National Institute for Clinical Excellence Cancer Treatment Induced Anaemia: Epoetin (alfa and beta) and Darbepoetin alfa Submission from: Breakthrough Breast Cancer CancerBACUP Leukaemia CARE 8 th November 2004
Contents 1. Who we are 2. Executive Summary 3. Introduction 4. Background 4.1 Anaemia in cancer patients 4.2 Definitions of anaemia 4.3 The impact of anaemia on cancer patients 4.4 Treatment for anaemia 5. The Patient Perspective 5.1 Fatigue 5.2 Blood transfusions 5.3 Patient choice 6. Conclusion 7. Declaration of interest 8. References 2
1. Who we are Breakthrough Breast Cancer Breakthrough Breast Cancer is a charity committed to fighting breast cancer through research and awareness, and has established the UK s first dedicated breast cancer research centre, in order to obtain our vision a future free from the fear of breast cancer. Breakthrough campaigns for policies that support breast cancer research and better services, as well as promoting breast cancer education and awareness amongst policy makers, health professionals and the media. This submission reflects the views of Breakthrough, including people with personal experience of, or who are concerned about, breast cancer. We have consulted with members of our Campaigns and Advocacy Network (CAN) for their views. Originally founded by women with personal experience of breast cancer, Breakthrough CAN brings together individuals, regional groups and national organisations to campaign for improvements in breast cancer research, treatments and services. Through supporting and training members to become patient advocates in their own right, Breakthrough CAN aims to increase the influence of patients in decisions regarding breast cancer issues. CancerBACUP CancerBACUP is the leading national charity providing information and support to people affected by cancer. The charity s specialist cancer nurses answer more than 60,000 enquiries a year from patients and carers on all aspects of cancer and its treatment. CancerBACUP s services include a telephone helpline, a wide range of booklets and factsheets, an award-winning website and a network of local information centres. In addition to providing information and support, CancerBACUP works to promote patient-centred services and equitable access to high quality treatment, information and support for everyone affected by cancer. Leukaemia CARE Leukaemia CARE is a national charity that provides care and support to patients, their families and carers during the difficult journey through the diagnosis and treatment of leukaemia, lymphoma or an allied blood disorder. Leukaemia CARE provides the only dedicated free phone CARE Line for patients and their families that enables people to discuss their feelings, concerns and emotions at such a difficult period of time. In addition, Leukaemia CARE provides information, holidays, limited financial support and operate CARE Teams throughout the United Kingdom to ensure that there is local support wherever a patient and their family live. 3
2. Executive summary To inform this submission Breakthrough Breast Cancer and CancerBACUP have reviewed the responses from surveys which asked cancer patients and their carers about their personal experience of anaemia, fatigue, blood transfusions and their treatment, if any, to correct anaemia. Calls to the cancer information and support help lines operated by CancerBACUP and Leukaemia CARE relating to anaemia and fatigue were also analysed for this exercise. Our research, as well as relevant scientific and medical papers, revealed that many cancer patients do not receive treatment for their anaemia and its associated side effects, which can include fatigue, breathlessness, lack of concentration and a general reduced quality of life (QoL). In more severe cases of anaemia, patients may receive blood transfusions. However, blood is a valuable resource in the UK and many patients have indicated to us their increasing concern over the safety of blood products. The administration of epoetin (alfa and beta) and darbepoetin (alfa) at recommended doses has been shown to correct anaemia and reduce the need for additional blood transfusions. The provision of the choice of erythropoietin products has been shown to be especially significant in QoL studies where the association between higher levels of haemoglobin and improved QoL indicators such as a reduction of fatigue has been demonstrated. 