losartan-potassium and Head-and-Neck-Neoplasms

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

Tumour hypoxia increases tumour invasiveness and has a negative impact on response to therapy. Hypoxic tumours are also associated with severely anaemic individuals. It has therefore been hypothesised that correcting anaemia, by increasing haemoglobin levels using erythropoietin, improves tumour oxygenation and consequently the patient's prognosis.. To assess whether combined treatment with radiotherapy and erythropoietin (RT plus EPO) is better than standard radiotherapy (RT alone) for the treatment of head and neck cancer patients.. We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; mRCT and additional sources for published and unpublished trials. The date of the most recent search was 24 February 2009.. Two independent authors assessed identified studies according to the eligibility criteria: RCTs which delivered radiotherapy combined with or without erythropoietin, in patients of any age with head and neck cancer of any stage or type. In addition, trials administering concomitant iron therapy among one or both arms were also eligible.. For statistical analysis of survival data, we computed a weighted estimate of the typical treatment effect across studies. We used Chi(2) heterogeneity tests to test for statistical heterogeneity among trials and performed the statistical analyses using Review Manager 5.0.. Five RCTs with a total of 1397 patients were included. Pooled data yielded a significantly worse overall survival (OS) for RT plus EPO as compared to RT alone (Peto odds ratio 0.73; 95% confidence interval (CI) 0.58 to 0.91; P = 0.005, five trials). For local regional tumour control (LRTC) analyses resulted in a small but non-significant difference between the RT alone group and the RT plus EPO group (RR 0.92; 95% CI 0.81 to 1.03; P = 0.15, four trials). In addition, the local regional progression free survival (LRPFS) measured in four studies was significantly different between groups (Peto odds ratio 0.63; 95% CI 0.49 to 0.80; P = 0.0002, four trials), in favour of the RT alone group. Two studies used supplemental iron in the RT plus EPO group and not in the RT alone group. When excluding these studies from the analyses, the statistically (non-) significant differences in OS, LRTC and LRPFS are maintained.. There are strong suggestions that RT plus EPO has a negative influence on outcome as opposed to RT alone. However, the target haemoglobin concentration, which was higher than recommended in four of the five included RCTs, may have had a significant role. Nevertheless, based on these findings EPO should not be administered as an addition to RT outside the experimental setting for patients with head and neck cancer.

Topics: Anemia; Cell Hypoxia; Chemotherapy, Adjuvant; Darbepoetin alfa; Erythropoietin; Head and Neck Neoplasms; Humans; Randomized Controlled Trials as Topic; Recombinant Proteins; Survival Analysis

Locoregional recurrence remains a major obstacle to achieving a cure of locally advanced head and neck cancers, despite multimodality therapy. Multiple studies report that a low hemoglobin (Hgb) before or during radiation therapy is an important risk factor for poor locoregional disease control and survival. Anemia is common in the head and neck cancer population and is suspected to contribute to intratumoral hypoxia with resultant radioresistance. Although having a low Hgb level has been shown to be detrimental, it is unclear as to exactly what the threshold should be for low Hgb (studies in this area have used thresholds ranging from 9-14.5 g/dL). Quality-of-life studies suggest that correction of moderately severe anemia may result in significant gains. Optimal Hgb levels for improving outcomes may vary across and within tumor types, and this is an area that requires further evaluation. However, the correction of anemia may be a worthwhile strategy for radiation oncologists to improve local control and survival. This article reviews the impact of anemia on outcomes after radiotherapy of head and neck cancers.

Topics: Anemia; Cell Hypoxia; Erythropoietin; Head and Neck Neoplasms; Humans; Neoplasm Recurrence, Local; Nitroimidazoles; Prognosis; Quality of Life; Risk Factors; Survival Analysis

Anemia is very common in head and neck cancer patients, and seems to be correlated with intratumoral hypoxia. Anemia is one of the main prognostic factors of locoregional recurrence and, in some studies, of poor survival. Blood transfusions and human recombinant erythropoietin (rHuEPO) are the two main methods used in clinical practice to correct hemoglobin level during curative treatment. Blood transfusions were rarely evaluated, and did not influence locoregional control of patients treated with radiotherapy with or without chemotherapy. Retrospective studies evaluating combined treatment of rHuEPO and radiotherapy reported positive impact on locoregional recurrence and actuarial survival. Since the end of 2003, this approach is a matter for debate after the negative results of a prospective randomized study on progression-free survival concerning head and neck cancer patients treated with definitive or postoperative external radiotherapy with or without rHuEPO. Although many biases were reported against this publication, several questions are to be answered in the near future. Among them, erythropoietin receptor expression and activation on tumour cell seem to be the more appropriate explanation of these negative results. In October 2004, preliminary results of the RTOG 99-03 study have been presented at the Astro annual meeting in Atlanta. This prospective randomized trial was designed to determine if concurrent rHuEPO administration (40,000 units) with radiotherapy (with or without chemotherapy) could improve locoregional control in non-operative head and neck cancers. In the rHuEPO arm, haemoglobin level was significantly increased compared with control arm. However, the addition of concurrent rHuEPO to definitive radiotherapy did not improve locoregional control or survival for mildly/moderately anemic patients with head and neck squamous cell carcinoma. Future clinical trials using biological markers are thus imperative to target which patients could benefit from these molecules.

Topics: Anemia; Blood Transfusion; Cell Hypoxia; Erythropoietin; Head and Neck Neoplasms; Hemoglobin A; Humans; Prognosis; Quality of Life; Recombinant Proteins

Hypoxia is a common feature of solid tumors that occurs across a wide variety of malignancies. Hypoxia and anemia (which contributes to tumor hypoxia) can lead to ionizing radiation and chemotherapy resistance by depriving tumor cells of the oxygen essential for the cytotoxic activities of these agents. Hypoxia may also reduce tumor sensitivity to radiation therapy and chemotherapy through one or more indirect mechanisms that include proteomic and genomic changes. These effects, in turn, can lead to increased invasiveness and metastatic potential, loss of apoptosis, and chaotic angiogenesis, thereby further increasing treatment resistance. Investigations of the prognostic significance of pretreatment tumor oxygenation status have shown that hypoxia (oxygen tension [pO(2)] value < or =10 mmHg) is associated with lower overall and disease-free survival, greater recurrence, and less locoregional control in head and neck carcinoma, cervical carcinoma, and soft-tissue sarcoma. In view of the deleterious effect of hypoxia on standard cancer treatment, a variety of hypoxia- and anemia-targeted therapies have been studied in an effort to improve therapeutic effectiveness and patient outcomes. Early evidence from experimental and clinical studies suggests the administration of recombinant human erythropoietin (rHuEPO) may enhance the effectiveness of radiation therapy and chemotherapy by increasing hemoglobin levels and ameliorating anemia in patients with disease- or treatment-related anemia. However, further research is needed in the area of hypoxia-related treatment resistance and its reversal.

