Treatment of anaemia in cancer patients: implications for supportive care in the National Health Service Cancer Plan

The National Health Service (NHS) Cancer Plan published in 2000 has a short-term focus on the most pressing problems of improving survival rates and replacing equipment. It also mentioned as a target 'improved quality of life for those affected by cancer'. Continuity of care for longer-term care programmes was seen predominantly in terms of palliative care. Recent National Institute for Clinical Excellence (NICE) reports may have reinforced this approach by focussing on the clinical and cost effectiveness of chemotherapy for late-stage cancer. The impact on local decision-makers has been that drug funds have been prioritised for use on survival-enhancing interventions, with few resources left for short and longer-term supportive care targeted primarily on improving quality of life. Within supportive care, resources are particularly limited for funding treatments such as erythropoietin for the management of cancer-related anaemia, a common and very debilitating side-effect of intensive therapy. The need for a re-focusing on supportive care is associated with cancer becoming, in many instances, a longer-term illness. The prevalence of cancer is rising markedly due to increased survival rates. However, this creates a new challenge of reducing disability and improving quality of life. In surveys, patients have rated fatigue associated with anaemia as one of the most debilitating effects of their cancer and its treatment with chemotherapy. This paper reviews the evidence demonstrating the quality of life benefits of erythropoietin, and then considers the policy constraints that have limited the adoption of this treatment within the NHS. Through co-ordinated planning there are opportunities for cancer networks and primary care trusts (PCTs) working with cancer centres to develop more support in ways which are feasible and fundable. The case is argued that PCTs and cancer networks, in implementing the Cancer Plan locally, need to integrate short- and longer-term supportive care into their cancer service development plans, and recognise the importance of anaemia management as an integral part of this. Lessons can be learnt from UK renal services where anaemia management with erythropoietin is standard practice.     

Epoetin Beta: a review of its clinical use in the treatment of anaemia in patients with cancer

Epoetin beta (NeoRecormon) is a recombinant form of erythropoietin. It increases reticulocyte counts, haemoglobin (Hb) levels and haematocrit. Epoetin beta administered subcutaneously once weekly corrected anaemia and had equivalent efficacy to that of epoetin beta administered three times weekly in patients with haematological malignancies. Subcutaneous epoetin beta reduced transfusion requirements and increased Hb levels versus no treatment in patients with solid tumours and chemotherapy-induced anaemia in nonblind, randomised trials. Anaemia and quality of life were also improved, and blood transfusion requirements were reduced to a significantly greater extent than placebo or no treatment (with supportive blood transfusion) in patients with haematological malignancies. Most patients were receiving chemotherapy. Subcutaneous epoetin beta was well tolerated by patients with cancer; adverse events with the drug occurred with a similar incidence to those with placebo or no treatment (with supportive blood transfusion). Hypertension was relatively uncommon with epoetin beta in clinical trials. Patients with haematological malignancies and a baseline platelet count > or =100 x 10(9)/L, Hb levels of > or =9 g/dL or lower erythropoietin levels have demonstrated better responses to epoetin beta than other patients in clinical trials. However, neither baseline erythropoietin level nor the observed to predicted ratio of erythropoietin levels correlated with the response to epoetin beta in patients with solid tumours and chemotherapy-induced anaemia. A decrease of <1 g/dL or an increase in Hb with epoetin beta during the first chemotherapy cycle indicated a low transfusion need in subsequent cycles in patients with ovarian carcinoma. In general, the efficacy of epoetin beta is not limited by tumour type. Response to the drug occurred irrespective of the nature (platinum- or nonplatinum-based) or presence of chemotherapy treatment in randomised trials. CONCLUSION: Epoetin beta has shown efficacy in the management of cancer-related anaemia in patients with haematological malignancies and of chemotherapy-induced anaemia in patients with solid tumours. Once-weekly administration provides added convenience for patients and may be cost saving, although additional research into the potential pharmacoeconomic benefits of this regimen are required. The drug is well tolerated in patients with cancer and is associated with little injection-site pain when administered subcutaneously. Epoetin beta is an important option in the prevention of chemotherapy-induced anaemia, and a valid and valuable alternative to blood transfusion therapy for the treatment of cancer-related or chemotherapy-induced anaemia.     

