losartan-potassium and Uterine-Cervical-Neoplasms

The risk of severe cardiovascular toxicity, specifically thromboembolic events (TE), in patients with cervical cancer receiving concurrent irradiation and cisplatin chemotherapy is reported to be less than 1% in several large prospective trials. However, the anecdotal risk appears to be far higher.. A review of several prospective trials demonstrates no treatment related grade 4 cardiovascular toxicities and only two grade 5 toxicities in 1424 (0.1%) collective patients. A recent publication and our own unpublished experience finds 6 of 128 (4.7%) patients developed grade 4 to 5 cardiovascular (thrombosis/embolism) toxicity. The difference in incidence of severe or life threatening cardiovascular toxicity of 0.1 versus 4.7% is highly statistically significant (p < 0.00001.). This dramatic difference in incidence of cardiovascular toxicity raises the possibility that cardiovascular toxicities were inadequately reported on the listed prospective trials. For those patients enrolled in prospective trials, we suggest that thromboses should be diligently documented and reported. Only after the true incidence of thromboses is established can we implement appropriate levels of early screening and intervention that may prevent life threatening complications.

Topics: Antineoplastic Agents; Cisplatin; Clinical Trials as Topic; Cohort Studies; Combined Modality Therapy; Erythropoietin; Female; Humans; Incidence; Prospective Studies; Research Design; Retrospective Studies; Thromboembolism; Treatment Outcome; Uterine Cervical Neoplasms

During the treatments of carcinomas of the cervix, anemia is relatively frequent and its origin is complex combining often hemorrhage, iron deprivation, inflammatory reactions and infection. The frequency of the primary anemia (hemoglobin level<12 g/dl) is correlated with clinical stage and varies from one publication to another, mainly from 25% for stage I, to 33% for stage II and can approach 40% for stage III. Anemia is correlated with patient survival and it appears to be one of the most powerful prognostic factor after clinical stage and tumor size. Anemia is a bad prognostic factor related to stage and tumor size but it has not been proven to be an independent factor. Anemia increases hypoxia of cervix carcinomas, which is an independent prognostic factor for patients N0. Moreover, we know that the oxygenation of these tumors is correlated with hemoglobin levels. The normalization of Hb levels by transfusion could certainly modify the prognosis of patients anemic before treatment, or of those becoming anemic during radiotherapy treatment. For smokers, anemia is certainly more important that we can appreciate from the Hb levels only, by the presence of carboxyhemoglobin. Concomitant chemotherapies with cisplatin compounds are actually standards and they can largely increase the risk of inducing anemia, therefore more than 50% of patients will experiment it during their different treatments. Transfusion is recommended by the SOR (Standards Options and Recommendations of the Fédération nationale des centres de lutte contre le cancer) under 10 g/dl. The use of erythropoietin is a therapeutic option for Hb levels between 10 and 12 g/dl and strongly recommended after a Hb normalization by blood transfusion. For 70% of patients who respond to erythropoietin, a better control of the Hb level is obtained. The impact of this anemia on quality of life and treatments compliance justifies the use of erythropoietin, especially in cancers for which treatments induce a deep fatigue and a very bad tolerance, which could be a limiting factor.

Topics: Anemia; Antineoplastic Agents; Blood Transfusion; Carboxyhemoglobin; Cell Hypoxia; Cisplatin; Combined Modality Therapy; Erythropoietin; Female; Hemoglobins; Humans; Incidence; Prognosis; Quality of Life; Radiotherapy; Radiotherapy Dosage; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Smoking; Uterine Cervical Neoplasms

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

Thirty per cent of cancer patients suffer from anemia before any treatment. This anemia is caused by haematopoiesis troubles related to cytokines production and by endogenous erythropoietin deficiency. Clinically, its symptoms, including fatigue, spoils patients'quality of life. Known as a prognostic factor for several cancers, anemia also lowers radiotherapy or chemotherapy efficiency by tumor hypoxia. Recombinant EPO restores normal haemoglobin level, quality of life and treatment efficiency.

Topics: Anemia, Aplastic; Cell Hypoxia; Erythropoietin; Fatigue; Female; Humans; Neoplasms; Oxygen Consumption; Quality of Life; Uterine Cervical Neoplasms

We investigated the role of hemoglobin level in chemoradiation therapy for patients with advanced cervical cancer by reviewing the literature for current therapeutic information. We found that anemia during chemoradiation therapy is an important physiological factor in determining the long-term prognosis of patients with advanced cervical cancer.

