losartan-potassium and Carcinoma--Squamous-Cell

Recurrent squamous cell carcinoma of the head and neck (SCCHN) carries a poor prognosis. Tumor hypoxia (TH) has been implicated as one of many factors contributing to SCCHN recurrence. TH leads to radiation resistance by reversing radiation-induced DNA damage. Effective strategies to overcome TH may improve outcomes in patients with SCCHN. We searched the English literature on PubMed and reviewed the reference sections of key articles related to TH (publications spanning from the early 1900s to the present). We summarized the underlying theory of TH in SCCHN, methods for quantifying it, and the numerous therapies developed to modulate it. We included articles that set the foundation of TH as a theory and the most relevant articles published within the last 15 years related to TH quantification and therapeutic targeting. Despite extensive research, targeting TH in SCCHN has not become a part of routine clinical practice in North America, and we analyze the pitfalls in hypoxia research that have led to this failure. We propose that future studies should test a combined approach of targeting the immune system in addition to cellular pathways rendered aberrant in TH and should include development of novel surrogate markers of TH and/or TH imaging.

Topics: Animals; Carcinoma, Squamous Cell; Erythropoietin; Head and Neck Neoplasms; Humans; Hyperthermia, Induced; Oxygen; Squamous Cell Carcinoma of Head and Neck; Tumor Hypoxia

Tumoral microenvironments play a key role in the evolution of solid tumors. Tumor hypoxia is actively involved in the promotion of genetic instability, the invasive capacity of tumor cells, metastasis, and a worsening of the clinical evolution. Endogenous hypoxia markers are controlled by hypoxia-related genes, formed by HIF-1, which is related to several target genes that involve the energy metabolism, angiogenesis, and transmembrane carbonic anhydrases (CAs), mainly CA-IX that is one of the tumor-related carbonic anhydrases. The goal of this paper is to establish the role of CA-IX as a hypoxia marker in OSCC, while analyzing its expression in this type of tumors and its relationship with several clinical and pathological parameters and prognosis, evaluating its relationship with angiogenesis, other hypoxia markers, and clarifying its role in chemotherapy and radiotherapy resistance.

Topics: Antigens, Neoplasm; Antineoplastic Agents; Carbonic Anhydrase IX; Carbonic Anhydrases; Carcinoma, Squamous Cell; Drug Resistance, Neoplasm; Erythropoietin; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glucose Transporter Type 1; Head and Neck Neoplasms; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Ki-67 Antigen; Mouth Neoplasms; Neovascularization, Pathologic; Radiation Tolerance; Receptors, Erythropoietin

The utilisation of nonviral gene delivery methods has been increasing steadily, however, a drawback has been the relative low efficiency of gene transfer with naked DNA compared with viral delivery methods. In vivo electroporation, which has previously been used clinically to deliver chemotherapeutic agents, also enhances the delivery of plasmid DNA and has been used to deliver plasmids to several tissue types, particularly muscle and tumour. Recently, a large number of preclinical studies for a variety of therapeutic modalities have demonstrated the potential of electrically mediated gene transfer. Although clinical trials using gene transfer with in vivo electroporation have not as yet been realised, the tremendous growth of this technology suggests that the first trials will soon be initiated.

Topics: Animals; Carcinoma, Squamous Cell; Electroporation; Erythropoietin; Forecasting; Gene Expression Regulation; Gene Transfer Techniques; Genetic Therapy; Growth Substances; Hematologic Diseases; Humans; Injections, Intramuscular; Interleukin-12; Melanoma; Plasmids; Protein Deficiency; Toxins, Biological; Vaccines, DNA

A review of the incidence and management of anemia in elderly patients with head and neck carcinoma treated with systemic chemotherapy. The role of recombinant human erythropoietin in preventing or correcting chemotherapy-related anemia has been focused. Data concerning the prospective use of recombinant human erythropoietin (rhEpo) in a series of unfit elderly patients (EPs) treated with carboplatin plus 5-fluorouracil. Patients were randomly assigned to receive subcutaneous rhEpo 10,000U three times per week (TIW) (23 elderly patients) or no treatment (22 control patients). Recombinant hEpo was able to prevent anemia and to reduce transfusional requirements in treated patients as compared to untreated controls with a statistically significant difference. rhEpo also caused a positive effect on quality of life (QoL) parameters.

Topics: Aged; Anemia; Antineoplastic Agents; Carcinoma, Squamous Cell; Erythropoietin; Head and Neck Neoplasms; Humans; Incidence; Recombinant Proteins

At the time of first diagnosis, patients with squamous cell carcinoma in the head and neck are often in the advanced stage of their disease, therefore surgery is not a viable option for treatment. These patients also present frequently a high grade of anaemia as a result of either the malignant process itself or of the following therapy. The incidence of anaemia and the need for transfusion depends on several factors, such as the type and intensity of radiotherapy and radiochemotherapy. Multimode therapeutic concepts such as radio-chemotherapy are being applied with increasing frequency, resulting in an ever increasing need for transfusion with great effects on the patient's quality of life. Even more important to tumour patients is the role of the haemaglobin (Hb) value as a prognostic factor for survival and/or local tumour control. A large number of studies show that recombinant human erythropoietin (r-HuEPO) is effective in the treatment of tumour-induced anaemia and prevention and correction of chemotherapy and radiotherapy-induced anaemia. The simultaneous application of r-HuEPO with chemotherapy can prevent patients with head and neck tumours from developing anaemia or can reduce the extent of the anaemia and the need for transfusion. Comparable effects were observed both in patients undergoing platinum-based and non-platinum-based chemotherapy. The direct correlation between anaemia, tumour hypoxia and poor response to radio and/or chemotherapy has been clinically proven. Recombinant human erythropoietin administration improves the therapeutic outcome and the patients' prognosis.

Topics: Anemia; Carcinoma, Squamous Cell; Erythropoietin; Head and Neck Neoplasms; Hemoglobins; Humans; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Quality of Life; Recombinant Proteins; Survival Rate; Treatment Outcome

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: 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

This paper reports long-term results of RTOG 9903, to determine whether the addition of erythropoietin (EPO) would improve the outcomes of radiation therapy (RT) in mildly to moderately anemic patients with head and neck squamous cell carcinoma (HNSCCa).. The trial included HNSCCa patients treated with definitive RT. Patients with stage III or IV disease received concomitant chemoradiation therapy or accelerated fractionation. Pretreatment hemoglobin levels were required to be between 9.0 and 13.5 g/dL (12.5 g/dL for females). EPO, 40,000 U, was administered weekly starting 7 to 10 days before RT was initiated in the RT + EPO arm.. A total of 141 of 148 enrolled patients were evaluable. The baseline median hemoglobin level was 12.1 g/dL. In the RT + EPO arm, the mean hemoglobin level at 4 weeks increased by 1.66 g/dL, whereas it decreased by 0.24 g/dL in the RT arm. With a median follow-up of 7.95 years (range: 1.66-10.08 years) for surviving patients and 3.33 years for all patients (range: 0.03-10.08 years), the 5-year estimate of local-regional failure was 46.2% versus 39.4% (P=.42), local-regional progression-free survival was 31.5% versus 37.6% (P=.20), and overall survival was 36.9% versus 38.2% (P=.54) for the RT + EPO and RT arms, respectively. Late toxicity was not different between the 2 arms.. This long-term analysis confirmed that despite the ability of EPO to raise hemoglobin levels in anemic patients with HNSCCa, it did not improve outcomes when added to RT. The possibility of a detrimental effect of EPO could not be ruled out.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Carcinoma, Squamous Cell; Chemoradiotherapy; Combined Modality Therapy; Disease-Free Survival; Epoetin Alfa; Erythropoietin; Female; Head and Neck Neoplasms; Hematinics; Hemoglobin A; Humans; Male; Middle Aged; Recombinant Proteins; Squamous Cell Carcinoma of Head and Neck; Time Factors

