- Email: [email protected]
Cachexia and cancer: A clinician's view
Annals oj Oncology 3 (Suppl.3): S25-S27, 1992. © 1992 Khiwer Academic Publishers. Printed in the Netherlands.
Original article Cachexia and cancer: A clinician's view T. A. W. Splinter Department of Medical Oncology, University Hospital Dijkzigt, Rotterdam, The Netherlands
with megestrol acetate (160 mg tid) because they complained of anorexia. After 10 days of treatment, megestrol acetate was continued only in those patients whose appetite and/or general well-being improved. Fifty-seven patients (32%) experienced such an improvement and asked for continuation of therapy. Many basic questions are still unanswered; nonetheless, from a practical clinical view it seems worthwhile to offer anorectic patients a chance to improve, especially since side effects of megestrol acetate are absent or mild, and the distinction between responders and nonresponders can be made by 10 days of treatment.
Cachexia is connected with advanced cancer and will affect any patient in the terminal disease phase. The causes of cachexia are not well understood, but seem to be multifactorial. In addition to reduced food intake, metabolic changes are observed. These changes seem comparable with those found during sepsis and trauma, but differ from those seen during starvation (reviewed in reference [1]). One consistent feature in metabolic studies of cancer patients is the interindividual range of responses to parenteral feeding, even when patients with the same diagnosis and disease stage are compared [2]. At first presentation, the degree of weight loss, which seems to differ markedly among patients, correlates with the type of cancer and disease extent. Almost invariably, no matter what the type of cancer, more than 5% weight loss before the start of treatment is an unfavorable prognostic factor and frequently correlates with decreased performance status. At the University Hospital Dijkzigt, patients with cancer of the esophagus, cardia, stomach, and pancreas, as well as those with small cell lung cancer, have the highest weight loss at first presentation. In contrast, weight loss is rarely observed in patients with testicular cancer, even with massive disease - sarcoma, breast cancer and ovarian cancer. The latter group has no weight loss at first presentation, even when ascites-related weight gain is considered. Anorexia is inevitably present in patients with gastric cancer, pancreatic cancer, and small cell lung cancer. Aside from loss of appetite, obstruc-
tion of the upper digestive tract plays an important role in the weight loss of patients with cancer of the esophagus and cardia. In summary, some tumors exert profound toxic effects that lead to anorexia, cachexia, and decreased performance status in the early stages of disease, whereas others exert such toxicity only during the terminal phase. Recent experimental studies have demonstrated that circulating factors, such as tumor necrosis factor alpha and interleukin-1 beta, produce anorexia and cachexia in animals [3,4]. The best treatment of the toxic syndrome of anorexia/cachexia/decreased performance status is effective reduction of the tumor load. Toxicity from ineffective chemotherapy may worsen the syndrome, albeit probably by a different mechanism. When left untreated, cachexia usually proceeds to increasing anorexia, loss of tissue mass, muscle wasting, inactivity, and heightened susceptibility to the toxicity of treatment [5-9]. Perhaps even more important than the physical problems are the psychosocial problems of the patient and the family members resulting from anorexia and aversion to food. Eating together is an important part of family life. Aversion to food may add a fourth aspect to the anorexia/cachexia/decreased performance status syndrome, i.e. the patient's feeling of being an outcast who is obstructing this essential part of family life precisely when he or she most needs family support. Therefore, as the Fig. 1 shows, when studying cachexia, distinctions should be made between problems
Key words: cachexia, anorexia, advanced cancer, palliative treatment, megestrol acetate
Downloaded from http://annonc.oxfordjournals.org/ at Karolinska Institutet on July 12, 2015
Summary. The cancer-related cachexia/anorexia syndrome is not well understood. It is related to several factors like metabolic changes, tumor types, and disease extent and is frequently accompanied by decreased performance status. An important aspect of anorexia is the psychosocial problem: the patient is unable to join the family for meals precisely when he or she most needs familial support. Several randomized studies have shown that megestrol acetate, possibly in a dose-dependent fashion, can improve appetite and lead to weight gain. This effect seems to be most prevalent in patients with breast cancer and also occurs in the absence of a tumor response. We have retrospectively analyzed 176 patients with cancer types other than breast cancer who received only palliative treatment. The patients were treated
26