Topics: Anemia; Cell Hypoxia; Combined Modality Therapy; Drug Resistance, Neoplasm; Erythropoietin; Female; Head and Neck Neoplasms; Hemoglobins; Humans; Radiation Tolerance; Sarcoma; Uterine Cervical Neoplasms

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

Although the association between low hemoglobin levels and poorer outcomes in radiation oncology has long been recognized, anemia is often overlooked and untreated. However, a growing body of clinical evidence now indicates that low hemoglobin levels during radiation treatment are associated with decreased response and survival following radiotherapy. For example, a large Canadian retrospective study in patients receiving radical radiotherapy for cervical cancer showed that the 5-year survival rate was 19% higher in those whose hemoglobin during radiation treatment was =12 g/dl compared to those with levels <12 g/dl. The data suggest that clinical trials need to be performed to determine whether increasing hemoglobin levels leads to improved local control and survival. The mechanism by which low hemoglobin levels could cause poorer outcomes is not well understood and needs further elucidation. It is postulated that lower hemoglobin levels resulting in decreased oxygen carrying capacity may lead to increased tumor hypoxia, radiation resistance and increased tumor angiogenesis. The interrelationship of low hemoglobin levels, hypoxia, tumor angiogenesis and survival is explored in this article.

Topics: Anemia; Cell Hypoxia; Chemotherapy, Adjuvant; Epoetin Alfa; Erythropoietin; Female; Head and Neck Neoplasms; Hematinics; Hemoglobins; Humans; Neoplasms; Neovascularization, Pathologic; Radiotherapy, Adjuvant; Recombinant Proteins; Survival Analysis; Survival Rate; Uterine Cervical Neoplasms

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

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

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

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

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

A total of 100 patients with stage III or IV head or neck cancer, a performance status of 0-1, and anemia with hemoglobin (Hb) < 10 g/dL at baseline who where to receive chemotherapy concomitantly or sequentially with radiotherapy were randomized to receive either epoetin beta 10,000 IU thrice weekly (TW) (n = 52) and oral iron starting 10-15 days before the start of treatment or epoetin beta 30,000 IU once weekly (OW) (n = 48) and oral iron before the start of treatment. The mean Hb in patients on the thrice weekly (11.96 g/dL) and once weekly (12.50 g/dL) dosing schedules increased significantly (p < 0.01) at the end of the treatment in comparison to respective baseline values of 9.38 g/dL and 9.41 g/dL; levels were 1.2-fold higher, which was significant (p < 0.01), for patients on the once weekly schedule. That said, there was significant improvement (p < 0.01) in mean linear analog scale assessment (LASA) scores for energy level (EL), ability to perform daily activities (AL), and overall quality of life (QOL) for patients on both dosing schedules but these improvements did not differ significantly between schedules (p > 0.05). The 2-year overall survival for patients on both dosing schedules did not differ significantly (p > 0.05). Epoetin beta therapy was found to be equally beneficial and well tolerated for patients on both thrice weekly and once weekly dosing schedules.

Topics: Aged; Anemia; Dose-Response Relationship, Drug; Erythropoietin; Head and Neck Neoplasms; Hemoglobins; Humans; Iron; Middle Aged; Prospective Studies; Quality of Life; Recombinant Proteins; 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

To determine efficacy and toxicities of postoperative concurrent chemoradiation using docetaxel in high-risk head and neck cancer.. High-risk patients were enrolled 2-8 weeks after surgery. Treatment included 60 Gy for 6 weeks with weekly docetaxel 25 mg/m(2) and erythropoietin alpha 40,000 U for hemoglobin < or =12 g/dL. Primary endpoints included locoregional control (LC), disease-free survival (DFS), and patterns of failure (POF). Secondary endpoints were toxicity and quality of life.. Eighteen patients were enrolled (14 male, 4 female), aged 24-70 years (median, 55 years). Primary site included oropharynx = 7, oral cavity = 8, hypopharynx = 1, and larynx = 2. Pathologic American Joint Committee on Cancer Stage was III = 3 patients, IV = 15 patients. High-risk eligibility included > or =2 positive lymph nodes = 13, extracapsular extension = 10, positive margins = 8 (11 patients with two or more risk factors). Docetaxel was reduced to 20 mg/m(2)/week after 5 patients had prolonged Grade 3 or higher mucositis. Overall, number of doses delivered was 2 of 6 = 1, 3 of 6 = 2, 4 of 6 = 2, 5 of 6 = 4, 6 of 6 = 9 patients. With median follow-up of 30 months (range, 5-66), 10 (56%) patients are alive and have no evidence of disease (NED); POF: three local recurrences (two with distant) and 1 distant only. One-year survival was 76%, median PFS and DFS had not been reached. Three-year LC was 82%. No Grade 3 or higher late toxicities were observed, although a few cases of prolonged mucositis and taste loss (>3 months) were seen, particularly at 25 mg/m(2)/week.. Postoperative radiation therapy with weekly docetaxel 20 or 25 mg/m(2)/week for high-risk postoperative head and neck cancer caused intolerable mucosal toxicity, prompting early study termination. Further studies should consider 15 mg/m(2). Actuarial 3-year LC is 82%, similar to cisplatin-based chemoradiation regimens. Distant metastasis remains an important issue requiring additional systemic interventions.

