Hospital Pharmacist
Vol 11 No 8 p337-338
September 2004

Tired of being tired — why we should treat cancer-related anaemia

By Nicola O’Connell

Anaemia is a common complication in people with cancer, affecting approximately 60 per cent of patients. It can have a significant impact on their quality of life but its importance is frequently under recognised.

Cancer-related anaemia can have many causes, some of which are a result of the cancer itself and others of the treatment. Main causes include chemotherapy, the anaemia of chronic disease, radiation therapy, bleeding, nutritional deficiency or malignancies of the haemotopoietic system. Myelosuppressive chemotherapy (most notably with platinum-based compounds) can make the development and progression of anaemia more likely.

Anaemia is the main cause of debilitating fatigue among cancer patients, which can have far-reaching consequences for patients as it interferes with fundamental activities. Fatigue is not the only problem — anaemia has a major impact on nearly all of the organ systems, causing patients to experience a wide range of symptoms including dizziness, inability to concentrate, vertigo, depression and hypersensitivity to cold.

Mild-to-moderate anaemia

Anaemia is normally considered severe when the haemoglobin (Hb) level falls below 8g/dL, but data now suggests that mild to moderate anaemia can have a significant impact on quality of life.¹ “Many patients with Hb levels of 9 and 10g/dL are symptomatic,” comments Dr Tim Littlewood, haematologist at the John Radcliffe Hospital, Oxford. Nevertheless, a patient’s care team often overlook the symptoms. Dr Littlewood explains: “Firstly, there is a lack of recognition that anaemia may be causing the patient’s problem. Secondly, for many years doctors have been educated that mild anaemia does not produce symptoms. It takes a long time to change the perception that mild to moderate anaemia may well be causing problems for the patient. It is easy to pass off fatigue as being due to the treatment or the tumour.”

Various studies have been undertaken to demonstrate the impact of anaemia on patients’ quality of life. One US telephone survey conducted among 379 cancer patients who had received chemotherapy in the past showed how debilitating fatigue can be. More than three quarters of patients experienced significant fatigue and of these, 88 per cent indicated that fatigue caused an alteration in their daily routine.² Of the patients in employment, 75 per cent said they changed their employment status as a result of fatigue. The findings indicate that cancer-related fatigue results in substantial adverse physical, psychological and economic consequences for both patients and their carers.

It appears that the majority of care teams are aware of the impact that the symptoms of anaemia may have. Surveys conducted among doctors and nurses during last year’s 10th World Conference of Lung Cancer and the 15th International Symposium of the Multinational Association of Supportive Care in Cancer show that professionals acknowledge the problem of fatigue among their patients — but they, nevertheless, underestimate the importance of this symptom. The 240 questionnaires revealed that 84 per cent of patients complained about fatigue.

“Surveys of cancer patients carried out 20 years ago showed that nausea and vomiting were the single most important symptoms affecting patients’ lives, particularly during periods of treatment. Fatigue came about third on the list,” says Dr Littlewood. “Treatment of nausea and vomiting with better drugs has meant these symptoms have now disappeared off the list, and recent surveys have demonstrated that fatigue is the single most important problem experienced by patients nowadays. But while the majority of oncologists consider treating pain, few prioritise treatment of fatigue. The survey findings conducted among professionals reveal that 23 per cent of oncologists said they would treat only if the patient complained of fatigue. So there is still a perception among professionals that other symptoms are more important.”

Hannah Rees, a pharmacist at The Bath Clinic (in Bath) also believes that both doctors’ and patients’ perspectives about the importance of fatigue are gradually changing, but messages must be reinforced if more patients are to benefit from recognition and treatment of anaemia. She says: “I think it’s always been accepted that as part of chemotherapy patients were sick and tired, and could no longer lead a normal life. But thanks to modern treatments this is no longer the case. However, alarm bells tend not to ring until a patient’s Hb level becomes very low, by which time the patient is extremely fatigued and has a poor quality of life.”

The impact of fatigue among cancer patients cannot be compared to that among the general population because evidence suggests that fatigue as a symptom among healthy adults is far less severe than it is among people with cancer. A large US study compared responses to questions about fatigue among three different groups: anaemic cancer patients, non-anaemic cancer patients and people in the general US population.³ The results showed that the fatigue scores of anaemic cancer patients were significantly worse than the scores of non-anaemic cancer patients. Nevertheless the scores among this group of patients were still worse than the scores of the general population.

Treating anaemia

Severe anaemia is typically managed with red blood cell transfusions because there is an urgent need to raise the haemoglobin level. Mild to moderate anaemia is either left untreated or managed with recombinant human erythropoietin (epoetin alfa and epoetin beta) or a blood transfusion.

Blood transfusions Blood transfusions are associated with distinct and important benefits. Not only are they the fastest way to alleviate the symptoms of anaemia, but they are also 100 per cent effective. Care teams are generally happy to administer a blood transfusion as they are familiar with the procedure.

Blood transfusions are, however, not without their risks. Possible complications include acute transfusion reactions, transfusion-related acute lung injury, transmission of viruses and prions, alloimmunisation, immuno-modulation and graft-versus-host disease.⁴

A multi-centre international study involving 3,543 patients from 146 western European intensive care units looked specifically at the potential benefits and risks associated with blood transfusion.⁵ The epidemiologic study provides evidence of an association between transfusions and diminished organ function as well as between transfusions and overall mortality. Of patients who were given a transfusion, 18.5 per cent died within 28 days, compared with 10.1 per cent of similarly ill patients who did not receive a transfusion.