Topics: Cell Hypoxia; Clinical Trials as Topic; Erythropoietin; Female; Hemoglobins; Humans; Prognosis; Recombinant Proteins; Uterine Cervical Neoplasms

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

A Consensus Conference on the use of recombinant human erythropoietin (rHuEPO, epoetin alfa) in gynecologic tumors was held in Rome in March 1999, and an associated consensus paper has been published in Italian. The current paper updates several discussions that took place at the 1999 meeting concerning epoetin alfa treatment in breast, ovarian, and cervical cancers; the role of epoetin alfa in mobilizing progenitor hematopoietic cells; administration of epoetin alfa in combination with granulocyte colony-stimulating factor; and the effect of hemoglobin levels on outcome of radiation or chemoradiation treatment.

Topics: Anemia; Antineoplastic Agents; Blood Transfusion; Breast Neoplasms; Epoetin Alfa; Erythropoietin; Female; Genital Neoplasms, Female; Granulocyte Colony-Stimulating Factor; Hematinics; Hematopoietic Stem Cell Mobilization; Hemoglobins; Humans; Ovarian Neoplasms; Quality of Life; Radiotherapy, Adjuvant; Recombinant Proteins; Uterine Cervical Neoplasms

This open-label, randomized phase III study was designed to investigate the effects of erythropoietin alfa (EPO) in addition to adjuvant chemotherapy and pelvic radiotherapy (CRT) in patients with stage IB to II cervical cancer who had undergone radical hysterectomy.. Two hundred fifty-seven patients were randomly assigned to four cycles of carboplatin/ifosfamide chemotherapy followed by external-beam pelvic radiotherapy (CRT group) or four cycles of carboplatin/ifosfamide chemotherapy and EPO followed by pelvic radiotherapy and EPO (CRT + EPO group). The primary end point was recurrence-free survival (RFS). Secondary end points included overall survival (OS), change in hemoglobin levels, and safety, including thromboembolic events.. The estimated 5-year RFS rates were 78% for patients receiving CRT + EPO and 70% for patients receiving CRT. There was no statistically significant difference in RFS, although a trend favoring patients treated with CRT + EPO was observed (hazard ratio [HR], 0.66; 95% CI, 0.39 to 1.12; log-rank P = .06). Exploratory analyses suggest a benefit with CRT + EPO for patients with stage IB to IIA disease (HR, 0.39; 95% CI, 0.18 to 0.85; P = .014) or patients with complete resection (HR, 0.55; 95% CI, 0.31 to 0.98; P = .039). OS was similar in both groups (HR, 0.88; 95% CI, 0.51 to 1.50; log-rank P = .63). Patients treated with EPO maintained higher hemoglobin levels throughout CRT. No significant differences in safety profiles were observed between the two groups. Incidence of thrombovascular events was low (2%) and comparable between both groups.. This study confirms that EPO can be added safely to CRT in patients with cervical cancer, but it failed to demonstrate a significant benefit in RFS and OS.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Chemoradiotherapy, Adjuvant; Disease-Free Survival; Epoetin Alfa; Erythropoietin; Female; Humans; Ifosfamide; Middle Aged; Neoplasm Staging; Recombinant Proteins; Risk Factors; Survival Analysis; Uterine Cervical Neoplasms; Young Adult