Epoetins and [symbol: see text] darbepoetin alfa in malignant disease

Anaemia is common in people with cancer, and may reduce their quality of life and life expectancy. Blood transfusion can increase haemoglobin levels but is usually reserved for those with moderate anaemia (haemoglobin level below 10 g/dL). A potential alternative is treatment with one of the human recombinant forms of erythropoietin, epoetin alfa (Eprex--Janssen-Cilag) or epoetin beta (NeoRecormon--Roche), or their hyperglycosylated derivative [symbol: see text] darbepoetin alfa (Aranesp--Amgen). These products have improved the management of patients with chronic renal failure who are anaemic. Here we assess the place of the epoetins and darbepoetin alfa in managing anaemia in patients with cancer.     

Epoetin alfa for the treatment of cancer- and chemotherapy-related anaemia: product review and update

Anaemia, often associated with chemotherapy, is a common and debilitating disorder in cancer patients. Recombinant human erythropoietin (epoetin alfa) was introduced in the 1990s for the treatment of chemotherapy-related anaemia. Data from randomised, double-blind, placebo-controlled studies and large, non-randomised, community-based studies have demonstrated that either of the FDA-approved dosing schedules of epoetin alfa 150 - 300 U/kg three times weekly or 40,000-60,000 U/week s.c., significantly increases haemoglobin levels, reduces transfusion requirements, and improves quality of life in anaemic cancer patients undergoing chemotherapy or chemoradiation therapy. Guidelines for the effective and safe use of epoetin alfa have been published by major oncology/haematology organisations and are reviewed in this article. Areas of recent and ongoing investigation with epoetin alfa are also covered in this review.     

Aplastic anaemia in childhood. Description of two cases and review of the literature

Childhood aplastic anaemia (AA) is an uncommon but potentially fatal haematological disorder. Patients with AA receive supportive care based on transfusions and timely treatment of opportunistic infections, along with specific therapies, which may be bone marrow transplantation and immunosuppressive therapy. Early diagnosis and supportive therapy are required to prevent fatal complications like overwhelming sepsis or life threatening haemorrhages. We report two cases of aplastic anaemia having a different aetiology. The diagnostic work-up and the therapeutic management for each case are described below.     

New Zealand cancer patients should have access to erythropoietin treatment

Erythropoietin was the first haematopoietic growth factor to be cloned and put to clinical use in patients with anaemia. In New Zealand, the agent is approved and funded for patients with anaemia secondary to renal failure. Although there is Medsafe approval for its use in various other conditions, including cancer patients, it is not funded by Pharmac for these conditions. There is good evidence that erythropoietin will induce meaningful increases in haemoglobin levels in approximately 60% of cancer patients. Non-responders can be identified within 2-4 weeks of starting therapy and the drug discontinued, thus improving the cost-effectiveness of the programme. Responders have a significant reduction in blood transfusions, have an improved quality of life, and possibly have a better tumour response to chemo-radiotherapy, thus resulting in longer survival. British and American guidelines advocate a significantly greater use of erythropoietin than the very restrictive New Zealand use. Pharmac should review the current evidence as to the benefits of increased erythropoietin usage in New Zealand, and endorse increased access to this agent.     

Management options for cancer therapy-related anaemia.

Anaemia is common in patients with haematological malignancy, occurring in the majority of patients with malignant disease who are treated with chemotherapy. Most patients will have their anaemia attributed to the cytokine-mediated anaemia of chronic disease. Many of these patients with anaemia will be symptomatic with fatigue, which is the single most important symptom reported. Data from many studies indicate that treatment of patients with anaemia with recombinant human erythropoietin (rHuEpo) will increase their haemoglobin level, decrease transfusion need and also improve their quality of life. Recent clinical and experimental work suggest that improving the haemoglobin level may improve the patients' prognosis but this finding needs to be confirmed. Treatment of anaemia with rHuEpo in patients with cancer may produce many benefits. Unfortunately, rHuEpo is effective in only around 60% of patients, is slow acting and is expensive. These drawbacks have restricted its use in many healthcare systems. However, a failure to treat anaemia may have important adverse effects for the patient both in terms of their quality of life and, just possibly, in terms of their life expectancy.     

