking during radiotherapy was almost significant. On univariate analysis, improved survival was associated with N stage 0 to 1 (p = 0.009), surgery (p = 0.039), hemoglobin levels of ≥12 g/d (p = 0.016), and no EPO expression (p = 0.001). On multivariate analysis, N stage 0 to 1 and no EPO expression maintained significance. Hemoglobin levels of ≥12 g/d were almost significant. On subgroup analyses, patients with tumors expressing both EPO and EPO-R had worse outcomes than those expressing either EPO or EPO-R and those expressing neither EPO nor RPO-R.. EPO expression of tumor cells was an independent prognostic factor for locoregional control and survival in patients irradiated for NSCLC. EPO-R expression showed a trend. Patients with tumors expressing both EPO and EPO-R have an unfavorable prognosis.

Topics: Age Factors; Aged; Analysis of Variance; Carcinoma, Non-Small-Cell Lung; Erythropoietin; Female; Hemoglobin A; Humans; Karnofsky Performance Status; Lung Neoplasms; Male; Middle Aged; Neoplasm Proteins; Neoplasm Staging; Prognosis; Radiotherapy, Conformal; Receptors, Erythropoietin; Sex Factors; Smoking

Lymphangioleiomyomatosis (LAM) is characterized by cystic lung destruction, resulting from proliferation of smooth-muscle-like cells, which have mutations in the tumor suppressor genes TSC1 or TSC2. Among 277 LAM patients, severe disease was associated with hypoxia and elevated red blood cell indexes that accompanied reduced pulmonary function. Because high red cell indexes could result from hypoxemia-induced erythropoietin (EPO) production, and EPO is a smooth muscle cell mitogen, we investigated effects of EPO in human cells with genetic loss of tuberin function, and we found that EPO increased proliferation of human TSC2-/-, but not of TSC2+/-, cells. A discrete population of cells grown from explanted lungs was characterized by the presence of EPO receptor and loss of heterozygosity for TSC2, consistent with EPO involvement. In LAM cells from lung nodules, EPO was localized to the extracellular matrix, supporting evidence for activation of an EPO-driven signaling pathway. Although the high red cell mass of LAM patients could be related to advanced disease, we propose that EPO, synthesized in response to episodic hypoxia, may increase disease progression by enhancing the proliferation of LAM cells.

Topics: Cell Division; Disease Progression; Erythropoietin; Genes, Tumor Suppressor; Humans; Lung Neoplasms; Lymphangioleiomyomatosis; Mutation; Signal Transduction; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Preliminary findings of various types of globin expressed in the respiratory bronchiolar and alveolar epithelium prompted us to compare the expression of erythropoietin (Epo) and its receptor (EpoR) in normal (healthy) human lung tissues with that in malignant lung tissues. The expression of Epo and EpoR was examined at the transcriptional and protein levels in normal and malignant lung tissues by reverse transcription-PCR, western blot, and immunohistochemical analyses. EpoR mRNA, but not Epo mRNA, was detected in all samples. In normal tissues, EpoR was detected in the mesothelium, chondrocytes, alveolar cells, vascular endothelial cells, smooth muscle fibers, macrophages, and neutrophils, while in malignant foci, the cancer cells of five malignant types showed various intensities of EpoR immunoreactivity. The pattern of staining of EpoR protein was generally stronger in the malignant tissues than in the normal samples. Phosphorylation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK-ERK1/2) was frequently seen in malignant cells, but not in the normal tissues, with the exception of macrophages. Based on the expression of Epo and EpoR mRNA with the EpoR in almost all cell components in normal tissues, we suggest that the normal lung may produce various types of globin through the autocrine and/or paracrine role of Epo. When the Epo signal is upregulated by hypoxic stress, the normal cells appear to transform into malignant cells and proliferate through activated MAPK signaling.

Topics: Autocrine Communication; Blotting, Western; Cell Transformation, Neoplastic; Erythropoietin; Globins; Humans; Hypoxia; Immunohistochemistry; Lung; Lung Neoplasms; MAP Kinase Signaling System; Paracrine Communication; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation

Anemia is common among patients with malignant tumors, due to the disease and chemotherapy. Anemia decreases patient's quality of life, and worsens the dose-intensity of chemotherapy. The aim of this retrospective data-analysis was to evaluate quality of life and hemoglobin levels in 19 consecutive lung cancer patients receiving beta-erythropoietin, due to chemotherapy induced anemia. A self developed, patient source data based quality of life questionnaire was used. The mean pre-erythropoietin hemoglobin concentration of the patients was 96.31±6.72 g/L (mean±SD), the post-treatment hemoglobin concentration 111.63±14.05 g/L (p<0.05). During the chemotherapy of the 19 patients with lung cancer, transfusion was given only four times. The mean quality of life total score of the patients increased significantly during erythropoietin treatment that was resulted by the improvements of scores determining dizziness, tachycardia, and fatigue. Main limitations of this real life data analysis are low patient number and the lack of validation in the used questionnaire. In summary, according to our experiences, the use of beta-erythropoietin in patients with lung cancer results improved quality of life and a low rate of transfusions.

Topics: Adult; Aged; Anemia, Hypochromic; Antineoplastic Agents; Blood Transfusion; Dizziness; Erythropoietin; Fatigue; Female; Hematinics; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Quality of Life; Recombinant Proteins; Retrospective Studies; Surveys and Questionnaires; Tachycardia; Treatment Outcome

Topics: Adenocarcinoma; Aged; Biopsy; Erythropoietin; Humans; Lung; Lung Neoplasms; Male; Neovascularization, Pathologic; Tomography, X-Ray Computed

Erythropoiesis-stimulating agents (erythropoietin and darbepoietin) have been approved to reduce the number of blood transfusions required during chemotherapy; however, concerns about the risks of venous thromboembolism and mortality exist.. We identified patients who were aged 65 years or older in the Surveillance, Epidemiology, and End Results-Medicare database; who were diagnosed with colon, non-small cell lung, or breast cancer or with diffuse large B-cell lymphoma from January 1, 1991, through December 31, 2002; and who received chemotherapy. The main outcome measures were claims for use of an erythropoiesis-stimulating agent, blood transfusion, venous thromboembolism (ie, deep vein thrombosis or pulmonary embolism), and overall survival. We used multivariable logistic regression models to analyze the association of erythropoiesis-stimulating agent use with clinical and demographic variables. We used time-dependent Cox proportional hazards models to analyze the association of time to receipt of first erythropoiesis-stimulating agent with venous thromboembolism and overall survival. All statistical tests were two-sided.. Among 56,210 patients treated with chemotherapy from 1991 through 2002, 15,346 (27%) received an erythropoiesis-stimulating agent. The proportion of patients receiving erythropoiesis-stimulating agents increased from 4.8% in 1991 to 45.9% in 2002 (P < .001). Use was associated with more recent diagnosis, younger age, urban residence, comorbidities, receipt of radiation therapy, female sex, and metastatic or recurrent cancer. The rate of blood transfusion per year during 1991-2002 remained constant at 22%. Venous thromboembolism developed in 1796 (14.3%) of the 12,522 patients who received erythropoiesis-stimulating agent and 3400 (9.8%) of the 34,820 patients who did not (hazard ratio = 1.93, 95% confidence interval = 1.79 to 2.07). Overall survival was similar in both groups.. Use of erythropoiesis-stimulating agent increased rapidly after its approval in 1991, but the blood transfusion rate did not change. Use of erythropoiesis-stimulating agents was associated with an increased risk of venous thromboembolism but not of mortality.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Anemia; Antineoplastic Agents; Blood Transfusion; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Colonic Neoplasms; Confounding Factors, Epidemiologic; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Humans; Lung Neoplasms; Lymphoma, Large B-Cell, Diffuse; Male; Medical Record Linkage; Medicare; Neoplasms; Practice Patterns, Physicians'; Recombinant Proteins; Retrospective Studies; Risk Factors; SEER Program; United States; Venous Thromboembolism

