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Effect of megestrol acetate on weight loss, body composition and blood screen of gastrointestinal cancer patients
C/mrw/A'utrrnon (1994)13:85-89 OLongmanGroup
Ltd 1994
Effect of megestrol acetate on weight loss, body composition and blood screen of gastrointestinal cancer patients D. C. McMILLAN”, J. M. SIMPSON*, T. PRESTON+, W. S. WATSON*, A. SHENKIN++, H. J. G. BURNS*, and C. S. McARDLE*
K. C. H. FEARON”“,
*University Department of Surgery, Royal Infirmary, Glasgow, +Department of Health Physics, SURRC, East Kilbride, *Department of Nuclear Medicine, Southern General Hospital, Glasgow, **University Department of Surgery, Royal Infirmary, Edinburgh, ++Department of Clinical Chemistry, Royal Liverpool Hospital, Liverpool (Correspondence to DCM, University Department of Surgery, Royal Infirmary, Glasgow G31 ZER, UK).
ABSTRACT-Reduced food intake is probably the major cause of continuing weight loss in cancer patients. Therefore, agents which stimulate food intake may be of significant benefit to such patients. To examine this, a randomized double-blind placebo controlled study of megestrol acetate was carried out. 38 gastrointestinal cancer patients with weight loss (8-43% of pre-illness stable weight) were entered into the study. 26 were evaluable at 6 weeks and 21 at 12 weeks. Clinical details, serum biochemistry and haematology were examined at 6 and 12 weeks and total body water, total body potassium at 12 weeks after the baseline assessment. There was no significant weight change in either group over the 6 or 12 weeks. Furthermore, there was no significant difference in total body water, total body potassium, blood biochemistry or haematology between the groups over the study period. It does not appear that megestrol acetate at a dose of 480 mg/day results in weight gain in advanced gastrointestinal cancer patients with weight loss.
Introduction
data on serum biochemistry and haematology in these patients. In order to obtain such data we undertook a study to assess the effect of megesterol acetate on weight loss, body composition and blood parameters of weight-losing gastrointestinal cancer patients.
The majority of cancer patients with progressive malignant disease lose weight and a proportion become emaciated to the extent that they appear to die primarily from cachexia (1, 2). Furthermore, cancer cachexia causes distress, loss of independence and is extremely difficult to reverse. Attempts to reverse this weight loss by enteral and parenteral nutrition have not been encouraging (3). Moreover, it would appear from these studies that when weight is gained it usually is due to an increase in body water and fat rather than protein (4). Studies using megestrol acetate, a progestational agent used to treat advanced breast cancer, have shown that a proportion of patients gain weight with few side-effects (5-7) over a range of doses up to 1600 mg daily (8, 9). However, due to the fluid retention induced by progestational agents it is not clear what the nature of the weight gain has been. There is little data on the effect of megestrol acetate on weight gain and body composition in gastrointestinal cancer patients. Furthermore, there is no
Materials and methods Study design 38 patients with histologically proven cancer of the gastrointestinal tract and documented weight loss of greater than 5% (843%) were randomised to receive megesterol acetate (480 mg/d) or placebo for 12 weeks. Each patient was questioned carefully about their pre-illness weight and weight-loss and these were recorded. Patients entered into the study were undergoing only palliative therapy and had a life expectancy of at least 2 months. Patients were excluded from the study if they had undergone surgery, radiotherapy or chemotherapy in the previous 2 months. No patient had physical or functional 85
86
MEGESTROL ACETATE IN CANCER CACHEXIA
obstruction to food intake. In particular, although patients with oesophageal cancer had presented with some degree of dysphagia, at the time of randomisation they had been treated such that they were able to swallow freely. No patient had abnormal liver function tests. Other exclusion criteria included poorly controlled hypertension, congestive heart failure or a history of veno-occlusive disease. The randomisation code was not known to any of the investigators and was only broken at the end of the study. Patients were not given any nutritional advice by dietitians during the study. Baseline measurements of height and weight, blood white cell count, differential white cell count, albumin, transferrin and c-reactive protein as well as routine biochemistry, were carried out. These measurements were repeated at 6 and 12 weeks later. Baseline total body water and total body potassium
Table 1
Characteristics
Patient
PLACEBO 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. Median Range MEGESTROL 1. 2. 3. 4. 5. 6. I. 8. 9. 10. 11. 12. Median Range
of weight-losing
measurements were also carried out on all patients and repeated 12 weeks later. The study was approved by the local hospital ethical committee. All patients gave written informed consent.