Topics: Adult; Aged; Antineoplastic Agents; Combined Modality Therapy; Disease-Free Survival; Docetaxel; Dose Fractionation, Radiation; Erythropoietin; Female; Head and Neck Neoplasms; Hemoglobin A; Humans; Male; Middle Aged; Mouth Mucosa; Prospective Studies; Radiation Injuries; Radiation-Sensitizing Agents; Radiotherapy Dosage; Stomatitis; Taxoids

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

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 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

Radiation treatment may induce acute skin reactions. There are several methods of managing them. Validity of these methods, however, is not sufficiently studied. We therefore investigated, whether moist skin care with 3% urea lotion will reduce acute radiation skin toxicity.. 88 patients with carcinomas of the head and neck undergoing radiotherapy with curative intent (mean total dose 60 Gy, range: 50-74 Gy) were evaluated weekly for acute skin reactions according to the RTOG-CTC score. In 63 patients, moist skin care with 3% urea lotion was performed. The control group consisted of 25 patients receiving conventional dry skin care. The incidence of grade I, II, and III reactions and the radiation dose at occurrence of a particular reaction were determined and statistically analyzed using the log-rank test. The dose-time relations of individual skin reactions are described.. At some point of time during radiotherapy, all patients suffered from acute skin reactions grade I, > 90% from grade II reactions. 50% of patients receiving moist skin care experienced grade I reactions at 26 Gy as compared to 22 Gy in control patients (p = 0.03). Grade II reactions occurred at 51 Gy versus 34 Gy (p = 0.006). Further, 22% of the patients treated with moist skin care suffered from acute skin toxicity grade III as compared to 56% of the controls (p = 0.0007).. Moist skin care with 3% urea lotion delays the occurrence and reduces the grade of acute skin reactions in percutaneously irradiated patients with head and neck tumors.

Topics: Amifostine; Azulenes; Clinical Trials as Topic; Data Interpretation, Statistical; Dose Fractionation, Radiation; Double-Blind Method; Erythropoietin; Female; Head and Neck Neoplasms; Hospitalization; Humans; Length of Stay; Lipids; Male; Multicenter Studies as Topic; Ointment Bases; Ointments; Particle Accelerators; Placebos; Radiation Injuries; Radiation-Protective Agents; Radiotherapy; Radiotherapy Dosage; Recombinant Proteins; Sesquiterpenes; Sesquiterpenes, Guaiane; Skin; Skin Care; Time Factors; Urea

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

To evaluate the efficacy of perioperative recombinant human erythropoietin (r-HuEPO, epoetin alfa) in stimulating hematopoiesis and reducing allogeneic blood transfusion requirements in major head and neck cancer surgery.. Double-blinded, placebo-controlled, randomized, prospective clinical trial.. Fifty-eight patients undergoing surgical resection of head and neck tumors at the University of Iowa hospitals completed this study. Patients were required to have a pre-study hemoglobin >/=10.0 g/dL and

Topics: Adult; Aged; Aged, 80 and over; Anemia; Blood Loss, Surgical; Blood Transfusion; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Head and Neck Neoplasms; Hematinics; Humans; Male; Middle Aged; Postoperative Complications; Prospective Studies; Recombinant Proteins

To investigate the influence of carbogen breathing on chemoradiation and the effects of erythropoietin on transfusions.. From March 1996 to April 2000, 42 (4 Stage III and 38 Stage IV) patients with head and neck cancer were treated with a twice-a-day hyperfractionated schedule. Each fraction 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 treated either by transfusion or by erythropoietin.. Forty-one patients tolerated the treatment as scheduled. All patients tolerated the planned radiation dose. Five transfusions were given in the first group, but no transfusion was needed in the erythropoietin group. Local toxicities remained at the level expected with irradiation alone. Chemotherapy toxicity was moderate. Forty-two complete responses were achieved. At two years actuarial local control, cause-specific survival and overall survival are respectively 85%, 69%, and 68%. At four years estimated probabilities of local control, cause-specific survival and overall survival are also 85%, 69%, and 68%.. These results compare favorably with those of most reported studies. The addition of carbogen breathing appears to improve the results of chemoradiation alone. Erythropoietin therapy avoided transfusions.

Topics: Administration, Inhalation; Adult; Aged; Anemia; Antineoplastic Agents; Carbon Dioxide; Carboplatin; Combined Modality Therapy; Dose Fractionation, Radiation; Erythrocyte Transfusion; Erythropoietin; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasm Staging; Oxygen; Radiation-Sensitizing Agents; Survival Rate

Autologous blood transfusion presents few infectious or immunologic side effects. The aim of the present study was to determine the impact of autologous blood transfusion with or without recombinant human erythropoietin (rHuEPO) in patients who underwent elective maxillofacial operations.. Seventy eight consecutive patients (29 men and 49 women) underwent elective maxillofacial operations during the years 1990-95.. The patients were randomly assigned to three groups: In group 1, 30 patients preoperatively underwent autologous blood predonation with intravenous injection of erythropoietin 600 lU/kg after each blood predonation and autologous blood transfusion intraoperatively; in group 2, 28 patients underwent the same procedure without erythropoietin and in group 3, 20 patients underwent homologous transfusion serving as control group. All patients received ferrous sulphate daily by mouth, preoperatively until one week postoperatively.. Group 1 patients showed higher levels of haematocrit, haemoglobin and red blood cell count pre- and postoperatively than the group 2 patients. It was also shown that the use of rHuEPO contributed to an improvement of the blood parameters of the patients in the group 1 compared with those of the patients in groups 2 and 3.

Topics: Administration, Oral; Adolescent; Adult; Analysis of Variance; Blood Transfusion; Blood Transfusion, Autologous; Elective Surgical Procedures; Erythrocyte Count; Erythropoietin; Facial Bones; Female; Ferrous Compounds; Follow-Up Studies; Head and Neck Neoplasms; Hematocrit; Hemoglobins; Humans; Injections, Intravenous; Male; Middle Aged; Orthognathic Surgical Procedures; Osteotomy; Premedication; Reactive Oxygen Species; Recombinant Proteins; Statistics as Topic

