Symptoms of Cancer Cachexia - Assignment Example

Question Cachexia is described as a medical with characteristic symptoms which manifest as metabolic abnormalities along three lines: relative hypermetabolism, which describes an abnormally high rate of catabolic activity which creates a negative metabolic balance, even in the presence of adequate nutritional intake; acute-phase protein response refers to a cascade of inflammatory processes mediated by protein-type inflammatory biochemicals in response to insult from cancer; and a failure of anabolism compounded by inadequate food intake, which means that the ability to assimilate nutrients for body-building is being compromised at the same time that the underlying disease is causing diminished appetite leading to poor feeding. Question 2 It is secondary protein energy malnutrition, which is a catabolic disorder secondary to inflammatory insult from certain chronic or end stage diseases. Question 3 Unlike primary protein energy malnutrition (which occurs in anorexia nervosa or kwashiorkor/marasmus), cachexia is induced by disease conditions. With primary protein energy malnutrition, the problem is one of inadequate nutritional intake. But in cachexia, the issue is that patients, regardless of the adequacy of nutritional intake, have abnormally accelerated disposition of nutrients, hence a negative balance of metabolism results (Fearon and Moses, 2002). Inflammatory processes are involved in secondary PEM which are absent in primary PEM, and while primary PEM can be reversed by bolstering nutrient intake, the same benefit cannot be obtained in secondary PEM. In primary PEM there is faster loss of adipose tissue than that of lean body mass, but the loss is equally from both compartments in cachexia. Skeletal muscle loss is a feature that is peculiar to the cachexic state (Tisdale, 2003). Question 4 Previous laboratory and clinical studies have shown that omega-3 fatty acids, especially eicosapentaenoic acid (EPA) and EPA-containing supplements demonstrate molecular anti-inflammatory activity which is relevant to the attenuation of cachexia, in both humans and animal models. However, past results from multiple studies have been equivocal in their findings, and this study aims to elicit independent objective evidence in favour of or against the proposition that EPA confers significant benefit in arresting the progress of cachexia in affected patients. Question 5 Yes. There was inadequate discussion of the basis for their using the type of EPA preparations they used, as opposed to other available types. The authors could also have done a better job of reviewing the literature on the mechanistic aspects of how cachexia develops and what bearing this information will have on the approach they used for their study in terms of study design, formulations used and patient selection strategies. Question 6 These patients have undergone treatment procedures that are potentially debilitating and could contribute directly or indirectly to changes in body mass or global physical status. Such changes may confound the results of the study. It is standard practice in conducting clinical trials to exclude patients who have such conditions as could independently contribute (whether negatively or positively) to the observed end points, otherwise type 1 (false positive) or type II (false negative) errors may result during the interpretation of the results. Question 7 C-reactive protein (CRP) measurement is being used as a marker of the severity of the acute inflammatory protein response which occurs in cachexia. CRP is an acute phase protein whose synthesis is induced in cachexia by interleukin-6 and tumor necrosis factor alpha, and its level has been correlated with severity of symptoms and adverse outcomes (Tisdale, 2003). Question 8 Only half of the original population enrolled completed the 8-week course of the trial, although this was attributed to miscellaneous reasons not linked to lack of compliance or adverse effects from the EPA preparations. For mean weight change over the 8-week period, the group receiving 2 g of EPA had an increase of 1.2 kg (95% CI, 0.0 kg to 2-3 kg), those receiving 4 g of EPA had an increase of 0.3 kg (95% CI, -0.9 kg to 1.5 kg, while those on placebo had a loss of 0.7 kg. These weight gains were determined to be statistically insignificant because the 95% confidence intervals were too wide to be meaningfully reliable. The 95% confidence interval describes the probability that the true value for the weight change lies within the intervals specified. Therefore a wide CI will in effect be tantamount to admitting that there is a good possibility that the mean weight “gain” value will be at the lower end, which for both treatment groups amount to no gain or even weight loss. Similarly, for lean body mass changes over 8 weeks, the 2 g EPA group gained a mean of 0.9 kg (95% CI, -0.3 kg to 2.0 kg), while the 4 g group lost a mean of 0.1 kg (95% CI, -1.3 kg to 1.1 kg), and the placebo group lost a mean of 0.3 g. Analysis of covariance between the three treatment groups was done in intention-to-treat analyses, and the results were nonsignificant. This implies that when adjustment was made for initial differences between the groups in the pretest