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Journal of the New Zealand Medical Association, 19-May-2006, Vol 119 No 1234

New Zealand cancer patients should have access to erythropoietin treatment

John Carter, Jennifer Clay

Abstract

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.

Medication	Recombinant human erythropoietin is available in New Zealand as epoetin alpha (Eprex. Janssen-Cilag) and epoetin beta (Recormin. Roche)
Indication	Medsafe registers both preparations, and usage indications include: Treatment of anaemia associated with chronic renal failure with or without dialysis; Treatment of anaemia associated with non-myeloid malignancies (including multiple myeloma, chronic lymphocytic leukaemia, non-Hodgkin’s lymphoma); and Adult patients with mild-to-moderate anaemia scheduled for elective surgery with an expected moderate blood loss. The prevention of the anaemia of prematurity. Increasing the yield of autologous blood from patients in a pre-donation programme.
Administration	Various dosages, intravenous (iv) or subcutaneous (sc) × 3/week
Regulation	Pharmac funding only for patients with the anaemia of chronic renal failure (with or without dialysis)

Background

Erythropoietin is a 166 amino acid glycosolated polypeptide produced by the kidneys and liver. There is a good understanding of the biochemistry and physiology of this natural hormone.1 While the cause of anaemia in cancer patients is often multifactorial, a significant factor is a relative decrease in erythropoietin production in these patients 2.

The encoding gene for erythropoietin is on the long arm of chromosome 7 (7q21). It was the first haematopoietic growth factor to be cloned (1985) and, 20years ago, the efficacy of erythropoietin in correcting the anaemia in renal dialysis patients was documented.3 Soon afterwards its use in solid tumours and haematological malignancies was being reported.4,5 Subsequent to these early studies, much literature has confirmed both the efficacy and safety of erythropoietin in treating the anaemia found in cancer patients.

Anaemia is common in patients with malignancy. A large prospective study in 24 European countries studied 15,000 cancer patients and found 67% had anaemia either at diagnosis or during treatment. Of these patients, only 40% ever received treatment for the anaemia (at a mean Hb level of 97g/L). A strong correlation between quality of life (QOL) and anaemia was found in that study.6 Indeed, the relationship between QOL and anaemia is significant.7 Patients place great importance on QOL issues, and of these issues, fatigue (which correlates well with the degree of anaemia) is given the highest rating.8

A large (2370 patients) prospective study showed a strong correlation between an erythropoietin-induced rise in haemoglobin and QOL in community-treated cancer patients.9 Functional improvement is seen up to an haemoglobin level of 120g/L; subcutaneous injections are acceptable to patients with cancer if they perceive the treatment as effective 10.

The ability of erythropoietin to improve the anaemia of malignancy has been studied in many randomised trials, and a meta-analysis of 19 trials conducted between 1993 and 2001 showed the effect of erythropoietin in reducing transfusion requirements with an OR = 0.41; 95%CI: 0.33–0.5 (p<0.00001). By using a cumulative meta-analysis methodology, these authors demonstrated that a statistically significant effect of erythropoietin had been demonstrated by 1995.11

There is a significant literature documenting the relationship between anaemia, tumour hypoxia, response to chemotherapy/radiotherapy, and survival in both haematological and solid tumours in man and experimental animals.12 From these studies, it can be concluded that the use of erythropoietin to raise haemoglobin levels (and reduce tissue hypoxia) may improve patient outcomes to treatment.

Cost-effectiveness studies are difficult for this treatment. A full evaluation of the societal costs of transfusion therapy has not been done in New Zealand, and dollar measurements of QOL gain are debated.13 Despite these problems, a US study demonstrated a 20% improvement in cost-effectiveness for erythropoietin use over 4 months in cancer patients.14

While approximately 60% of patients will respond to erythropoietin with a rise of haemoglobin >20g/L, it would be cost-effective to be able to recognise non-responders early. An accurate prediction of response is possible within a few weeks of starting therapy by using assays for erythropoietin, transferrin receptor and reticulocyte and haemoglobin response. Such monitoring should be incorporated into treatment protocols and costing studies.15

As a result of data confirming the efficacy and safety of erythropoietin in treating anaemia in cancer patients, evidence-based clinical guidelines have been produced by British/European and American Professional groups.16,17 New Zealand clinicians are unable to provide care to cancer patients at the levels recommended in these standards due to funding constraints.

Comment

Anaemia is common in patients with cancer and results in significant morbidity. It is under-treated, and reliance on blood transfusions as therapy is associated with significant problems.

Erythropoietin is a safe and effective agent for increasing haemoglobin levels in the majority of patients with cancer. In those patients that respond, prospective, randomised, controlled trials show a significant improvement in formal quality of life scores, reduced use of blood transfusions, and possibly improved tumour response to chemotherapy and radiotherapy, thus leading to longer survival. Patients place a high utility on treatment that improves quality of life, and are increasingly asking clinicians for access to this treatment.

The reduced need for blood transfusions that would result from the funding of erythropoietin therapy is important. One of the guiding principles of the New Zealand Blood Service is to minimise waste of the blood donor’s gift. Similarly, when synthetic medications can substitute for donor blood they should (in principle) be used.

As erythropoietin is not funded for use in cancer patients in New Zealand, very few patients receive this agent. It is possible to apply to the Hospital Exceptional Circumstances Panel for approval for use in a specific patient (with payment coming from the hospital budget). This process is time-consuming and frustrating for clinicians who therefore seldom proceed down this pathway. The outcomes of such applications are inconsistent (records on file). The combination of a limited number of applications and variable outcomes means there is not uniform access of patients to this treatment. This is inconsistent with Government policy for healthcare in New Zealand that places great emphasis on equity of care across the Public Health System.

Evidence-based Best Practice Guidelines from several countries, including Great Britain, recommend the use of erythropoietin in the management of cancer patients. As a result of a failure to fund this agent, New Zealand is failing to deliver patient care to the standard being delivered by countries our Ministry of Health usually choses to benchmark against.

We consider it is appropriate for PHARMAC to consider expanding access to erythropoietin to patients with cancer.

Disclosures: None.

Author information: John M Carter, Associate Professor, Wellington School of Medicine and Health Sciences, University of Otago, Wellington; Jennifer Clay, House Surgeon, Wellington Blood and Cancer Centre, Wellington Hospital, Wellington

Correspondence: Associate Professor John Carter, Wellington School of Medicine and Health Sciences, University of Otago, PO Box 7343, Wellington. Fax (04) 385 5930; email: vanness@orcon.net.nz

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