A very interesting observation in this study was the significant reduction in nausea and vomiting. A preliminary report of another randomized study has recently been published [15], in which patients with advanced cancer, who were candidates for palliative Metabolic changes Food intake therapy only, were randomized to receive a placebo or 480 or 960 mg megestrol acetate for 8 weeks. A tendency for weight gain and improved appetite was observed with active treatment, especially with the 960mg dose of megestrol acetate, in approximately 60% of Anorexia Obstruction patients. However, increased appetite and weight gain were also observed in 1 of 8 control patients. The numbers of patients are still too small to reach statistical sigTumor type Tumor type Disease extent Individual patient nificance. In summary, these studies indicate that high-dose megestrol acetate may improve appetite, cause weight gain, and reduce the side effects of chemotherapy, esEffective, ineffective, or no treatment pecially nausea and vomiting. The data suggest the presence of a dose-response relationship, which needs Fig. I. Several factors influence cancer-related cachexia. further investigation. Furthermore, there is a suggestion that breast cancer patients may respond better to megestrol acetate than do patients with other types of of food intake and metabolic changes; between tumor cancer. Finally, the study by Loprinzi et al. [14] points types, extent of disease, and individual response to out the difficulty of assessing the response to megestrol feeding; and between effective treatment, ineffective acetate when it is administered together with chemotreatment, and no treatment. therapy. However, the study also raises the interesting question of whether megestrol acetate may preclude chemotherapy-induced anorexia and thereby prevent transient weight loss. Treatment of anorexia/cachexia In 1989, we began a randomized study of megestrol The possible role of megestrol acetate acetate 160 mg tid vs. no treatment at the University Hospital Dijkzigt in lung cancer patients who fulfilled In a review of megestrol acetate in breast cancer, the following criteria: weight loss of more than 5% in Canetta et al. [10] described weight gain as an impor- the previous 3 months with or without severe anorexia tant side effect that occurred in 15% to 70% of pa- and with or without an albumin level <35 g/L. One tients. Tchekmedyian et al. [11] were the first to recog- year later the study was closed because of lack of acnize the possibly positive aspect of this side effect and crual. Patients, who did not want to be randomized, performed a phase I/II trial of escalating doses of asked for treatment, and physicians, because of their megestrol acetate in patients with breast cancer. An up- 2-year experience with megestrol acetate, had already date of this trial has been reported by Aisner et al. [12]. realized that some patients do respond favorably to this Doses of megestrol acetate ranging from 480 to 1,600 drug. mg/d were administered. Overall, 81% of the patients Since 1987, patients who complained about anogained weight. Weight gain was a function of time and rexia during palliative symptomatic treatment have occurred independent of the presence or absence of a been given megestrol acetate 160 mg tid. All of these tumor response. Based on this study it was postulated patients have reached the terminal disease phase. that megestrol acetate stimulated appetite and, in addi- Based on our experience that any improvement in aption, probably affected metabolism on a cellular level. petite will be evident within 10 days of starting treatIn another study of 33 patients with advanced can- ment, patients receive megestrol acetate for 10 days cer other than breast cancer who received megestrol and continue treatment only if appetite and/or general acetate 160 mg, 27% gained weight and 42% reported well-being improves. As Table 1 shows, 176 patients an improved sense of well-being [13]. Recently, Lop- have received megestrol acetate. The majority of them rinzi et al. [14] reported a randomized trial of 133 pa- had lung cancer or cancer of the esophagus and cardia tients who receive megestrol acetate 800 mg or pla- without obstruction. Fifty-seven patients (32%) asked cebo. The patients had advanced cancer other than to continue therapy because of the improvement in apbreast cancer. Sixty percent of the patients in both petite and/or general well-being. They were able to join groups received chemotherapy. Overall, 48% of the pa- the family for dinner again and had no aversion to the tients taking megestrol acetate and 39% of those taking smell of food cooking. Six patients refused treatment placebo gained weight. A weight gain of more than very soon after it began because of severe stomach 10% was observed only in the megestrol acetate group. pain, which disappeared after withdrawal of megestrol Cachexia
Downloaded from http://annonc.oxfordjournals.org/ at Karolinska Institutet on July 12, 2015
27 Table 1. Megestrol acetate in anorectic patients. Total no. patients Male/female NSCLC SCLC Esophageal cancer Cardiac cancer Gastric cancer Pancreatic cancer Hepatoma Mesothelioma
176
136/40 58 31 35 26 7 9 5 5
NSCLC = non-small cell lung cancer; SCLC = small cell lung cancer.