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

To evaluate the effect of epoetin alfa on local disease-free survival (DFS), overall survival (OS), and cancer treatment-related anemia and fatigue in patients with head and neck cancer receiving radical radiotherapy with curative intent.. Patients (N = 301) with hemoglobin (Hb) less than 15 g/dL were randomly assigned in a ratio of 1:1 to receive radiotherapy plus epoetin alfa (10,000 U subcutaneously [SC] three times weekly if baseline Hb was < 12.5 g/dL; 4,000 U SC three times weekly if baseline Hb > or = 12.5 g/dL) or radiotherapy alone. Hb levels were monitored weekly. The primary end point was local DFS, defined as the time from random assignment to local disease recurrence or death. Secondary efficacy end points included OS, local tumor response, and local tumor control. Patients were followed at 1, 4, 8, and 12 weeks postradiotherapy and annually for 5 years. Cancer treatment-related anemia and fatigue were evaluated with the Functional Assessment of Cancer Therapy-Anemia and Functional Assessment of Cancer Therapy-Head and Neck. Adverse events were recorded up to 12 weeks postradiotherapy.. Hb levels increased from baseline with epoetin alfa. The median duration of local DFS was not statistically different between groups (observation, 35.42 months; epoetin alfa, 31.47 months; hazard ratio, 1.04; 95% CI, 0.77 to 1.41). Groups did not significantly differ in DFS, OS, tumor outcomes, or cancer treatment-related anemia or fatigue. No new or unexpected adverse events were observed.. Addition of epoetin alfa to radical radiotherapy did not affect survival, tumor outcomes, anemia, or fatigue positively or negatively in patients with head and neck cancer.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Carcinoma, Squamous Cell; Disease Progression; Disease-Free Survival; Epoetin Alfa; Erythropoietin; Fatigue; Female; Head and Neck Neoplasms; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Recombinant Proteins; Survival Rate

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 topic of this article is the quantitative and semiquantitative assessment of bone marrow signal alteration in magnetic resonance imaging (MRI) of the lumbar spine in patients with tumor anemia during therapy with epoietin beta or placebo.. We examined 32 patients with head or neck cancer (16 epoietin beta, 16 placebo) during radiotherapy in a double-blind multicenter trial. During radiotherapy, the patients underwent epoietin beta therapy for 7-9 weeks. Lumbar spine measurements using T1-w SE, OPP and Turbo- STIR were taken prior to the first epoietin beta or placebo therapy, after the acquired hemoglobin level had been reached, and after the final radiotherapy. The semiquantitative assessment was made blinded by 2 independent radiologists.. We found significant differences between both groups. The first MRI showed normal marrow signals. The second MRI revealed a quantified decrease in bone marrow signal in T1-w SE (p < 0.018) and an increase in OPP (p < 0.01) and Turbo-TIR (p < 0.048) sequences. At the third MR imaging, quantified relative marrow signals returned to baseline level in all sequences. Semiquantitative assessment confirmed these results.. In both analyses, lumbar spine MRI demonstrates significant bone marrow changes in T1-w SE, OPP and Turbo-STIR sequences during epoietin beta therapy.

Topics: Adult; Aged; Anemia; Bone Marrow; Carcinoma, Squamous Cell; Double-Blind Method; Erythropoietin; Female; Follow-Up Studies; Hematocrit; Hemoglobinometry; Humans; Image Processing, Computer-Assisted; Lumbar Vertebrae; Magnetic Resonance Imaging; Male; Middle Aged; Otorhinolaryngologic Neoplasms

To determine whether the addition of recombinant human erythropoietin (Epo) could improve the outcomes of anemic patients receiving definitive radiotherapy for squamous cell carcinoma of the head and neck (SCCHN).. Eligible patients had SCCHN, with a plan for continuous-course definitive radiotherapy (66-72 Gy) with or without chemotherapy. Patients with Stage III or IV SCCHN were required to undergo concurrent chemoradiotherapy and/or accelerated fractionation radiotherapy. Preradiotherapy hemoglobin was required to be between 9.0 g/dL and 13.5 g/dL (12.5 g/dL for women). Patients randomized to Epo received 40,000 U once weekly, starting 7-10 days before start of radiotherapy.. A total of 148 patients were enrolled; 141 were evaluable. Median pretreatment hemoglobin was 12.1 g/dL. Hemoglobin levels at 4 weeks rose by an average of 1.66 g/dL in the Epo arm, compared with an average 0.24 g/dL decrease in the control arm (p = 0.0001). Median follow-up was 2.5 years (3.1 years for surviving patients). There was no statistically significant difference in the primary endpoint of local-regional failure (LRF) rate between the treatment arms. The 3-year LRF rate was 36% for control and 44% for Epo (p = 0.56). There were also no significant differences in local-regional progression-free survival (LRPFS), patterns of failure, overall survival, or toxicity. The 3-year LRPFS rate was 52% for control and 47% for Epo. The overall survival rate was 57% and 56%, respectively.. The addition of Epo to definitive radiotherapy for SCCHN did not improve outcomes. The study was not specifically designed to detect a potential negative association between Epo and tumor progression/survival.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Carcinoma, Squamous Cell; Combined Modality Therapy; Disease-Free Survival; Drug Administration Schedule; Erythropoietin; Female; Head and Neck Neoplasms; Hematinics; Hemoglobin A; Humans; Male; Middle Aged; Recombinant Proteins; Treatment Outcome

This prospective, nonrandomized study evaluates the effectiveness of epoetin alfa to maintain the hemoglobin levels at 12 to 14 g/dL (optimal range for tumor oxygenation) during chemoradiation for Stage III esophageal cancer and its impact on overall survival (OS), metastatic-free survival (MFS), and locoregional control (LC).. Ninety-six patients were included. Forty-two patients received epoetin alfa (150 IU/kg, 3 times a week) during radiotherapy, which was started at hemoglobin less than 13 g/dL and stopped at 14 g/dL or higher. Hemoglobin levels were measured weekly during RT.. Both groups were balanced for age, sex, performance status, tumor length/location, histology, grading, T-stage/N-stage, chemotherapy, treatment schedule, and hemoglobin before RT. Median change of hemoglobin was +0.3 g/dL/wk with epoetin alfa and -0.5 g/dL/wk without epoetin alfa. At least 60% of hemoglobin levels were 12 to 14 g/dL in 64% and 17% of the patients, respectively (p < 0.001). Patients who received epoetin alfa had better OS (32% vs. 8% at 2 years, p = 0.009) and LC (67% vs. 15% at 2 years, p = 0.001). MFS was not significantly different (42% vs. 18% at 2 years, p = 0.09).. The findings suggest that epoetin alfa when used to maintain the hemoglobin levels at 12 to 14 g/dL can improve OS and LC of Stage III esophageal cancer patients.

Topics: Adenocarcinoma; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Epoetin Alfa; Erythropoietin; Esophageal Neoplasms; Female; Fluorouracil; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Radiotherapy Dosage; Recombinant Proteins

To explore the role of religious belief in coping with disease symptoms and treatment-related side effects in patients with head-and-neck cancer under radiotherapy.. Prospectively collected data were used with a cohort of head-and-neck cancer patients treated by radiotherapy and epoetin beta or placebo within a double-blind multicenter trial. All patients were divided into believers and nonbelievers. Answers to a quality of life questionnaire at four points in time during radiotherapy were analyzed according to both groups. Clinical parameters and therapy side effects were controlled regularly.. 62.1% of the patients (66/105) sent back a baseline questionnaire discriminating between believers and nonbelievers. For 34.2% (40/105) data of all four measures could be obtained. On average, believers felt better in all categories of side effects at all points of time before, during and directly after therapy.. Religious faith seems to play an important role in coping strategies of radiotherapy patients. More research in this area would be worthwhile.