stage, the mean change values obtained posttreatment remained statistically insignificant. In terms of physical function parameters, patients on 2 g EPA showed statistically significant improvement of about 7% (P = 0.4) as opposed to those on placebo, while the 4 g EPA treatment group showed a reduction of about 5% . However, laboratory parameters like C-reactive protein or albumin levels showed no significant changes between treatment and non-treatment groups. Also, appetite and Karnofsky performance status did not appear to be improved by treatment as compared to placebo. The type of cancer appears to play a role, as patients with gastrointestinal cancer had statistically significant improvement in weight compared with placebo; such benefit not being obtained in those with lung cancer. However, this failed to produce proof of differential response because a test of interaction was not significant. There was no statistically significant improvement in survival times among the three groups, although the 2 g group showed longer survival times. Median survival values were 155 days for the 2g EPA treatment group (95% CI, 136 days to 173 days), 142 days for the 4 g EPA treatment group (95% CI, 106 days to 177 days), and 140 days for the placebo group (95% CI, 104 days to 176 days) (Fearon et al., 2006). Question 9 In my opinion, there was inadequate placement of their research discussion in the context of available literature. For instance, the role of EPA in cancer cachexia has been mechanistically explained not only by anti-inflammatory action (Lundholm et al., 1994), but also antiproliferative activity (Jho et al., 2004). Hence there is a place for investigating not only benefits in terms of catabolic retardation (which their study focuses on) but also direct inhibition of malignancy. Also, the immune-promoting effects of EPA were not considered in their review , which has an important effect on certain categories of patients, for example those undergoing surgical interventions (Jho et al., 2004). There has been mention of evidence for the possible benefit of EPA as an enhancing component of adjuvant chemoradiotherapy (Jho et al., 2004). In addition, the role of EPA in combination with nutritional supplementation was not discussed, which formed the basis of a positive finding (Tisdale, 2003), as well as potential appetite-improving properties (Tisdale, 2003). In making reference to similar studies, the authors did not adequately discuss fundamental differences between elements of their study design and those of other trials that could possibly account for the divergence in the results obtained. These differences include types of cancer studied, stage of disease, pharmaceutical preparations used, concomitant administration of therapies or nutritional supplementation, statistical analysis, and patient demographics (Barber et al., 2000, Beck et al., 1991, Bruera et al., 2003, Fearon et al., 2003, Wigmore et al., 2000). Question 10 I do agree with the authors’ conclusion that there was no statistically significant benefit proven from their study for the use of EPA to improve patient parameters defined by the end points of the study. I also agree with their observation that the minor benefits obtained with the 2 g preparation, while statistically insignificant, may be clinically important in relevant patient subgroups. However, I consider some aspects of their conclusions unjustified. The authors make a concluding assertion that omega-3 fatty acids provide marginal benefits (if any) and they suggest that focus should be moved from them to other agents in the development of cachexia amelioration strategies. This conclusion does not fully acknowledge the preponderance of contrary evidence from other studies, and ignores the limitations of their own study in terms of the type of patient population studied, dosage regimen/dosage forms and length of study. In the face of apparently contradictory research results, the only valid way to make a definite recommendation is to conduct a systematic meta-analysis of multiple studies. The result obtained from one trial cannot by itself invalidate the results from other studies. This is all the more important when I consider that they used a novel oral diester formulation that could have provided suboptimal therapeutic blood levels of the drug. Also, the concluding discussion on interaction between EPA and nonsteroidal anti-inflammatory drugs (NSAIDS) appears to digress from the declared goals of the study as stated at the beginning, and the negative finding in that respect is probably better ignored, as the authors also admit, although for different reasons. Moreover, the authors conclude that “…it is clear that the optimum dose, formulation, route of administration, and target population remain to be defined”. This statement, while valid in itself, does not directly follow from the particular investigations they carried out in their study. There was no evidence that they compared formulations, administration routes, or diverse patient groups (other than the fact that they studied patients with two different types of cancer). PART 3 Hi Cynthia, I would like to briefly address the questions raised in your letter about your mother’s condition. Cachexia is a wasting