To evaluate the influence of blood hemoglobin concentration on the radiosensitivity of acutely reacting normal tissues.. Weekly scores (EORTC/RTOG criteria) for acute reactions of skin and mucosa are available for 60 patients with cancer of the head and neck undergoing a standard conventional radiotherapy. The prognostic significance of blood hemoglobin levels on the development of acute reactions is studied by multivariate analysis (Cox Proportional Hazards Model). Further, the incidence and the time to development of these reactions is looked at in cohorts of patients with different mean blood hemoglobin concentrations during radiotherapy. Patients are therefore classified into a "severely anemic group" (hemoglobin < 11.0 g/100 mL), and into a cohort with a blood hemoglobin value equal or above 11.0 g/100 mL.. Normal tissue scoring and monitoring of blood hemoglobin levels allows for a detailed analysis of possible correlations. A decrease in the mean blood hemoglobin value of 1 g/100 mL predicts a reduced risk to develop a skin reaction of Grade 2 or 3 (RR = 0.9; p = 0.08; RR = 0.8; p = 0.26, respectively) or a mucosa reaction of Grade 3 (RR = 0.8; p = 0.16), independent from the radiation dose, the treatment time and from previous surgery within the radiation volume (multivariate analysis). Likewise, patients with severe anemia develop grade 3 mucositis or dermatitis less often (0%; 13%) as compared to those with blood hemoglobin concentrations equal or above 11.0 g/100 mL (21%; 19%). Skin and mucosa reactions further tend to occur later in the course of radiation. The observations are not statistically significant and possible reasons will be discussed.. A decreased blood hemoglobin concentration may-perhaps by an impaired tissue oxygenation-reduce the radiosensitivity of normal tissue such as skin and mucosa. However, the data is preliminary and needs further confirmation.

Topics: Adult; Anemia; Cohort Studies; Double-Blind Method; Erythropoietin; Female; Head and Neck Neoplasms; Hemoglobin A; Humans; Male; Middle Aged; Mucous Membrane; Multivariate Analysis; Pilot Projects; Proportional Hazards Models; Prospective Studies; Radiation Tolerance; Radiodermatitis; Radiotherapy Dosage; Recombinant Proteins; Skin

To evaluate the feasibility and efficacy of using recombinant human erythropoietin (rhEPO) to correct decreased hemoglobin levels in patients undergoing radiotherapy and to get an estimate of its influence on the efficacy of radiotherapy.. Fifty patients with cancer of the head and neck and the pelvis were randomized before radiotherapy to different rhEPO treatments (none, 3 x 150 U/kg per week i.v., 3 x 300 U/kg per week i.v. and 3 x 150 U/kg per week s.c.). Hematological parameters were evaluated weekly and the locoregional tumor control rates were determined in 38 patients with head and neck cancer.. rhEPO-treated patients showed a significant increase in their hemoglobin values (0.7 g/100 ml per week). The rhEPO response was comparable for patients with cancer of the head and neck and the pelvis. A delayed recovery was seen when iron deficiency or impaired iron mobilization was present. No serious toxicity was observed. Locoregional tumor control was improved, although not statistically significantly, in those head and neck cancer patients who experienced a rapid rise of hemoglobin.. Low hemoglobin levels can be safely and quickly corrected with rhEPO. This may improve the effectiveness of radiotherapy.

Topics: Adolescent; Adult; Aged; Colorectal Neoplasms; Dose Fractionation, Radiation; Erythropoietin; Female; Follow-Up Studies; Head and Neck Neoplasms; Hemoglobins; Humans; Iron; Male; Middle Aged; Pelvic Neoplasms; Pilot Projects; Prospective Studies; Recombinant Proteins; Safety; Treatment Outcome

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

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

The effects of weekly subcutaneous recombinant human erythropoietin (r-hEPO) administration on anemia during chemotherapy including cisplatin and 5-fluorouracil in patients with head and neck carcinomas were examined. Weekly subcutaneous r-hEPO administration in cancer patients has not been investigated previously. Patients were treated with r-hEPO 100 IU/kg (2 patients), 200 IU/kg (6 patients), or 400 IU/kg (5 patients), or placebo, and effectiveness was evaluated by monitoring hemoglobin concentration changes after administration for 8 weeks. Hemoglobin concentrations in all 3 r-hEPO dosage groups were higher than that in the control group during chemotherapy. All r-hEPO doses produced improvements in the anemia induced by chemotherapy; however, the 400 IU/kg dose was most effective. The requirement for blood transfusions decreased in patients receiving r-hEPO therapy, and no significant side-effects were associated with r-hEPO administration. These results suggest that chemotherapy-induced anemia can be prevented by weekly subcutaneous r-hEPO administration.

Topics: Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Cisplatin; Drug Administration Schedule; Erythropoietin; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Injections, Subcutaneous; Male; Middle Aged; Recombinant Proteins

The authors report on anemia observed during preoperative paclitaxel and carboplatin chemotherapy in patients with advanced head and neck carcinoma and discuss how the use of recombinant human erythropoietin (r-HuEPO) ameliorates this anemia, reducing the need for subsequent packed red blood cell (PRBC) transfusions.. Response to r-HuEPO was defined as reduced hemoglobin fall during preoperative chemotherapy and reduced transfusion requirements during surgery. Thirty-six patients with advanced head and neck carcinoma were evaluable after treatment with preoperative chemotherapy using paclitaxel and carboplatin. Group 1 was comprised of 14 patients who empirically received r-HuEPO at a dose of 150 U/kg 3 times per week for 3 weeks; in patients deemed nonresponders, the dose was increased to 300 U/kg and 450 U/kg in the subsequent courses. Group 2 was comprised of 22 patients who did not receive r-HuEPO.. During preoperative chemotherapy, the mean hemoglobin fall was 0.5 g/dL in Group 1 (P = 0.40). In Group 2 there was a statistically significant mean hemoglobin fall of 3.3 g/dL (P < 0.0001). There was also a nonstatistically significant trend toward fewer PRBC transfusions: none of 14 patients (0%) in Group 1 versus 4 of 22 patients (18%) in Group 2 (P = 0.141).. A significant fall in hemoglobin and an increase in the need for transfusions were observed in head and neck carcinoma patients receiving carboplatin and paclitaxel chemotherapy prior to surgery. Empiric r-HuEPO therapy appeared to prevent anemia and reduced the need for PRBC transfusions.