1. Douglas RG, Shaw JHF. Metabolic effects of cancer. Br J Surg 1990; 77: 246-54. 2. Holroyde CP, Skutches CL, Boden G et al. Glucose metabolism in cachectic cancer patients with colorectal cancer. Cancer Res 1984; 44: 5910-3. 3. Beck SA, Tisdale MJ. Production of lipolytic and proteolytic factors by a murine tumor producing cachexia in the host. Cancer Res 1987; 47: 5919-23. 4. Ternell M, Moldawer LC, Lonnroth C et al. Plasma protein synthesis in experimental cancer compared to paraneoplastic conditions, including monokine administration. Cancer Res 1987; 47: 5825-30. 5. DeWys WD. Anorexia as a general effect of cancer. Cancer 1979; 43: 2013-9. 6. Knox LS, Crosby LO, Feurer ID et al. Energy expenditure in malnourished cancer patients. Ann Surg 1983; 197: 152-62. 7. Young VR. Energy metabolism and requirements in the cancer patient. Cancer Res 1977; 37: 2336-47. 8. Nixon D, Heymsfield SB, Cohen AE et al. Protein-calorie undernutrition in hospitalized cancer patients. Am J Med 1980; 68: 683-90. 9. Brennan MF, Burt ME. Nitrogen metabolism in cancer patients. Cancer Treat Rep 1981; 65 (suppl 5): 65-77. 10. Canetta R, Florentine S, Hunter H et al. Megestrol acetate. Cancer Treat Rev 1983; 10: 141-57. 11. Tchekmedyian NS, Tait N, Moody M. High-dose megestrol acetate. JAMA 1987; 257: 1195-8. 12. Aisner J, Tchekmedyian NS, Tait N et al. Studies of high-dose megestrol acetate: potential applications in cachexia. Semin Oncol 1988; 15 (suppl 1): 68-75. 13. Tchekmedyian NS, Tait N, Moody M et al. Appetite stimulation with megestrol acetate in cachectic cancer patients. Semin Oncol 1986; 13 (suppl 4): 37-43. 14. Loprinzi CL, Ellison NM, Schaid DJ. Controlled trial of megestrol acetate for the treatment of cancer anorexia and cachexia. J Natl Cancer Inst 1990; 82: 1127-32. 15. Schmoll E, Wilke H, Rhole R et al. Megestrol acetate in cancer cachexia. Semin Oncol 1991; 18 (suppl 2): 32-4. Correspondence to: Ted A. W. Splinter, MD Department of Medical Oncology University Hospital Dijkzigt Dr. Molewaterplein 40 3015 GD Rotterdam The Netherlands
Downloaded from http://annonc.oxfordjournals.org/ at Karolinska Institutet on July 12, 2015
acetate. One patient refused further treatment because of severe drowsiness, which started immediately after treatment commenced. This retrospective analysis lacks a control arm and cannot be used as proof of the appetite-stimulating effect of megestrol acetate. However, our results plus the aforementioned data from randomized studies lead to the conclusion that the administration of megestrol acetate 160 mg tid may offer important palliation of psychosocial problems to approximately 30% of those patients for whom only palliative treatment is available. The observation that only 30% of patients respond to megestrol acetate with improved appetite may indicate that different cause of anorexia exist. It will take many investigations to understand the cancer-related anorexia/cachexia syndrome. From a practical clinical view, it seems worthwhile to offer anorectic patients a chance for improvement, especially since the side effects of megestrol acetate are absent or mild and the distinction between responders and nonresponders can be made by day 10 of treatment.