Topics: Adaptation, Psychological; Carcinoma, Squamous Cell; Cohort Studies; Data Interpretation, Statistical; Double-Blind Method; Erythropoietin; Female; Follow-Up Studies; Head and Neck Neoplasms; Humans; Interviews as Topic; Male; Neoplasm Staging; Pain; Placebos; Prospective Studies; Quality of Life; Radiotherapy; Radiotherapy Dosage; Recombinant Proteins; Religion and Medicine; Spirituality; Surveys and Questionnaires; Time Factors

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 expand on our experience with the combination of paclitaxel, fluorouracil, hydroxyurea, and twice daily irradiation (T-FHX) and to assess the impact of weekly administration of erythropoietin (r-HuEpo) on transfusion requirements, we conducted a Phase II multi-institutional trial with a simplified 1-h paclitaxel infusion schedule and randomized patients to receive weekly doses of r-HuEpo.. A total of 90 patients with locally advanced head and neck cancers (stage IV, 96%; N(2)/N(3), 66%) were treated on a regimen of 1-h infusion of paclitaxel (100 mg/m(2)/day, day 1), 120-h infusion of 5-fluorouracil (600 mg/m(2)/day, days 0-5); hydroxyurea 500 mg p.o. every 12 h for 11 doses; and radiation 150cGy bid, days 1-5 of each 14-day cycle repeated for five cycles over 10 weeks (7200-7500 cGy). Before initiating therapy, patients were randomized to receive r-HuEpo 40,000 IU s.c. once weekly.. At median follow-up of 40 months, 3-year progression-free survival is 62%, locoregional control is 84%, and systemic control is 79%. Overall survival is 59%. Anemia, leucopenia, dermatitis, and mucositis were the most frequent grade 3 or 4 toxicities. Patients randomized to erythropoietin experienced less grade 2/3 anemia (52 versus 77%; P = 0.02), but transfusion requirements were not significantly different.. T-FHX is an active and tolerable regimen inducing local tumor control and promising survival with organ preservation in high-risk patients. One h infusion of paclitaxel simplified the regimen without compromising efficacy. Addition of erythropoietin does not reduce the need for transfusion with this nonplatinum-containing regimen. T-FHX should be advanced to a randomized trial and compared with a cisplatin-based concomitant regimen.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Combined Modality Therapy; Drug Administration Schedule; Erythropoietin; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Hydroxyurea; Male; Middle Aged; Paclitaxel; Recombinant Proteins; Survival Rate; Treatment Outcome

Anaemia is associated with poor cancer control, particularly in patients undergoing radiotherapy. We investigated whether anaemia correction with epoetin beta could improve outcome of curative radiotherapy among patients with head and neck cancer.. We did a multicentre, double-blind, randomised, placebo-controlled trial in 351 patients (haemoglobin <120 g/L in women or <130 g/L in men) with carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients received curative radiotherapy at 60 Gy for completely (R0) and histologically incomplete (R1) resected disease, or 70 Gy for macroscopically incompletely resected (R2) advanced disease (T3, T4, or nodal involvement) or for primary definitive treatment. All patients were assigned to subcutaneous placebo (n=171) or epoetin beta 300 IU/kg (n=180) three times weekly, from 10-14 days before and continuing throughout radiotherapy. The primary endpoint was locoregional progression-free survival. We assessed also time to locoregional progression and survival. Analysis was by intention to treat.. 148 (82%) patients given epoetin beta achieved haemoglobin concentrations higher than 140 g/L (women) or 150 g/L (men) compared with 26 (15%) given placebo. However, locoregional progression-free survival was poorer with epoetin beta than with placebo (adjusted relative risk 1.62 [95% CI 1.22-2.14]; p=0.0008). For locoregional progression the relative risk was 1.69 (1.16-2.47, p=0.007) and for survival was 1.39 (1.05-1.84, p=0.02).. Epoetin beta corrects anaemia but does not improve cancer control or survival. Disease control might even be impaired. Patients receiving curative cancer treatment and given erythropoietin should be studied in carefully controlled trials.

Topics: Anemia; Antineoplastic Protocols; Carcinoma, Squamous Cell; Comorbidity; Disease-Free Survival; Erythropoietin; Head and Neck Neoplasms; Humans; Proportional Hazards Models; Radiation Oncology; Recombinant Proteins; Treatment Outcome

The goal of this National Cancer Institute-sponsored phase I trial is to determine the feasibility, toxicity, and pharmacokinetics of continuous-infusion (24 hr/d, 7 d/wk, 7-week total) intravenous paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combined with standard curative radiotherapy (RT) for previously untreated, locally advanced head and neck squamous cell cancers. Eligible patients have squamous cell cancers of the head and neck with expected 5-year survival rates of < or =25%; a good performance status; adequate hematologic, hepatic, and renal functions; and no distant metastases. All patients receive 70 Gy megavoltage RT in 7 weeks (2 Gy/d x 5 d/wk). Paclitaxel is delivered by protracted venous infusion starting 48 hours before RT and continuing for its duration. Biopsies for cell-cycle distribution analyses and paclitaxel tissue levels are obtained, if possible, before beginning paclitaxel and after 48 hours just before RT begins. The dose of paclitaxel is escalated in cohorts of three patients. Eighteen patients are evaluable for toxicity. Treatment has been completed through the 6.5 mg/m2/d dose level and is ongoing at 10.5 mg/m2/d. There has been no dose-limiting toxicity thus far. With the exception of anemia, toxicity is commensurate with what would be expected from RT alone. A slowly progressive normocytic anemia with no renal dysfunction was found to be associated with an acquired hypoerythropoietin state. Tumor biopsies have suggested the possibility of paclitaxel-induced mitotic arrest. This therapy is feasible and has been well tolerated through current dose levels with no dose-limiting toxicity. There is a suggestion of biologic activity evidenced by the anemia and the possibility of alteration in cell-cycle distributions. Dose escalation is ongoing.

Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Squamous Cell; Combined Modality Therapy; Erythropoietin; Female; Head and Neck Neoplasms; Hemoglobinometry; Humans; Infusions, Intravenous; Male; Paclitaxel

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 evaluate erythropoietin-producing hepatocellular carcinoma (Eph)/Eph receptor-interaction protein (ephrin) expression in oral squamous cell carcinoma (OSCC) and oral epithelial precursor lesions (OEPLs), EphA2, EphB4, and ephrinB2 were examined and compared with microvessel density (MVD) and lymphatic vessel density (LVD). Samples from 73 OSCC and 43 OEPLs patients were immunohistochemically analyzed with antibodies against EphA2, EphB4, ephrinB2, CD34, and D2-40. Results were compared with clinicopathological findings. Immunohistochemical reactivity for EphA2, EphB4, and ephrinB2 was detected in epithelial cells and some stromal vascular cells in OEPLs and OSCC, proportionately with the level of malignancy. The number of blood vessel endothelial cells stained with CD34 and lymphatic vessel endothelial cells stained with D2-40 was increased in OEPLs and OSCC. In OSCC, ephrinB2 and EphB4 exhibited significant correlation with recurrence and invasion depth, respectively. MVD was significantly lower in slight lymphocytic reaction than in prominent stromal reaction. Association was found between LVD and T classification, postoperative metastasis, survival, mode of invasion, and invasion depth. Expression of EphA2, EphB4, ephrinB2, MVD, and LVD might be associated with malignant potential of the oral epithelium. Angiogenesis and lymphangiogenesis appear to be related to progression of potentially malignant oral lesions.

Topics: Carcinoma, Squamous Cell; Endothelial Cells; Ephrins; Erythropoietin; Humans; Mouth Neoplasms; Neoplasm Recurrence, Local

Topics: Anemia; Blood Transfusion; Carcinoma, Squamous Cell; Cell Hypoxia; Clinical Trials as Topic; Erythropoietin; Etanidazole; Female; Head and Neck Neoplasms; Humans; Male; Misonidazole; Radiation-Sensitizing Agents; Receptors, Erythropoietin; Treatment Failure; Uterine Cervical Neoplasms

Topics: Anemia; Carcinoma, Squamous Cell; Erythropoietin; Female; Head and Neck Neoplasms; Hematinics; Hemoglobin A; Humans; Male

We report a case of an 80-year-old Caucasian woman on maintenance hemodialysis for almost three years through a right-tunneled jugular catheter. She presented with recurrent epistaxis for which she was periodically blood transfused despite erythropoietin therapy. She continued manifesting epistaxis, which was progressively emerging as a sign related to superior vena cava syndrome due to mediastinal mass. Laboratory investigations revealed active immunological abnormalities thereafter. Malignant superior vena syndrome remains an uncommon com-plication in this population related to a history of or ongoing central vein catheterization. Prolonged oozing from the vascular site was the first alerting sign of the existence of this syndrome. We conclude that sometimes the transformation of undifferentiated connective tissue disease in the presence of epidermoid carcinoma of the superior mediastinum may be revealed during the use of catheters in dialysis.