1 Correction of anaemia through treatment with epoetin alfa has been evaluated in anaemic cancer patients and shown to improve QoL. 2 Breakthrough Breast Cancer, CancerBACUP and Leukaemia CARE therefore consider that epoetin (alfa and beta) and darbepoetin alfa should be offered to cancer patients to alleviate the symptoms of anaemia induced by cancer treatment, within their licensed indications. Cancer patients should be offered epoetin (alfa and beta) and darbepoetin alfa as part of a range of treatments in accordance with their individual needs and preferences. However, the potential side effects of any new treatments are of particular concern to patients. In order that patients are able to make informed choices in partnership with their clinician, patients should be provided with information relating to any potential side effects and potential risks of these products, especially at high doses. 4
3. Introduction Breakthrough Breast Cancer, CancerBACUP and Leukaemia CARE welcome the opportunity to contribute to the National Institute for Clinical Excellence (NICE) Health Technology Appraisal Cancer treatment induced anaemia: Epoetin (alfa and beta) and Darbepoetin alfa. As patient representative organisations, we have regular contact with cancer patients and seek to represent their views at the policy-making level. We therefore welcome the opportunity to ensure that the patient perspective is a key consideration in NICE s decision-making process. Our joint submission has three key aims: - to contribute to NICE s understanding of: 1. What it is like to suffer from anaemia 2. The concerns and preferences of cancer patients regarding anaemia alleviation 3. What it is like to be treated with blood transfusions It is essential that NICE gain an understanding of what it is like to live with cancer. Quality of life (QoL) judgements should be central to the evaluation of the impact of any new treatment and we want NICE to understand the existing QoL issues facing cancer patients. Through this, we hope to help NICE develop a clearer understanding of the trade offs that cancer patients are already making, as part of their everyday lives, and prior to access to any new treatments. In this technology appraisal, epoetin (alfa and beta) and darbepoetin alfa are proposed for the treatment of cancer treatment induced anaemia. In order to inform this submission, members of Breakthrough s Campaigns and Advocacy Network (CAN) were approached and asked to respond to a questionnaire to tell us in their own words about their, or someone else s, experience of anaemia as a result of living with cancer. 1 Their comments are equally relevant to other cancer patients. In addition, the database of callers to helplines at Leukaemia CARE and CancerBACUP were also consulted to inform this submission. For example, 6% of the total calls received by Leukaemia CARE s helplines from September 2003 to September 2004 were from people concerned about anaemia, tiredness or fatigue. CancerBACUP received 486 enquiries in the year 2003/4 from people affected by anaemia induced by cancer treatment. Analysis of calls to CancerBACUPs helpline show that it is also the most frequently highlighted side effect. 1 Members of CAN were asked to contribute their thoughts during September 2004. 5
4. Background Whilst we recognise that NICE has commissioned its own assessment from the NHS Centre for Reviews and Dissemination at the University of Birmingham, we would also like to comment on some of the published data, with the patient perspective in mind. 4.1 Anaemia in cancer patients Anaemia is defined within the scope of this appraisal as a reduction of haemoglobin concentration, red-cell count, or packed cell volume (PCV) to below normal levels. A reduction in red blood cells can result from either the defective production of red blood cells or an increased rate of loss of cells, either by premature destruction or bleeding. 3 Anaemia is common amongst cancer patients and is recorded in some patients prior to treatment. The prevalence and severity of anaemia in cancer patients depends on a number of factors, including the type of cancer, stage and grade of tumour. The type and intensity of previous treatments as well as nutritional status are also important factors. 4 5 Chemotherapy and/or radiotherapy, as well as surgical procedures are also considered to be principal contributors to anaemia in cancer patients. For example, the European Cancer Anaemia Survey (ECAS) 6 reported that overall 62.7% of cancer patients who received chemotherapy, 19.5% of cancer patients who received radiotherapy and 41.9% of cancer patients who received concomitant chemoradiotherapy were anaemic. 4.2 Definitions of Anaemia Anaemia is generally reported in terms of decreases in haemoglobin levels. The more severe grades of anaemia are similarly categorised by both the World Health Organisation (WHO) as well as the National Cancer Institute (NCI). 