AbstractProgress made in the palliation of those with terminal cancers has allowed most symptoms to be controlled if not completely alleviated. For many in this situation now, the most overwhelming and unpleasant ongoing problems are related to the accompanying cachexia.
Cachexia - (Greek,kakos-bad, hexis-condition) a wasting syndrome that causes weakness and a loss of weight, fat, and muscle(1)
Cachexia has direct and tangible consequences such as reducing independence to a level where the patient requires institutional end of life care rather than being able to die in their own home or a place of their choosing. It also reduces survival independent of the primary disease histology, stage or the patient’s performance score(2)
Upper gastrointestinal adenocarcinomas (i.e. oesophagus, gastric, pancreas, ampullary) often result in profound cachexia. Indeed unexplained weight loss is often the presenting symptom. There are often few other symptoms and consequently diagnosis is often made relatively late in the disease process, when the tumour has spread beyond the possibility of surgical cure. For a proportion of patients, chemotherapy and radiotherapy can offer substantial improvements but side effects often outweigh benefits. Many then either decide never to take these options or elect to stop taking them during the treatment course. A substantial proportion of people in this situation have no acceptable treatment options available to them.
Previous attempts to medically manipulate this condition have been largely unsuccessful. Early small trials using thalidomide have pointed to a possible role in reducing loss of lean body mass but none have demonstrated a functional benefit or investigated underlying mechanisms.
In this trial we aimed to draw definite conclusions as to whether patients with terminal upper gastrointestinal adenocarcinomas would benefit from taking thalidomide. We also investigated the likely biological mechanisms underlying any effects.
One of our major challenges was identifying a practical method for measuring lean body mass in a clinical setting. Measurement of lean body mass by Dual Energy X-ray Absorptiometry (DEXA) is accurate but expensive, bulky, immobile and entails a small radiation dose. Our comparisons between methods of lean body mass measurement showed that anthropometry was a reasonable alternative to DEXA scanning (Gold Standard) but that bio-impedance produced an even more accurate result. We concluded that bioimpedance could be used as a valid alternate to DEXA in this population with the proviso that it as lean body mass falls it will tend to be underestimated by bioimpedance.
We found thalidomide to be well tolerated but to offer no clinical benefit overall. In fact, at the three month visit those in the thalidomide group had a significant greater reduction in measured grip strength and the functional aspect of their quality of life as measured by questionnaire. Neither change was sustained at the six month visit. There was no measurable change in lean body mass between groups. The average survival was slightly higher in the placebo group but this difference was not significant (mean survival thalidomide group 83 days, placebo group 88 days).
There was also a suggestion of some benefit of thalidomide therapy in those presenting with a more inflammatory disease as measured by plasma IL-6 and CRP. Sub-group analysis revealed that the thalidomide treatment group had a significantly longer survival over the placebo treated group if they presented with a higher than average IL-6 and a reduction in weight loss. Survival was significantly shorter with thalidomide treatment for those presenting with a lower than average IL-6. Thalidomide led to a significant suppression of plasma IL-6 levels over time. Unfortunately the survival advantage seen with thalidomide treatment in those with a more inflammatory state was not associated with any improvement in quality of life. The reduction in grip strength and functional quality of life was less marked in the thalidomide treated group but still present.
It may be that thalidomide treatment leads to an overall reduction of muscular strength through its known side effect of somnolence leading to inactivity but that in treating the inflammatory component of cachexia it is able to improve survival. We suggest that future clinical trials of cachexia include measurement of peripheral cytokine measurements which seem to be strongly associated with outcomes. There may be a different anti-inflammatory medication or combination of treatments that could successfully treat the cachexia without the same side effect profile of thalidomide. Clinical benefits may be dictated by the degree of inflammation present at presentation and patients may need to be stratified for future therapies.
|Date of Award||2015|
|Supervisor||Geoff Pilkington (Supervisor)|