Topics: Adolescent; Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Erythrocyte Transfusion; Erythropoietin; Head and Neck Neoplasms; Hemoglobin A; Humans; Middle Aged; Paclitaxel; Recombinant Proteins

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

The therapeutic effects of intravenous recombinant human erythropoietin (r-hEPO) administration on anemia induced by radiation therapy (3 cases), chemotherapy (18 cases) and combined therapies (5 cases) in patients with head and neck malignancies were examined. The effectiveness was evaluated by the changes in the hemoglobin concentration examined before and after the r-hEPO administration. The r-hEPO administration combined with anticancer therapies improved anemia induced by all three treatments. The therapeutic effectiveness of r-hEPO injection was also noted on anemia induced by all of four different chemotherapeutic regimens that have been ordinarily used for head and neck malignancies. Furthermore, the efficacy of the different dose schedules, 3000 IU (12 cases) or 6000 IU (14 cases), three times a week, was compared. Both of the r-hEPO dose schedules were effective for anemia, but the efficacy of 6000 IU was superior to that of 3000 IU. No significant changes were observed in the number of white blood cells and platelets and the results of biochemical examinations after the r-hEPO injection. There were no objective side-effects related to the r-hEPO administration. These results suggest that anemia induced by chemotherapy and/or radiotherapy could be prevented by r-hEPO administration. The addition of r-hEPO to anticancer therapies would make it possible to pursue the planned therapeutic schedules, prevent the decrease of immunity after allogeneic blood transfusion and bring about an-improvement in the prognosis of patients with malignancies.

Topics: Adult; Aged; Anemia; Antineoplastic Agents; Erythropoietin; Head and Neck Neoplasms; Humans; Injections, Intravenous; Middle Aged; Radiotherapy; Recombinant Proteins

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

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

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

Head and neck squamous cell carcinoma (HNSCC) represents an ideal model for assessing the impact of anemia and tumor hypoxia on the response to radiotherapy (RT). Various treatment strategies aimed at increasing tumor oxygenation in HNSCC patients have been studied and these studies have been fueled by evidence that hypoxia and, unexpectedly, erythropoietin (EPO), adversely affect the radiosensitivity of cells. The purpose of the present study was to experimentally examine the relationship between hypoxia, EPO, its receptor EPOR, EGFR and their effects on the survival and radiosensitivity of HNSCC cells underwent hypoxia.. We used Cal-166 head and neck cell line to investigate different cellular responses after RT given in oxic and hypoxic conditions, focusing on the role of EPO administration in cell proliferation and in regulating response to RT.. Our results show that EPO do not evoke a physiologic response on EPOR-bearing tumor cells as assessed by cellular growth and proliferation. In addition, we present some indications that EPO could activate opposite signals related to proliferation, DNA repair and apoptosis. Among them, EGFR and AKT phosphorylation may play a role in radioresistance.. We concluded that the expression of the EPOR in Cal-166 cells does not seem essential for their growth and that administration of EPO does not affect RT efficacy.

Topics: Apoptosis; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Cytoprotection; DNA Repair; DNA-Binding Proteins; ErbB Receptors; Erythropoietin; Head and Neck Neoplasms; Humans; Proto-Oncogene Proteins c-akt; Receptors, Erythropoietin; X-ray Repair Cross Complementing Protein 1

Despite the prevalence of anemia in cancer, recombinant erythropoietin (Epo) has declined in use because of recent Phase III trials showing more rapid cancer progression and reduced survival in subjects randomized to Epo. Since Epo receptor (EpoR), Jak2, and Hsp70 are well-characterized mediators of Epo signaling in erythroid cells, we hypothesized that Epo might be especially harmful in patients whose tumors express high levels of these effectors. Because of the insensitivity of immunohistochemistry for detecting low level EpoR protein, we developed assays to measure levels of EpoR, Jak2 and Hsp70 mRNA in formalin-fixed paraffin-embedded (FFPE) tumors. We tested 23 archival breast tumors as well as 136 archival head and neck cancers from ENHANCE, a Phase III trial of 351 patients randomized to Epo versus placebo concomitant with radiotherapy following complete resection, partial resection, or no resection of tumor. EpoR, Jak2, and Hsp70 mRNA levels varied >30-fold, >12-fold, and >13-fold across the breast cancers, and >30-fold, >40-fold, and >30-fold across the head and neck cancers, respectively. Locoregional progression-free survival (LPFS) did not differ among patients whose head and neck cancers expressed above- versus below-median levels of EpoR, Jak2 or Hsp70, except in the subgroup of patients with unresected tumors (n = 28), where above-median EpoR, above-median Jak2, and below-median Hsp70 mRNA levels were all associated with significantly poorer LPFS. Our results provide a framework for exploring the relationship between Epo, cancer progression, and survival using archival tumors from other Phase III clinical trials.

Topics: Breast Neoplasms; Cell Line, Tumor; Clinical Trials, Phase III as Topic; Disease-Free Survival; Erythropoietin; Female; Flow Cytometry; Head and Neck Neoplasms; HSP70 Heat-Shock Proteins; Humans; Immunohistochemistry; Janus Kinase 2; Phosphorylation; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; STAT5 Transcription Factor

Topics: Anemia; Cell Hypoxia; Erythropoietin; Head and Neck Neoplasms; Humans; Radiotherapy; Recombinant Proteins

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

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

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

Topics: Adult; Aged; Aged, 80 and over; Carcinoma; Disease Progression; Erythropoietin; Female; Gene Expression Profiling; Head and Neck Neoplasms; Humans; Immunohistochemistry; Male; Middle Aged; Prognosis; Randomized Controlled Trials as Topic; Receptors, Erythropoietin; Recombinant Proteins; Retrospective Studies; Survival Analysis; Treatment Outcome

Topics: Biomarkers, Tumor; Biopsy, Needle; Disease Progression; Erythropoietin; Head and Neck Neoplasms; Humans; Immunohistochemistry; Neovascularization, Pathologic; Prognosis; Receptors, Erythropoietin; Risk Factors; Sensitivity and Specificity; Tumor Cells, Cultured

Topics: Erythropoietin; Head and Neck Neoplasms; Humans; Receptors, Erythropoietin; Recombinant Proteins

Topics: Carcinoma; Disease Progression; Erythropoietin; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; HSP70 Heat-Shock Proteins; Humans; Prognosis; Randomized Controlled Trials as Topic; Receptors, Erythropoietin; Recombinant Proteins; Treatment Outcome