5 The World Health Organisation states anaemia in adults as haemoglobin levels lower than 13 g/dl (males) or 12 g/dl (females). The National Cancer Institute considers normal haemoglobin levels as 12-16g/dl (females) and 14 18 g/dl (males). Most studies referred to for this response have adopted the grading system of the NCI as outlined below. 5 Table 1 WHO and NCI Anaemia Grading System Severity WHO NCI Grade 0 (WNL)* >11.0g/dL WNL Grade 1 (mild) 9.5-10.9 g/dl 10.0 g/dl to WNL Grade 2 (moderate) 8.0-9.4 g/dl 8.0-10.0 g/dl Grade 3 (serious/severe) 6.5-7.9 g/dl 6.5-7.9 g/dl Grade 4 (Life threatening) <6.5 g/dl <6.5 g/dl * WNL within normal limits The table above is adapted from the grading system table in Groopman and Itri (1999) 5 6
4.3 The impact of anaemia on cancer patients The symptoms of anaemia vary according to individual patients. Bohlius et al (2004) 7 describe headaches, breathlessness and palpitations as the typical symptoms of mild to moderate anaemia. Severe anaemia in turn can affect the cardiovascular system, immune system, lungs, kidneys, muscles and the central nervous system. 7 Moreover, research suggests that anaemia in patients with malignancies increases the frequency of complications, impacts on physical well-being and QoL - especially by increasing fatigue. Studies also indicate tumour resistance against radiotherapy and chemotherapy. 7 Low haemoglobin levels are associated with negative prognostic factors. 7 The presence of anaemia has a substantial impact on the QoL of patients and their ability to perform every day activities. 5 Fatigue is the most common symptom of anaemia and has been to shown to have a significant impact on cancer patients, their families and carers further illustrated by the comments from cancer patient we have included in section 5. Patients, particularly those with myeloma/myelodysplasia, have also highlighted feeling cold. 8 In turn, mental health, concentration levels, personal relationships, participation in social activities as well as earning capacity may all be affected. 5 Clinical studies included in the recent Cochrane Review (2004) 7 of erythropoietin for patients with malignant disease have shown correlations between haemoglobin levels and quality of life domains, for example, mood, appetite 7 and the ability to work. 7 Anaemia in terms of haemoglobin levels significantly correlates with QoL, 6 where higher haemoglobin levels are associated with less fatigue and better QoL. 5 In addition, correction of anaemia through treatment with epoetin alfa has been evaluated in anaemic cancer patients and shown to improve QoL. 1 2 In addition to concerns related to QoL issues, cancer-associated anaemia may also affect clinical treatment. Anaemia may be independently associated with shorter survival times in patients with cancer 9 6 and its correction may therefore have a positive impact on treatment outcomes. 6 According to the ECAS study (2004) 6 only 26.2% of breast cancer patients were likely to receive anaemia treatment compared to other tumour groups. Similarly, 53.3% of leukaemia patients, 47.4% of lymphoma/myeloma patients, 47.7% of lung cancer patients, 46.1% of head and neck cancer patients, 43.0% of urogential cancer patients and 33.0% of GI colorectal patients were treated for anaemia. 6 In spite of the recognised debilitating symptoms of anaemia, research suggests that anaemic patients frequently do not receive treatment until their haemoglobin levels are below 9.0 g/dl. 6 7
4.3 Treatment for Anaemia Traditionally, mild to moderate anaemia has often been clinically managed conservatively and in many cases is not treated at all. The reasons for this are unclear but may include the fact that the current standard treatment for anaemia correction is blood transfusion, predominantly used to treat severe anaemia only. This is probably partly due to the fact that blood is a limited resource. 5 Furthermore, patients may assume that the symptoms of anaemia, particularly fatigue, are a normal part of having cancer. As such it may be taken for granted by both patients and oncologists and seldom treated unless severe and attributable to other indicators. At present in the UK, there does not appear to be a clear decision making framework for the treatment of anaemia, which varies according to clinical priorities and judgement. 