Cervical cancer, in women, is the second most common cancer world wide, next to breast cancer. During the treatment of carcinoma cervix, anemia is selectively frequent and its origin is complex combining hemorrhage, iron deprivation, inflammatory reactions and infection. The objective of this study is to evaluate the role of epoetin in correction of anemia and on treatment outcomes in patients with advanced cervical cancer receiving concurrent chemoradiotherapy.. A total of 120 patients were enrolled in the study of which 60 patients were randomized to receive epoetin beta in the treatment arm and 60 patients were in control arm where epoetin beta was not given. Total two and three patients absconded during treatment from treatment and control arm respectively; therefore total evaluable patients were 115. Mean Hb at baseline in the control arm was 10.70 g/dl +/- 0.62 g/dl and 10.45 g/dl +/- 0.43 g/dl in the treatment arm (p > 0.05). At the end of treatment period mean Hb increased by 1.55 g/dl in patients receiving epoetin beta (p < 0.01), but decreased by 1.50 g/dl in the control arm (p < 0.01). There was significant reduction in blood transfusion in patients receiving epoetin beta (p < 0.01). At the end of treatment there was significant improvement in energy level, activity level and overall quality of life in the treatment arm (p < 0.01). There was no significant difference in overall survival (p > 0.05), or disease free survival (p > 0.05) between the two study arms. Adverse events were well matched between the two study arms. No Thromboembolic events associated with epoetin beta was observed in our study.. Total 120, stage IIB to IIIB cervical cancer patients, aged 18-70 years with 9.50-12.50 gm/dl baseline Hb value who were to receive radiotherapy together with cisplatin were randomized to receive either epoetin beta 10,000 IU thrice weekly and oral iron starting 10-15 days before their 5-week course of whole pelvic irradiation and weekly cisplatin (treatment arm) or standard supportive care (control arm), where epoetin beta was not given. Blood transfusion was given in patients of both the arms if hemoglobin was < or =10 gm/dl.. Treatment with epoetin beta safely and effectively corrects anemia in patients with advanced cervical cancer receiving chemoradiotherapy and is not associated with adverse effects on response rate, overall survival, disease free survival and chemoradiotherapy related acute and late toxicities.

Topics: Adolescent; Adult; Aged; Blood Transfusion; Combined Modality Therapy; Erythropoietin; Female; Humans; Middle Aged; Neoplasm Staging; Recombinant Proteins; Survival Analysis; Survivors; Time Factors; Uterine Cervical Neoplasms; Young Adult

To determine whether maintaining HGB levels > or = 12.0 g/dL with recombinant human erythropoietin (R-HUEPO) compared to "standard" treatment (transfusion for HGB < or = 10.0 g/dL) improves progression-free survival (PFS), overall survival (OS) and local control (LC) in women receiving concurrent weekly cisplatin and radiation (CT/RT) for carcinoma of the cervix. In addition, to determine whether platinum-DNA adducts were associated with clinical characteristics or outcome.. Patients with stage IIB-IVA cervical cancer and HGB < 14.0 g/dL were randomly assigned to CT/RT+/-R-HUEPO (40,000 units s.c. weekly). R-HUEPO was stopped if HGB > 14.0 g/dL. Endpoints were PFS, OS and LC. Platinum-DNA adducts were quantified using immunocytochemistry assay in buccal cells.. Between 08/01 and 09/03, 109 of 114 patients accrued were eligible. Fifty-two received CT/RT and 57 CT/RT+R-HUEPO. The study closed prematurely, with less than 25% of the planned accrual, due to potential concerns for thromboembolic event (TE) with R-HUEPO. Median follow-up was 37 months (range 9.8-50.4 months). PFS and OS at 3 years should be 65% and 75% for CT/RT and 58% and 61% for CT/RT+R-HUEPO, respectively. TE occurred in 4/52 receiving CT/RT and 11/57 with CT/RT+R-HUEPO, not all considered treatment related. No deaths occurred from TE. High-platinum adducts were associated with inferior PFS and LC.. TE is common in cervical cancer patients receiving CT/RT. Difference in TE rate between the two treatments was not statistically significant. The impact of maintaining HGB level > 12.0 g/dL on PFS, OS and LC remains undetermined.

Topics: Adult; Aged; Anemia; Antineoplastic Agents; Cisplatin; Combined Modality Therapy; DNA Adducts; Erythropoietin; Female; Hemoglobins; Humans; Middle Aged; Neoplasm Staging; Recombinant Proteins; Thromboembolism; Uterine Cervical Neoplasms