There are further factors to take into account when assessing the benefits of blood transfusions in cancer patients with anaemia, not least of which is the inconvenience of a longer hospital stay. “In previous years patients who had lots of transfusions were in hospital every few days, either for chemotherapy or for a blood transfusion,” says Ms Rees. “We are now transfusing much less because we catch patients’ Hb levels before they get below 9 or 10g/dL and we treat with epoetin. Not only are there risks associated with blood transfusions but blood supply is increasingly limited.”

Epoetin Epoetin has been used to treat patients with cancer-related anaemia since the late 1980s. It works by replicating the action of naturally occurring erythropoietin (the hormone produced in the kidney that stimulates the bone marrow to produce red blood corpuscles) and is indicated in the prevention and treatment of anaemia in patients with a variety of tumours. According to Dr Littlewood: “Epoetin has the advantage of a sustained rise of the Hb level, whereas blood transfusions only work for two to four weeks before their impact wares off and the patient is back to square one. Blood transfusions can be inconvenient for patients and many patients remain worried about possible side effects.”

There is a large body of literature showing that epoetin is effective, safe and well-tolerated in the treatment of cancer-related anaemia, although cases of pure red-cell aplasia associated with epoetin alfa have been reported.

Not all patients respond to epoetin, however. Findings show that the therapy works in 50 to 70 per cent of patients. One study of patients receiving epoetin beta showed that the product resulted in an increase of Hb level in 67 per cent of patients with haematological malignancies.⁶ And the result is not immediate: in most cases it is approximately one month before the treatment takes effect.

There is also the issue of cost, which is, perhaps, the biggest challenge for most hospitals and cancer centres to overcome. Although Andrew Standley, pharmacist at City Hospital, Birmingham considers epoetin a highly effective treatment, its cost means that it can only have limited use within the unit at his hospital. He says: “In an ideal world we would put many more patients on epoetin, but sadly it comes down to cost. Blood is expensive –– and getting more expensive –– but all patients benefit from a transfusion straightaway. Our standard practice is to give blood transfusions to patients whose Hb levels fall to 8.5g/dL and below. “It could be argued that as every patient on chemotherapy runs the risk of becoming anaemic, all patients should be put on epoetin from day one. This would be similar to a US prophylactic prevention model, but the NHS just doesn’t work in that way.”

But are blood transfusions dramatically cheaper? As Dr Littlewood points out: “There are hidden costs associated with blood transfusions. The cost of a bag of red blood corpuscles goes up all the time, and there are the costs of sitting in the clinic, getting the patient to the clinic and loss of earnings for patients or their carers.”

Hannah Rees has compared the costs of epoetin and blood transfusions and she concludes: “I don’t think treating with epoetin is any more expensive when taking everything into consideration, from patients’ loss of earnings to the risks of administering transfusions. We monitor patients’ Hb levels when they are on epoetin and sometimes we’re able to reduce the dose as a maintenance therapy, making it more cost effective.” The ability to self-administer epoetin is welcomed by patients, says Ms Rees.

It is also possible that treating anaemia might improve survival prospects for patients with cancer, because an emerging body of evidence suggests an association between low Hb levels and prognosis for survival in patients who receive radiotherapy or chemotherapy.⁷ The BRAVE study (BReast cancer – Anaemia and the Value of Erythropoietin) is now being conducted to further investigate this proposed link.

Despite the effectiveness, safety and quality of life benefits epoetin treatment brings, decisions about whether or not to prescribe it primarily come down to affordability. According to Dr Littlewood: “In countries where there are different health economics, including the US, France, Germany, Italy and Spain, epoetin is widely used.” In the meantime, NICE guidelines on the use of epoetin in chemotherapy-induced anaemia are due for publication by the end of 2005, so whether its use among NHS centres will increase remains to be seen.

References

1. Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: incidence and treatment. Journal of the National Cancer Institute 1999;91:1616–34

2. Curt GA, Breitbart W, Cella D, Groopman JE, Horning SJ, Itri LM et al. Impact of cancer-related fatigue on the lives of patients: new findings from the Fatigue Coalition. Oncologist 2000;5:353–60

3. Cella D, Lai JS, Chang CH, Peterman A, Slavin M. Fatigue in cancer patients compared with fatigue in the general United States population. Cancer 2002;94:528–38.

4. Engert A. Recombinant Human Erythropoietin as an Alternative to Blood Transfusion in Cancer-Related Anaemia. Disease Management and Health Outcomes 2000;8:259–72.

5. Vincent JL, Baron JF, Reinhart K, Gattinoni L, Thijs L, Webb A et al. Anemia and blood transfusion in critically ill patients. Journal of the American Medical Association 2002;288:1499–507

6. Osterborg A, Brandberg Y, Molostova V, Iosava G, Abdulkadyrov K, Hedenus M, Messinger D. Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin Beta, in hematologic malignancies. Journal of Clinical Oncology 2002;20:2486–94

7. Littlewood TJ, Bajetta E, Nortier JW, Vercammen E, Rapoport B. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. Journal of Clinical Oncology 2001;19:2865–74