Anaemia is a common problem in patients with cancer who receive chemotherapy and is normally associated with a negative impact on patients' quality of life (QOL), poor cancer control and diminished survival. In clinical trials, recombinant human erythropoietin has been shown to correct and prevent anaemia, decrease the need for blood transfusions and improve cancer patients' QOL.. A retrospective study followed lung cancer patients who received first-line chemotherapy in our hospital in 1998 and in 2005. The incidence of anaemia was analysed, as was the impact of incorporating erythropoietin into the treatment.. The incidence of anaemia was 68% (69% of which reported asthenia) in 1998 vs. 54% (60% with asthenia) in 2005. The comparison of anaemia rates (1998 vs. 2005) were grade 1 (16% vs. 32%), grade 2 (36% vs. 16%), grade 3 (16% vs. 5%) and grade 4 (none). Treatment for anaemia included transfusion 52%, intravenous iron 5% and epoetin 4% in 1998. In 2005 anaemia was treated with transfusion 9%, intravenous iron 41%, and epoetin 49%. Median survival (1998 vs. 2005) was 242 days [95% confidence interval (CI) 217-329) vs. 356 days (95% CI 322-382).. Erythropoietin is a valid alternative for cancer patients with anaemia undergoing chemotherapy. It can possibly avoid the need for transfusions without negatively impacting survival.

Topics: Adult; Aged; Anemia; Antineoplastic Agents; Blood Transfusion; Erythropoietin; History, 17th Century; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Quality of Life; Recombinant Proteins; Retrospective Studies

Topics: Anemia; Antineoplastic Agents; Blood Transfusion; Cell Hypoxia; Erythropoietin; Head and Neck Neoplasms; Hemoglobins; Humans; Lung Neoplasms; Prognosis; Radiotherapy; Randomized Controlled Trials as Topic; Retrospective Studies; Survival Analysis

The angiotensin-converting enzyme (ACE) plays an important role not only in the regulation of vascular homeostasis but also in stimulation of hematopoiesis. We aimed to evaluate the association between insertion/deletion (I/D) polymorphism of the ACE gene and anemia at the time of the diagnosis. We enrolled 75 patients with non-small-cell lung cancer (NSCLC) and 85 age- and sex-matched healthy control participants. The I/D polymorphism of ACE was identified by using polymerase chain reaction from peripheral blood samples. Statistical analyses were performed with SPSS for Windows. The distributions of the ACE genotypes and alleles are similar in patients and in healthy participants (P=0.29 and P=0.08, respectively). In patients with NSCLC, 34 (45.3%) had anemia; of whom 3 (8.8%) had genotype II, 24 (70.6%) had genotype ID, and 7 (20.6%) had genotype DD (P=0.001). The patients with the II and ID genotypes had more frequent anemia at the time of the diagnosis (odds ratio = 6.02; P=0.001). Our findings suggest that I/D polymorphism of the ACE gene may influence the development of anemia in patients with NSCLC.

Topics: Alleles; Anemia; Carcinoma, Non-Small-Cell Lung; Case-Control Studies; Erythropoietin; Female; Genetic Predisposition to Disease; Genotype; Humans; Lung Neoplasms; Male; Middle Aged; Polymorphism, Genetic; Renin

Topics: Antibody Specificity; Carcinoma, Non-Small-Cell Lung; Cross Reactions; Disease Progression; Erythropoietin; Humans; Lung Neoplasms; Neoplasm Invasiveness; Prognosis; Recombinant Proteins; Survival Analysis

Anemia is common among patients with malignant tumors, due to the disease and chemotherapy. Anemia decreases patient's quality of life, and worsens the dose intensity of chemotherapy. The aim of this retrospective data-analysis was to determine the rate of transfusions and the maintenance of chemotherapeutic dose intensity in 9 small cell lung cancer patients receiving beta-erythropoietin, due to anemia observed after the first cycle of chemotherapy. The mean pre-treatment hemoglobin concentration of the patients was 116.67+/-8.17 g/L (mean+/-SD). The mean pre-erythropoietin hemoglobin concentration at baseline was 103.11+/-7.52 g/L. Six cycles of platinum compounds and etoposide were used. The post-treatment hemoglobin concentration of patients was 110.11+/-5.37 g/L (p = 0,028 vs. baseline). During these 54 chemotherapeutic cycles, only 2 patients needed transfusion, each of them once. According to our experience, the use of beta-erythropoietin in 9 anemic small cell lung cancer patients resulted in a low rate of transfusions and maintenance of cytotoxic treatment dose intensity. The adequate use of beta-erythropoietin is of great help to the physician in the management of small cell lung cancer patients.

Topics: Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Small Cell; Cisplatin; Erythropoietin; Etoposide; Female; Hematinics; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Retrospective Studies; Treatment Outcome

Recent evidence confirms the presence of erythropoietin receptors on a variety of cancer cells. This has raised concerns about the use of erythropoiesis-stimulating agents in the treatment of cancer-related anemia. Having previously identified expression of functional erythropoietin receptors in a non-small cell lung carcinoma cell line, H838, which activated key signaling pathways in response to erythropoietin stimulation, we now demonstrate impaired downregulation of the erythropoietin receptor in these tumor cells. The erythropoietin receptor is not ubiquitinated following erythropoietin stimulation in this cancer cell line, and there is no turnover of the receptor in either unstimulated or stimulated cells. Compounding this blunted response is impaired SOCS3 induction downstream of erythropoietin stimulation and an extremely delayed SOCS1 response. If this finding in non-small cell lung carcinoma is a widespread phenomenon, then impaired erythropoietin receptor downregulation and degradation in tumor cells has clinical implications for those patients receiving erythropoiesis-stimulating agents for cancer-related anemia.

Topics: Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cycloheximide; Down-Regulation; Erythropoietin; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Lysosomes; Proteasome Endopeptidase Complex; Protein Biosynthesis; Protein Processing, Post-Translational; Receptors, Erythropoietin; Recombinant Proteins; RNA, Messenger; Suppressor of Cytokine Signaling Proteins; Ubiquitins

Anemia occurs frequently in patients with lung cancer receiving chemotherapy and has a negative impact on quality of life (QoL). Erythropoietic proteins effectively increase hemoglobin (Hb) levels, reduce transfusion requirements and improve QoL in anemic patients with a range of malignancies. This prospective, observational study evaluated epoetin beta 30,000 IU once weekly in patients with lung cancer in a real-life, clinical-practice setting. Forty patients (72.5% with NSCLC and 27.5% with SCLC) were treated with epoetin beta during any cycle of chemotherapy when Hb decreased to <12 g/dL. Hb levels were assessed at regular intervals and transfusion needs were monitored throughout the study. In total, 72.5% of patients required epoetin treatment by the second cycle of chemotherapy. Epoetin beta treatment duration ranged from 1 to >9 (median 4) weeks. Mean (+/-S.D.) baseline Hb was 10.4+/-1.2 g/dL. Epoetin beta was associated with a rapid increase in Hb levels, with a mean increase of 1.3 g/dL by week 4. Most patients (95%) remained transfusion-free throughout the study. Epoetin beta was well tolerated. This early intervention strategy with epoetin beta 30,000 IU once weekly is an effective and well-tolerated therapy for anemia in patients with lung cancer.