Topics: Aged, 80 and over; Blood Transfusion; Carcinoma, Squamous Cell; Cell Differentiation; Epistaxis; Erythropoietin; Female; Hematinics; Humans; Kidney Failure, Chronic; Mediastinal Neoplasms; Recurrence; Renal Dialysis; Risk Factors; Superior Vena Cava Syndrome; Tomography, X-Ray Computed; Treatment Outcome

Conflicting results have been reported for adeno- and adenosquamous carcinomas of the cervix with respect to their response to therapy and prognosis. The current study sought to evaluate impact of adeno- and adenosquamous histology in the randomized trials of primary cisplatin-based chemoradiation for locally advanced cervical cancer.. Patients with adeno- and adenosquamous cervical carcinomas were retrospectively studied and compared to squamous cell carcinomas in GOG trials of chemoradiation.. Among 1671 enrolled in clinical trials of chemoradiation, 182 adeno- and adenosquamous carcinomas were identified (10.9%). A higher percentage of adeno- and adenosquamous carcinomas were stage IB2 (27.5% versus 20.0%) and fewer had stage IIIB (21.4% versus 28.6%). The mean tumor size was larger for squamous than adeno- and adenosquamous. Adeno- and adenosquamous carcinomas were more often poorly differentiated (46.2% versus 26.8%). When treated with radiation therapy alone, the 70 patients with adeno- and adenosquamous carcinoma of the cervix showed a statistically poorer overall survival (p=0.0499) compared to the 647 patients with squamous cell carcinoma of the cervix. However, when treated with radiation therapy with concurrent cisplatin-based chemotherapy, the 112 patients with adeno- and adenosquamous carcinomas had a similar overall survival (p=0.459) compared the 842 patients with squamous cell carcinoma. Adverse effects to treatment were similar across histologies.. Adeno- and adenosquamous carcinomas of the cervix are associated with worse overall survival when treated with radiation alone but with similar progression-free and overall survival compared to squamous cell carcinomas of the cervix when treated with cisplatin based chemoradiation.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Adenosquamous; Carcinoma, Squamous Cell; Chemoradiotherapy; Cisplatin; Erythropoietin; Female; Fluorouracil; Humans; Hydroxyurea; Middle Aged; Multivariate Analysis; Neoplasm Staging; Prognosis; Proportional Hazards Models; Radiotherapy; Recombinant Proteins; Retrospective Studies; Treatment Outcome; Tumor Burden; Uterine Cervical Neoplasms

Several studies on the use of erythropoietin (Epo) to treat anaemia in patients undergoing cancer treatment have shown adverse effects on tumour control and survival. Experimental studies indicate that this could be linked to an interaction with wound healing processes and not an effect on tumour cells per se. We have previously shown that erythropoietin in combination with surgical trauma stimulates tumour growth. In the present study, we investigated the effect of surgery and Epo on gene expression.. Human tumours from oral squamous cell cancer were xenotransplanted to nude mice treated with Epo. The tumours were then transected in a standardised procedure to mimic surgical trauma and the change in gene expression of the tumours was investigated by microarray analysis. qRT-PCR was used to measure the levels of mRNAs of pro-apoptotic genes. The frequency of apoptosis in the tumours was assessed using immunohistochemistry for caspase-3.. There was little change in the expression of genes involved in tumour growth and angiogenesis but a significant down-regulation of the expression of genes involved in apoptosis. This effect on apoptosis was confirmed by a general decrease in the expression of mRNA for selected pro-apoptotic genes. Epo-treated tumours had a significantly lower frequency of apoptosis as measured by immunohistochemistry for caspase 3.. Our results suggest that the increased tumour growth during erythropoietin treatment might be due to inhibition of apoptosis, an effect that becomes significant during tissue damage such as surgery.This further suggests that the decreased survival during erythropoietin treatment might be due to inhibition of apoptosis.

Topics: Animals; Apoptosis; Carcinoma, Squamous Cell; Caspases; Cell Line, Tumor; Cell Proliferation; Erythropoietin; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Mice; Mice, Nude; Neoplasm Transplantation

This study investigated the prognostic role of tumor cell expression of erythropoietin (EPO) and its receptor (EPO-R) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) treated with surgery plus radiotherapy.. The impact of EPO, EPO-R, and 11 additional factors on locoregional control (LRC), metastases-free survival (MFS), and overall survival (OS) was retrospectively evaluated in 144 patients. Additional factors were age, gender, performance status, preradiotherapy (pre-RT) hemoglobin levels, tumor site, histologic grade, T category, N category, human papillomavirus (HPV) status, extent of resection, and chemotherapy. Univariate analyses were performed with the Kaplan-Meier method and the log-rank test, multivariate analyses with the Cox proportional hazard model.. On multivariate analysis, improved LRC was significantly associated with no EPO expression (risk ratio [RR] 3.72; 95 % confidence interval [CI] 1.35-15.42; p = 0.008), lower T category (RR 1.60; 95 %CI 1.14-2.32; p = 0.005), and oropharynx or larynx cancer (RR 1.23; 95 %CI 1.02-1.49; p = 0.033). Improved MFS was significantly associated with no EPO expression (RR 5.45; 95 %CI 1.13-97.81; p = 0.031), lower T category (RR 1.66; 95 %CI 1.11-2.65; p = 0.013), lower N category (RR 2.44; 95 %CI 1.04-6.66; p = 0.039), HPV positivity (RR 3.14; 95 %CI not available; p = 0.034), and oropharynx or larynx cancer (RR 1.28; 95 %CI 1.01-1.61; p = 0.041). Improved OS was significantly associated with no EPO expression (RR 4.77; 95 %CI 1.63-20.68; p = 0.003), no EPO-R expression (RR 2.36; 95 %CI 1.22-4.92; p = 0.010), lower T category (RR 1.44; 95 %CI 1.04-2.04; p = 0.027), oropharynx or larynx cancer (RR 1.30; 95 %CI 1.08-1.57; p = 0.007), and pre-RT hemoglobin ≥ 12 g/dl (RR 1.94; 95 %CI 1.03-3.65; p = 0.042).. EPO expression of tumor cells was an independent prognostic factor for LRC, MFS, and OS. EPO-R expression was an independent prognostic factor for OS.

Topics: Carcinoma, Squamous Cell; Chemoradiotherapy, Adjuvant; Combined Modality Therapy; Erythropoietin; Female; Humans; Laryngeal Neoplasms; Larynx; Male; Middle Aged; Multivariate Analysis; Neoplasm Grading; Oropharyngeal Neoplasms; Oropharynx; Prognosis; Receptors, Erythropoietin; Survival Rate

We describe the first reported case, in an 82-year-old man, of erythrocytosis caused by an erythropoietin (EPO)-producing thymic carcinoma. The patient underwent computed tomography-guided fine-needle aspiration of a 6-cm anterior mediastinal mass, and histological findings revealed thymic squamous cell carcinoma. The existence of EPO was confirmed immunohistochemically using the tumor tissue. Postoperative clinical improvement of erythrocytosis and the decline of EPO suggest a paraneoplastic nature of erythrocytosis as seen in this patient.

Topics: Aged, 80 and over; Biopsy, Fine-Needle; Carcinoma, Squamous Cell; Erythropoietin; Humans; Immunohistochemistry; Male; Paraneoplastic Syndromes; Phlebotomy; Polycythemia; Thymectomy; Thymoma; Thymus Neoplasms; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

Erythropoiesis-stimulating agents (ESAs) are used in cancer therapy to reverse anaemia. It has been suggested that ESAs might improve treatment outcome by reducing tumour hypoxia, but ESAs might also increase tumour growth. In this work, the effect of recombinant human erythropoietin (rHuEpo) beta was investigated on a human head and neck squamous carcinoma cell (HNSCC) line in vitro. The cell line was previously growth stimulated in combination with surgery in a xenograft model and the investigation was initiated to see if rHuEpo directly affects the tumour cell line, alone or in combination with cell stress, or if the in vivo effect should be attributed to secondary effects.. The cell line LU-HNSCC-7 was grown in vitro and treated with rHuEpo alone or in combination with radiation, cisplatin, hypoxia or tumour extracts. The expression of the Epo receptor (EpoR) was investigated by western blotting after one- and two-dimensional electrophoresis, RT-PCR and through analysis of the effect on EpoR signalling.. The cell line was shown not to express EpoR. Furthermore, it was only possible to detect a minor effect on cell growth (1.4 times over control, p < 0.001) under specific conditions and at supra-pharmacological concentrations of rHuEpo beta. No effect was detected on cell migration. None of the cell stressing treatments could enhance the minor growth stimulatory effect of rHuEpo beta.. The conclusion is that rHuEpo beta does not stimulate tumour growth of the investigated cell line through a direct interaction with tumour cells. We hypothesise that interactions with stromal cells and the stimulation of wound healing responses might, at least partly, explain the negative effects of ESA administration during cancer treatment. We propose that EpoR expression in HNSCC tumour cells might not be a good marker for prediction of ESA induced worsening of outcomes after cancer treatment.