The survival of cervix cancer patients is associated with their hemoglobin (Hgb) level during radiotherapy. The Southwest Oncology Group (SWOG) conducted a phase II trial to determine whether recombinant human erythropoietin (rHuEPO) safely corrects anemia during chemoradiotherapy for cervix cancer.. Patients had stage IIB-IVA cervix cancer and a Hgb between 8.0 and 12.5 g/dl. All patients received rHuEPO thrice weekly and oral iron starting 10-15 days before their 5-week course of whole pelvic irradiation and weekly cisplatin followed by intracavitary brachytherapy.. Fifty-three patients from 26 institutions received the protocol treatment. The mean Hgb was 10.4 +/- 1.3 g/dl on the first day of rHuEPO administration (baseline), 11.0 +/- 1.6 g/dl on the first day of chemoradiotherapy, 11.6 +/- 1.9 g/dl at the midpoint of chemoradiotherapy, and 11.8 +/- 2.2 g/dl at the end of chemoradiotherapy. The target Hgb level of 12.5 g/dl was achieved in 40% of patients (95% CI 26-56%) by the midpoint of Chemoradiotheraphy. Change in Hgb was associated with baseline serum iron (P = 0.008) and transferrin saturation (P = 0.05) levels, but not with baseline Hgb or serum ferritin, or patient age. Seven patients developed deep vein thrombosis. Two-year progression-free survival (PFS) was 43% and overall survival (OS) was 51%. Survival was significantly associated with Hgb level at the end of chemoradiotherapy, but not with the baseline Hgb level.. rHuEPO and iron gradually increased Hgb levels in anemic women with local advanced cervix cancer during chemoradiotherapy. There was a higher than expected incidence of deep vein thrombosis. The progression-free and overall survival rates were lower than reported for women with normal Hgb levels.

Topics: Adult; Aged; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Iron; Middle Aged; Recombinant Proteins; Uterine Cervical Neoplasms

Anemia during radiation therapy independently predicts poor outcome in patients with cervical cancer. Despite a randomized trial demonstrating red cell transfusions improve local control and survival, many patients are not transfused due to toxicity concerns. This study evaluates the efficacy of recombinant human erythropoietin (r-HuEPO) in reversing anemia in patients undergoing radiation therapy.. Twenty patients with criteria of anemia (Hgb < 12.5 g/dL) and surgically staged cervical cancer FIGO stages IB (n = 7), IIA (n = 1), IIB (n = 9), and IIIB (n = 3), ranging in ages from 23-75 years (median 43), were included in this Phase I/II study. Fifteen were treated with r-HuEPO (200 U/kg/day) and ferrous sulfate 5-10 days prior to initiation of external beam radiation therapy, continuing until Hgb was < or = 14 g/dL or completion of radiation therapy. Five patients were treated with ferrous sulfate alone. An additional 61 historical controls meeting eligibility criteria were analyzed. All received external beam radiation therapy and two intracavitary cesium applications. Cisplatinum chemotherapy (20 mg/m2/week) was given as a radiosensitizer in 14 r-HuEPO patients, 4 concurrent controls, and 17 historical controls.. A marked reticulocytosis was seen in the r-HuEPO group, but not the study controls. In the r-HuEPO group, the mean +/- SD serum Hgb rose + 30% over the course of radiation therapy from a baseline of 10.3 +/- 1.04 g/dL to 13.2 +/- 1.7 g/dL. Average increase in Hgb was 0.5 g/dL per week. Average Hgb during RT was 13.4 g/dL. In study and historical controls, mean initial Hgb levels were 10.7 +/- 1.04 g/dL and 11.1 +/- 1.3g/dL, respectively, remaining unchanged over the course of radiation therapy. Average Hgb levels during radiation therapy were 11.1 g/dL in study controls and 11.4 g/dL in historical controls, significantly lower than r-HuEPO patients (p = 0.0001). Erythropoietin was well tolerated. There were no significant differences in white blood counts (p = 0.6) or platelet counts (p = 0.4) between r-HuEPO patients and both control groups. No patients had blood pressure changes during r-HuEPO therapy. The only possible side effect was deep venous thrombosis, occurring in two patients who were withdrawn from r-HuEPO therapy. Two additional patients developed deep venous thrombosis 9 and 10 days after radiation therapy and r-HuEPO were completed.. Erythropoietin appears to be both safe and effective at raising Hgb levels in anemic cervical cancer patients receiving radiation therapy and chemotherapy.

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Middle Aged; Pilot Projects; Quality of Life; Radiation Injuries; Recombinant Proteins; Reticulocytes; Uterine Cervical Neoplasms