10 Data from Roche (2002) 11 reveal that in the UK where anaemia requires treatment, blood transfusions are used in 91% of such cases. This is in contrast to France where blood transfusions are used in only 46% of cases. Similarly, in the UK erythropoietin products are only used in 4% of cases for anaemia alleviation. The use of other combination treatments for anaemia e.g. transfusion and epoetin; transfusion, epoetin and iron; transfusion and iron; iron replacement only; or epoetin and iron are used in less than 5 % of cases overall in the UK 11. This is in contrast to the situation in France where epoetin alone is used in 20% of cases and epoetin and iron is used in an additional 19% of cases and probably reflects the current licensing indication of these drugs in the UK. Blood transfusion seems to be the fastest method to alleviate the symptoms of anaemia, however, as with most treatments, studies have suggested that both short and long-term risks exist. 7 Potential complications associated with blood transfusion include the transmission of infectious diseases, adverse transfusion reactions, alloimmunisation, over-transfusion and immune modulation with possible adverse effects on tumour growth. 7 Similarly, drugs to treat anaemia such as epoetin (alfa and beta) and darbepoetin alfa may also have adverse side effects. For example, the European Organisation on Research and Treatment of Cancer (EORTC) guidelines state that there is some evidence to suggest an increase in the risk of thrombosis or related complications such as transient ischaemic attacks, stroke, pulmonary embolism or myocardial infarction in patients with chemotherapy induced anaemia receiving epoetin. 12. Similarly, a recent study by Henke et al (2003) 13 stated that epoetin beta is associated with increased vascular disorders, including hypertension, haemorrhage, venous thrombosis, pulmonary embolism and cerevascular disorders. The doses of epoetin for the Henke study were double the standard, approved weekly epoetin dose of current licensing regimes. Moreover, the Breast Cancer Erythropoietin Trial (BEST) by Leyland-Jones et al 14 was terminated due to an increase in mortality in the first 4 months of this study in the epoetin group. The epoetin group mortality was 6% and the placebo arm was 3%. 8
However, this study was investigational in nature and the drug used was administered outside of its current licensed indications in patients with only mild anaemia or normal haemoglobin levels in order to prevent anaemia during chemotherapy. Both the Henke and BEST studies have been disputed for their design and methodology. 15 The recent Cochrane Review (2004), which included studies up to the end of 2001, 7 found insufficient evidence to conclude that erythropoietin use increases the risk of these complications. 7 The outcome of the BReast cancer Anaemia and the Value of Erythropoietin (BRAVE) study, 15 as well as other meta analysis, are expected to clarify some concerns in due course. 5. Patient Experience Using open-ended self-administered questionnaires in September - October 2004, Breakthrough CAN members were asked if they or someone else they knew had suffered from the symptoms of anaemia. They were asked to describe their experience in their own words and the effect this had on their family and QoL. Questions were also included about how they felt about blood transfusions and whether they would prefer to take a drug to alleviate the symptoms of anaemia. Overall, the responses we received highlighted the fact that patients were not able to differentiate between cancer treatment induced anaemia and the fatigue they assumed was a natural part of having cancer and its subsequent treatment. The responses, and indeed lack of responses we received, also indicated that very few cancer patients (particularly breast cancer patients) received treatment for their anaemia. There were a number of issues which were of particular concern to patients, highlighted below. 5.1 Fatigue Fatigue is the most commonly reported symptom by cancer patients 5 and nearly all patients responding to the Breakthrough survey have included this as of particular concern. It is clear from patient accounts that fatigue is distressing, both physically and emotionally, and that its impact is immense both on those who experience anaemia and their families. 5 In 2002, CancerBACUP ran a national advertising campaign to raise awareness of cancer-related fatigue. In a follow-up questionnaire, which received 550 responses, 21 percent of patients had not been told before treatment to expect fatigue. Patients were also asked to rate their fatigue into the following categories: Mild 12 % Moderate 49 % Severe 39 % Many of the people we spoke to highlighted fatigue as particularly debilitating. 9