Topics: Anemia; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Erythropoietin; Head and Neck Neoplasms; Humans; Prognosis; Receptors, Erythropoietin; Recombinant Proteins; Treatment Outcome

Despite its primary hematopoietic function, erythropoietin (Epo) is a pleiotropic cytokine that exerts various biological functions in many different non-hematopoietic cells and cancers, and its stimulatory effects are mediated through activation of its receptor (EpoR). Recent studies have shown that Epo and EpoR may be involved in carcinogenesis, angiogenesis, and invasion. We have investigated the expression of Epo and EpoR in a series of 65 resected squamous cell carcinomas (SCC) of the tongue using immunohistochemical staining. The proportion of Epo and EpoR changes in them was greater than those in normal squamous epithelium (P<0.05). Epo expression was associated with age, density of microvessels, and the stage of the tumour (P<0.05). EpoR expression was associated with microvascular density alone (P<0.05). After adjusting for other clinicopathological factors, Epo and EpoR expression remained independent adverse prognosticators for postoperative survival (P<0.05). Our findings support the hypothesis that the Epo and EpoR systems influence the prognosis of carcinogenesis, angiogenesis, and malignant progression of SCC of the tongue, and confirm that Epo and EpoR are independent prognostic markers.

Topics: Adult; Age Factors; Aged; Carcinoma, Squamous Cell; Erythropoietin; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Neovascularization, Pathologic; Prognosis; Proportional Hazards Models; Receptors, Erythropoietin; Tongue Neoplasms

To investigate the impact of tumor erythropoietin receptors (Epo-R) and erythropoietin (Epo) expression in 64 patients with Stage III esophageal cancer receiving or not receiving erythropoietin during chemoradiation.. The impact of tumor Epo-R expression, Epo expression, and 10 additional factors (age, Karnofsky-Performance-Score [KPS], tumor length, T and N stage, histology and grading, hemoglobin during radiotherapy, erythropoietin administration, surgery) on overall survival (OS) and locoregional control (LC) was evaluated.. Improved OS was associated with low (< or =20%) Epo expression (p = 0.049), KPS >80 (p = 0.008), T3 stage (p = 0.010), hemoglobin > or =12 g/dL (p < 0.001), and surgery (p = 0.010). Erythropoietin receptor expression showed a trend (p = 0.09). Locoregional control was associated with T stage (p = 0.005) and hemoglobin (p < 0.001), almost with erythropoietin administration (p = 0.06). On multivariate analyses, OS was associated with KPS (p = 0.045) and hemoglobin (p = 0.032), LC with hemoglobin (p < 0.001). Patients having low expression of both Epo-R and Epo had better OS (p = 0.003) and LC (p = 0.043) than others. Two-year OS was nonsignificantly better (p = 0.25) in patients with low Epo-R expression receiving erythropoietin (50%) than in those with higher Epo-R expression receiving erythropoietin (21%), low Epo-R expression/no erythropoietin administration (29%), or higher Epo-R expression/no erythropoietin administration (18%). Two-year LC rates were, respectively, 65%, 31%, 26%, and 29% (p = 0.20). Results for Epo expression were similar.. Higher Epo-R expression or Epo expression seemed to be associated with poorer outcomes. Patients with low expression levels receiving erythropoietin seemed to do better than patients with higher expression levels or not receiving erythropoietin. The data need to be confirmed in a larger series of patients.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Carcinoma, Squamous Cell; Combined Modality Therapy; Disease Progression; Erythropoietin; Esophageal Neoplasms; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Proteins; Prognosis; Receptors, Erythropoietin; Retrospective Studies; Treatment Outcome

To attempt to improve results of chemoradiation for head and neck cancer.. From March 1996 to April 2007, 98 patients with head and neck cancer (15 Stage III and 83 Stage IV) were treated with a twice-daily hyperfractionated schedule. Eleven patients presented with N0, 11 with N1, 13 with N2A, 17 with N2B, 24 with N2C, and 22 with N3. Each fraction of treatment consisted of 5 mg/m(2) of carboplatin plus 115 cGy with carbogen breathing. Treatment was given 5 days per week up to total doses of 350 mg/m(2) of carboplatin plus 8050 cGy in 7 weeks. Anemia was corrected with erythropoietin.. Ninety-six patients tolerated the treatment as scheduled. All patients tolerated the planned radiation dose. Local toxicity remained at the level expected with irradiation alone. Chemotherapy toxicity was moderate. Ninety-seven complete responses were achieved. After 11 years of follow-up (median, 81 months), actuarial locoregional control, cause-specific survival, overall survival, and nodal control rates at 5 and 10 years were, respectively, 83% and 83%, 68% and 68%, 57% and 55%, and 100% and 100%. Median follow-up of disease-free survivors was 80 months. No significant differences in survival were observed between the different subsites or between the pretreatment node status groups (N0 vs. N+, N0 vs. N1, N0 vs. N2A, N0 vs. N2B, N0 vs. N2C, and N0 vs. N3).. Improving results of chemoradiation for advanced head and neck cancer up to the level obtained with current treatments for early-stage tumors is a potentially reachable goal.

Topics: Administration, Inhalation; Adult; Aged; Anemia; Antineoplastic Agents; Carbon Dioxide; Carboplatin; Carcinoma, Squamous Cell; Clinical Protocols; Combined Modality Therapy; Disease-Free Survival; Dose Fractionation, Radiation; Erythropoietin; Female; Follow-Up Studies; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasm Staging; Oxygen; Radiation Injuries; Radiation-Sensitizing Agents; Recombinant Proteins; Salvage Therapy

Malignant phenotypic traits are caused by microenvironmental selection pressures during carcinogenesis. Hypoxia can drive a tumor toward a more aggressive malignant phenotype. The objective was to better understand the role of the hypoxia-regulated genes in cervical carcinogenesis.. We analyzed the expression of the hypoxia-regulated genes, including hypoxia-inducible factor-1alpha (HIF-1alpha), erythropoietin (Epo), vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT1), carbonic anhydrase IX (CAIX), and MET, in cervical cell lines and human tissue samples of cervical intraepithelial neoplasia (CIN I-III) and invasive squamous cell carcinoma (ISCC).. CAIX and MET were expressed in cervical carcinoma cell lines, but not in normal or human papillomavirus-immortalized cervical cells. In clinical tissue samples, Epo, VEGF, GLUT1, and CAIX were not detected in normal squamous epithelia. GLUT1 was expressed in nearly all cases of CIN and ISCC, however, CAIX was expressed only in CIN III and ISCC. HIF-1alpha and MET expression was confined to the basal cells in normal squamous epithelia and was detected in the dysplastic cells of CIN and ISCC.. The role of HIF-1alpha and MET changes from response to proliferation to tumor progression during cervical carcinogenesis. GLUT1 expression, a glycolytic phenotype adaptive to glycolysis, occurs early during cervical carcinogenesis and is a specific marker for dysplasia or carcinoma. MET and CAIX may contribute tumor progression in later stage. CAIX expression, an acid-resistant phenotype, may be a powerful adaptive advantage during carcinogenesis. Successful adaptation to the hypoxia-glycolysis-acidosis sequence in a microenvironment is crucial during carcinogenesis.

Topics: Blotting, Western; Carcinoma, Squamous Cell; Cell Hypoxia; Cell Line, Tumor; Cell Transformation, Neoplastic; Erythropoietin; Female; Gene Expression Regulation, Neoplastic; Glucose Transporter Type 1; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Middle Aged; Papillomaviridae; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Jehovah's Witnesses' religious convictions disallow blood transfusion. Major surgery in these patients is therefore problematic. The objective of this study is to describe our experience with microvascular reconstruction of complex head and neck defects in Jehovah's Witness patients.. This was a retrospective review of all Jehovah's Witnesses' patients undergoing head and neck free-flap reconstruction at a tertiary academic referral center from 1997 to 2006.. Five Jehovah's Witnesses patients underwent a total of 7 free-flap reconstructions (6 radial, 1 rectus). Four flaps were immediate: 1 osteocutaneous radial forearm, 2 fasciocutaneous radial forearm, and 1 rectus abdominus myocutaneous. One fasciocutaneous radial forearm flap was staged. Two patients were planned secondary reconstructions, both facsciocutaneous radial forearm. Iron supplements and/or erythropoietin were administered perioperatively in 6 of the 7 microvascular reconstructions. Selective external carotid embolization was performed preoperatively in 1 patient. Hematocrit levels were 36% to 46% preoperatively and 30% to 41% postoperatively. Immediate postoperative hematocrit decline was 5.2% (3.0% to 6.0%). No transfusions or blood products were administered.. Our case series supports the feasibility of head and neck free-flap reconstruction in these challenging patients.