Evolving cancer pain treatments: rational approaches to improve the quality of life for cancer patients

Most cancer patients will experience moderate to severe pain and/or neuropathy during the course of their disease. Recent improvements in the primary treatment of cancer have increased the life span of cancer patients, but not necessarily their quality of life (QoL). The pain and suffering cancer patients experience may be the result of the tumor itself, or the treatments required to arrest tumor growth and progression. In contrast to the rapid, highly mechanistic, tailored medicine approach used to target and treat the primary tumor burden, the evolution of pain and other supportive treatment approaches for cancer patients have been slow to non-existent. A movement is emerging to use more rational mechanistic approaches to the treatment of pain created by cancer and chemotherapeutics. This review briefly describes the most severe and debilitating symptoms (endophenotypes) from the cancer patient's perspective, the biochemical/neurobiological sequalae associated with tumor growth and therapies designed to arrest tumor progression, and highlights some promising pharmacologic mechanisms that may be used to treat cancer-related pain, sensory neuropathies, and associated endophenotypes. Delivering improved broader spectrum supportive care medicines to cancer patients will fill a significant unmet need and enable them to live productive, fulfilling lives that preserve their overall QoL.     

Sickle cell anaemia: progress in pathogenesis and treatment

The phenotypic expression of sickle cell anaemia varies greatly among patients and longitudinally in the same patient. It influences all aspects of the life of affected individuals including social interactions, intimate relationships, family relations, peer interactions, education, employment, spirituality and religiosity. The clinical manifestations of sickle cell anaemia are protean and fall into three major categories: anaemia and its sequelae;pain and related issues; andorgan failure including infection. Recent studies on the pathogenesis of sickle cell anaemia have centred on the sequence of events that occur between polymerisation of deoxy haemoglobin (Hb) S and vaso-occlusion. Cellular dehydration, inflammatory response and reperfusion injury seem to be important pathophysiological mechanisms. Management of sickle cell anaemia continues to be primarily palliative in nature, including supportive, symptomatic and preventative approaches to therapy. Empowerment and education are the major aspects of supportive care. Symptomatic management includes pain management, blood transfusion and treatment of organ failure. Pain managment should follow certain priniciples that include assessment, individualisation of therapy and proper utilisation of opioid and nonopioid analgesics in order to acheive adequate pain relief. Blood selected for transfusion should be leuko-reduced and phenotypically matched for the C, E and Kell antigens. Exchange transfusion is indicated in patients who are transfused chronically in order to prevent or delay the onset of iron-overload. Acute chest syndrome is the most common form of organ failure and its management should be agressive, including adequate ventilation, multiple antibacterials and simple or exchange blood transfusion depending on its severity. Preventitive therapy includes prophylactic penicillin in infants and children, blood transfusion (preferably exchange transfusion) in patients with stroke, and hydroxyurea in patients with frequent acute painful episodes. Bone marrow and cord blood transplantation have been successful modalities of curative therapy in selected children with sickle cell anaemia. Newer approaches to preventative therapy include cellular rehydration with agents that inhibit the Gardos channel or the KCl co-transport channel. Curative gene therapy continues to be investigational at the level of the test tube and transgenic mouse models.     

Epoetin alfa (Eprex) and quality of life

Several recently published clinical trials in anaemic patients with cancer provide convincing evidence that the quality of life of such patients is considerably impaired and that a significant improvement in quality of life can be achieved if their anaemia is corrected by treatment with recombinant erythropoietin (epoetin alfa, Eprex). Findings of some of the major studies are summarised in this issue. These summaries have been prepared to make the findings more accessible to busy clinicians who may not have time to read longer reports in specialist journals but who need to understand the important clinical implications of this research.     

Pharmacotherapy of chemotherapy-induced anaemia

Anaemia in cancer patients is multifactorial. Anaemia of chronic disease due to the effects of cancer, as well as side effects of cancer treatment, are important factors. The impact of anaemia on the quality of life and social function of cancer patients has recently become more acknowledged. The traditional treatment for chemotherapy-induced anaemia (CIA) has been the use of red blood cell transfusions, with only short-lived effects and all their inherent risks. The finding of deficiency in erythropoietin, the endogenous hormone responsible for the production and maintenance of red blood cells in these patients, was the basis for the therapeutic development of erythropoietic proteins. With the introduction of epoetins (recombinant forms of human erythropoietin) in oncology and more recently, the novel long-acting darbepoetin alpha, physicians gained new pharmacotherapeutic approaches to treat CIA. Several forms of erythropoietic proteins are available in various regions of the world. Their characteristics, clinical evidence for use, guidelines for clinical administration and their safety are described in this review.     