Recent reports suggest that cancer control may worsen if erythropoietin is administered. We investigated whether erythropoietin receptor expression on cancer cells may correlate with this unexpected finding.. Cancer tissue from patients with advanced carcinoma of the head and neck (T3, T4, or nodal involvement) and scheduled for radiotherapy was assayed retrospectively for erythropoietin receptor expression by immunohistochemistry. Patients were anemic and randomized to receive epoetin beta (300 U/kg) or placebo under double-blind conditions, given three times weekly starting 10 to 14 days before and continuing throughout radiotherapy. We administered 60 Gy following complete resection or 64 Gy subsequent to microscopically incomplete resection; 70 Gy were given following macroscopically incomplete resection or for definitive radiotherapy alone. We determined if the effect of epoetin beta on locoregional progression-free survival was correlated with the expression of erythropoietin receptors on cancer cells using a Cox proportional hazards regression model.. We studied 154 of 157 randomly assigned patients; 104 samples were positive, and 50 were negative for receptor expression. Locoregional progression-free survival was substantially poorer if epoetin beta was administered to patients positive for receptor expression compared with placebo (adjusted relative risk, 2.07; 95% CI, 1.27 to 3.36; P < .01). In contrast, epoetin beta did not impair outcome in receptor-negative patients (adjusted relative risk, 0.94; 95% CI, 0.47 to 1.90; P = .86). The difference in treatment associated relative risks (2.07 v 0.94) was borderline statistically significant (P = .08).. Erythropoietin might adversely affect prognosis of head and neck cancer patients if cancer cells express erythropoietin receptors.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma; Disease Progression; Erythropoietin; Female; Gene Expression Profiling; Head and Neck Neoplasms; Humans; Immunohistochemistry; Male; Middle Aged; Prognosis; Randomized Controlled Trials as Topic; Receptors, Erythropoietin; Recombinant Proteins; Retrospective Studies; Survival Analysis; Treatment Outcome

Erythropoietin, an oxygen-regulated glycoprotein hormone, is a hematopoietic cytokine that stimulates erythropoiesis by binding to its cellular receptor [erythropoietin receptor (EPOR)]. The recombinant form of human erythropoietin is used to prevent or treat anemia in cancer patients. However, in a recent randomized, placebo-controlled trial involving patients receiving curative radiotherapy for squamous cell carcinoma of the head and neck, erythropoietin treatment was associated with poorer locoregional progression-free survival. The purpose of our study was to determine whether EPOR and its ligand erythropoietin are expressed in primary head and neck cancer. We also investigated the hypothesis that erythropoietin expression in malignant cells may be associated with the presence of tumor hypoxia, an important factor involved in resistance to radiation treatment, tumor aggressiveness, and poor prognosis.. Twenty-one patients received an i.v. infusion of the hypoxia marker pimonidazole hydrochloride before multiple tumor biopsies. Contiguous sections from 74 biopsies were analyzed by immunohistochemistry for EPOR and erythropoietin expression and pimonidazole binding.. EPOR expression was present in tumor cells in 97% of the biopsies. Coexpression of erythropoietin was observed in 90% of biopsies. Erythropoietin and pimonidazole adduct staining did not always colocalize within tumors, but there was a significant positive correlation between levels of microregional erythropoietin expression and pimonidazole binding.. The coexpression of erythropoietin and EPOR in tumor cells suggests that erythropoietin may potentially function as an autocrine or paracrine factor in head and neck cancer. The expression of the hypoxia-inducible protein erythropoietin in tumor cells correlates with levels of tumor hypoxia.

Topics: Disease-Free Survival; Erythropoietin; Head and Neck Neoplasms; Humans; Hypoxia; Immunohistochemistry; Ligands; Nitroimidazoles; Prognosis; Radiation-Sensitizing Agents; Receptors, Erythropoietin; Recombinant Proteins; Time Factors

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

The concurrent use of erythropoietin beta (EPO)and radiotherapy in head and neck cancer patients has been reported by Henke et al (Lancet 2003;362:1255-60) to correct anemia and impair cancer control. Due to the potential impact in daily clinical practice of this information a systematic critical review of the mentioned article was performed. Authors selected 10 arguments to question the contents regarding methodological and statistical aspects of the trial, and added 14 comments of controversy in more basic scientific concepts mentioned in the text as published. The panel including epidemiologist and radiation oncologists with expertise in clinical research concluded with 5 additional remarks recommending caution in interpretation of these results in terms of changes in daily practice of anemic patients support, and advising not to use EPO at experimental doses or after reaching physiological concentrations of hemoglobin.

Topics: Anemia; Erythropoietin; Head and Neck Neoplasms; Humans

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

Tumour hypoxia has been shown to increase mutation rate, angiogenesis, and metastatic potential, and decrease response to conventional therapeutics. Improved tumour oxygenation should translate into increased treatment response. Exogenous recombinant erythropoietin (rEpo) has been recently shown to increase tumour oxygenation in a mammary carcinoma model. The mechanism of this action is not yet understood completely. The presence of Epo and its receptor (EpoR) have been demonstrated on several normal and neoplastic tissues, including blood vessels and various solid tumours. In addition, rEpo has been shown in two recent prospective, randomized clinical trials to negatively impact treatment outcome. In this study, we attempt to characterize the direct effects of rEpo on tumour growth and angiogenesis in two separate rodent carcinomas. The effect of rEpo on R3230 rat mammary adenocarcinomas, CT-26 mouse colon carcinomas, HCT-116 human colon carcinomas, and FaDu human head and neck tumours, all of which express EpoR, was examined. There were no differences in tumour growth or proliferation (measured by Ki-67) between placebo-treated and rEpo-treated tumours. In the mammary window chamber, vascular length density (VLD) measurements in serial images of both placebo-treated and Epo-treated rats revealed no difference in angiogenesis between the Epo-treated tumours and placebo-treated tumours at any time point. These experiments are important because they suggest that the recent clinical detriment seen with the use of Epo is not due to its tumour growth effects or angiogenesis. These studies also suggest that further preclinical studies need to examine rEpo's direct tumour effects in efforts to improve the therapeutic benefits of Epo in solid tumour patients.