References
Original article Cachexia and cancer: A clinician's view T. A. W. Splinter Department of Medical Oncology, University Hospital Dijkzigt, Rotterdam, The Netherlands
with megestrol acetate (160 mg tid) because they complained of anorexia. After 10 days of treatment, megestrol acetate was continued only in those patients whose appetite and/or general well-being improved. Fifty-seven patients (32%) experienced such an improvement and asked for continuation of therapy. Many basic questions are still unanswered; nonetheless, from a practical clinical view it seems worthwhile to offer anorectic patients a chance to improve, especially since side effects of megestrol acetate are absent or mild, and the distinction between responders and nonresponders can be made by 10 days of treatment.
Cachexia is connected with advanced cancer and will affect any patient in the terminal disease phase. The causes of cachexia are not well understood, but seem to be multifactorial. In addition to reduced food intake, metabolic changes are observed. These changes seem comparable with those found during sepsis and trauma, but differ from those seen during starvation (reviewed in reference [1]). One consistent feature in metabolic studies of cancer patients is the interindividual range of responses to parenteral feeding, even when patients with the same diagnosis and disease stage are compared [2]. At first presentation, the degree of weight loss, which seems to differ markedly among patients, correlates with the type of cancer and disease extent. Almost invariably, no matter what the type of cancer, more than 5% weight loss before the start of treatment is an unfavorable prognostic factor and frequently correlates with decreased performance status. At the University Hospital Dijkzigt, patients with cancer of the esophagus, cardia, stomach, and pancreas, as well as those with small cell lung cancer, have the highest weight loss at first presentation. In contrast, weight loss is rarely observed in patients with testicular cancer, even with massive disease - sarcoma, breast cancer and ovarian cancer. The latter group has no weight loss at first presentation, even when ascites-related weight gain is considered. Anorexia is inevitably present in patients with gastric cancer, pancreatic cancer, and small cell lung cancer. Aside from loss of appetite, obstruc-
tion of the upper digestive tract plays an important role in the weight loss of patients with cancer of the esophagus and cardia. In summary, some tumors exert profound toxic effects that lead to anorexia, cachexia, and decreased performance status in the early stages of disease, whereas others exert such toxicity only during the terminal phase. Recent experimental studies have demonstrated that circulating factors, such as tumor necrosis factor alpha and interleukin-1 beta, produce anorexia and cachexia in animals [3,4]. The best treatment of the toxic syndrome of anorexia/cachexia/decreased performance status is effective reduction of the tumor load. Toxicity from ineffective chemotherapy may worsen the syndrome, albeit probably by a different mechanism. When left untreated, cachexia usually proceeds to increasing anorexia, loss of tissue mass, muscle wasting, inactivity, and heightened susceptibility to the toxicity of treatment [5-9]. Perhaps even more important than the physical problems are the psychosocial problems of the patient and the family members resulting from anorexia and aversion to food. Eating together is an important part of family life. Aversion to food may add a fourth aspect to the anorexia/cachexia/decreased performance status syndrome, i.e. the patient's feeling of being an outcast who is obstructing this essential part of family life precisely when he or she most needs family support. Therefore, as the Fig. 1 shows, when studying cachexia, distinctions should be made between problems
Key words: cachexia, anorexia, advanced cancer, palliative treatment, megestrol acetate
Downloaded from http://annonc.oxfordjournals.org/ at Karolinska Institutet on July 12, 2015
Summary. The cancer-related cachexia/anorexia syndrome is not well understood. It is related to several factors like metabolic changes, tumor types, and disease extent and is frequently accompanied by decreased performance status. An important aspect of anorexia is the psychosocial problem: the patient is unable to join the family for meals precisely when he or she most needs familial support. Several randomized studies have shown that megestrol acetate, possibly in a dose-dependent fashion, can improve appetite and lead to weight gain. This effect seems to be most prevalent in patients with breast cancer and also occurs in the absence of a tumor response. We have retrospectively analyzed 176 patients with cancer types other than breast cancer who received only palliative treatment. The patients were treated
26