Topics: Adult; Aged; Anemia; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Recombinant Proteins

To assess recent developments in the use of transfusions.. Data from hospital-based sources were condensed in a single spread sheet covering 1611 transfusions of a total of 881 patients together with data on 25,264 treatment sessions in 6137 patients within a time period between 1 August 2001 and 31 July 2004.. Our audit showed an increase in transfusions of 25% in 3 years. This was accompanied by an increased threshold for transfusions, as shown by a significant rise in mean haemoglobin trigger levels from 8.53 to 8.86 g/dl (P<0.001) as well as an increase in treatment sessions and patient numbers - especially for chemotherapy or combinations of chemotherapy and radiotherapy. The highest transfusion rates and also the greatest increments occurred in patients with carcinoma of the ovary, lung and pancreas. Within these groups, treatment regimens as well as treatment lines were additional predictive factors.. This audit gives a detailed view on rising trends in transfusion requirements and, in light of anticipated restrictions on resources, it identifies high-risk areas, where the use of alternatives, such as erythropoietin, could be considered.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Breast Neoplasms; Cost-Benefit Analysis; Database Management Systems; England; Erythropoietin; Female; Health Services Needs and Demand; Hemoglobins; Hospitals, University; Humans; Lung Neoplasms; Male; Medical Audit; Medical Oncology; Ovarian Neoplasms; Pancreatic Neoplasms; Radiation Oncology; Utilization Review

This study was designed to evaluate the prognostic effect of erythropoietin (EPO) and EPO receptor (EPO-R) expression in stage I non-small cell lung cancer (NSCLC) patients.. EPO and EPO-R expression in 158 tumor samples from resected stage I NSCLC was evaluated using immunohistochemistry and tissue array technology.. EPO-R and EPO were highly expressed in 20.9% and 35.4% of tumors, respectively. High EPO-R expression compared with negative or low-level expression was associated with a poor 5-year disease-specific survival (60.6% versus 80.8%; P = 0.01, log-rank test). High EPO expression compared with negative and low-level expression was associated with a trend toward a poor 5-year disease-specific survival (69.6% versus 80.4%; P = 0.13, log-rank test). A high level of EPO-R and EPO coexpression was associated with a poor 5-year disease-specific survival compared with other groups of patients (50.0% versus 80.0% survival at the end of follow-up; P = 0.005, log-rank test). In multivariate analysis for disease-specific survival, high-level EPO-R and EPO coexpression was an independent prognostic factor for disease-specific survival (hazard ratio, 2.214; 95% confidence interval, 1.012-4.848; P = 0.046).. These results establish the pejorative prognostic value of EPO and EPO-R expression in early-stage resected NSCLC and suggest a potential paracrine and/or autocrine role of endogenous EPO in NSCLC aggressiveness.

Topics: Aged; Carcinoma, Non-Small-Cell Lung; Erythropoietin; Female; Humans; Immunohistochemistry; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Prognosis; Proportional Hazards Models; Receptors, Erythropoietin; Recombinant Proteins; Tissue Array Analysis

Despite the clinical efficacy of recombinant human erythropoietin (RHE) on chemotherapy-induced anemia, most cost-effectiveness studies have given unfavorable results.. To determine the cost of managing anemia in unselected patients receiving chemotherapy for lung cancer, and the efficacy and cost-effectiveness of RHE.. We constructed Markov models of two cohorts of patients who received (n=94) or did not receive (n=89) darbepoetin (one weekly injection when the hemoglobin level fell below 11 g/dl), focusing on changes in hemoglobin levels, transfusion requirements, anemia management costs, and the cost-effectiveness ratios of the two management strategies.. The use of RHE significantly reduced the proportion of patients needing transfusions (from 33.6% to 19.1%, p<0.05) and the number of red cell units used by transfusion (from 2.97+/-1.47 to 2.11+/-0.47, p<0.01). Markov modeling showed that the RHE strategy significantly increased the mean Hb level (13+/-0.5 g/dl versus 11.9+/-1g/dl, p<0.001), at the price of an increase in the main cost (respectively, US$ 1732+/-897 and 996+/-643; p<0.01). The cost-effectiveness ratio favored the RHE strategy (7.02 versus 9.04). Sensitivity analysis showed that the RHE strategy remained dominant in most situations.. Routine use of RHE appears to be cost-effective in patients receiving chemotherapy for lung cancer.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Agents; Blood Transfusion; Costs and Cost Analysis; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Humans; Lung Neoplasms; Male; Markov Chains; Middle Aged

Suppression of the effect of the hormone erythropoietin (EPO) on the bone marrow, and an inadequate EPO response to anaemia have been shown to be factors in the genesis of cancer related anaemia. Low haemoglobin (Hb) concentration pre-operatively has been shown to have prognostic significance in patients with surgically resected NSCLC. This study investigates the relationship between pre-operative EPO and survival in patients having surgery for NSCLC.. Pre-operative plasma EPO concentration and haemoglobin concentration were analysed in patients undergoing surgery for NSCLC between April 1998 and January 1999. Full follow-up was available for all patients.. Forty two patients were included. Median EPO concentration was 9.4 mIU/ml, range (3.7-56.4) with 17 patients (40.4%) having values above the normal range. Median haemoglobin concentration was 13.3g/dl (range 8.5-16.8) with 15 patients (26%) anaemic pre-operatively. Pathological staging revealed 17 (40.4%) patients with stage I, 6 (14.3%) with stage II, 19 (45.3%) with stage III disease. Ten patients had irresectable disease. There was a significant difference in median EPO but not haemoglobin concentration, between the different pathological stages. Survival was significantly lower in patients with pre-operative EPO >10.5 mIU.. Raised pre-operative EPO is associated with reduced survival in patients having surgery for NSCLC. Its measurement should be considered in the pre-operative assessment of patients undergoing surgery for NSCLC. Further research is required to further investigate the biological relationship between EPO and NSCLC.

Topics: Adult; Aged; Carcinoma, Non-Small-Cell Lung; Erythropoietin; Female; Humans; Lung Neoplasms; Male; Middle Aged; Preoperative Care; Prognosis; Proportional Hazards Models; Statistics, Nonparametric; Survival Analysis

Erythropoiesis is maintained by the hormone erythropoietin (Epo) binding to its cognate receptor (EpoR) on erythroid progenitor cells. The Epo-EpoR interaction initiates a signal transduction process that regulates the survival, growth and differentiation of these cells. Originally perceived as highly lineage-restricted, Epo is now recognised to have pleiotropic effects extending beyond the maintenance of red cell mass. Functional interactions between Epo and EpoR have been demonstrated in numerous cells and tissues. EpoR expression on neoplastic cells leads to concern that recombinant human erythropoietin, used to treat anaemia in cancer patients, may augment tumour growth. Here we demonstrate that EPO, at pharmacological concentrations, can activate three major signalling cascades, viz. the Jak2/STAT5, Ras/ERK and PI3K/Akt pathways in non-small cell lung carcinoma (NSCLC) cell lines. EpoR synthesis is normally under the control of GATA-1, but NSCLC cells exhibit decreased GATA-1 levels compared to GATA-2, -3 and -6, suggesting that GATA-1 is not essential for EpoR production. The increased Epo-induced signalling was not associated with a growth advantage for the NSCLC cells.

