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Fatigue: a challenge to cancer treatment

Management of anaemia associated with cancer treatment was discussed at a meeting organised by Roche Products in Monte Carlo at the beginning of last month. Maxwell Summerhayes reports

Fatigue is often an overwhelming and yet underestimated symptom of cancer-associated anaemia: one study has revealed that over 10 per cent of cancer patients felt so debilitated that they would prefer to be dead. The challenge has been to develop effective treatment of anaemia and research suggests that epoetin (recombinant human erythropoe-itin, EPO) is one such candidate.

This was emphasised by Professor John Glaspy from the University of California at Los Angeles, who said that two recent surveys of one million US households looked at the impact of cancer in the general population. They found that 75 per cent of cancer patients reported themselves to feel fatigued and that 12 per cent were so worn out that they would rather be dead. He added that a greater understanding has now developed of the role of anaemia in the aetiology of fatigue.

Only half a decade ago mild-to-moderate anaemia was believed to be clinically unimportant so little effort was made to keep the haemoglobin (Hb) levels of cancer patients within the normal range. It is now understood that even modest deficits in Hb can lead to significant impairment of functional status and quality of life (QoL). Recent research has established that the relationship between Hb levels and physiological and QoL endpoints is non-linear so that significantly greater incremental improvement in both can be achieved by increasing the Hb from 10 to 12g/dL than from 8 to 10g/dL.

He admitted that although this finding seemed counterintuitive, it should not really surprise us given the way that the body “jealously defends” normal Hb levels with vigorous physiological responses to even small falls in Hb. Logically, any intervention that helps maintain Hb levels in the physiological range should help prevent fatigue and its corrosive effect on cancer patients.

Benefits of EPO

Professor Glaspy said that there is now ample evidence that EPO is such a treatment, since it is well tolerated and it decreases transfusion requirements for patients undergoing chemotherapy. He pointed out that the positive impact of EPO on quality of life has now been demonstrated in at least six trials making it possibly the most consistent finding in oncology research. He added that in one trial, in which 375 patients, with a variety of solid and haematological malignancies, were randomised to receive EPO or not during chemotherapy, hinted at another possible benefit of the growth factor. In this study, EPO not only increased Hb levels, decreased transfusion requirements and improved quality of life, but also increased one year survival from 49 to 60 per cent and median survival from 11 to 17 months. He concluded that although the apparent impact of EPO on survival should be viewed cautiously — survival was not a prospective endpoint in the study and trial entrants were not stratified for survival factors — it is an interesting observation.

Better understood is the link between anaemia and poor outcomes in radiotherapy. As Dr Nicholas Reed from the Beatson Oncology Institute, Glasgow, explained, it was shown, as long ago as 1909, that hypoxia rendered cells resistant to radiation, and, more than 50 years ago, that hypoxic areas were demonstrated in human tumours. Tumour hypoxia results from high levels of demand for oxygen by rapidly dividing tumour cells, poor tumour vascularity and anaemia. He added that more recent studies have shown that tumour hypoxia has a number of other consequences which might be expected to worsen prognosis. Dr Reed explained that tumour hypoxia has real clinical significance. For example, only 45 per cent of patients treated with radiotherapy for hypoxic head and neck tumours achieve two-year local control of their cancer compared with 90 per cent of those with oxygenated tumours. Those with hypoxic tumours also have a worse overall survival.

Dr Robert Lavey from the University of Southern California at Los Angeles, explained that intervention can reverse the effects of anaemia present at the start of treatment. This indicates that anaemia per se has a negative impact on outcome and is not merely an indicator of unfit and, therefore, poor prognosis patients.

For example, in one study, patients with a pre-treatment Hb level of 12.5g/dL or less were randomly assigned to one of two groups: one in which blood transfusions were used to maintain Hb in the range 10–12 g/dL or the other where the transfusion target was greater than 12.5g/dL. Local disease control was achieved in 85 per cent of patients transfused to the higher level compared with only 56 per cent of those in the other group. Importantly, local control in the intensively transfused group was equivalent to that achieved in a third group of patients with Hb above 12.5g/dL at study entry.

This indicates that although it is important for patients to have an adequate Hb level, how it is achieved is not. Dr Lavey explained that there are now several studies showing that EPO is effective in raising Hb levels in anaemic patients receiving combined radio- and chemotherapy for cervical cancer and that comparison with historical controls suggests that such a use of EPO substantially improves long-term disease control.

Real impact awaits trials

The real impact of EPO on the long-term effectiveness of anticancer treatment awaits the results of prospective clinical trials and include two sponsored by Roche Products that were described by Dr Frank Dougherty from F-Hoffman-La Roche, Basel, Switzerland. The ENHANCE study is looking at the impact of epoetin beta on time to local relapse in patients receiving radiotherapy for advanced head and neck cancer, and the MARCH trial is examining the effect of epoetin beta on outcomes in women receiving chemoradiotherapy for advanced cervical cancer.

The use of EPO has significant budgetary implications, particularly — as was explained by Heinz Ludwig of the Wilhelminen Hospital, Vienna, Austria — because cancer is associated with the production of cytokines such as interferon-gamma, interleukin-1 and tumour necrosis factor which lead to relative resistance to the effects of EPO, resulting in the need for relatively large doses. However, as Mario Cazzola, University of Pavia Medical School, Pavia, Italy, explained, the costs of EPO therapy could be significantly reduced if its use could be targeted at the 60 per cent of patients likely to respond to it and if non-responding patients could be detected before they have received quantities of the drug.

He said that of the predictive factors examined, the baseline blood level of endogenous EPO and the platelet count appear to be the most useful. If the ratio of observed to predicted EPO levels (EPO levels normally rise with worsening anaemia) is less than 0.8, then the patient has a relative deficit of EPO and is likely to respond to exogenous EPO. If the platelet count is low, the patient may have impaired bone marrow that is not likely to respond to EPO stimulation

During treatment, Hb levels rise only slowly and it may be several weeks before it is clear whether or not EPO is of benefit to a particular patient. However, the mobilisation of reticulocytes from bone marrow into the peripheral blood and the increase in soluble transferrin receptors in plasma may provide much earlier indicators of response, enabling treatment to be curtailed in unresponsive patients. Dr Cazzola said that although further work is needed to validate these measurers it seems likely that it will soon be possible to target EPO therapy much more precisely.

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Maxwell Summerhayes is principal oncology pharmacist at Guy's and St Thomas' Hospital Trust and undertakes consultancy work for a number of pharmaceutical companies including Roche Products, manufacturer of Neo-Recormon, a brand of epoetin