Topics: Animals; Carcinoma; Cell Hypoxia; Cell Proliferation; Colonic Neoplasms; Erythropoietin; Head and Neck Neoplasms; Humans; Mammary Neoplasms, Animal; Mice; Neovascularization, Pathologic; Placebos; Random Allocation; Rats; Recombinant Proteins; Tumor Cells, Cultured

Topics: Anemia; Combined Modality Therapy; Erythropoietin; Head and Neck Neoplasms; Humans; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome

Topics: Anemia; Antineoplastic Protocols; Combined Modality Therapy; Erythropoietin; Head and Neck Neoplasms; Humans; Patient Selection; Randomized Controlled Trials as Topic; Research Design

Topics: Anemia; Combined Modality Therapy; Erythropoietin; Head and Neck Neoplasms; Hemoglobins; Humans; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome

Topics: Anemia; Disease-Free Survival; Erythropoietin; Head and Neck Neoplasms; Humans; Iron; Randomized Controlled Trials as Topic

Topics: Anemia; Erythropoietin; Head and Neck Neoplasms; Humans; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome

Topics: Anemia; Apoptosis; Cell Division; Disease-Free Survival; Erythropoietin; Head and Neck Neoplasms; Humans; Neovascularization, Pathologic; Randomized Controlled Trials as Topic

Topics: Anemia; Cell Hypoxia; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease Models, Animal; Dose Fractionation, Radiation; Epoetin Alfa; Erythropoietin; Female; Head and Neck Neoplasms; Hematinics; Hemoglobins; Humans; Male; Meta-Analysis as Topic; Neoplasm Recurrence, Local; Neoplasms; Pelvic Neoplasms; Placebos; Prognosis; Radiotherapy Dosage; Recombinant Proteins; Retrospective Studies; Risk; Risk Factors; Time Factors; Treatment Outcome; Uterine Cervical Neoplasms

Topics: Anemia; Erythropoietin; Head and Neck Neoplasms; Humans; Radiotherapy; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Anemia; Disease-Free Survival; Erythropoietin; Head and Neck Neoplasms; Hemoglobins; Humans; Radiotherapy; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome

Topics: Anemia; Erythropoietin; Head and Neck Neoplasms; Hemoglobins; Humans; Radiotherapy; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome

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

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

Topics: Anemia; Breast Neoplasms; Erythropoietin; Female; Head and Neck Neoplasms; Humans; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins

Topics: Anemia; Cytokines; Erythropoietin; Head and Neck Neoplasms; Humans; Randomized Controlled Trials as Topic

Allogeneic transfusions are necessary in 14% to 80% of patients undergoing major head and neck cancer surgery. Defining the risk for receiving allogeneic transfusion allows for informed decisions regarding appropriateness of type and crossmatch, preoperative autologous blood donation, and priming with erythropoietin. Based on logistic regression analysis of transfusion risk factors in 438 patients, we developed a transfusion prediction risk assessment (TPRA) model to determine the need for transfusion based on the preoperative hemoglobin value, tumor stage, and need for flap reconstruction.. To examine the utility of this TPRA model in clinical practice by assessing the performance of the model in a validation set of patients.. Between 1996 and 1999, 125 consecutive patients entered into a clinical care pathway underwent major surgical procedures. The ability of the model to discriminate between patients requiring and those not requiring transfusion was assessed using the area under the receiver operating characteristic curve. The agreement between actual and predicted risks was tested using the chi2 goodness-of-fit statistic.. The overall transfusion rate was 25%. A 1-U transfusion was required in 7 patients, and multiple units were necessary for 24 patients. Flap reconstruction was required in 63 patients, 44 patients had preoperative anemia by normative values, and 64 had T3/T4 tumors. Among the low-risk non-T3/T4 patients whose preoperative hemoglobin level was normal, the actual/predicted transfusion rate without flap reconstruction was 10%/2%. For high-risk patients with T3/T4 tumors, anemia, and flap reconstruction, the actual/predicted transfusion rate was 43%/65%. The area under the receiver operating characteristic curve was 0.72. The goodness-of-fit statistic indicated lack of fit of the original model, but a recalibrated model fit the observed data well.. In general, the TPRA model identifies patients at low or high risk for allogeneic transfusion and provides guidelines for preoperative counseling regarding the risk of receiving a transfusion. Knowledge of a patient's risk can help direct cost-effective utilization of type and crossmatch, preoperative autologous blood donation, and preoperative priming with erythropoietin.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Blood Grouping and Crossmatching; Blood Transfusion; Cost-Benefit Analysis; Critical Pathways; Discriminant Analysis; Erythropoietin; Female; Head and Neck Neoplasms; Hemoglobins; Humans; Logistic Models; Male; Middle Aged; Needs Assessment; Neoplasm Staging; Patient Education as Topic; Practice Guidelines as Topic; Predictive Value of Tests; Preoperative Care; Risk Assessment; Risk Factors; ROC Curve; Surgical Flaps

Topics: Anemia; Erythropoietin; Head and Neck Neoplasms; Humans; Quality of Life; Randomized Controlled Trials as Topic

To determine the feasibility of perioperative erythropoietin to avoid blood transfusion in head and neck cancer surgery.. Retrospective chart review.. Ninety-nine patients undergoing surgical resection of head and neck tumors at our institution were assessed for demographic data, nutritional parameters, tumor/surgical information, hematological/transfusion data, and contraindications to erythropoietin. Each transfusion was classified as to its appropriateness, and the potential benefit of erythropoietin was assessed in each patient. A cost analysis was also performed.. Most transfused patients (63%) received too many units. A subgroup at high risk of transfusion was identified who would benefit most from perioperative erythropoietin. Assuming that perioperative erythropoietin therapy is equivalent to the transfusion of 4 units, we estimate that the majority (741%) of transfused patients would not have required a transfusion if more stringent transfusion criteria were followed and those at high risk were given perioperative erythropoietin. Although the cost for transfusing 4 units is equivalent to that of a perioperative course of erythropoietin, the overall direct cost of erythropoietin treatment would actually have been more expensive.. Perioperative erythropoietin therapy may be appropriate for a subgroup of head and neck cancer patients, but a prospective randomized controlled study in such a subgroup is needed to better define those most likely to benefit from it and to assess actual cost/benefit ratios.