At times I was too exhausted to do anything and with 2 young children this was difficult for all of us. My husband found it hard to cope with work and managing the house. I was unable to work My father s quality of life was significantly affected [by his anaemia]. He was very tired, breathless etc I had a young teenage family so was constantly tired The effect [of anaemia] was exhaustion, perhaps made worse, as I returned to work shortly after radiotherapy. I was surprised to hear that all my breathlessness and being cold was finally explained as anaemia. I don t know why they didn t warn me before. I wish I had known this earlier 5.2 Blood Transfusions In our survey of Breakthrough CAN members we also asked whether anyone had ever been treated for anaemia. Surprisingly, considering how many cancer patients experience symptoms of anaemia, very few had. The overall low number of callers to CancerBACUP and to Leukaemia CARE concerned about fatigue and anaemia also reflected how patients accepted tiredness as a natural part of living with cancer and receiving treatment. Nevertheless, some Breakthrough CAN members who responded to our questionnaire described what it was like to have a blood transfusion and their concerns about this treatment. My father received many transfusions during the last months of his life. Some, when he was able, were given on a day patient basis. He was admitted for blood when he was very unwell. The actual process was not terrible it was the time it took away from the family, in his precious last weeks and months. I d do anything to avoid more transfusions. I have had a blood transfusion for severe anaemia following constant haemorrhaging. The actual transfusion was not unpleasant but I have been slightly concerned about the risk of contaminated blood. Considering the element of risk in blood products such as vcjd [I am concerned about more blood transfusions]. I know blood transfusions are safer these days, but I would still only want a transfusion of my own blood (HIV, vcjd etc) 10
I was never given a choice or had anything explained about the risks of blood transfusion. I discovered all this later. I hope I am given more information on the side effects of the drugs. 5.3 Patient Choice The responses we received highlighted that whilst patients wanted to be given a choice of treatments to alleviate the symptoms of anaemia, they were particularly concerned about long term side effects and wanted as much information as possible. It would be extremely nice to have the choice: whilst I m sure there will be side effects of the drugs: blood transfusions are not pleasant and carry other risks It would be much better to be able to take a drug instead of a transfusion. After treatment with chemotherapy or radiotherapy, the cancer patient does not want to go through further trauma therefore medication to correct the anaemia would be very beneficial. Taking drugs would be simpler than a blood transfusion although patients would have to be competent at self medication in veins I have always been treated for anaemia in the past, but have not always found it easy to take iron (slow release ones were better) so would welcome a new drug. Had such a drug been available, it might have given us more very precious days with my father. It could also have prevented the awful tiredness, breathlessness etc. I hope they will explain the side effects of the drugs more to us before giving them. 6.0 Conclusions Breakthrough Breast Cancer, CancerBACUP and Leukaemia CARE consider that epoetin (alfa and beta) and darbepoetin alfa are important additions to the armoury of treatments available to alleviate the symptoms of anaemia in cancer patients. We hope that NICE will positively appraise these drugs for use in the NHS within their licensed indications i.e. in a corrective setting for patients with cancer who become anaemic as a result of their cancer treatment. The comments we have received from patients, and the research evidence we have included in this submission, make it clear that anaemia and its associated side effects such as fatigue are distressing both physically and emotionally for patients. Despite the adverse effects on the QoL of cancer patients, our research suggests that some cancer patients are not receiving treatment for anaemia induced by their cancer treatment. Unfortunately, our experience from the questionnaire used to inform this submission and from calls to our dedicated help lines is that many cancer patients assume the symptoms of anaemia are a natural part of having cancer we would like to see this 11