Topics: Adenocarcinoma; Aged; Carcinoma, Squamous Cell; Carotid Artery, External; Embolization, Therapeutic; Erythropoietin; Female; Ferrous Compounds; Head and Neck Neoplasms; Hematocrit; Humans; Jehovah's Witnesses; Male; Microsurgery; Middle Aged; Perioperative Care; Preoperative Care; Retrospective Studies; Surgical Flaps; Treatment Outcome

Tumor-induced anemia often occurs in cancer patients, and is corrected by recombinant human erythropoietins (rHuEPOs). Recent studies indicated that, besides erythroid progenitor cells, tumor and endothelial cells express erythropoietin receptor (EPOR) as well; therefore, rHuEPO may affect their functions. Here, the effect of rHuEPOalpha on irradiation in EPOR-positive human squamous cell carcinoma xenograft was tested.. A431 tumor-bearing SCID mice were treated from the tumor implantation with rHuEPOalpha at human-equivalent dose. Xenografts were irradiated (5 Gy) on day 14, and the final tumor mass was measured on day 22. The systemic effects of rHuEPOalpha on the hemoglobin level, on tumor-associated blood vessels and on hypoxia-inducible factor-(HIF-)1alpha expression of the tumor xenografts were monitored. The proliferation, apoptosis and clonogenic capacity of A431 cancer cells treated with rHuEPOalpha and irradiation were also tested in vitro.. In vitro, rHuEPOalpha treatment alone did not modify the proliferation of EPOR-positive A431 tumor cells but enhanced the effect of irradiation on proliferation, apoptosis and clonogenic capacity. In vivo, rHuEPOalpha administration compensated the tumor-induced anemia in SCID mice and decreased tumoral HIF-1alpha expression but had no effect on tumor growth. At the same time rHuEPOalpha treatment significantly increased the efficacy of radiotherapy in vivo (tumor weight of 23.9 +/- 4.7 mg and 34.9 +/- 4.6 mg, respectively), mediated by increased tumoral blood vessel destruction.. rHuEPOalpha treatment may modulate the efficacy of cancer radiotherapy not only by reducing systemic hypoxia and tumoral HIF-1alpha expression, but also by destroying tumoral vessels.

Topics: Animals; Apoptosis; Carcinoma, Squamous Cell; Cell Division; Cell Line, Tumor; Erythropoietin; Female; Humans; In Vitro Techniques; Mice; Mice, SCID; Neoplasm Transplantation; Radiation-Sensitizing Agents; Recombinant Proteins; Soft Tissue Neoplasms; Transplantation, Heterologous; Tumor Stem Cell Assay

According to recent data erythropoietin receptor (EPOR) is expressed not only by bone marrow erythroid progenitors but by endothelial- and cancer cells and it was suggested that erythropoietin (EPO) may affect their functions as well. We have analyzed the effects of recombinant human erythropoietin-alpha (rHuEPOalpha) on radiation sensitivity of EPOR+ human epidermoid carcinoma (A431) xenograft model. In vivo rHuEPOalpha treatment was started after tumor cell inoculation into SCID mice. 5 Gy irradiation was performed on day 14, the effect of which was measured on day 22. Hemoglobin level, tumor-associated microvessels and HIF-1alpha expression of the xenograft were monitored during the experiment. rHuEPOalpha administration prevented the development of tumor-induced anemia of SCID mice and reduced the level of HIF-1alpha expression of the xenograft tumor without affecting tumor growth. We have found that rHuEPOalpha treatment significantly increased the efficacy of antitumor effect of irradiation which was partly mediated by complex effects on tumor-associated microvessels. In vitro rHuEPOalpha did not affect proliferation of A431 cells but enhanced the antiproliferative and proapoptotic effects of irradiation. We concluded that rHuEPOalpha administration positively modulated the antitumoral effects of irradiation at least by two pathways, decreasing systemic hypoxia resulting in decreased tumoral HIF-1alpha expression and enhancing direct effects on tumor-associated microvessels.

Topics: Anemia, Hypochromic; Animals; Carcinoma, Squamous Cell; Cell Line, Tumor; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, SCID; Microcirculation; Polymerase Chain Reaction; Radiation-Sensitizing Agents; Recombinant Proteins; Transplantation, Heterologous

Treatment of anaemia with recombinant human erythropoietin beta (rHuEpo) in patients with squamous cell carcinoma of the head and neck (HNSCC) undergoing curative radiotherapy does not improve cancer control. In fact, incompletely resected patients with HNSCC receiving radiation in combination with rHuEpo showed poorer loco-regional progression-free survival than patients receiving radiation in combination with placebo. It could be hypothesized that the effects of rHuEpo on tumour cell growth might only be manifested in vivo and after cell trauma, and that treating anaemia with rHuEpo might contribute to poor outcome after incomplete surgical resection.. The aim of the present study was to examine the effect of rHuEpo alone and in combination with surgical trauma on the growth of human squamous cell carcinoma in vivo, xenografted onto nude mice.. The surgical trauma was inflicted through subcutaneous transection of the tumour with a needle. Immunohistochemical staining verified expression of the EPO receptor in tumour cells.. rHuEpo alone had no effect on the growth of xenografted HNSCC. However, a significant increase in tumour growth was observed after surgical trauma in combination with rHuEpo compared with surgery alone (p = 0.0008).

Topics: Animals; Carcinoma, Squamous Cell; Cell Division; Cell Transformation, Neoplastic; Cheek; Erythropoietin; Humans; Mice; Mice, Nude; Mouth Neoplasms; Neoplasm Recurrence, Local; Neoplasm Transplantation; Recombinant Proteins; Xenograft Model Antitumor Assays

Darbepoietin alfa (DA) is a long-acting analogue of erythropoietin that has reduced receptor affinity and enhanced biological activity. Experiments were done to test the hypothesis that correction of anemia in tumor-bearing mice by DA would increase tumor oxygenation and potentiate radiation-induced tumor cell killing. A SCC VII tumor model was used to study tumor responses to fractionated radiation therapy in mice with anemia induced by total body irradiation. Administration of DA reduced the extent and duration of anemia and associated tumor hypoxia, protected the bone marrow cells and prevented the body weight loss from the effect of irradiation, and facilitated the recovery in a time-dependent manner, with the administration of DA prior to total body irradiation having the greatest protective effect. When combined with fractionated radiation therapy, DA increased the tumor growth delay time from 2.7 days for irradiation alone to 7.3 to 10.6 days for combination of DA and irradiation. The effect of DA on tumor responses to fractionated radiation therapy was observed when DA was given 18 to 4 days before starting radiation therapy, but DA was also equally effective as a radiosensitizer when given only 2 hours before fractionated irradiation therapy. Weekly dosing of DA was as efficacious for the enhancement of radiation responses of tumors as biweekly dosing. Similar results were obtained in the RIF-1 fibrosarcoma tumor model. These studies show that DA can effectively correct anemia in tumor-bearing mice and sensitize tumor cells to fractionated radiation therapy. Importantly, DA was also able to sensitize tumors to radiation in mice with uncorrected anemia and hypoxia, suggesting that the effect of DA on radiosensitivity was independent of these factors and a different mechanism of action may be responsible for this effect.