Topics: Adult; Blood Transfusion; Chi-Square Distribution; Contraindications; Costs and Cost Analysis; Erythropoietin; Feasibility Studies; Female; Head and Neck Neoplasms; Humans; Logistic Models; Male; Neoplasm Staging; Preoperative Care; Retrospective Studies; Risk Factors

Severe cisplatin (CP)-induced anaemia significantly impairs the patient's quality of life. Prevention based on erythropoietin (EPO) administration would be cost-effective providing that individual predictive factors of anaemia are identified. The aim of the present study was to identify parameters able to predict the occurrence of CP-related anaemia. This prospective study was conducted on 40 head and neck cancer patients receiving a CP (100 mg/m(2), intravenous (i. v.) on day 1) - 5-fluorouracil (5-FU, 1 g/m(2)/dx5 days by continuous infusion) induction chemotherapy. Three cycles were given at 3-weekly intervals. Platinum pharmacokinetics (total and ultrafilterable plasma platinum concentration measured 16 h after CP administration) and 5-FU pharmacokinetics (full-cycle plasma area under the curve, (AUC(0-105h)30 g/l) occurred in 15 patients (38%) and 3 of them also received a blood transfusion. Patient age, 5-FU AUC(0-105h) and total platinum concentration were unrelated to Hb loss. In contrast, ultrafilterable (UF) platinum concentration was significantly correlated to Hb loss: the higher the UF platinum concentration, the greater the Hb loss (P=0.015). A discriminant analysis allowed a cut-off value for UF platinum to be proposed to identify patients developing significant loss of Hb: 91% of patients exhibiting a UF platinum concentration above 50 ng/ml developed significant loss of Hb in contrast to 18% in the group of patients with a UF platinum concentration below 50 ng/ml (odds ratio (95% confidence interval, CI) of 46 (4.7-446)). In conclusion, the present platinum pharmacokinetic survey may be proposed as a valuable approach to identify patients at risk for developing severe anaemia.

Topics: Adult; Aged; Anemia; Antineoplastic Agents; Cisplatin; Erythropoietin; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Quality of Life

To determine whether preoperative erythropoietin can raise the hemoglobin levels of head and neck cancer patients prior to major ablative surgery.. Prospective, consecutive series.. Ten patients who were to undergo major head and neck surgery were scheduled to receive subcutaneous doses of erythropoietin (600 IU/kg) on days 21, 14, 7, and 1 prior to surgery. Serial hemoglobin levels and reticulocyte counts were obtained throughout the course of treatment.. Eight patients experienced a significant increase in hemoglobin. There were two nonresponders. The mean preoperative hemoglobin level for all 10 patients increased 12.6 g/L, from 135.5 +/- 16.2 g/L (baseline) to 148.1 +/- 23.7 g/L (1 day preoperatively, p < .0001).. Erythropoietin significantly increases hemoglobin levels in patients awaiting major head and neck oncologic surgery. It can be viewed as an important adjunct to other well-established blood conservation techniques aimed at reducing perioperative transfusion rates.

Topics: Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Head and Neck Neoplasms; Humans; Injections, Subcutaneous; Preoperative Care; Prospective Studies; Treatment Outcome

Platinum chemotherapy has been shown to have potent antineoplastic activity against various tumours, especially testicular, bladder, ovarian, head and neck cancers. This activity is accompanied by side-effects of nephrotoxicity and cumulative myelosuppression, the latter frequently presenting as severe anaemia. Cisplatin and carboplatin nephrotoxicity might lower erythropoietin (Epo) secretion and, by this mechanism, contribute to the anaemia that follows therapy with this chemotherapeutic agent. The aim of the present work is to study the plasma immunoerythropoietin and haemoglobin levels of cancer patients treated with platinum or 5-fluorouracil-based chemotherapy.. Plasma was obtained from 25 patients who were about to receive chemotherapy for advanced malignancy: 15 treated with cisplatin or carboplatin and 10 with nonplatinum drugs. Blood was collected on the first day (before drug administration) and around day 15 of every chemotherapy course. Complete blood count, creatinine and immunoreactive Epo levels were also measured in 22 healthy volunteers.. An increase in Epo levels occurred following every course of 5-FU or platinum based chemotherapy in patients with steady concentrations of creatinine and decreased levels of haemoglobin (Hb). In particular, we observed an increase after about 15 days of the chemotherapy treatment and the Epo levels declined toward normal just before the following course. This phenomenon was evident in every course.. Our results suggest that chemotherapy administration, using the current standards of hydration and forced diuresis, slightly lowered Hb levels but did not depress Epo production, both in 5-FU and in platinum treated subjects.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Colorectal Neoplasms; Erythropoietin; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasms

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

To study the present status of blood transfusion in head and neck surgery, we investigated recent cases of intraoperative transfusion in our department. In addition, we present our autologous blood transfusion cases, presently involved in an ongoing clinical trial for patients with head and neck cancer in our department which began in 1989. 1. Investigation of intraoperative blood transfusion cases There were 37 cases of intraoperative blood transfusion among 677 cases who underwent surgery under general anesthesia during the period from May, 1991 to December, 1993. We divided these 37 cases into three groups according to the amount of intraoperative blood loss: less than 600ml (10 cases), more than 600ml and less than 1200ml (11 cases), and more than 1200ml (16 cases). Average amounts of intraoperative blood transfusion in each group were 195ml, 475ml and 780ml, respectively. As we noted that most of these 37 cases received a blood transfusion of less than 800ml, the majority needing intraoperative blood transfusion during head and neck surgery are potential candidates for autologous blood transfusion. Therefore, we have promoted autologous blood transfusion for intraoperative blood transfusion in head and neck surgery. Thus, the patients undergoing intraoperative autologous blood transfusion increased to seven annually as of 1994. 2. Clinical studies on autologous blood transfusion Among 677 cases of head and neck surgery conducted during a six year period (1989-1994), we experienced ten cases of autologous blood transfusion. For the prevention of anemia due to repeated blood withdrawal, we administered an iron preparation. Patients who preoperatively showed a low value of Hb (less than 11g/ dl) received intravenous drip infusion of erythropoietin. Since some patients selected for autologous blood transfusion, who also received neo-adjuvant chemotherapy and preoperative radiotherapy, exhibited a generally chronic anemia status, an iron preparation and erythropoietin should be preoperatively administered in combination.

Topics: Adolescent; Adult; Aged; Blood Transfusion, Autologous; Erythropoietin; Female; Head and Neck Neoplasms; Hemoglobins; Humans; Intraoperative Care; Iron; Male; Middle Aged

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