losartan-potassium and Carcinoma--Non-Small-Cell-Lung

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

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

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

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

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

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

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

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 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

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

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

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

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

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

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 (rhuEpo) is currently under debate for the treatment of chemotherapy-induced anemia due to clinical trials showing adverse effects in Epo-treated patients and the discovery of the erythropoietin-receptor (EpoR) in tumor and endothelial cells. Here, using Epo-Cy5.5 as theranostic near-infrared fluorescent probe we analyzed the effects of rhuEpo as co-medication to carboplatin in non-small-cell-lung-cancer (NSCLC)-xenografts with different tumor cell EpoR-expression (H838 ~8-fold higher than A549). Nude mice bearing subcutaneous A549 and H838 NSCLC-xenografts received either only carboplatin or carboplatin and co-medication of rhuEpo in two different doses. Tumor sizes and relative blood volumes (rBV) were longitudinally measured by 3D-contrast-enhanced ultrasound (3D-US). Tumoral EpoR-levels were determined by combined fluorescence molecular tomography (FMT)/ micro computed tomography (µCT) hybrid imaging. We found that rhuEpo predominantly acted on the tumor endothelium. In both xenografts, rhuEpo co-medication significantly increased vessel densities, diameters and the amount of perfused vessels. Accordingly, rhuEpo induced EpoR-phoshorylation and stimulated proliferation of endothelial cells. However, compared with solely carboplatin-treated tumors, tumor growth was significantly slower in the groups co-medicated with rhuEpo. This is explained by the Epo-mediated vascular remodeling leading to improved drug delivery as obvious by a more than 2-fold higher carboplatin accumulation and significantly enhanced tumor apoptosis. In addition, co-medication of rhuEpo reduced tumor hypoxia and diminished intratumoral EpoR-levels which continuously increased during carboplatin (Cp) -treatment. These findings suggest that co-medication of rhuEpo in well balanced doses can be used to improve the accumulation of anticancer drugs. Doses and indications may be personalized and refined using theranostic EpoR-probes.

Topics: Animals; Antineoplastic Agents; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Disease Models, Animal; Erythropoietin; Female; Heterografts; Humans; Mice, Nude; Neovascularization, Pathologic; Perfusion; Therapeutic Uses

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

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

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

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

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

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

Treating anemia associated with chemotherapy and many cancers is often necessary. However, patient satisfaction with anemia treatment is limited by the lack of validated instruments. We developed and validated a new treatment-specific patient satisfaction instrument: the Patient Satisfaction Questionnaire for Anemia Treatment (PSQ-An). Treatment burden and overall satisfaction scales were designed for ease of use in clinical practice.. 312 cancer patients (141 breast, 69 gynecological, and 102 non-small cell lung) were targeted to complete the PSQ-An at 4 week intervals. Data from weeks 5 and 9 were analyzed. Patients also completed the MOS SF-36 Global Health assessment and questions concerning resources devoted to anemia treatment. Item reduction used endorsement rates, floor/ceiling effects, and item-item correlations. Factor analysis identified meaningful subscales. Test-retest reliability was assessed. Construct validity was tested, using Pearson's correlations, by comparing subscale scores to Global Health, hemoglobin levels, and resources devoted to anemia treatment.. The overall response rate was 92.9% (264/284) at week 5. Most (84.2%) of the patients were female, and the mean (SD) age was 60.2 (+/- 11.8) years. Two distinct subscales were identified measuring treatment burden (7 items) and overall satisfaction (2 items). Test-retest reliability was examined (ICC: 0.45-0.67); both were internally consistent (alpha = 0.83). Both subscales exhibited convergent and divergent validity with independent measures of health. ANOVA results indicated that the PSQ-An Satisfaction subscale discriminated between 5 levels of MOS SF-36 Global Health (P = 0.006).. The PSQ-An is a validated, treatment-specific instrument for measuring satisfaction with anemia treatment for cancer patients. PSQ-An subscales reflect the burden of injection anemia treatment on cancer patients and their assessment of the overall treatment value.

Topics: Aged; Anemia, Hemolytic; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Factor Analysis, Statistical; Female; Genital Neoplasms, Female; Hematinics; Humans; Karnofsky Performance Status; Male; Middle Aged; Multicenter Studies as Topic; Outcome Assessment, Health Care; Patient Satisfaction; Psychometrics; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Surveys and Questionnaires

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

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

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

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

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