Topics: Anemia; Animals; Carcinoma, Squamous Cell; Darbepoetin alfa; Disease Models, Animal; Erythropoietin; Kinetics; Male; Mice; Mice, Inbred C3H; Radiotherapy; Whole-Body Irradiation

It has been suggested that hemoglobin levels of 12-14 g/dL are optimal for tumor oxygenation, radiosensitivity, and prognosis. In this prospective study, the authors evaluated the effectiveness of epoetin-alpha to maintain hemoglobin levels at 12-14 g/dL during radiotherapy (RT) for patients with UICC Stage III esophageal carcinoma, and they examined the impact of erythropoetin on overall survival (OS), metastatic-free survival (MFS), and local control (LC).. Sixty patients who received RT between March, 2001 and September, 2004, were included in this prospective, nonrandomized study. Thirty patients received epoetin-alpha (150 IU/kg 3 times per week) during RT (Group A), and 30 patients did not receive epoetin-alpha (Group B). Epoetin-alpha was started at hemoglobin levels < 13 g/dL and was stopped at hemoglobin levels > or = 14 g/dL. Hemoglobin was measured before RT and once weekly during RT.. Both patient groups were balanced for age, gender, performance status, tumor location/length, histology, grading, tumor classification, lymph node status, chemotherapy, treatment (45-50.4 grays [Gy] plus resection vs. 45.0-50.4 Gy vs. 59.4-66.0 Gy), and hemoglobin level before RT. In 20 of 30 patients (67%) from Group A and in 3 of 30 patients (10%) from Group B, > or = 60% of hemoglobin levels during RT were 12-14 g/dL (P = 0.003). The median change in hemoglobin was + 0.4 g/dL per week in Group A and - 0.4 g/dL per week in Group B. LC was significantly better in Group A (66% vs. 38% at 1 year, respectively; P = 0.012), a trend was observed for OS (59% vs. 33%, respectively; P = 0.08), and MFS did not differ significantly (43% vs. 38%, respectively; P = 0.34). No epoetin-alpha-related toxicity was observed.. Epoetin-alpha was effective in maintaining the hemoglobin levels at 12-14 g/dL during RT. The application of epoetin-alpha significantly improved LC, and a trend was observed for OS.

Topics: Adenocarcinoma; Carcinoma, Squamous Cell; Combined Modality Therapy; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Esophageal Neoplasms; Female; Gamma Rays; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Survival Rate

Originally characterized as a growth factor for erythrocytes, erythropoietin (EPO) is used to treat anemia and fatigue in cancer patients receiving radiation therapy and chemotherapy. EPO and the EPO receptor (EPOR) are expressed in nonhematopoietic cells and cancers. However, the role of EPO and EPOR within nonhematopoietic cancer cells remains incompletely understood. Although a recent clinical trial demonstrated worse tumor control and survival in head and neck cancer patients treated with EPO, the role of EPO and EPOR in head and neck squamous cell carcinoma (HNSCC) has not been examined. In the present study, we demonstrate the previously unrecognized EPO-mediated invasion by HNSCC cells through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway. Furthermore, we confirmed the expression of EPO and EPOR in a panel of human HNSCC cell lines and tissue specimens. Pharmacological doses of EPO also had a limited proliferation effect in these cell lines. These results define a novel role for EPO in mediating tumor cell invasion. Increased levels of EPO and EPOR in lymph node metastases as compared to primary tumors from HNSCC patients further support the role of EPO/EPOR in HNSCC disease progression and metastasis.

Topics: Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; DNA-Binding Proteins; Enzyme Activation; Erythropoietin; Female; Head and Neck Neoplasms; Humans; Janus Kinase 2; Male; Middle Aged; Milk Proteins; Mutation; Neoplasm Invasiveness; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Receptors, Erythropoietin; Signal Transduction; STAT5 Transcription Factor; Trans-Activators; Tyrphostins

Erythropoietin (Epo) is used for managing anemia in cancer patients. However, recent studies have raised concerns for this practice. We investigated the expression and function of Epo and the erythropoietin receptor (EpoR) in tumor biopsies and cell lines from human head and neck cancer. Epo responsiveness of the cell lines was assessed by Epoetin-alpha-induced tyrosine phosphorylation of the Janus kinase 2 (JAK2) protein kinase. Transmigration assays across Matrigel-coated filters were used to examine the effects of Epoetin-alpha on cell invasiveness. In 32 biopsies, we observed a significant association between disease progression and expression of Epo and its receptor, EpoR. Expression was highest in malignant cells, particularly within hypoxic and infiltrating tumor regions. Although both Epo and EpoR were expressed in human head and neck carcinoma cell lines, only EpoR was upregulated by hypoxia. Epoetin-alpha treatment induced prominent JAK2 phosphorylation and enhanced cell invasion. Inhibition of JAK2 phosphorylation reduced both basal and Epo-induced invasiveness. Our findings support a role for autocrine or paracrine Epo signaling in the malignant progression and local invasiveness of head and neck cancer. This mechanism may also be activated by recombinant Epo therapy and could potentially produce detrimental effects in rhEpo-treated cancer patients.

Topics: Biopsy; Blotting, Western; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Collagen; Dose-Response Relationship, Drug; Drug Combinations; Erythropoietin; Gene Expression Regulation; Head and Neck Neoplasms; Humans; Hypoxia; Immunohistochemistry; Immunoprecipitation; Janus Kinase 2; Laminin; Models, Statistical; Neoplasm Invasiveness; Phosphorylation; Protein-Tyrosine Kinases; Proteoglycans; Proto-Oncogene Proteins; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Tyrosine

Recombinant human erythropoietin (rHuEPO) is widely used for correction of hemoglobin level in cancer patients. However, apart from hematopoiesis, rHuEPO reportedly has an effect on endothelial cells. We describe here how rHuEPOalpha can modulate tumor vasculature in human squamous cell (A431) and colorectal carcinoma (HT25) xenograft models. In vivo rHuEPO treatment of xenografts at human-equivalent dose significantly increased the proliferation index of the tumor-associated endothelial cells and the size of CD31-positive intratumoral blood vessels, whereas the pericyte coverage became fragmented. Moreover, rHuEPO administration resulted in decreased expression of vascular endothelial growth factor both by cancer cells and tumor stroma, measured by quantitative PCR. Due to the morphologic alterations in tumoral microvessels, DNA-binding agents (Hoechst and Doxorubicin) labeled significantly larger areas in the tumor mass. Furthermore, rHuEPO treatment led to a significantly improved efficacy of 5-fluorouracil (5-FU) chemotherapy in the case of both tumor xenografts. Meanwhile, rHuEPO had no effect on the in vitro proliferation of erythropoietin receptor-positive tumor cells, and did not interfere with the effects of 5-FU either. These data reveal a new effect of rHuEPO administration: remodeling tumoral microvessels, suppressing vascular endothelial growth factor expression, thereby augmenting antitumor effects of a cancer drug, 5-FU, even in erythropoietin receptor-positive human cancer xenografts.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cell Line, Tumor; Colorectal Neoplasms; Drug Synergism; Erythropoietin; Female; Fluorouracil; Humans; Mice; Mice, SCID; Neovascularization, Pathologic; Pericytes; Receptors, Erythropoietin; Recombinant Proteins; RNA, Messenger; Xenograft Model Antitumor Assays

The use of erythropoietin in head and neck squamous cell carcinoma (HNSCC) has been associated with poor survival. This study examines the protein and mRNA expression of erythropoietin and erythropoietin receptor in HNSCC and their relation to hypoxia, hemoglobin (Hb), and clinical outcome.. The immunohistochemical expression of erythropoietin and erythropoietin receptor was assessed in 151 cases of HNSCC. Expression was compared with the hypoxia-dependent proteins hypoxia-inducible factor-1alpha (HIF-1alpha) and carbonic anhydrase-9 (CA-9) and correlated with clinical outcome. The mRNA expression of erythropoietin and erythropoietin receptor was measured in paired samples of HNSCC.. Erythropoietin and erythropoietin receptor were expressed in 95% and 99% of tumors, respectively. Using a weighed expression score, there was a positive correlation between erythropoietin and erythropoietin receptor expression (r = 0.18, P = 0.03). HIF-1alpha (r = 0.38, P < 0.01) and CA-9 (r = 0.26, P = 0.002) correlated with erythropoietin expression, but there was no correlation with erythropoietin receptor. No correlation was found between Hb and erythropoietin (r = 0.07, P = 0.36) or erythropoietin receptor (r = -0.02, P = 0.8), and no survival difference between high and low erythropoietin or erythropoietin receptor expression (P = 0.59 and P = 0.98, respectively). The mRNA expression of erythropoietin (P = 0.03) but not erythropoietin receptor (P = 0.62) was significantly increased in 11 paired samples of HNSCC.. In vivo, the HIF pathway regulates erythropoietin at the mRNA level but not erythropoietin receptor expression in HNSCC. Anemia does not seem to influence the hypoxic microenvironment of tumors sufficiently to alter the expression of erythropoietin. The effects of exogenous erythropoietin may be acting via receptors expressed on tumor cells in vivo, or on vascular cells, which also express the pathway.