Erythropoietin (Epo) is used for the treatment of cancer‑associated anaemia. However, certain studies have identified that the administration of Epo mediates the acquisition of resistance to cisplatin, which is widely used to treat cervical cancer. Our group previously reported that cervical cancer cells express Epo receptor and that exogenous Epo induces cell proliferation and migration. However, the effect of Epo on cervical cancer cell death mediated by chemotherapeutic agents has not yet been evaluated. Thus, the aim of the present study was to assess the potential effect of Epo on the cytotoxic activity of cisplatin in cervical cancer cells. The effect of Epo was assessed in 3 cervical cancer‑derived cell lines. It was observed that pre‑incubation with Epo induced a significant reduction of cisplatin‑induced apoptosis in vitro and in vivo. Incubation with Epo induced the expression and activation of the transcriptional factor signal transducer and activator of transcription 3 (STAT3), which in turn stimulated the expression and activation of the anti‑apoptotic protein survivin. The cytotoxicity of cisplatin was partially restored by treating the cells with MY155, an inhibitor of survivin. Conversely, inhibition of STAT3 activation using sub‑lethal doses of WP1066, completely abolished the cytoprotective effect of Epo. These observations indicated that Epo was able to hinder the cytotoxic effect of cisplatin in cervical cancer cells by activating anti‑apoptotic responses regulated by STAT3.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cisplatin; Drug Resistance, Neoplasm; Erythropoietin; Female; Humans; Pyridines; STAT3 Transcription Factor; Survivin; Tyrphostins; Uterine Cervical Neoplasms

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

The cytokines erythropoietin (Epo) and stem cell factor (SCF), coupled with the cooperation between their receptors (EpoR and c-Kit), are essential components of normal physiological erythropoiesis. In earlier studies, we demonstrated the expression of c-Kit and EpoR in cervical cancer cells. It was identified that SCF is a survival factor, whereas Epo promotes cell proliferation. Cooperation between EpoR and SCF in cervical cancer has rarely been studied, despite the fact that cell migration and anchorage independent growth are considered initial steps in metastasis. Thus, the aim of this study was to analyse the effect of SCF and Epo alone, or in combination, on the migration and anchorage independent growth of two cervical cancer-derived cell lines. First, we demonstrated the expression of EpoR and c-Kit in the cell lines. Next, we evaluated anchorage independent growth, and identified that Epo and SCF produced a modest number of colonies, whereas the combination Epo/SCF induced a significantly higher number of colonies. Migration was then evaluated in Boyden chambers. Co-stimulation with Epo/SCF induced a significantly higher number of migrating cells than either cytokine alone. SCF-, Epo- and Epo/SCF-induced migration was inhibited by blocking phosphorylation of Janus kinase 2 (JAK2). Accordingly, western blot analysis demonstrated that the JAK2/signal transducer and activator of transcription-5 (STAT5) axis was activated in all cases. By contrast, inhibition of extracellular signal-related kinase (ERK) 1/2 abrogated migration induced by SCF and Epo/SCF only. Concurrently, Epo induced a modest, transient activation of ERK1/2, whereas SCF and Epo/SCF prompted a strong, sustained phosphorylation of ERK1/2. The results from this study have revealed that co-stimulation with Epo/SCF promotes migration and anchorage independent cell growth, and that co-signalling from EpoR and c-Kit converge on JAK2/STAT5 activation. Furthermore, SCF- and Epo/SCF-induced migration depends on the sustained activation of ERK1/2. These results indicate that co-signalling from different cytokine receptors induces migration, and this suggests that migratory behaviour may be regulated by the cooperative activity of Epo and SCF in cells expressing their cognate receptors.

Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Erythropoietin; Female; Gene Expression Regulation, Neoplastic; Humans; Janus Kinase 2; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Proto-Oncogene Proteins c-kit; Receptors, Erythropoietin; Signal Transduction; STAT5 Transcription Factor; Stem Cell Factor; Uterine Cervical Neoplasms

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

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

Erythropoietin (Epo) regulates erythropoiesis by binding to its receptor (EpoR) and promoting cell proliferation, differentiation and inhibition of apoptosis. Epo is widely used to treat cervical cancer-related anaemia. However, there are data suggesting that administration of Epo is associated with an increment in recurrence rate, and decreased disease-free and overall survival. In the present study, we investigated the expression of Epo and EpoR on cervical cancer cell lines. We observed that both EpoR and extracellular Epo are constitutively expressed in cervical cancer cells. Inhibition of either Epo or EpoR expression with siRNA attenuated cell proliferation, whereas addition of exogenous Epo led to a significant increase in cell growth, both in vitro and in vivo. Epo-induced proliferation was associated with the activation of JAK2, JAK3, STAT3 and STAT5 but not JAK1 and STAT1. Our results are consistent with the existence of a functional, endogenous Epo/EpoR system in cervical cancer with the capacity to activate the transduction of signals resulting in an increased proliferation potential.

