- Email: [email protected]
Workshop summary and conclusions
CACHEXIA-ANOREXIA WORKSHOP
Workshop Summary and Conclusions Many important questions are evident as one reviews the current state of research. These include: 1. Is it correct to lump cachexia and anorexia under the single syndrome rubric? 2. How common are mechanisms across various forms of cancer and across various diseases? Are we dealing with a multifactorial problem variably expressed in different situations? 3. What is the role of individual cytokines? Are we faced with a cytokine cascade? If so, what is the sequence and profile of this cascade? Are cytokines responsible only indirectly? Are they implicated in all aspects of the syndrome? 4. Is local synthesis of cytokines in an organ (e.g., brain) required? What is the significance of the circadian rhythmicity in human cytokine production? 5. Weight loss is associated with neuroendocrine axis activity and with changes in central autonomic nerve control. Are autonomic nervous system alterations clinically relevant? Autonomic abnormalities may account for the sudden death of cachectic patients, and could also contribute to observed changes in cardiac reflexes and gastric emptying.1,2 6. What is the universal clinical significance of the cachexiainducing factor reported by Tisdale and his colleagues? Does the cachexia-inducing factor further enhance proteolysis in a muscle prepared for insult because of the upstream effects of cytokines on appetite, intermediary metabolism, prostaglandin production, and other chemical mediators; or does it act independent of these factors? Are centrally mediated features of the cachexia-anorexia syndrome, such as loss of appetite, independent of events at the level of muscle? 7. We have not discussed the pathophysiological aspects of fatigue. Little is known about potential abnormalities in nerve-muscle function that may cause fatigue in cancer patients (fatigue is also common in advanced cancer patients who are not malnourished). In addition to rare paraneoplastic syndromes such as the Warner–Lambert syndrome, is it possible that less clearly delineated abnormalities at the neuromuscular junction exist in cancer patients? What are the inherent biochemical abnormalities in the muscle function of cancer patients that may trigger fatigue? What is the relative contribution of changes in central nervous system activity and changes at the peripheral (muscle) level in the development or progression of fatigue? Are there longstanding postchemotherapy effects on muscle function? 8. Research on gender differences in pathophysiology and therapy is necessary. Why do male patients with some cachexia-inducing tumors fare poorly in comparison with females?3 These questions represent only a few of the stimulating puzzles that come to mind upon reviewing current basic science literature on the cachexia-anorexia syndrome. Although full details on this
Correspondence to: Neil MacDonald, CM, MD, FRCP(C), FRCP(Edin), Director, Cancer Ethics Programme, Center for Bioethics, Clinical Research Institute of Montreal, Montreal, Quebec, Canada. E-mail: [email protected] Date accepted: June 7, 2000. Nutrition 16:1019 –1020, 2000 ©Elsevier Science Inc., 2000. Printed in the United States. All rights reserved.
syndrome are not yet available, we strongly concur that the current state of the art lends itself to presenting a set of recommendations. These include:
Taxonomy Conducting clinical trials will be enhanced following the introduction of common terminology and staging for the cachexiaanorexia-asthenia syndrome. The National Cancer Institute of Canada, with the NCI (US), could sponsor a panel to address this issue.
Assessment Criteria for assessment of patients with the cachexia-anorexia syndrome should be more clearly defined. As recommended above, an international panel should be formed to define appropriate assessment criteria for clinical trials on cachexia-anorexia. In the course of their work, panel members could recommend assessment tools that would lend themselves to introduction into routine clinical practice today. Categories for assessment should include: ● functional status (today, reasonably established); ● body composition studies—what are the simplest approaches?; ● measurement of metabolic abnormality; ● coordinated assessment of associated neurologic, immunologic, neuroendocrine, and metabolic abnormalities.