Pharmacotherapy of chemotherapy-induced anaemia

Anaemia in cancer patients is multifactorial. Anaemia of chronic disease due to the effects of cancer, as well as side effects of cancer treatment, are important factors. The impact of anaemia on the quality of life and social function of cancer patients has recently become more acknowledged. The traditional treatment for chemotherapy-induced anaemia (CIA) has been the use of red blood cell transfusions, with only short-lived effects and all their inherent risks. The finding of deficiency in erythropoietin, the endogenous hormone responsible for the production and maintenance of red blood cells in these patients, was the basis for the therapeutic development of erythropoietic proteins. With the introduction of epoetins (recombinant forms of human erythropoietin) in oncology and more recently, the novel long-acting darbepoetin alpha, physicians gained new pharmacotherapeutic approaches to treat CIA. Several forms of erythropoietic proteins are available in various regions of the world. Their characteristics, clinical evidence for use, guidelines for clinical administration and their safety are described in this review.     

The impact of anaemia and its treatment on employee disability and medical costs

OBJECTIVE: Anaemia is a common haematological complication of cancer and cytotoxic treatment. The incremental economic burden associated with medical care and short-term disability of anaemia in patients with malignancy and receiving chemotherapy has not been well documented. This study evaluates the effect of anaemia on the costs associated with cancer treated with chemotherapy. METHODS: Patients receiving chemotherapy within 6 months of their initial cancer diagnosis were identified in a commercial claims database for 1999-2000. Data for these individuals were linked to their employers' short-term disability records via unique encrypted personal identification numbers provided by employers. Patients with anaemia were identified by a diagnosis of anaemia or treatment with transfusion or erythropoietin alfa (EPO). Healthcare expenditure and short-term disability leave were observed for up to 6 months following initial cancer diagnosis and were summarised into monthly averages. Exponential conditional mean models and zero-inflated negative binomial models were used to analyse mean monthly healthcare expenditures and short-term disability days. RESULTS: Twenty-five percent of the 619 newly diagnosed cancer patients treated with chemotherapy had anaemia. The presence of anaemia and longer length of transfusion therapy were associated with increased expenditures, while longer length of EPO treatment was associated with lower expenditures. The incremental costs due to anaemia among patients receiving chemotherapy were US$5,538 (year 2001 values) per month in the first 6 months following cancer diagnosis, 10.8% of which were costs related to short-term disability leave. CONCLUSION: Anaemia in patients undergoing chemotherapy presents a substantial burden to employers and payers. The findings also suggest that patients with anaemia treated with erythropoietin alfa can achieve expenditure levels similar to those patients without anaemia.     

Management of anaemia: a critical and systematic review of the cost effectiveness of erythropoiesis-stimulating agents

Erythropoiesis-stimulating agents (ESAs) are genetically engineered forms of erythropoietin that are used in the treatment of anaemia. Their successful use in the treatment of anaemia associated with renal disease, cancer and other diseases, as well as the development of multiple agents, has increased the visibility of these agents in the clinical and health economics literature. The circumstances under which the use of ESAs is cost effective, or indeed, whether it is cost effective, is of central concern for clinicians and payers who must make informed decisions regarding the management of these costly resources. Much of the recent literature on ESAs in the treatment of anaemia associated with chronic kidney disease and cancer, the two major therapeutic areas for ESA treatment, has focused on comparisons between individual ESAs, particularly epoetin alfa and darbepoetin alfa. While there have been some studies of cost effectiveness, many studies in these treatment areas have employed a cost-minimization approach and have relied on published prices rather than actual market prices. In general, this review of the literature suggests a cost advantage for epoetin alfa relative to darbepoetin alfa in the treatment of anaemia in renal and oncology indications. For other indications in which the literature is less developed, such as anaemia induced by antiviral therapy and blood management in surgery, small prospective studies or decision-analytic models comparing ESA therapy and standard care have been most common. Few conclusions can be drawn about the overall and relative costs or cost effectiveness of ESAs in these treatment areas.With the recent concerns about the safety of ESAs, especially when used outside the approved product labelling, future evaluations of epoetin alfa and darbepoetin alfa should factor their safety profiles into estimates of cost effectiveness. Moreover, additional studies are needed to evaluate whether the treatment of anaemia with ESAs is cost effective compared with no treatment or minimal blood transfusions, and whether the cost effectiveness of ESAs would be improved if ESA doses and durations were reduced.With the introduction of new longer-acting ESAs, such as the continuous erythropoietin receptor activator, the relative cost effectiveness among the different ESAs will continue to be an important question for public and private payers, policy makers and clinicians who must consider the emergence of new data and changing dosing patterns when making decisions about the use of these important but costly agents.     