A very interesting observation in this study was the significant reduction in nausea and vomiting. A preliminary report of another randomized study has recently been published [15], in which patients with advanced cancer, who were candidates for palliative Metabolic changes Food intake therapy only, were randomized to receive a placebo or 480 or 960 mg megestrol acetate for 8 weeks. A tendency for weight gain and improved appetite was observed with active treatment, especially with the 960mg dose of megestrol acetate, in approximately 60% of Anorexia Obstruction patients. However, increased appetite and weight gain were also observed in 1 of 8 control patients. The numbers of patients are still too small to reach statistical sigTumor type Tumor type Disease extent Individual patient nificance. In summary, these studies indicate that high-dose megestrol acetate may improve appetite, cause weight gain, and reduce the side effects of chemotherapy, esEffective, ineffective, or no treatment pecially nausea and vomiting. The data suggest the presence of a dose-response relationship, which needs Fig. I. Several factors influence cancer-related cachexia. further investigation. Furthermore, there is a suggestion that breast cancer patients may respond better to megestrol acetate than do patients with other types of of food intake and metabolic changes; between tumor cancer. Finally, the study by Loprinzi et al. [14] points types, extent of disease, and individual response to out the difficulty of assessing the response to megestrol feeding; and between effective treatment, ineffective acetate when it is administered together with chemotreatment, and no treatment. therapy. However, the study also raises the interesting question of whether megestrol acetate may preclude chemotherapy-induced anorexia and thereby prevent transient weight loss. Treatment of anorexia/cachexia In 1989, we began a randomized study of megestrol The possible role of megestrol acetate acetate 160 mg tid vs. no treatment at the University Hospital Dijkzigt in lung cancer patients who fulfilled In a review of megestrol acetate in breast cancer, the following criteria: weight loss of more than 5% in Canetta et al. [10] described weight gain as an impor- the previous 3 months with or without severe anorexia tant side effect that occurred in 15% to 70% of pa- and with or without an albumin level <35 g/L. One tients. Tchekmedyian et al. [11] were the first to recog- year later the study was closed because of lack of acnize the possibly positive aspect of this side effect and crual. Patients, who did not want to be randomized, performed a phase I/II trial of escalating doses of asked for treatment, and physicians, because of their megestrol acetate in patients with breast cancer. An up- 2-year experience with megestrol acetate, had already date of this trial has been reported by Aisner et al. [12]. realized that some patients do respond favorably to this Doses of megestrol acetate ranging from 480 to 1,600 drug. mg/d were administered. Overall, 81% of the patients Since 1987, patients who complained about anogained weight. Weight gain was a function of time and rexia during palliative symptomatic treatment have occurred independent of the presence or absence of a been given megestrol acetate 160 mg tid. All of these tumor response. Based on this study it was postulated patients have reached the terminal disease phase. that megestrol acetate stimulated appetite and, in addi- Based on our experience that any improvement in aption, probably affected metabolism on a cellular level. petite will be evident within 10 days of starting treatIn another study of 33 patients with advanced can- ment, patients receive megestrol acetate for 10 days cer other than breast cancer who received megestrol and continue treatment only if appetite and/or general acetate 160 mg, 27% gained weight and 42% reported well-being improves. As Table 1 shows, 176 patients an improved sense of well-being [13]. Recently, Lop- have received megestrol acetate. The majority of them rinzi et al. [14] reported a randomized trial of 133 pa- had lung cancer or cancer of the esophagus and cardia tients who receive megestrol acetate 800 mg or pla- without obstruction. Fifty-seven patients (32%) asked cebo. The patients had advanced cancer other than to continue therapy because of the improvement in apbreast cancer. Sixty percent of the patients in both petite and/or general well-being. They were able to join groups received chemotherapy. Overall, 48% of the pa- the family for dinner again and had no aversion to the tients taking megestrol acetate and 39% of those taking smell of food cooking. Six patients refused treatment placebo gained weight. A weight gain of more than very soon after it began because of severe stomach 10% was observed only in the megestrol acetate group. pain, which disappeared after withdrawal of megestrol Cachexia
Downloaded from http://annonc.oxfordjournals.org/ at Karolinska Institutet on July 12, 2015
27 Table 1. Megestrol acetate in anorectic patients. Total no. patients Male/female NSCLC SCLC Esophageal cancer Cardiac cancer Gastric cancer Pancreatic cancer Hepatoma Mesothelioma
176
136/40 58 31 35 26 7 9 5 5
NSCLC = non-small cell lung cancer; SCLC = small cell lung cancer.