Translational Research Interest in nutritional aspects of cancer has foundered to a certain extent because of an intercept between basic science laboratories (many of which are addressing nutritional problems seemingly independent of cancer) and the clinical research oncology community. NCI-Canada, and sister granting agencies, should consider the merit of promulgating [request for application (RFAs)] for coordinated research on the cachexia-anorexia syndrome. Specific research opportunities include (after Michael R. McKenzie): ● Research to identify potential markers of response to therapy, e.g., changes in proteolysis-inducing factor following therapy. ● Characterization of molecular mechanisms in the cachexia and anorexia syndrome, including abnormal carbohydrate, lipid, and protein metabolism. Which tumor- and host-related factors are important, and what is their role in various cancers? ● Identification of possible antagonists of proteolysis and lipolysis. ● Further development of animal models, to elucidate the pathophysiology of autonomic and central nervous system (especially hypothalamic) dysfunction, and abnormal muscle function and catabolism. ● Research on the impact of agents commonly used to treat cancer on protein turnover, central and peripheral nervous system function, and muscle function in cachexia and anorexia. ● Functional imaging studies, e.g., magnetic resonance imaging to evaluate muscle function and positron emission tomography to evaluate central nervous system function. 0899-9007/00/$20.00
1020
MacDonald
Therapy At this point, it is reasonable to study combination therapies aimed at controlling loss of appetite, abnormalities in intermediary metabolism, and muscle protein synthesis. Examples of combination approaches include: ● progestational agents (PA) ⫹ -3 fatty acids; ● PA ⫹ -3 fatty acids ⫹ androgens; ● PA ⫹ -3 fatty acids ⫹ growth hormone (are we sufficiently secure that the latter agents will not stimulate tumor growth?); ● nutritional supplementation with -3 fatty acids with or without branched chain amino acids; ● factoring cannabinoids, cyclosporins, cytokine antibodies, receptor antagonists, or thalidomide into -3 fatty acid studies. Studies involving these agents could be mounted today. In the near future, newer approaches may include the use of specific inhibitors of muscle proteolysis, and agents directly attacking specific neuromuscular abnormalities, if any are delineated. These pharmacological approaches could also be combined with nonpharmacological interventions such as physical exercise and psychological support.4 Depression may be marked in patients with cachexia-anorexia, and may induce a feedback with deleterious consequences (further anorexia, exacerbation of fatigue, and possible immunosuppression). Patients should be screened for neuropsychiatric disturbances. Readers of the reports emanating from an NCI-Canada workshop in 19935 may rightly state that the present proposals on taxonomy, assessment, and the priority of clinical trials closely echo the proposals arising from that meeting. Alas, progress has
Nutrition Volume 16, Number 10, 2000 not matched opportunity and need in the past 4 years. We restate our belief that it is both an ethical and a scientific imperative for oncology leaders and granting agencies to adopt proactive measures to organize and fund research on the devastating but potentially remediable problem of cancer patient malnutrition.