Topics: Carcinoma, Non-Small-Cell Lung; Cell Division; Cell Line, Tumor; Erythroid Cells; Erythropoietin; GATA1 Transcription Factor; GATA2 Transcription Factor; GATA3 Transcription Factor; GATA4 Transcription Factor; GATA5 Transcription Factor; GATA6 Transcription Factor; Gene Expression; Humans; Lung Neoplasms; Receptors, Erythropoietin; Recombinant Proteins; RNA, Messenger; Signal Transduction

Anemia is a common complication of cancer patients. Recombinant human erythropoietin (rhEPO) can alleviate the symptoms of cancer-related anemia. However, the optimal use of rhEPO is still on investigation. This study was to find out the optimal use of rhEPO in anemic cancer patients undergoing chemotherapy.. From May, 2004 to Feb, 2005, 30 patients with cancer-related anemia receiving concurrent chemotherapy were enrolled. This open-labeled, non-randomized, and pilot study evaluated the response rate of induction rhEPO 120,000 U (40,000 U was subcutaneously injected on d1, 3, 5) followed by subcutaneous injection of maintenance dose of 40,000 U once a week for 3 weeks (d8, 15, 22). Hemoglobin (Hb) and hematocrit (Hct) were measured before treatment and fortnightly during the treatment.. Mean Hb maintained increasing during treatment. In week 2 (n=29) and week 4 (n=21), there were 27.59% and 61.90% patients, respectively, whose Hb value had increased more than 20 g/L from the baseline (79.56 g/L) and mean Hb were 90.26 g/L and 96.81 g/L respectively (P<0.05). And mean Hct at week 2 and week 4 were 27.01% and 30.17% respectively, which were higher than the baseline (24.29%)(P=0.062 and 0.001 respectively). All patients demonstrated fine tolerance.. Induction therapy followed by maintenance with rhEPO can improve the level of hemoglobin significantly and quickly in anemic cancer patients.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Injections, Subcutaneous; Lung Neoplasms; Male; Middle Aged; Pilot Projects; Recombinant Proteins

Anemia is very common among patients with malignant tumors, due to the disease and chemotherapy. Anemia decreases the patient's quality of life. Erythropoietin therapy is accessible in Hungary for the treatment of chemotherapy-induced anemia in patients suffering from small cell lung cancer. In our case report we present the case of a 62-year-old female small cell lung cancer patient with severe anemia, treated by erythropoietin-beta. The erythropoietin treatment provided the possibility of effective chemo- and radiotherapy. The patient's quality of life greatly improved due to the lack of the symptoms of anemia. The adequate use of erythropoietin is of great help to the physician in the management of small cell lung cancer patients, by improving the quality of life.

Topics: Anemia, Hypochromic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Chemotherapy, Adjuvant; Erythropoietin; Female; Hematinics; Hematocrit; Hemoglobins; Humans; Lung Neoplasms; Middle Aged; Quality of Life; Radiography; Radiotherapy, Adjuvant; Recombinant Proteins; Treatment Outcome

Expression of erythropoietin (Epo) and its receptor (Epo-R) has been shown in various normal and neoplastic nonhematopoietic tissues. This study, in non-small cell lung carcinoma, was designed to investigate the previously unreported expression of Epo and Epo-R as well as hypoxia-inducible factor-1alpha (HIF-1alpha), which is known to control Epo expression.. Samples from lung squamous cell carcinomas (n = 17) and adenocarcinomas (n = 12) were obtained from patients undergoing curative surgery. mRNA transcripts of Epo, Epo-R, soluble Epo-R (sEpo-R), HIF-1alpha, and factor inhibiting HIF-1 (FIH-1) were evaluated by reverse transcription-PCR, whereas localization of Epo, Epo-R, and HIF-1alpha was assessed by immunohistochemistry.. Epo, Epo-R, sEpo-R, HIF-1alpha, and FIH-1 transcripts were detected by reverse transcription-PCR in all samples tested, but with heterogeneous levels of expression for Epo, Epo-R, and sEpo-R. Coordinated levels of mRNA were observed for HIF-1alpha and FIH-1.Epo was detected in carcinomatous cells by immunohistochemistry in 50% of samples and Epo-R was detected in 96% of samples. Co-expression of Epo and Epo-R was observed on contiguous sections from 50% of tumors. HIF-1alpha was immunolocalized in 80% of non-small cell lung carcinomas.. Epo-R was expressed in almost all samples and Epo was expressed in one half of samples on immunohistochemistry and in 100% of samples by mRNA detection, suggesting a potential paracrine and/or autocrine role of endogenous Epo in non-small cell lung carcinoma. The detection of stabilized HIF-1alpha suggests a possible role in Epo expression. Moreover, in the light of these results, the potential interactions between therapeutic recombinant Epo and the putative neoplastic Epo/Epo-R signaling pathways must be considered.

Topics: Carcinoma, Non-Small-Cell Lung; Erythropoietin; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Ki-67 Antigen; Lung Neoplasms; Mixed Function Oxygenases; Receptors, Erythropoietin; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transcription Factors

Use of erythropoietin (EPO) for chemotherapy-induced anemia and biphosphonates (BP) for bone metastasis has increased steadily. However, there are no guidelines on their use in many situations such as non small cell lung carcinoma (NSCLC), which frequently alters quality of life markedly. Therefore, a multicentric survey was designed to assess the treatment of anemia and bone metastasis in chemotherapy-treated patients with non-small-cell lung carcinoma. Nine representative centers of the oncology working party of the French respiratory society (Groupe d'Oncologie de la Société de Pneumologie de Langue Française) participated. Inclusion criteria were stage IV NSCLC and at least one course of chemotherapy in the last 3 months. A total of 148 and 50 patients (pts) were included in the anemia and bone metastasis surveys, respectively. Anemia was present in 60.8% of patients, and was not treated in 75%; 15 patients received EPO (10.1%). Independent predictors of EPO use were presence of anemia-related symptoms, hemoglobin level, age and center: the rate of prescription in patients with anemia varied from 13 to 73% between centers. BP were administered in 38% of patients with bone metastasis. Independent predictors of BP use were calcium serum level, pain, and center with a rate of prescription ranging from 0 to 80% between centers. This study reveals that, in France, most patients with anemia are not treated, EPO being seldom prescribed. The use of both EPO and BP is highly variable between centers. Guidelines on the use of these supportive treatments could help improve the care for lung cancer patients receiving chemotherapy.

Topics: Anemia; Bone Neoplasms; Carcinoma, Non-Small-Cell Lung; Diphosphonates; Erythropoietin; France; Health Surveys; Humans; Lung Neoplasms; Practice Guidelines as Topic; Practice Patterns, Physicians'; Quality of Life

Tumor cells in hypoxic areas of solid tumors are resistant to conventional chemotherapy and radiotherapy and thus are obstacles of cancer therapy. We report here the feasibility of applying hypoxia-regulated expression of diphtheria toxin A (DT-A) for killing hypoxic tumor cells. The expression vector was constructed to express DT-A fused with hypoxia-inducible factor-1alpha (HIF-1alpha) oxygen-dependent degradation (ODD) domain under the control of vascular endothelial growth factor gene promoter and contain erythropoietin mRNA-binding protein (ERBP)-binding sequence downstream of the DT-A/ODD sequence. In vitro ubiquitination assay showed that DT-A/ODD, but not DT-A, was ubiquitinated as efficient as HIF-1alpha under normoxic conditions in a von Hippel-Lindau- and oxygen-dependent manner. DT-A/ODD exhibited a comparable translation inhibitory activity to DT-A. ERBP-binding sequence was effective in stabilizing mRNA under hypoxic conditions in various cell types. Transfection of the vector expressing DT-A/ODD into high-metastatic Lewis lung carcinoma (3LL) A11 cells resulted in induction of apoptosis independently of hypoxia, probably due to its extreme toxicity. However, transfection of the vector expressing attenuated DT-A(W153F)/ODD or DT-A(H21A)/ODD resulted in a hypoxia-dependent induction of apoptosis. Liposomal gene transfer of the vector encoding DT-A(W153F)/ODD induced apoptosis in hypoxic, but not in normoxic, areas of solid tumors established by A11 variant cells with higher resistance to hypoxia-induced apoptosis and inhibited the growth of hypoxic tumors established by 3LL-P29 cells. These results suggest that hypoxia-regulated expression of attenuated DT-A(W153F)/ODD fusion protein is potentially of use for killing hypoxic tumor cells with minimizing the damage to normoxic normal tissues.