situation change and studies have shown that erythropoietin drugs (i.e. epoetin alfa) are effective at raising haemoglobin levels and significantly improving QoL. 1 Patients have also expressed concern about the safety of blood transfusions. Whilst some of these concerns may not be entirely substantiated they are important points to consider and will further add to the stress and worry that cancer patients experience. We are also aware of the value of the limited blood stocks within the UK and the recent Cochrane review 7 states that there is consistent evidence that the administration of erythropoietin reduces the number of blood units transfused in cancer patients. Wherever possible, patients and clinicians should have a range of treatments to choose from, as drugs affect patients in different ways and no single treatment will be suitable for all patients. However, the potential side effects of any new treatments are of particular concern to patients. This may be particularly important for the drugs in this appraisal as our understanding is that the side effects could potentially be severe, particularly with high doses. We would therefore recommend monitoring patients who receive these drugs. In addition, cancer patients must be given all the information, including new data when it becomes available, relating to any potential side effects so they can make informed choices in partnership with their clinician. 7. Declarations of interest Breakthrough Breast Cancer In the financial year (2003/04) Breakthrough Breast Cancer was given 31,000 by Roche to help support the costs of the Westminster Fly In, The Advocate and the All Party Parliamentary Group on Breast Cancer. The Westminster Fly-In is an annual training and lobbying event for Breakthrough CAN members and involves the meeting of MPs to improve breast cancer services. In 2002/03 Amgen gave 20 for no specified purpose. Breakthrough has not received any other support from OrthoBiotech, Amgen or Roche in the last two financial years. CancerBACUP CancerBACUP has received sponsorship from Amgen, OrthoBiotech and Roche, the manufacturers of erythropoetin (alpha and beta) and darbepoetinimatinib, for several publications and projects. Leukaemia CARE A wide range of pharmaceutical companies provide assistance to Leukaemia CARE through a number of methods including the provision of information for patients, health professionals and volunteers. Leukaemia CARE has received a financial contribution from Roche Pharmaceuticals for the production of patient information booklets. 12
8. References 1 Fallowfield et al. Multivariate regression analyses of data from a randomised, double blind, placebo-controlled study confirm quality of life benefit of epoetin alfa in patients receiving non-platinum chemotherapy. British Journal of Cancer 2002; 87:1341-1353 2 Jones et al. Epoetin alfa improves quality of life in patients with cancer. Cancer 2004; 101 (8): 1720-1732 3 National Institute of Clinical Excellence Heath Technology Appraisal. Final Scope for the appraisal of anaemia (cancer treatment induced): Epoetin (alfa and beta) and darbepoetin. Final Scope Appendix A July 2004 4 Kirshner J, Hatch M, Hennessy DD, Fridman M, Tannous RE. Anaemia in stage II and III breast cancer patients treated with adjuvant doxorubicin and cyclophosphamide chemotherapy. The Oncologist 2004; 9:25-32 5 Groopan JE and Itri LM. Chemotherapy induced anaemia in adults: incidence and treatment. Journal of the National Cancer Institute 1999; 91 (19) 6 Ludwig H et al. The European Cancer Anaemia Survey (ECAS): A large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. European Journal of Cancer 40 2004; 2293-2306 7 Bohlius J, Langensiepen S, Schwarzer G, Seidenfeld J, Piper M, Bennet C, Engert A. Erythropoietin for patients with malignant disease. The Cochrane Library, Issue 3, 2004; (recent amendment 27 May 2004) 8 Personal communication with Marc Stowell, Leukaemia Care 1/11/2004 9 Knight K, Wade S, Balducci L. Prevalence and Outcome of Anaemia in Cancer: A Systematic review of the Literature. American Journal of Medicine 2004; 116 (7a) 10 Personal communication with Rebecca Hunt, Roche 29/10/2004 11 NOP, Roche data on file. UK vs Europe: Breakdown of cancer-related anaemia treatment. 2002 12 Bokemeyer C et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. European Journal of Cancer. 2004; 40 (15): 2201-16 13 Henke M, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. The Lancet. 2003; 362 14 Leyland-Jones B. Breast cancer trial with erythropoeitin terminated unexpectedly. Lancet Oncology 2003; 4: 459-460 15 Glaspy J and Dunst J. Can erythropoietin therapy improve survival? Oncology 2004; 67 (suppl 1):5-11 13