Neil MacDonald, CM, MD, FRCP(C), FRCP(Edin) Center for Bioethics Clinical Research Institute of Montreal McGill University Montreal, Quebec, Canada
REFERENCES 1. Bruera E, Chadwick S, Fox R, Hanson J, MacDonald N. Study of cardiovascular autonomic insufficiency in advanced cancer patients. Cancer Treat Rep 1986;70: 997 2. Bruera E, MacDonald N, Catz Z, Hooper R, Lentle B. Chronic nausea and anorexia in advanced cancer patients: the possible role for autonomic dysfunction. J Pain Symptom Manage 1987;2(1):19 –21 3. Chlebowski RT, Palomares MR, Illington L, Grosvenor M. Recent implications of weight loss in lung cancer management. Nutrition 1996;12(suppl):S43 4. MacDonald N, Ayoub JP, Barkun A, et al. Carcinoma of the pancreas: an integrated programme. Cancer Strategy 2000;2(1):17–24 5. MacDonald N, Alexander HR, Bruera E. Cachexia-Anorexia-Asthenia. J Pain Symptom Manage 1995;10(2):151–155
PII S0899-9007(00)00417-2
Workshop Summary and Conclusions Many important questions are evident as one reviews the current state of research. These include: 1. Is it correct to lump cachexia and anorexia under the single syndrome rubric? 2. How common are mechanisms across various forms of cancer and across various diseases? Are we dealing with a multifactorial problem variably expressed in different situations? 3. What is the role of individual cytokines? Are we faced with a cytokine cascade? If so, what is the sequence and profile of this cascade? Are cytokines responsible only indirectly? Are they implicated in all aspects of the syndrome? 4. Is local synthesis of cytokines in an organ (e.g., brain) required? What is the significance of the circadian rhythmicity in human cytokine production? 5. Weight loss is associated with neuroendocrine axis activity and with changes in central autonomic nerve control. Are autonomic nervous system alterations clinically relevant? Autonomic abnormalities may account for the sudden death of cachectic patients, and could also contribute to observed changes in cardiac reflexes and gastric emptying.1,2 6. What is the universal clinical significance of the cachexiainducing factor reported by Tisdale and his colleagues? Does the cachexia-inducing factor further enhance proteolysis in a muscle prepared for insult because of the upstream effects of cytokines on appetite, intermediary metabolism, prostaglandin production, and other chemical mediators; or does it act independent of these factors? Are centrally mediated features of the cachexia-anorexia syndrome, such as loss of appetite, independent of events at the level of muscle? 7. We have not discussed the pathophysiological aspects of fatigue. Little is known about potential abnormalities in nerve-muscle function that may cause fatigue in cancer patients (fatigue is also common in advanced cancer patients who are not malnourished). In addition to rare paraneoplastic syndromes such as the Warner–Lambert syndrome, is it possible that less clearly delineated abnormalities at the neuromuscular junction exist in cancer patients? What are the inherent biochemical abnormalities in the muscle function of cancer patients that may trigger fatigue? What is the relative contribution of changes in central nervous system activity and changes at the peripheral (muscle) level in the development or progression of fatigue? Are there longstanding postchemotherapy effects on muscle function? 8. Research on gender differences in pathophysiology and therapy is necessary. Why do male patients with some cachexia-inducing tumors fare poorly in comparison with females?3 These questions represent only a few of the stimulating puzzles that come to mind upon reviewing current basic science literature on the cachexia-anorexia syndrome. Although full details on this
Correspondence to: Neil MacDonald, CM, MD, FRCP(C), FRCP(Edin), Director, Cancer Ethics Programme, Center for Bioethics, Clinical Research Institute of Montreal, Montreal, Quebec, Canada. E-mail: [email protected] Date accepted: June 7, 2000. Nutrition 16:1019 –1020, 2000 ©Elsevier Science Inc., 2000. Printed in the United States. All rights reserved.
syndrome are not yet available, we strongly concur that the current state of the art lends itself to presenting a set of recommendations. These include:
Taxonomy Conducting clinical trials will be enhanced following the introduction of common terminology and staging for the cachexiaanorexia-asthenia syndrome. The National Cancer Institute of Canada, with the NCI (US), could sponsor a panel to address this issue.
Assessment Criteria for assessment of patients with the cachexia-anorexia syndrome should be more clearly defined. As recommended above, an international panel should be formed to define appropriate assessment criteria for clinical trials on cachexia-anorexia. In the course of their work, panel members could recommend assessment tools that would lend themselves to introduction into routine clinical practice today. Categories for assessment should include: ● functional status (today, reasonably established); ● body composition studies—what are the simplest approaches?; ● measurement of metabolic abnormality; ● coordinated assessment of associated neurologic, immunologic, neuroendocrine, and metabolic abnormalities.