Topics: Animals; Apoptosis; Autocrine Communication; Blotting, Western; Cell Proliferation; Erythropoietin; Female; Flow Cytometry; Humans; Immunoenzyme Techniques; Immunoprecipitation; Janus Kinase 1; Janus Kinase 2; Janus Kinase 3; Janus Kinases; Mice; Mice, Nude; Paracrine Communication; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; STAT1 Transcription Factor; STAT3 Transcription Factor; STAT5 Transcription Factor; Uterine Cervical Neoplasms

Topics: Anemia; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Quality of Life; Recombinant Proteins; Uterine Cervical Neoplasms

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

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

The objectives of the present study were to evaluate hemoglobin levels and consequent clinical behaviors related to anemia developed in patients affected by locally advanced cervical cancer treated with neo-adjuvant chemotherapy in the last decade and to evaluate the impact that the introduction of erythropoietic growth factors had in the clinical practice.. Blood chemistries, prospectively recorded from 98 cervical cancer patients, treated with neo-adjuvant chemotherapy and, if necessary, erythropoietic growth factors, were compared with matched historical controls before the introduction of growth factors in clinical practice.. Hemoglobin level in the study group did not differ significantly during chemotherapy. At the third cycle of chemotherapy and at the end of chemotherapy, hemoglobin level was significantly higher in the study group compared with the control group. Transfusion rates in the study group were significantly lower. The analysis within the study group revealed that hemoglobin level in patients who suffer at diagnosis from anemia tends to increase whereas hemoglobin level in nonanemic patients tends to decrease.. Erythropoietic growth factors increase hemoglobin level and reduce blood transfusions in cervical cancer patients undergoing neo-adjuvant chemotherapy followed by radical surgery. An appropriate autologous blood donation program can noticeably reduce homologous blood transfusions.

Topics: Adult; Aged; Anemia; Blood Transfusion; Chemotherapy, Adjuvant; Erythropoietin; Female; Hemoglobins; Humans; Middle Aged; Neoadjuvant Therapy; Uterine Cervical Neoplasms

We had previously reported an association between the use of recombinant human erythropoietin (rHuEPO) and thrombosis in patients with cervix and vulvo-vaginal cancer treated with chemotherapy and radiation. We hypothesized that low-dose warfarin would be effective prevention for thromboembolic events in this setting.. A retrospective analysis of patients with cervical or vulvo-vaginal carcinoma receiving chemoradiation and rHuEpo was performed. Thirty-two patients received rHuEpo alone, and 24 received warfarin (1-2 mg) and rHuEpo. The primary endpoint was objectively proven symptomatic venous thrombosis.. There was no difference in the baseline characteristics (e.g. age, stage, body mass index, mean and peak hemoglobin, WBC and platelet counts, and number of transfusions) between these two groups. The rate of thrombosis also was not statistically different (P = 0.62). Nine of 24 patients had a symptomatic deep vein thrombosis (DVT) while receiving warfarin compared to 10 of 32 patients not on warfarin. There was no difference between the two groups in the percentage of patients with upper extremity DVT (P = 0.83) or lower extremity DVT (P = 0.64).. Daily low-dose warfarin did not alter the incidence of symptomatic DVT in patients with cervical or vulvo-vaginal cancer who received rHuEpo in conjunction with chemoradiation.

Topics: Anticoagulants; Dose-Response Relationship, Drug; Erythropoietin; Female; Genital Neoplasms, Female; Humans; Middle Aged; Recombinant Proteins; Retrospective Studies; Thrombosis; Uterine Cervical Neoplasms; Vaginal Neoplasms; Vulvar Neoplasms; Warfarin