disease that occurs in people with some types of chronic disease, including cancer, especially at the terminal stages. It is not so much a condition caused by insufficient nutrient intake as it is one of excessive nutrient breakdown. It involves a cascade of inflammatory response to the debilitation caused by cancer, which makes her body to aggressively produce biochemicals that kind of sends her metabolism into overdrive. Breakdown of body fat and protein reserves occurs at such an abnormally high rate that outpaces the assimilation of nutrients such that there is effectively a deficit of nutrition which causes the emaciation that you observe. This is the reason why the nutritional supplements which have been given to her have seemed not to be helpful – they just cannot keep up with the accelerated breakdown. Unfortunately, this condition is highly common in pancreatic cancer patients, and it is not unexpected that your mother is suffering from this. It also indicates that she is at an advanced, and possibly terminal, stage of her disease. The usefulness of omega 3 fatty acids has been a subject of widespread interest in recent years. Quite a lot of research has shown that omega 3 fatty acids can modify the process of cachexia to confer benefits on patients with regard to their body mass and quality of life. However, extensive clinical testing has produced a mix of results, ranging from proven benefit to doubtful benefit and in some cases, no benefit at all. Hence the usefulness of omega 3 fatty acids is still a matter of debate, and this is not reflected in the exuberant advertising you may see on internet websites. It is a known fact that claims of efficacy for new medicinal agents are often exaggerated on the internet for commercial purposes. There still remain poorly understood issues surrounding the use of omega-3 fatty acids, which include the question of which dosage forms are best, which kind of cancer patients would benefit the most, and at which stage of disease the treatment would confer the greatest benefit. Generally, consensus recommendations on novel treatments are not made in the medical community until there is overwhelming proof of benefit, and this takes a large number of clinical trials extending over many years, and studying a wide variety of relevant patient populations. In conclusion, because there is indeed some evidence of benefit, and the treatment is neither overly expensive nor dangerous (most known side effects are limited to abdominal discomfort), my recommendation would be that you give it a try. There is a chance it could benefit your mother, and even if it does not, no real harm is done, and you would have the satisfaction of having tried your best for her. However, you must be prepared for the real possibility that you may not see any significant change in her condition, or the improvement you will see may be limited to better physical function and general health status without any change to her body weight. Of course, any improvement will be worth the while, to make her terminal state more bearable for both you and her. List of References BARBER, M. D., MCMILLAN, D. C., PRESTON, T., ROSS, J. A. & FEARON, K. C. (2000) Metabolic response to feeding in weight-losing pancreatic cancer patients and its modulation by a fish-oil-enriched nutritional supplement.[see comment]. Clinical Science, 98, 389-99. BECK, S., SMITH, K. & TISDALE, M. J. (1991) Anticachexic and Antitumor Effect of Eicosapentaenoic Acid and its Effect on Protein Turnover. Cancer Research, 51, 6089-6093. BRUERA, E., STRASSER, F., PALMER, J. L., WILLEY, J., CALDER, K., AMYOTTE, G. & BARACOS, V. (2003) Effect of fish oil on appetite and other symptoms in patients with advanced cancer and anorexia/cachexia: a double-blind, placebo-controlled study.[see comment]. Journal of Clinical Oncology, 21, 129-34. FEARON, K. C. & MOSES, A. G. (2002) Cancer Cachexia. International Journal of Cardiology, 85, 73-81. FEARON, K. C. H., BARBER, M. D., MOSES, A. G., AHMEDZAI, S. H., TAYLOR, G. S., TISDALE, M. J. & MURRAY, G. D. (2006) Double-Blind, Placebo-Controlled, Randomized Study of Eicosapentaenoic Acid Diester in Patients With Cancer Cachexia. Journal of Clinical Oncology, 24, 3401-3407. FEARON, K. C. H., VON MEYENFELDT, M. F., MOSES, A. G. W., VAN GEENEN, R., ROY, A., GOUMA, D. J., GIACOSA, A., VAN GOSSUM, A., BAUER, J., BARBER, M. D., AARONSON, N. K., VOSS, A. C. & TISDALE, M. J. (2003) Effect of a protein and energy dense N-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomised double blind trial.[see comment]. Gut, 52, 1479-86. JHO, D. H., COLE, S. M., LEE, E. M. & ESPAT, N. J. (2004) Role of omega-3 fatty acid supplementation in inflammation and malignancy. Integrative Cancer Therapies, 3, 98-111. LUNDHOLM, K., GELIN, J., HYLTANDER, A., LONNROTH, C., SANDSTROM, R. & SVANINGER, G. (1994) Anti-inflammatory Treatment May Prolong Survival in Undernourished Patients with Metastatic Solid Tumors. Cancer Research, 54, 5602-5606. TISDALE, M. J. (2003) Pathogenesis of cancer cachexia. The Journal of Supportive Oncology, 1, 159-68. WIGMORE, S. J., BARBER, M. D., ROSS, J. A., TISDALE, M. J. & FEARON, K. C. (2000) Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer. Nutrition & Cancer, 36, 177-84.  Read More