Topics: Animals; Apoptosis; Carcinoma, Lewis Lung; Cell Hypoxia; Diphtheria Toxin; Erythropoietin; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney Neoplasms; Liposomes; Liver Neoplasms, Experimental; Lung Neoplasms; Mice; Mice, Inbred C57BL; Oxygen; Peptide Fragments; Promoter Regions, Genetic; Protein Biosynthesis; Protein Structure, Tertiary; Recombinant Fusion Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA-Binding Proteins; RNA, Messenger; Transfection; Tumor Cells, Cultured; Ubiquitin; Vascular Endothelial Growth Factor A; Von Hippel-Lindau Tumor Suppressor Protein

In this study, we assessed the ability of erythropoietin (EPO) to synergize with various chemotherapeutic agents and suppress the growth and metastasis of solid tumors. Animals were inoculated with Lewis lung carcinoma (LLC) cells and treated with EPO alone, the designated chemotherapeutic drug (cisplatin, mitomycin C or cyclophoshamide) alone, or EPO and the drug. Tumor volume was monitored daily. Thirteen days following cell injection, tumor mass was determined. In addition, the number of the metastatic foci in the lungs was determined. Cisplatin alone was capable of inducing a 7-fold decrease in final tumor volume compared to tumor-bearing animals injected with saline. However, when EPO was combined with cisplatin, the animals experienced an 11-fold reduction in final tumor volume compared to saline-injected animals (P<0.001). A 2.5-fold reduction in tumor mass was observed in animals treated with cisplatin, compared to the saline-injected groups. Furthermore, injections of EPO and cisplatin induced a 4-fold reduction in tumor mass (P<0.001). Blood analysis indicated that a significant increase of more than 30% in WBC was found in animals injected concurrently with cisplatin and EPO, as compared to saline-injected mice (P<0.03). When EPO and mitomycin C were injected together, tumor mass was further reduced by 14% compared to that seen in mice treated with mitomycin C alone. However, this difference was not statistically significant. We conclude from this study that EPO can synergize with chemotherapeutic agents to further suppress the growth of tumors. The level of synergism is drug related.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents; Carcinoma, Lewis Lung; Cisplatin; Cyclophosphamide; Disease Models, Animal; Drug Interactions; Erythropoietin; Female; Humans; Lung Neoplasms; Mice; Mice, Inbred C57BL; Mitomycin; Neoplasm Metastasis

Lung cancer is associated with the one of the highest rates of anaemia of all solid tumours. Anaemia has a negative impact on treatment outcome and overall survival of patients with cancer and also affects their quality of life. Recombinant human erythropoietin (epoetin) provides an effective and safe treatment of cancer-related anaemia without the risks associated with red blood cell transfusion. Epoetin therapy increases haemoglobin levels, reduces the need for blood transfusions and improves the quality of life of patients with anaemia and lung cancer. Epoetin beta is also effective for preventing the development of anaemia and decreasing transfusion requirements when administered with concomitant platinum-based chemotherapy. In addition, preliminary evidence suggests that treatment with erythropoietic agents may improve survival of lung cancer patients, although this needs to be verified in prospective clinical trials specifically designed to evaluate survival. Therefore, early initiation of epoetin beta to prevent chemotherapy-associated anaemia may represent the best strategy for patients with lung cancer being treated with chemotherapy.

Topics: Anemia; Antineoplastic Agents; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Lung Neoplasms; Quality of Life; Recombinant Proteins; Survival

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Darbepoetin alfa; Double-Blind Method; Drug Administration Schedule; Drug Costs; Epoetin Alfa; Erythropoiesis; Erythropoietin; Humans; Lung Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins; United States

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Darbepoetin alfa; Erythropoiesis; Erythropoietin; Humans; Lung Neoplasms; Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Reproducibility of Results; Treatment Outcome

Our objective was to assess, using clinical trial simulation, the feasibility of a fixed 200-microg dose of darbepoetin alfa (Aranesp) administered every 2 weeks in chemotherapy-induced anemia. A pharmacokinetic/pharmacodynamic model was developed using clinical data from 547 cancer patients who received darbepoetin alfa at various doses and schedules. Monte Carlo simulations were performed for weight-based (3 microg/kg every 2 weeks) and fixed-dose (200 microg every 2 weeks) regimens and were compared with observed clinical data. Mean hemoglobin changes from baseline to end of treatment were +1.61 g/dL, +1.83 g/dL, and +1.79 g/dL for observed data, the weight-based simulation, and the fixed-dose simulation, respectively. The rates of required transfusions (hemoglobin < or = 8 g/dL) were also similar between groups. For patients between 45 and 95 kg (over 90% of the population), the impact of a fixed dose on mean hemoglobin change was negligible. There was a slight weight effect at body weight extremes (< 45 kg and > 95 kg). Clinical outcomes from simulations of weight-based andfixed dosing of darbepoetin alfa were similar to those of observed weight-based data. Given the weight distribution of a typical cancer population, the majority would be expected to benefit equally from weight-based and fixed-dose darbepoetin alfa in the amelioration of chemotherapy-induced anemia.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Body Weight; Breast Neoplasms; Clinical Trials as Topic; Computer Simulation; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Gastrointestinal Neoplasms; Genital Neoplasms, Female; Genital Neoplasms, Male; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Monte Carlo Method

The goal of this study was to evaluate serum level of EPO in 32 men with lung cancer (Squamous cell lung cancer N = 11, Adenocarcinoma N = 10, Small cell lung cancer N = 11) in relation to the degree of anemia, stage of disease and the regimen of anticancer therapy. The control group consisted of 29 men, among whom were 15 patients with posthemorrhagic anemia. Blood samples were withdrawn for assessment of blood count, serum concentration of EPO, iron, total iron binding capacity (TIBC) and ferritin. The assessment of all parameters was repeated after 3 months of therapy:. Patients suffering from lung cancer were characterized by a lower hemoglobin level and higher level of EPO as compared with the control group. A significant negative correlation was found between hemoglobin level and EPO serum concentration in all groups of patients and in the control group. The strongest correlation was observed in the control group t = -0.812. In each group of patients the serum level of EPO increased after treatment; although a significant increase was found only in surgically treated patients and patients after chemotherapy. After treatment the correlation between hemoglobin and EPO became stronger especially in the group of patients with small cell lung cancer.. 1. Patients with lung cancer are characterized by inappropriately low serum EPO levels when related to the degree of anemia, 2. The suppressive effect of lung cancer on EPO secretion depends on the histological type of the cancer (with the exception of small cell lung cancer). 3. The increase of EPO level after treatment seems to be caused not only by a decrease of hemoglobin concentration, but also by reduction of the tumor mass.

