Recombinant human erythropoietin in the treatment of chemotherapy-induced anemia and prevention of transfusion requirement associated with solid tumors: A randomized, controlled study

Background: Anemia is a common side effect of anticancer chemotherapy. Blood transfusion, previously the only available treatment for chemotherapy-induced anemia, may result insome clinical or subclinical adverse effects in the recipients. Recombinant human erythropoietin (rhEPO) provides a new treatment modality for chemotherapy-induced anemia. Patients and methods: To evaluate the effect of rhEPO onthe need for blood transfusions and on hemoglobin (Hb)concentrations, 227 patients with solid tumors and chemotherapy-induced anemia were enrolled in a randomized, controlled, clinical trial. Of 189 patients evaluable for efficacy, 101 received 5000 IU rhEPO daily s.c, while 88 patients received no treatment during the 12-week controlled phase of the study. Results: The results demonstrate a statistically significant reduction in the need for blood transfusions (28% vs. 42%, P = 0.028) and in the mean volume of packed red blood cells transfused (152 ml vs. 190 ml, p = 0.044) in patients treated with rhEPO compared to untreated controls. This effect was even more pronounced in patients receiving platinum-based chemotherapy (26% vs. 45%, % 0.038). During the controlled treatment phase, the median Hb values increased in the rhEPO patients while remaining unchanged in the control group. The response was seen in all tumor types. Conclusions: RhEPO administration at a dose of 5000 IU daily s.c. increases hemoglobin levels and reduces transfusionrequirements in chemotherapy-induced anemia, especially during platinum-based chemotherap

Early changes in the haemostatic and procoagulant systems after chemotherapy for breast cancer

Venous thromboembolism (VTE) following breast cancer chemotherapy is common. Chemotherapy-induced alterations in markers of haemostasis occur during chemotherapy. It is unclear how rapidly this occurs, whether this is upregulated in patients developing VTE and whether changes predict for VTE. Markers of haemostasis, functional clotting assays and vascular endothelial growth factor were measured before chemotherapy and at 24 h, 4 days, 8 days and 3 months following commencement of chemotherapy in early and advanced breast cancer patients and in age- and sex-matched controls. Duplex ultrasound imaging was performed after 1 month or if symptomatic. Of 123 patients, 9.8% developed VTE within 3 months. Activated partial thromboplastin time (APTT), prothrombin time (PT), D-dimer, fibrinogen, platelet count, VEGF and fibrinogen were increased in cancer. Fibrinogen, D-dimer, VEGF and tissue factor were increased, at baseline, in patients subsequently developing VTE. D-dimer of less than 500 ng ml−1 has a negative predictive value of 97%. Activated partial thromboplastin time, PT and thrombin–antithrombin showed significantly different trends, as early as within 24 h, in response to chemotherapy in patients subsequently developing VTE. Markers of coagulation and procoagulants are increased, before chemotherapy, in patients who subsequently develop VTE. A group of patients at minimal risk of VTE can be identified, allowing targeted thrombopropylaxis to the higher risk group

Erythropoietin, uncertainty principle and cancer related anaemia

BACKGROUND: This study was designed to evaluate if erythropoietin (EPO) is effective in the treatment of cancer related anemia, and if its effect remains unchanged when data are analyzed according to various clinical and methodological characteristics of the studies. We also wanted to demonstrate that cumulative meta-analysis (CMA) can be used to resolve uncertainty regarding clinical questions. METHODS: Systematic Review (SR) of the published literature on the role of EPO in cancer-related anemia. A cumulative meta-analysis (CMA) using a conservative approach was performed to determine the point in time when uncertainty about the effect of EPO on transfusion-related outcomes could be considered resolved. Participants: Patients included in randomized studies that compared EPO versus no therapy or placebo. Main outcome measures: Number of patients requiring transfusions. RESULTS: Nineteen trials were included. The pooled results indicated a significant effect of EPO in reducing the number of patients requiring transfusions [odds ratio (OR) = 0.41; 95%CI: 0.33 to 0.5; p < 0.00001;relative risk (RR) = 0.61; 95% CI: 0.54 to 0.68]. The results remain unchanged after the sensitivity analyses were performed according to the various clinical and methodological characteristics of the studies. The heterogeneity was less pronounced when OR was used instead of RR as the measure of the summary point estimate. Analysis according to OR was not heterogeneous, but the pooled RR was highly heterogeneous. A stepwise metaregression analysis did point to the possibility that treatment effect could have been exaggerated by inadequacy in allocation concealment and that larger treatment effects are seen at hb level > 11.5 g/dl. We identified 1995 as the point in time when a statistically significant effect of EPO was demonstrated and after which we considered that uncertainty about EPO efficacy was resolved. CONCLUSION: EPO is effective in the treatment of anemia in cancer patients. This could have already been known in 1995 if a CMA had been performed at that time