Scottish Antimicrobial Prescribing Group (SAPG): development and impact of the Scottish National Antimicrobial Stewardship Programme

In 2008, the Scottish Management of Antimicrobial Resistance Action Plan (ScotMARAP) was published by the Scottish Government. One of the key actions was initiation of the Scottish Antimicrobial Prescribing Group (SAPG), hosted within the Scottish Medicines Consortium, to take forward national implementation of the key recommendations of this action plan. The primary objective of SAPG is to co-ordinate and deliver a national framework or programme of work for antimicrobial stewardship. This programme, led by SAPG, is delivered by NHS National Services Scotland (Health Protection Scotland and Information Services Division), NHS Quality Improvement Scotland, and NHS National Education Scotland as well as NHS board Antimicrobial Management Teams. Between 2008 and 2010, SAPG has achieved a number of early successes, which are the subject of this review: (i) through measures to optimise prescribing in hospital and primary care, combined with infection prevention measures, SAPG has contributed significantly to reducing Clostridium difficile infection rates in Scotland; (ii) there has been engagement of all key stakeholders at local and national levels to ensure an integrated approach to antimicrobial stewardship within the wider healthcare-associated infection agenda; (iii) development and implementation of data management systems to support quality improvement; (iv) development of training materials on antimicrobial stewardship for healthcare professionals; and (v) improving clinical management of infections (e.g. community-acquired pneumonia) through quality improvement methodology. The early successes achieved by SAPG demonstrate that this delivery model is effective and provides the leadership and focus required to implement antimicrobial stewardship to improve antimicrobial prescribing and infection management across NHS Scotland.     

Selexipag for the treatment of pulmonary arterial hypertension

Chemotherapy-induced anaemia, with its important consequences on quality of life and social function of cancer patients, can be improved with erythropoietic therapy. Darbepoetin alfa is the first of a novel generation of erythropoietic proteins with a unique molecular structure and a circulating half-life that is threefold longer than that of the previous recombinant human erythropoietin. The efficacy and safety of weekly administration have been confirmed in different Phase II and III randomised trials. In order to optimise the efficacy profile of darbepoetin alfa, extended dosing intervals and front-loading regimens are evaluated, as well the optimal haemoglobin level to initiate therapy. Across all trials, darbepoetin alfa was shown to be a well-tolerated and safe therapy. The possible favourable effect on the outcome of cancer patients needs to be further elucidated.     

Acute myocardial infarction and subacute stent thrombosis associated with cabazitaxel: a case report

Case Although newer cancer treatments and supportive care treatments have led to vast improvements in the management of complications associated with cancer treatment, sometimes they might cause serious side effects such as coronary artery disease, myocardial infarction and heart failure. These complications may occur any time during or after chemotherapeutics. In this report we present a patient with prostate cancer who experienced myocardial infarction and stent thrombosis probably caused by cabazitaxel -a new chemotherapeutic agent- administration. Conclusion Cardiologists and oncologists should take into consideration the cardiac side effects of new chemotherapeutic agents with the aim of maximizing both quality of life and survival.     

The use of darbepoetin alfa for the treatment of chemotherapy-induced anaemia

Chemotherapy-induced anaemia, with its important consequences on quality of life and social function of cancer patients, can be improved with erythropoietic therapy. Darbepoetin alfa is the first of a novel generation of erythropoietic proteins with a unique molecular structure and a circulating half-life that is threefold longer than that of the previous recombinant human erythropoietin. The efficacy and safety of weekly administration have been confirmed in different Phase II and III randomised trials. In order to optimise the efficacy profile of darbepoetin alfa, extended dosing intervals and front-loading regimens are evaluated, as well the optimal haemoglobin level to initiate therapy. Across all trials, darbepoetin alfa was shown to be a well-tolerated and safe therapy. The possible favourable effect on the outcome of cancer patients needs to be further elucidated.     

Novel treatments for cancer cachexia

Cancer cachexia is a debilitating and life-threatening syndrome characterised by anorexia, body weight loss, loss of adipose tissue and skeletal muscle, and accounts for > or = 20% of deaths in neoplastic patients. Cancer cachexia significantly impairs quality of life and response to antineoplastic therapies, increasing the morbidity and mortality of cancer patients. Muscle wasting is the most important phenotypic feature of cancer cachexia and the principle cause of function impairment, fatigue and respiratory complications, and is mainly related to a hyperactivation of muscle proteolytic pathways. Existing therapeutic strategies have proven to be only partially effective. In the last decade, the correction of anorexia, the inhibition of catabolic processes and the stimulation of anabolic pathways in muscle has been attempted pharmacologically, giving encouraging results in animal models and through preliminary clinical trials.