Topics: Anemia; Antigens, Neoplasm; Carbonic Anhydrase IX; Carbonic Anhydrases; Carcinoma, Squamous Cell; Cytoplasm; Disease-Free Survival; DNA, Complementary; Erythropoietin; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Hemoglobins; Humans; Hypoxia; Immunohistochemistry; Male; Protein Array Analysis; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Transcription, Genetic; Treatment Outcome

Tissue hypoxia is a characteristic property of cervical cancers that makes tumors resistant to chemo- and radiation therapy. Erythropoietin (Epo) is a hypoxia-inducible stimulator of erythropoiesis. Acting via its receptor (EpoR), Epo up-regulates bcl-2 and inhibits apoptosis of erythroid cells and rescues neurons from hypoxic damage. In addition to human papillomavirus infection, increased bcl-2 expression and decreased apoptosis are thought to play a role in the progression of cervical neoplasia. Using reverse transcriptase-polymerase chain reaction and Western blotting we showed that HeLa and SiHa cervical carcinoma cells and human cervical carcinomas express EpoR, and that hypoxia enhances EpoR expression. Exogenous Epo stimulated tyrosine phosphorylation and inhibited the cytotoxic effect of cisplatin in HeLa cervical carcinoma cells. Using immunohistochemistry, we examined the expression of Epo, EpoR, p16, hypoxia-inducible factor (HIF)-1alpha, and bcl-2 in benign and dysplastic cervical squamous epithelia and invasive squamous cell carcinomas (ISCCs). EpoR expression in benign epithelia was confined to the basal cell layers, whereas in dysplasias it increasingly appeared in more superficial cell layers and showed a significant correlation with severity of dysplasia. Diffuse EpoR expression was found in all ISCCs. Expression of Epo and HIF-1alpha was increased in dysplasias compared to benign epithelia. Focal Epo and HIF-1alpha expression was seen near necrotic areas in ISCCs, and showed correlation in their spatial distribution. Significant correlation was found between expression of EpoR, and p16 and bcl-2 in benign and dysplastic squamous epithelia. Our results suggest that increased expression of Epo and EpoR may play a significant role in cervical carcinogenesis and tumor progression. Hypoxia-inducible Epo signaling may play a significant role in the aggressive behavior and treatment resistance of hypoxic cervical cancers.

Topics: Carcinoma, Squamous Cell; Cell Hypoxia; Cell Survival; Cyclin-Dependent Kinase Inhibitor p16; Disease Progression; Dose-Response Relationship, Drug; Erythropoietin; Female; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Neoplasm Staging; Proto-Oncogene Proteins c-bcl-2; Receptors, Erythropoietin; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Transcription Factors; Tumor Cells, Cultured; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

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

We assessed the influence of hemoglobin level and r-HuEPO administration on response to chemoradiotherapy, locoregional tumor control, and overall survival in patients treated with neoadjuvant chemoradiotherapy and surgery for a squamous cell carcinoma of the oral cavity or oropharynx.. The 191 study patients were treated with mitomycin C (15 mg/m(2) day 1), 5-fluorouracil (750 mg/m(2)/day, days 1-5), and radiotherapy (50 Gy in 25 fractions weeks 1-5), followed by resection of the primary tumor bed and neck dissection at the General Hospital Vienna, Austria, between November 1989 and October 1998 for a T2-4, N0-3, M0 SCC of the oral cavity or oropharynx. Starting in May 1996, patients with a low hemoglobin (Hgb) before or during chemoradiotherapy received r-HuEPO 10,000 IU/kg s.c. 3-6 times/week until the week of surgery.. On multivariate analysis, Hgb level and use of r-HuEPO were independent prognostic factors for response to chemoradiotherapy and locoregional tumor control (p < 0.01). Pathologic response to neoadjuvant therapy was also predictive of locoregional control (p < 0.001). Patients with a pretreatment Hgb > or = 14.5 g/dL had significantly higher complete response, locoregional control, and survival rates than the patients with a pretreatment Hgb < 14.5 g/dL who did not receive r-HuEPO (p < 0.05). The response, control, and survival rates in patients with a pretreatment Hgb < 14.5 g/dL given r-HuEPO were significantly higher than in low Hgb patients not given r-HuEPO (p < or = 0.001) and equivalent to patients with a pretreatment Hgb > 14.5 g/dL (p > or = 0.3).. Low pretreatment Hgb is a negative prognostic factor for oral cavity and oropharyngeal SCCA patients, but was completely abrogated by r-HuEpo administration during neoadjuvant chemoradiotherapy. Randomized trials of radiation and/or chemotherapy with or without r-HuEPO for patients whose Hgb level is either low at the start of therapy or is anticipated to become low during therapy are indicated.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Erythropoietin; Female; Fluorouracil; Hemoglobins; Humans; Male; Middle Aged; Mitomycin; Mouth Neoplasms; Neoadjuvant Therapy; Neoplasm Staging; Oropharyngeal Neoplasms; Preoperative Care; Recombinant Proteins; Retrospective Studies

Numerous publications have reported an impaired radiocurability when anemia is present. Tissue hypoxia and consecutive radioresistance are speculated to be the underlying causes.. Our own retrospective data impressively confirm these observations: in an analysis of 889 patients homogeneously irradiated for head and neck cancer for locoregional tumor control and survival, anemia has proven to be a highly significant risk factor. Furthermore, hemoglobin content is an independent and, at least equally powerful predictor for outcome when compared to the known risk factors of site, treatment modality, resection status, T-, and N-stage.. In an attempt to improve therapeutic outcome, 50 anemic patients undergoing radiotherapy were treated with erythropoietin (rhEPO). A weekly increment in hemoglobin content of 0.7 g/dl was documented without any major side effects. Additionally, it seems that patients reacting sufficiently to rhEPO stimulation can expect better locoregional tumor control within the irradiation volume. This, however, awaits confirmation in an ongoing trial.

Topics: Anemia; Carcinoma, Squamous Cell; Erythropoietin; Follow-Up Studies; Head and Neck Neoplasms; Hemoglobins; Humans; Neoplasm Recurrence, Local; Pilot Projects; Prospective Studies; Radiotherapy, Adjuvant; Recombinant Proteins; Retrospective Studies; Treatment Outcome

This report describes the peri- and postoperative management of a patient with a critical blood loss (hemoglobin of 22 g/l) as a consequence of a surgical intervention, i.e. a radical resection of an advanced malignant gynecological tumor. The patient refused autologous and homologous blood transfusions for religious reasons (Jehovah's Witness). During surgery, hemodilution and cell salvage were used. Postoperatively she developed coagulopathy and hemorrhage with the lowest hemoglobin value of 22 g/l. The patient recovered under a therapy regimen of recombinant human erythropoietin and parenteral iron. The hemoglobin values returned to the lower normal range within 4 weeks. Consequences of hypoxia could not be seen.

Topics: Adult; beta-Thalassemia; Blood Loss, Surgical; Carcinoma, Squamous Cell; Christianity; Combined Modality Therapy; Erythropoietin; Female; Hemodilution; Hemoglobinometry; Hemorrhage; Humans; Iron; Postoperative Complications; Religion and Medicine; Uterine Cervical Neoplasms

In order the investigate mechanisms of diminished red cell production in malignancy, we assayed erythroid progenitor cell proliferative responses to erythropoietin in plasma clot cultures of bone marrow cells from 34 cancer patients. Erythroid colony growth by marrow cells of 11 healthy donors (means of 58 CFU-E and 19 BFU-E derived colonies/6 X 10(4) cells) was similar to that in cultures of cells from patients either with (means of 44 CFU-E and 22 BFU-E derived colonies/6 X 10(4) cells) or without (means of 50 CFU-E and 19 BFU-E derived colonies/6 X 10(4) cells) myelophthisis. Colony formation was normal at all erythropoietin concentrations tested, indicating that both the CFU-E and BFU-E retain normal erythropoietin sensitivity in vitro. CFU-E proliferation correlated negatively (r = -0.56; P less than 0.001) with the level of hemoglobin. In contrast to marrow cell proliferative responses to erythropoietin, serum erythropoietin levels were inappropriately reduced in all 19 patients in whom they were measured, a finding which may be important in the pathogenesis of anemia in patients with cancer.

Topics: Carcinoma, Squamous Cell; Cell Division; Cells, Cultured; Erythropoiesis; Erythropoietin; Female; Hematologic Diseases; Hematopoietic Stem Cells; Hemoglobins; Humans; Leukemia; Lymphoma; Male; Middle Aged

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