Effect of treatment with epoetin-β on survival, tumour progression and thromboembolic events in patients with cancer: an updated meta-analysis of 12 randomised controlled studies including 2301 patients

Epoetin-β is used to treat patients with metastatic cancer undergoing chemotherapy to alleviate the symptoms of anaemia, reduce the risk of blood transfusions and improve quality of life. This meta-analysis of 12 randomised, controlled studies evaluated the impact of epoetin-β on overall survival, tumour progression and thromboembolic events (TEEs). A total of 2297 patients were included in the analysis (epoetin-β, n=1244; control, n=1053; 65% solid and 35% nonmyeloid haematological malignancies). A prespecified subgroup analysis assessed the effects in patients with a baseline Hb⩽11 g dl−1, corresponding to current European Organisation for Research and Treatment of Cancer (EORTC) guidelines. No statistically significant effect on mortality was observed with epoetin-β vs control, both overall (hazard ratio (HR)=1.13; 95% CI: 0.87, 1.46; P=0.355) and in patients with baseline Hb⩽11 g dl−1 (HR=1.09; 95% CI: 0.80, 1.47; P=0.579). A trend for a beneficial effect on tumour progression was seen overall (HR=0.85; 95% CI: 0.72, 1.01; P=0.072) and in patients with an Hb⩽11 g dl−1 (HR=0.80; 95% CI: 0.65, 0.99; P=0.041). An increased frequency of TEEs was seen with epoetin-β vs control (7 vs 4% of patients); however, TEEs-related mortality was similar in both groups (1% each). The results of this meta-analysis indicate that when used within current EORTC treatment guidelines, epoetin-β has no negative impact on survival, tumour progression or TEEs-related mortality

Effect of treatment with epoetin beta on short-term tumour progression and survival in anaemic patients with cancer: a meta-analysis

To assess the early effect of epoetin beta on survival and tumour progression in anaemic patients with cancer, data were pooled from nine randomised clinical trials comparing epoetin beta with placebo or standard care. Studies were not primarily designed to assess these end points. Follow-up was for treatment duration plus 4 weeks following therapy completion. All adverse events (AEs) were retrospectively reviewed blinded, for progression. Thromboembolic events were also assessed. Data analysis involved standard statistical tests. Overall, 1413 patients were included (epoetin beta, n=800; control, n=613; 56% haematological, and 44% solid). Median initial epoetin beta dose was 30 000 IU/week. Overall survival during months 0–6 was similar with epoetin beta and control (0.31 vs 0.32 deaths/patient-year). No increased mortality risk was seen with epoetin beta (relative risk (RR) 0.97, 95% CI: 0.69, 1.36; P=0.87). There was a significantly reduced risk of rapidly progressive disease for epoetin beta (RR 0.78, 95% CI: 0.62, 0.99; P=0.042). Epoetin beta was associated with a slightly higher frequency of thromboembolic events vs control (5.9% vs 4.2% of patients) but thromboembolic-related mortality was identical in both groups (1.1%). Epoetin beta provided a slight beneficial effect on tumour progression and did not impact on early survival or thromboembolic-related mortality

Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes

BACKGROUND: Cancer patients often develop the potentially debilitating condition of anaemia. Numerous controlled studies indicate that erythropoiesis-stimulating agents (ESAs) can raise haemoglobin levels and reduce transfusion requirements in anaemic cancer patients receiving chemotherapy. To evaluate recent safety concerns regarding ESAs, we carried out a meta-analysis of controlled ESA oncology trials to examine whether ESA use affects survival, disease progression and risk of venous-thromboembolic events

Derivation of clinical pathways using evidence-based clinical practice guidelines, illustrated by female breast cancer treatment