Physiologically, hypoxia induces the expression of erythropoietin (Epo) in adult kidney cells. Epo, in turn, acts on the Epo receptor (EpoR) in RBC precursors to stimulate growth and prevent apoptosis. Because hypoxia plays a major role in the malignant progression of tumors and Epo and its receptors have also been detected in malignant tumors, we investigated the expression of Epo and EpoR and their relationship with hypoxia, proliferation, apoptosis, and clinicopathologic variables in cervical cancer.. Intratumoral oxygen measurement and needle biopsies of the tumors were done in 48 patients with cervical cancer. The obtained tissue was analyzed by immunohistochemistry with antibodies against Epo, EpoR, and Ki-67 as well as by terminal deoxynucleotidyl transferase-mediated deoxyuracil triphosphate nick-end labeling assays.. Epo and EpoR were expressed in 88% and 92% of samples, respectively. Cervical cancers with higher Epo expression showed a significantly reduced overall survival (3 years, 50.0% versus 80.6%; P = 0.0084). Epo and EpoR expression correlated significantly with apoptosis (r = 0.49, P = 0.001 and r = 0.36, P = 0.021). Furthermore, EpoR expression correlated significantly with tumor size (r = 0.32, P = 0.032) and was significantly associated with the presence of lymphovascular space involvement (P = 0.037). However, we observed no correlation between Epo or EpoR expression and intratumoral hypoxia, although in well-oxygenated tumors, EpoR localized significantly more often to the invasion front (P = 0.047).. This study analyzes Epo/EpoR expression and their relationship with intratumoral pO(2) levels as well as with survival in patients with cervical cancer. The data suggest a critical role of the endogenous Epo/EpoR system in cervical cancer.

Topics: Adult; Aged; Apoptosis; Cell Proliferation; Disease Progression; Disease-Free Survival; Erythropoietin; Female; Follow-Up Studies; Humans; Hypoxia; Immunohistochemistry; Kaplan-Meier Estimate; Middle Aged; Neoplasm Staging; Predictive Value of Tests; Receptors, Erythropoietin; Recurrence; Survival Rate; Treatment Outcome; Uterine Cervical Neoplasms

Topics: Anemia, Iron-Deficiency; Erythropoietin; Female; Hemoglobins; Humans; Iron; Recombinant Proteins; Uterine Cervical Neoplasms

Topics: Chemotherapy, Adjuvant; Cisplatin; Clinical Trials, Phase II as Topic; Erythropoietin; Female; Hemoglobins; Humans; Iron; Neoplasm Staging; Recombinant Proteins; Uterine Cervical Neoplasms

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

Recent studies suggest that erythropoietin plays an important role in the process of neoplastic transformation and malignant phenotype progression observed in malignancy. To study the role of erythropoietin and its receptor (EPOR) on the response of cancer cells in vitro, we used two solid tumor cell lines, namely the human malignant glioma cell line U87 and the primary cervical cancer cell line HT100. All experiments were done with heat-inactivated fetal bovine serum in order to inactivate any endogenous bovine erythropoietin. The expression of the EPOR in these cells was confirmed with immunoblot techniques. The addition of exogenous recombinant human erythropoietin (rhEPO) induces the cancer cells to become more resistant to ionizing radiation and to cisplatin. Furthermore, this rhEPO-induced resistance to ionizing radiation and to cisplatin was reversed by the addition of tyrphostin (AG490), an inhibitor of JAK2. Our findings indicate that rhEPO result in a significant, JAK2-dependent, in vitro resistance to ionizing radiation and to cisplatin in the human cancer cells lines studied in this report.

Topics: Animals; Antineoplastic Agents; Cattle; Cisplatin; Drug Resistance, Neoplasm; Erythropoietin; Female; Glioma; Humans; Janus Kinase 2; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Radiation Tolerance; Radiation, Ionizing; Receptors, Erythropoietin; Recombinant Proteins; Tumor Cells, Cultured; Tyrphostins; Uterine Cervical Neoplasms

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

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

Because studies have suggested that anemia has an adverse effect on outcome for patients with cervical carcinoma who are treated with radiation, recombinant human erythropoietin (rHuEpo) has been used increasingly to maintain hemoglobin levels in these patients. Erythropoietin may increase the risk of thrombosis. The authors performed a retrospective analysis to determine whether there was an increased rate of symptomatic venous thrombosis associated with the use of rHuEpo in patients with carcinoma of the uterine cervix and vagina.. A retrospective, case-control study was performed on consecutive patients with localized carcinoma of the uterine cervix or vagina who were treated with chemotherapy and radiation (chemoradiotherapy). The primary outcome was symptomatic venous thrombosis.. One hundred forty-seven patients were reviewed. When they were divided into women who received rHuEpo (n = 75 patients) and women who did not receive rHuEpo (n = 72 patients), there were no significant differences in age, height, weight, disease stage, or body mass index. Fewer patients in the rHuEpo group required transfusions. In the rHuEpo group, 17 of 75 patients had either an upper extremity thrombosis (n = 12 patients) or a lower extremity thrombosis (n = 7 patients): 2 patients had both, and 2 patients had more than 1 event. Two of 72 patients who did not receive rHuEpo had symptomatic thrombosis. Patients who received rHuEpo had an odds ratio (OR) of developing thrombosis of 10.3 (95% confidence interval [95% CI], 2.3-46.2). Multiple logistic regression revealed that only the use of rHuEpo was associated with an increased risk of thrombosis (OR, 15.3; 95% CI, 3.1-76.7).. Patients with cervical carcinoma who received chemoradiotherapy and rHuEpo had an increased risk of symptomatic venous thrombosis.