Topics: Adenocarcinoma; Anemia; Biomarkers; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Case-Control Studies; Erythropoietin; Ferritins; Hemoglobin A; Humans; Iron; Lung Neoplasms; Male; Middle Aged; Time Factors

Topotecan is a new antineoplastic agent active in ovarian cancer, with promising activity in small cell lung cancer and predictable toxicity. As a part of our ongoing attempt to optimize the use of disease-specific drugs as circulating progenitor cell (CPC) priming in solid tumors, we have evaluated the effects on CPC release of single-agent Topotecan followed by granulocyte colony-stimulating factor (G-CSF) + human recombinant erythropoietin (rhEPO), together with the cell cycle status of the collected CD34+ cells. Ten pretreated patients with small cell lung cancer received Topotecan (1 mg/m2, i.v. for 5 consecutive days) followed by G-CSF (5 microg/kg/day, s.c.) + rhEPO (10,000 I.U. daily, s.c.), starting 24 h after Topotecan. The combination was well tolerated and no relevant side-effects were recorded. On day +10 (range +9 to +11) after the last dose of Topotecan, the median WBC count and the CD34+ cell peak were 8.2 x 10(3) microl (range 4.9-13.9) and 55 microl (range 28-75), respectively. Using flow cytometry, a detailed cell cycle analysis was performed on these CD34+ cells. The cell cycle distribution was determined by DNA content coupled with bromodeoxyuridine incorporation analysis. Apoptosis was evaluated by quantitating DNA strand breaks. The percentage of CD34+ cells in active S-phase was 10.2+/-5%, while early apoptotic CD34+ cells were detected in a low percentage (5.5+/-3%). Topotecan followed by G-CSF + rhEPO mobilizes CPCs effectively. This sequence exerts a stimulation on CD34+ cell cycle with a protective effect from chemotherapy-induced apoptosis. Taken together, these data could be of value for the incorporation of Topotecan, as well as of the combination of G-CSF and rhEPO, into high-dose chemotherapy programs with CPC support.

Topics: Adult; Aged; Antigens, CD34; Apoptosis; Bromodeoxyuridine; Carcinoma, Small Cell; Cell Cycle; Drug Therapy, Combination; Erythropoietin; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Leukocyte Count; Lung Neoplasms; Middle Aged; Platelet Count; Recombinant Proteins; Time Factors; Topotecan

The serum erythropoietin level increases markedly during chemotherapy for leukemia. A number of hypotheses have been built for the mechanism, none of them satisfactory. Difficulty in evaluating bone marrow activity hampers the elucidation. Therefore, we focused on patients who had non-hematological cancer and no evidence of bone marrow suppression.. Twelve patients, who had lung cancer (four with small cell cancer and eight with non-small cell cancer) and who had not undergone any chemotherapy, were studied. During chemotherapy, we measured serum erythropoietin, serum iron, unsaturated iron binding capacity and hemoglobin concentration in these patients.. The serum erythropoietin level before chemotherapy (10.8 +/- 7.4 mU/ml) was within the normal range but the peak values after the first treatment (73.4 +/- 90.4 mU/ml) increased in all patients. In the patients with small cell cancer, a transient but marked increase in erythropoietin value (204.6 +/- 167.3 mU/ml) was observed after each session of chemotherapy while hemoglobin concentration decreased gradually. Throughout treatments, elevation of the serum iron concentration and concomitant reduction of unsaturated iron binding capacity were observed after each session of chemotherapy. They regained their original values whilst the serum erythropoietin level decreased after each chemotherapy session was completed.. It is suggested that the suppression of erythroid marrow by chemotherapeutic agents causes the changes in serum erythropoietin level during chemotherapy in patients with lung cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Erythropoietin; Female; Hemoglobins; Humans; Iron; Lung Neoplasms; Male; Middle Aged; Protein Binding

Advanced cancer is commonly associated with significant anemia which worsens with the administration of cytotoxic drugs. Erythropoietin (EPO) levels in these patients are usually inappropriately low for the degree of anemia. We evaluated the effect of subcutaneous administration of recombinant human erythropoietin (r-HuEPO) on hematologic parameters and transfusion requirements in anemic cancer patients who were receiving platinum-based chemotherapy. Baseline studies included complete hemogram, reticulocyte count, serum iron, TIBC, ferritin and determination of performance status and quality of life (QOL). Twenty-three patients, 13 females, 10 males with mean age 52 years received 150 units/kg of r-HuEPO three times weekly for a minimum of 10 weeks. They also received supplemental iron. Ovarian cancer was the commonest underlying malignancy. Most of the patients received platinum-based combination chemotherapy. Mean duration of r-HuEPO therapy was 12.6 weeks. Average baseline reticulocyte count was 1.8% which increased to 7.0% after one week therapy. Eight patients had normalization of hemoglobin values. Another eight patients improved their hemoglobin by at least 2 g/dl, however, hemoglobin values remained below the normal range. Two patients had only slight increase in hemoglobin but never required blood transfusion. Three patients who were transfusion dependent had decrease in the transfusion requirements. Two patients had no significant benefit. In most patients response was evident within 2 weeks. All responders had improvement in QOL. No significant toxicity was observed. We conclude that r-HuEPO, given subcutaneously, is highly effective in amelioration of anemia and prevention of or reduction in transfusion requirements in cancer patients receiving platinum-based chemotherapy.

Topics: Activities of Daily Living; Anemia; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Cisplatin; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Injections, Subcutaneous; Iron; Lung Neoplasms; Male; Middle Aged; Neoplasms; Ovarian Neoplasms; Quality of Life; Recombinant Proteins; Reticulocyte Count

Many studies have been done in order to elucidate the pathogenesis of the anaemia of chronic disorders accompanying cancer, with conflicting results. This is probably due to the heterogeneity of the patient population selected for these studies (many patients treated by chemotherapy). To avoid this pitfall, in this study a very homogenous group of chemotherapy and radiotherapy-naive patients with lung cancer were selected. Serum erythropoietin and soluble transferrin receptor measurements suggested that the anaemia of non-treated lung cancer is mainly due to an impaired erythroid marrow response to erythropoietin stimulation. However, a relative inadequacy of erythropoietin production may also contribute.

Topics: Anemia; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Erythropoiesis; Erythropoietin; Female; Humans; Lung Neoplasms; Male; Receptors, Transferrin

We examined the efficacy of low-dose erythropoietin in the management of chemotherapy-related anaemia in patients with small cell lung cancer (SCLC). We gave recombinant human erythropoietin A (rHuEPO) to 63 SCLC patients, 30 with limited disease (LD) and 33 with extensive disease (ED) who underwent chemotherapy with carboplatin, etoposide and ifosfamide and had previously received blood transfusions for chemotherapy-related anaemia. rHuEPO was given at a dose of 2000 IU subcutaneously three times per week for 2 weeks after every chemotherapy cycle, starting 48 h after the end of chemotherapy. Before the use of rHuEPO, all patients in both groups had to be transfused after a mean of 5.5 CT cycles. In 64 CT cycles following administration of rHuEPO, only 5/30 LD patients (17%) had to be transfused in six cycles (9%). In 88 cycles following the use of rHuEPO, 7/33 ED patients (21%) had to be transfused in 11 cycles (12.5%). Haemoglobin values in patients with ED (but not those with LD) were significantly improved after rHuEPO administration on both day 14 and day 28 after chemotherapy. No adverse effects were recorded. rHuEPO considerably decreased the degree of anaemia and the need for blood transfusion at doses markedly lower (25-30 IU/kg body weight) than those reported in the literature so far (150 IU/kg body weight), without toxicity.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Small Cell; Erythropoietin; Etoposide; Humans; Ifosfamide; Lung Neoplasms; Male; Middle Aged; Recombinant Proteins; Retrospective Studies

We have reviewed the incidence of cisplatin-induced anaemia in patients affected with solid tumours treated with at least three courses of first-line cisplatin-containing regimens. In our experience, a low percentage (5%) of patients required transfusions of red blood cells. We think it is of the utmost importance to adopt uniform criteria in monitoring and treatment of patients at risk of developing cisplatin anaemia and to identify subsets of patients to eventually treat with erythropoietin.