Introduction: The use of evidence-based Clinical Practice Guidelines may contribute to the assurance and enhancement of medical services. A practice oriented realisation within a process- and reference-model supports its implementation and acceptance through reduction of implementation-costs. This article aims at developing a method that allows the derivation of a clinical pathway by using a practical-oriented reference model which is based upon a Clinical Practice Guideline. Methods: For the methodological development both concepts - Clinical Practice Guideline and clinical pathway - will be contrasted on a normative-analytical level. This helps finding out similarities and differences of the concepts. Secondly we develop a suitable procedure for deducting a clinical pathway from a Clinical Practice Guideline. The clinical pathways of "Uni-Brustzentrum Essen" and the evidence-based guidelines for breast cancer ("Diagnostik, Therapie und Nachsorge des Mammakarzinoms der Frau") have been used additionally. Results: The results of the normative-analytical comparison show that - even when the concepts differ in some way - the Clinical Practice Guideline may define general conditions which can be specified by a clinical pathway. The procedure of derivation divides itself into three categories with each two special phases: Derivation of an evidence-based reference model, adaptation to the individual organisation and thirdly implementation of the evidence-based clinical pathway. This method is exemplified by a guideline dealing with breast cancer. Diskussion/Conclusion: A publication of evidence-based Clinical Practice Guidelines as evidence-based reference models would be a support for the transfer from scientific study to practical work. This could contribute to a more frequent use of evidence-based guidelines. The restriction of physician´s decisions and treatments - as a negative effect - is finally contrasted by positive effects like transparency and general comparability of medical services.Einleitung: Zur Förderung der Implementierung aktueller wissenschaftlicher Erkenntnisse in der Praxis, als ein wichtiges Qualitätskriterium im Gesundheitswesen, stellen öffentlich akzeptierte Anbieter, wie z.B. die Medizinischen Fachgesellschaften indikationsspezifische Empfehlungen in Form von evidenzbasierten Leitlinien zu Verfügung. Deren Implementierung und Akzeptanz kann durch eine praxisorientierte Umsetzung als Prozess- bzw. Referenzmodell aktiv unterstützt werden. Ziel der Arbeit ist die Entwicklung eines Verfahrens, welches eine Ableitung eines Klinischen Pfades aus einer evidenzbasierten Leitlinie über ein praxisorientiertes Referenzmodell systematisch ermöglicht und die Disseminierung von evidenzbasierten Leitlinien unterstützt. Methoden: In einem ersten Schritt wurden beide Konzepte - Klinischer Pfad und evidenzbasierte Leitlinie - auf einer normativ-analytischen Ebene gegenüber gestellt, um grundsätzliche Gemeinsamkeiten und Differenzen der Konzepte herauszuarbeiten. Auf Basis dieser Ergebnisse wird in einem zweiten Schritt ein Verfahren zur Ableitung eines Klinischen Pfades aus einer evidenzbasierten Leitlinie entwickelt. Als Entwicklungs- und Anwendungsbeispiel dienen die Klinischen Pfade des Uni-Brustzentrums Essen und die evidenzbasierte Leitlinie zur "Diagnostik, Therapie und Nachsorge des Mammakarzinoms der Frau". Ergebnisse: Das Ergebnis des normativ-analytischen Vergleichs zeigt, dass - auch wenn die Schwerpunkte der Konzepte hinsichtlich einzelner Kriterien divergieren - die Leitlinie einen evidenzbasierten Rahmen bildet, der durch den Klinischen Pfad in der klinischen Praxis konkretisiert und implementiert werden kann. Die Ableitungsmethodik gliedert sich in drei Stufen mit je zwei Phasen: Ableitung eines evidenzbasierten Referenzmodells, Adaption auf die individuelle Einrichtung und Implementierung des evidenzbasierten Klinischen Pfades. Die Methodik wird exemplarisch bei Behandlung des Mammakarzinoms der Frau erprobt. Diskussion/Fazit: Eine Veröffentlichung von evidenzbasierten Leitlinien als evidenzbasierte Referenzmodelle würde es den Leistungsanbietern erleichtern, Erkenntnisse aktueller wissenschaftlicher Studien systematisch in der Praxis umzusetzen. Der individuelle Implementierungsaufwand wird damit verringert und gleichzeitig die inhaltliche Umsetzungsqualität gesteigert. Möglichen problematischen Effekten aus einer weiteren Verbreitung von evidenzbasierten Leitlinien, wie z.B. Einschränkungen in der ärztlichen Entscheidungs- und Behandlungsfreiheit stehen positive Effekte im Bereich der Transparenz und der Vergleichbarkeit verschiedener Einrichtungen gegenüber