1. Douglas RG, Shaw JHF. Metabolic effects of cancer. Br J Surg 1990; 77: 246-54. 2. Holroyde CP, Skutches CL, Boden G et al. Glucose metabolism in cachectic cancer patients with colorectal cancer. Cancer Res 1984; 44: 5910-3. 3. Beck SA, Tisdale MJ. Production of lipolytic and proteolytic factors by a murine tumor producing cachexia in the host. Cancer Res 1987; 47: 5919-23. 4. Ternell M, Moldawer LC, Lonnroth C et al. Plasma protein synthesis in experimental cancer compared to paraneoplastic conditions, including monokine administration. Cancer Res 1987; 47: 5825-30. 5. DeWys WD. Anorexia as a general effect of cancer. Cancer 1979; 43: 2013-9. 6. Knox LS, Crosby LO, Feurer ID et al. Energy expenditure in malnourished cancer patients. Ann Surg 1983; 197: 152-62. 7. Young VR. Energy metabolism and requirements in the cancer patient. Cancer Res 1977; 37: 2336-47. 8. Nixon D, Heymsfield SB, Cohen AE et al. Protein-calorie undernutrition in hospitalized cancer patients. Am J Med 1980; 68: 683-90. 9. Brennan MF, Burt ME. Nitrogen metabolism in cancer patients. Cancer Treat Rep 1981; 65 (suppl 5): 65-77. 10. Canetta R, Florentine S, Hunter H et al. Megestrol acetate. Cancer Treat Rev 1983; 10: 141-57. 11. Tchekmedyian NS, Tait N, Moody M. High-dose megestrol acetate. JAMA 1987; 257: 1195-8. 12. Aisner J, Tchekmedyian NS, Tait N et al. Studies of high-dose megestrol acetate: potential applications in cachexia. Semin Oncol 1988; 15 (suppl 1): 68-75. 13. Tchekmedyian NS, Tait N, Moody M et al. Appetite stimulation with megestrol acetate in cachectic cancer patients. Semin Oncol 1986; 13 (suppl 4): 37-43. 14. Loprinzi CL, Ellison NM, Schaid DJ. Controlled trial of megestrol acetate for the treatment of cancer anorexia and cachexia. J Natl Cancer Inst 1990; 82: 1127-32. 15. Schmoll E, Wilke H, Rhole R et al. Megestrol acetate in cancer cachexia. Semin Oncol 1991; 18 (suppl 2): 32-4. Correspondence to: Ted A. W. Splinter, MD Department of Medical Oncology University Hospital Dijkzigt Dr. Molewaterplein 40 3015 GD Rotterdam The Netherlands
Downloaded from http://annonc.oxfordjournals.org/ at Karolinska Institutet on July 12, 2015
acetate. One patient refused further treatment because of severe drowsiness, which started immediately after treatment commenced. This retrospective analysis lacks a control arm and cannot be used as proof of the appetite-stimulating effect of megestrol acetate. However, our results plus the aforementioned data from randomized studies lead to the conclusion that the administration of megestrol acetate 160 mg tid may offer important palliation of psychosocial problems to approximately 30% of those patients for whom only palliative treatment is available. The observation that only 30% of patients respond to megestrol acetate with improved appetite may indicate that different cause of anorexia exist. It will take many investigations to understand the cancer-related anorexia/cachexia syndrome. From a practical clinical view, it seems worthwhile to offer anorectic patients a chance for improvement, especially since the side effects of megestrol acetate are absent or mild and the distinction between responders and nonresponders can be made by day 10 of treatment.
References