Translational Research Interest in nutritional aspects of cancer has foundered to a certain extent because of an intercept between basic science laboratories (many of which are addressing nutritional problems seemingly independent of cancer) and the clinical research oncology community. NCI-Canada, and sister granting agencies, should consider the merit of promulgating [request for application (RFAs)] for coordinated research on the cachexia-anorexia syndrome. Specific research opportunities include (after Michael R. McKenzie): ● Research to identify potential markers of response to therapy, e.g., changes in proteolysis-inducing factor following therapy. ● Characterization of molecular mechanisms in the cachexia and anorexia syndrome, including abnormal carbohydrate, lipid, and protein metabolism. Which tumor- and host-related factors are important, and what is their role in various cancers? ● Identification of possible antagonists of proteolysis and lipolysis. ● Further development of animal models, to elucidate the pathophysiology of autonomic and central nervous system (especially hypothalamic) dysfunction, and abnormal muscle function and catabolism. ● Research on the impact of agents commonly used to treat cancer on protein turnover, central and peripheral nervous system function, and muscle function in cachexia and anorexia. ● Functional imaging studies, e.g., magnetic resonance imaging to evaluate muscle function and positron emission tomography to evaluate central nervous system function. 0899-9007/00/$20.00
1020
MacDonald
Therapy At this point, it is reasonable to study combination therapies aimed at controlling loss of appetite, abnormalities in intermediary metabolism, and muscle protein synthesis. Examples of combination approaches include: ● progestational agents (PA) ⫹ -3 fatty acids; ● PA ⫹ -3 fatty acids ⫹ androgens; ● PA ⫹ -3 fatty acids ⫹ growth hormone (are we sufficiently secure that the latter agents will not stimulate tumor growth?); ● nutritional supplementation with -3 fatty acids with or without branched chain amino acids; ● factoring cannabinoids, cyclosporins, cytokine antibodies, receptor antagonists, or thalidomide into -3 fatty acid studies. Studies involving these agents could be mounted today. In the near future, newer approaches may include the use of specific inhibitors of muscle proteolysis, and agents directly attacking specific neuromuscular abnormalities, if any are delineated. These pharmacological approaches could also be combined with nonpharmacological interventions such as physical exercise and psychological support.4 Depression may be marked in patients with cachexia-anorexia, and may induce a feedback with deleterious consequences (further anorexia, exacerbation of fatigue, and possible immunosuppression). Patients should be screened for neuropsychiatric disturbances. Readers of the reports emanating from an NCI-Canada workshop in 19935 may rightly state that the present proposals on taxonomy, assessment, and the priority of clinical trials closely echo the proposals arising from that meeting. Alas, progress has
Nutrition Volume 16, Number 10, 2000 not matched opportunity and need in the past 4 years. We restate our belief that it is both an ethical and a scientific imperative for oncology leaders and granting agencies to adopt proactive measures to organize and fund research on the devastating but potentially remediable problem of cancer patient malnutrition.
Neil MacDonald, CM, MD, FRCP(C), FRCP(Edin) Center for Bioethics Clinical Research Institute of Montreal McGill University Montreal, Quebec, Canada
REFERENCES 1. Bruera E, Chadwick S, Fox R, Hanson J, MacDonald N. Study of cardiovascular autonomic insufficiency in advanced cancer patients. Cancer Treat Rep 1986;70: 997 2. Bruera E, MacDonald N, Catz Z, Hooper R, Lentle B. Chronic nausea and anorexia in advanced cancer patients: the possible role for autonomic dysfunction. J Pain Symptom Manage 1987;2(1):19 –21 3. Chlebowski RT, Palomares MR, Illington L, Grosvenor M. Recent implications of weight loss in lung cancer management. Nutrition 1996;12(suppl):S43 4. MacDonald N, Ayoub JP, Barkun A, et al. Carcinoma of the pancreas: an integrated programme. Cancer Strategy 2000;2(1):17–24 5. MacDonald N, Alexander HR, Bruera E. Cachexia-Anorexia-Asthenia. J Pain Symptom Manage 1995;10(2):151–155
PII S0899-9007(00)00417-2