Topics: Anemia; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Erythrocyte Transfusion; Erythropoietin; Evaluation Studies as Topic; Female; Humans; Incidence; Lung Neoplasms; Male; Ovarian Neoplasms; Prostatic Neoplasms; Retrospective Studies; Risk Factors

Serial serum erythropoietin (EPO) levels were measured in 12 adult lung cancer patients during cancer chemotherapy. In major cases, EPO levels increased significantly after chemotherapy while the hemoglobin (Hb) remained at initial levels. EPO fell gradually or rapidly to initial levels after a peak, although the patients were anemic. The increase of EPO levels was linearly related to the decrease in Hb (y = 17.48x + 1.003). The mechanism of the rapid increase of EPO is not simply explained by anemia, but might be related to new synthesis, corresponding to depressed bone marrow.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Erythropoietin; Female; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds

Topics: alpha-Fetoproteins; Carcinoma, Small Cell; Erythropoietin; Humans; Lung Neoplasms; Male; Middle Aged; Polycythemia

Recombinant glycosylated erythropoietin (EPO) was biotinylated with biotin-aminocaproyl hydrazide via periodate-treated sialic acid moieties and applied to sections of 64 tumors of the lower respiratory tract, comprising 19 primary adenocarcinomas, 19 epidermoid carcinomas, 13 large cell anaplastic carcinomas, 11 small cell lung carcinomas, 11 intrapulmonary metastases, 1 mesothelioma and 1 lymphocytic interstitial pneumonia. The formalin-fixed, paraffin-embedded specimens were incubated with labelled EPO at room temperature and a concentration of 10 micrograms/ml for 60 min. The expression of the EPO-binding sites was visualized by the ABC technique. All of the analyzed large cell anaplastic carcinomas and the majority of the epidermoid carcinoma (89%), adenocarcinoma (79%), and metastases (82%) displayed binding capacities for EPO. Five out of the eleven small cell lung carcinomas, the analyzed mesothelioma and lymphocytic interstitial pneumonia revealed definite staining, too. Binding sites could, in addition, be seen in air dried, non-fixed, acetone-fixed, and ether-ethanol-fixed cytological specimens. The data indicate that the expression of binding sites with specificity for EPO can be frequently seen in human bronchial malignancies.

Topics: Binding Sites; Biotin; Carcinoma; Erythropoietin; Glycosylation; Humans; Lung; Lung Neoplasms; Mesothelioma; Pneumonia; Receptors, Erythropoietin; Recombinant Proteins

Serum immunoerythropoietin (SIE) levels were studied of 25 randomly chosen cancer patients undergoing cisplatin-based chemotherapy and ten head and neck cancer patients who were studied prospectively before and during cisplatin-based therapy. The SIE levels were determined by standard radioimmunoassay, and the results were interpreted relative to erythropoietin levels and hematocrits of 17 aplastic or nutritionally anemic patients who were believed to have a normal erythropoietin response. Of the 25 randomly chosen patients, SIE levels were inappropriately low in four patients. In this population, there was a greater likelihood of erythropoietin deficiency in the patients with a hematocrit less than 30% compared with those with higher values (P less than 0.001), although there was no correlation between SIE level and the amount of cisplatin these patients received or their degree of renal impairment. Of the ten head and neck cancer patients, five were found to have inappropriately low SIE levels before therapy, and two additional patients had a decrease of SIE levels during therapy, in one patient to an abnormally low level. The anemia associated with malignancy was concluded to be in part associated with a relative erythropoietin deficiency, and in certain individuals, cisplatin therapy may contribute to that deficiency.

Topics: Adult; Aged; Anemia; Carcinoma, Non-Small-Cell Lung; Cisplatin; Cohort Studies; Erythropoietin; Female; Head and Neck Neoplasms; Hematocrit; Humans; Lung Neoplasms; Lymphoma; Male; Middle Aged; Neoplasms; Ovarian Neoplasms; Prospective Studies

The present studies were undertaken to assess the effects of atrial natriuretic factor (ANF) on erythropoietin (Ep) secretion in Ep-producing renal carcinoma (RC) cells using a sensitive radioimmunoassay for Ep. Human ANF produced a significant dose-related increase in Ep secretion at concentrations of 10(-7) and 10(-6) M when compared with vehicle controls. ANF (greater than or equal to 10(-9) M) also significantly increased the intracellular guanosine 3',5'-cyclic monophosphate (cGMP) concentration after 5-min incubation with the RC cells. Scatchard analysis of the human 125I-labeled ANF binding data indicated that the RC cells contain a single class of binding sites with a dissociation constant (Kd) of 93 +/- 1 pM and a binding capacity of 2,190 +/- 750 sites/cell. Incubation of the RC cells with 8-bromo-cGMP in concentrations of 10(-7)-10(-5) M also produced a significant dose-related enhancement of Ep secretion. These findings suggest that the increase in Ep secretion in response to ANF can be attributed, at least in part, to activation of guanylate cyclase, which is coupled to specific ANF receptors on the RC cell.

Topics: Atrial Natriuretic Factor; Carcinoma, Renal Cell; Cyclic GMP; Erythropoietin; Humans; Kidney Neoplasms; Kinetics; Lung Neoplasms; Tumor Cells, Cultured

The relationships between prognostic factors and duration of survival in small cell lung cancer were investigated in a consecutive series of 874 patients treated with combination chemotherapy with or without irradiation. The series included 443 patients with limited and 431 patients with extensive stage disease based on staging including bone marrow examination and peritoneoscopy with liver biopsy but no routine scans. The median durations of survival for the two disease categories were 48 and 30 weeks, respectively. The influence on survival of various pretreatment factors was investigated by use of univariate methods and Cox's multivariate regression model. Patients in each stage were treated according to one of three controlled trials. Variations among the applied treatment regimens did not result in significant differences in duration of survival among patients with limited disease. An alternating regimen was superior to continuous therapy in patients with extensive disease and raised serum lactate dehydrogenase. Prognosis was correlated with disease extent. Surgical resection as well as limited stage disease thus both contributed to survival. Poor performance status, reduced hemoglobin concentration, and raised values for serum lactate dehydrogenase were significantly associated with a reduced duration of survival in both stages. Females with limited disease lived significantly longer than males while advanced age was a negative prognostic factor in extensive disease. Plasma sodium and serum urate were both predictive of survival in limited disease. Proved metastatic disease affecting specific sites or total number of metastatic sites did not carry significant prognostic information in a model including a general variable characterizing stage of disease. Fifty of the 778 patients, on whom the multiple regression model was based, were alive and disease free 2 years after the start of the treatment. Two-year survival rates were strongly correlated to groupings based on prognostic factors, and information about disease extent was not mandatory for predicting the probability of long term disease-free survival.

Topics: Adult; Aged; Alkaline Phosphatase; Carcinoma, Small Cell; Combined Modality Therapy; Erythropoietin; Female; Hormones, Ectopic; Humans; L-Lactate Dehydrogenase; Lung Neoplasms; Male; Middle Aged; Models, Biological; Neoplasm Metastasis; Prognosis; Regression Analysis; Risk; Vasopressins

Measurements of erythropoietin (Ep) levels in patients with the anaemia of chronic disorders due to malignant disease have given variable results. This variation may be due to the wide range of malignancies studied and the assay method (whole animal) used. In this study Ep levels were measured, using the foetal mouse liver assay, in 39 patients with lung cancer and 19 controls. Twelve patients had reduced haemoglobin levels (Hb less than 11.5 g/dl for males and 11 g/dl for females) and the features of the anaemia of chronic disorders. Their mean Ep level was 0.21 iu/ml. This was significantly lower than for the normal controls, whose mean value was 0.31 iu/ml (P less than 0.02). This data supports the concept that lack of an appropriate Ep response to anaemia is one factor in the genesis of anaemia in malignancy.