Topics: Adult; Age Distribution; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Case-Control Studies; Combined Modality Therapy; Confidence Intervals; Erythropoietin; Female; Follow-Up Studies; Humans; Incidence; Logistic Models; Middle Aged; Multivariate Analysis; Radiotherapy; Recombinant Proteins; Retrospective Studies; Risk Factors; Severity of Illness Index; Survival Rate; Uterine Cervical Neoplasms; Venous Thrombosis

Red blood cell (RBC) transfusions or erythropoietin (EPO) can be used to evade the detrimental effects of anemia during radiotherapy, but the economic consequences of selecting either intervention are not well defined. The RBC transfusion needs during chemoradiotherapy for cervix cancer were quantified to allow comparison of RBC transfusion costs with the projected cost of EPO in this setting.. For patients receiving pelvic radiotherapy, weekly cisplatin, and brachytherapy, the RBC units transfused during treatment were tallied. RBC transfusion costs per unit included the blood itself, laboratory fees, and expected value (risk multiplied by cost) of transfusion-related viral illness. EPO costs included the drug itself and supplemental RBC transfusions when hemoglobin was not adequately maintained. An EPO dosage based on reported usage in cervix cancer patients was applied.. Transfusions were given for hemoglobin <10 g/dL. Among 12 consecutive patients, 10 needed at least 1 U of RBC before or during treatment, most commonly after the fifth week. A total of 37 U was given during treatment, for an average of 3.1 U/patient. The sum total of the projected average transfusion-related costs was $990, compared with the total projected EPO-related costs of $3869.. Because no proven clinical advantage has been documented for EPO compared with RBC transfusions to maintain hemoglobin during cervix cancer treatment, for most patients, transfusions are an appropriate and appealingly less expensive option.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Agents; Brachytherapy; Cisplatin; Costs and Cost Analysis; Erythrocyte Transfusion; Erythropoietin; Female; Hepatitis B; Hepatitis C; HIV Infections; Humans; Middle Aged; Probability; Radiation-Sensitizing Agents; Retrospective Studies; Uterine Cervical Neoplasms

Topics: Adult; Anesthesia, Epidural; Anesthesia, Inhalation; Blood Transfusion, Autologous; Erythropoietin; Female; Humans; Hypotension, Controlled; Hysterectomy; Middle Aged; Recombinant Proteins; Uterine Cervical Neoplasms

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

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

The possibility of serious complications of infection and GVHD and adverse prognosis in cancer patients resulting from homologous blood transfusions has been reported. We used recombinant human erythropoietin (rHuEPO) in autologous blood transfusions for radical hysterectomies to avoid the risks associated with transfusions. rHuEPO efficacy, stability and influence on hemodynamics were investigated. All patients were able to donate 1,200 ml of autologous blood prior to surgery, and anemia did not result despite phlebotomy three times each week. Elevation in Hb concentration was calculated at 0.78 +/- 0.37 g/dl over the first 7 days, and 2.12 +/- 0.35 g/dl over the first 14 days. No adverse side effects were observed in any patient. The serum EPO level was measured by RIA, and compared to the homologous blood transfusion group. rHuEPO did not influence postoperative EPO secretion. Autologous blood transfusion with rHuEPO in radical hysterectomy was extremely effective in mitigating the risks associated with homologous blood transfusions.

Topics: Blood Transfusion, Autologous; Erythropoietin; Female; Humans; Hysterectomy; Recombinant Proteins; Uterine Cervical Neoplasms

Topics: Absorption; Animals; Erythropoietin; Female; Hematocrit; Humans; Iron; Iron Isotopes; Mice; Reticulocytes; Uterine Cervical Neoplasms