Topics: Anemia; Biological Assay; Erythropoietin; Female; Hemoglobins; Humans; Iron; Lung Neoplasms; Male

Erythroid-potentiating activity (EPA) was detected in culture medium conditioned by a human cancer cell line (KONT) that produces colony-stimulating activity (CSA), using erythroid colony formation in vitro. EPA in the medium conditioned by the KONT cells (KONT-CM) was markedly heat stable. After treating KONT-CM at 80 degrees C for 30 min, 30% EPA remained, while CSA was completely inactivated. Both EPA and CSA appeared in approximately the same fractions of the gel filtration, indicating a molecular weight of approximately 30,000 daltons. EPA bound partially to Concanavalin-A Sepharose, whereas CSA almost did not bind. Our results indicate that EPA can be separated from CSA based on heat stability and binding to Concanavalin-A Sepharose.

Topics: Cell Division; Clone Cells; Colony-Stimulating Factors; Culture Media; Erythrocytes; Erythropoiesis; Erythropoietin; Hematopoietic Stem Cells; Hot Temperature; Humans; Lung Neoplasms

A young woman who had a right glomus jugulare paraganglioma had diffuse pulmonary metastases three years after surgical excision of the paraganglioma. Associated with these developments were profound anemia and an extraordinarily rapid ESR. These findings have been previously noted in patients with metastatic paraganglioma and have not as yet, to our knowledge, had a satisfactory explanation. Noteworthy in our patient was a diminished serum erythropoietin level, which may indicate that metastatic paragangliomas inhibit production of or interfere with maintenance of serum erythropoietin. Symptomatic palliation of the severe anemia was attained in this patient by injections of nandrolone decanoate. Follow-up examinations of patients with paragangliomas should include surveillance of the CBCs and ESR, both of which may reflect tumor activity.

Topics: Adult; Anemia; Erythropoietin; Female; Glomus Jugulare Tumor; Humans; Lung Neoplasms; Nandrolone; Nandrolone Decanoate; Paraganglioma, Extra-Adrenal

Erythropoietin was measured by exhypoxic polycythemic mouse method in the course of a 64-yr-old male with renal cell carcinoma associated with erythrocytosis. Serum erythropoietin fluctuated with progression of the disease. Preoperative elevated erythropoietin (0.11 U/ml, p greater than 0.05) subsided after nephrectomy and again increased with developing lung metastasis (0.1 U/ml, p greater than 0.02). Erythropoietin was markedly increased in the tumorous extracts from primary renal cell carcinoma in the kidney (0.2 U/g, p greater than 0.01) and lung metastasis (0.8 U/g, p greater than 0.01). Renal cell carcinoma from the lung metastasis was transplanted into nude mice, resulting in erythrocytosis in some of these mic. In the erythrocytotic mice, erythropoietin was elevated to levels of 0.25--0.9 U/g (p greater than 0.01) in the tumorous extracts and increased (0.67 U/ml, p greater than 0.02) in the serum. These results indicate that this renal cell carcinoma is an erythropoietin-producing tumor, and this tumor has been successfully transplanted in nude mice for the first time.

Topics: Adenocarcinoma; Animals; Erythropoietin; Humans; Kidney Neoplasms; Lung Neoplasms; Male; Mice; Mice, Nude; Middle Aged; Neoplasm Metastasis; Neoplasm Transplantation

A case study is presented of a 55-year-old man who had clear cell renal carcinoma with pulmonary metastases and erythrocytosis. The increase in red blood cell mass was associated with an elevation in erythropoietic stimulatory activity in serum, pleural fluid, and tumor-cyst fluid as determined by the exhypoxic polycythemic mouse assay. It is postulated that the increased erythropoietic stimulatory activity represents autonomous tumor secretion of erythropoietin or an erythropoietin-like material. Electron microscopic studies confirmed the proximal tubular origin of this tumor.

Topics: Adenocarcinoma; Erythropoiesis; Erythropoietin; Humans; Hypoxia; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Polycythemia; Renal Veins; Vascular Diseases

Topics: Adrenal Gland Neoplasms; Adult; alpha-Fetoproteins; Carcinoma, Hepatocellular; Erythropoietin; Heart Neoplasms; Hemochromatosis; Humans; Hypoglycemia; Iron; Liver; Liver Neoplasms; Lung Neoplasms; Male; Neoplasm Metastasis; Polycythemia; Precancerous Conditions

Among the malignant tumors of nonendocrine origin that are capable of producing polypeptide hormones and of manifesting as different endocrine syndromes discussed here are ectopic ACTH syndrome, SIADH, and ectopic gonadotropin-producing tumors.

Topics: Adrenocorticotropic Hormone; Carcinoma, Hepatocellular; Carcinoma, Small Cell; Chorionic Gonadotropin; Cushing Syndrome; Diagnosis, Differential; Erythropoietin; Follicle Stimulating Hormone; Gynecomastia; Hormones, Ectopic; Humans; Hyperthyroidism; Hypoglycemia; Hyponatremia; Liver Neoplasms; Lung Neoplasms; Luteinizing Hormone; Male; Paraneoplastic Endocrine Syndromes; Polycythemia; Puberty, Precocious; Thyrotropin; Vasopressins; Water Intoxication

Topics: Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Erythropoietin; Gonadotropins, Pituitary; Growth Hormone; Humans; Insulin; Insulin Secretion; Liver Neoplasms; Lung Neoplasms; Malignant Carcinoid Syndrome; Melanocyte-Stimulating Hormones; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Prolactin; Serotonin; Thymus Neoplasms; Vasopressins

Topics: Adenocarcinoma; Animals; Disease Models, Animal; Erythropoietin; Hematocrit; Kidney; Kidney Neoplasms; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Nephrectomy; Organ Size; Splenic Neoplasms; Time Factors

Topics: Abdominal Neoplasms; Adenocarcinoma; Adenoma; Animals; Carcinogens; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Erythropoietin; Esters; Female; Injections, Intraperitoneal; Lung Neoplasms; Male; Mediastinal Neoplasms; Methane; Neoplasms, Experimental; Nephrectomy; Pituitary Neoplasms; Rats; Sarcoma; Sex Factors; Sulfonic Acids; Thyroid Neoplasms; Time Factors

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Animals; Brain Neoplasms; Child; Child, Preschool; Dogs; Electric Stimulation; Erythropoiesis; Erythropoietin; Ethacrynic Acid; Haplorhini; Humans; Hydronephrosis; Hypertension; Hypothalamus; Infant; Iron Isotopes; Kidney Diseases; Kidney Neoplasms; Lung Neoplasms; Male; Mice; Middle Aged; Polycythemia Vera; Rats; Testicular Neoplasms; Testosterone; Urinary Calculi; Urologic Diseases; Wilms Tumor; Wounds and Injuries

Topics: Adenocarcinoma; Blood Cell Count; Carcinoma, Renal Cell; Epoetin Alfa; Erythropoietin; Geriatrics; Humans; Kidney Neoplasms; Lung Neoplasms; Mercaptopurine; Neoplasm Metastasis; Neoplasms; Neoplasms, Second Primary; Nephrectomy