Analytical methods Total body water. 3.7 MBq of tritium labelled water taken orally was allowed to equilibrate for 4 h before blood samples were taken. Corrections were made for the fraction of the dose excreted in urine. Total body potassium. This was determined by measuring the amount of the naturally occurring radioisotope, 40K, in each patient using a shielded room scanning whole body counter (10). Albumin and transferrin. They were analysed by immunoturbidometric methods on an Encore centrifugal analyser (Baker Instruments). Antisera for these
cancer patients
Sex
Age
Ht (cm)
wt loss (%)
Baseline Wt (kg)
M M F F M M M M F M M M M F
60 69 75 15 63 60 59 74 70 68 13 75 70 74 70 59 75
170 174 147 154 176 154 163 167 146 170 161 163 171 157 163 146 176
38 13 26 25 18 38 22 15 15 17 9 23 18 11 18 9 38
38.7 68.5 41.6 37.3 67.2 53.1 48.9 53.3 53.1 57.0 63.0 48.8 60.2 45.4 53.1 31.3 68.5
182 159 167 165 172 151 157 173 156 154 150 181 162 150 182
21 29 13 22 18 29 30 43 11 24 18 18 21 11 43
72.8 40.5 60.6 49.1 60.1 38.4 44.0 54.4 55.8 50.1 44.3 62.1 52.3 38.4 72.8
ACETATE M 72 F 15 M 76 M 65 M 61 F 74 F 63 M 16 M 73 F 72 F 17 M 55 73 55 II
Wt gain (kg) 12 wk 6wk
Cancer site
XI.6 -8.5 1.4 -2.3 0.8 -0.1 2.1 -2.3 0.9 -1.0 6.0 -1.8 3.8 -0.4 -0.3 -8.5 6.0
W W -2.0 W -3.2 -1.1 1.1 W -3.6 1.0 7.0 1.2 7.8 3.6 1.1 -3.6 7.8
Oesophagus Colon Stomach Colon Stomach Oesophagus Colon Pancreas Oesophagus Oesophagus Colon Stomach Colon Colon
11.8 0.3 4.6 -3.1 0.9 -2.4 -2.0 -1.4 -0.8 -2.1 1.7 1.3 -1.7 A.8 1.7
-2.8 W -7.6 0.9 -2.1 A.4 4.0 0.6 -2.5 -1.1 2.1 4.4 -2.1 7.6 4.4
Pancreas Colon Colon Stomach Pancreas Oesophagus Colon Stomach Oesophagus Stomach Colon Oesophagus
W = withdrawn, Ht = height, Wt loss = weight loss, Baseline wt = baseline weight Wt gain = weight gain.
CLINICAL NUTRITION
proteins were obtained from the Scottish Antibody Production Unit (Carluke, Scotland). C-reactive protein. Serum c-reactive protein was measured by Fluorescence Polarisation Immunoassay using an Abbott TDX analyser and Abbott reagents. The limit of detection of this assay is a C-reactive protein concentration of 10 mg/l. Calculations Data are presented as median and range. Where appropriate, differences between placebo and treatment group data were tested for statistical significance using the Mann-Whitney U test. Data from different time periods within each group were tested for statistical significance using the Freidman test and where appropriate, comparisons of data from different time periods were carried out using the Wilcoxon signed rank test (Minitab Inc., PA, USA).
Results Of the 38 weight-losing gastrointestinal cancer patients entered into the study 12 patients (4 placebo, 8 megestrol acetate) withdrew due to disease progression (2 died, 10 admitted to hospital for supportive care/pain control) leaving 26 patients for assessment at 6 weeks. The clinical and body composition characteristics of the 26 evaluable patients are shown in Table 1. The placebo and megestrol acetate groups were not significantly different (p > 0.05) with reference to height, pre-illness body weight, and percentage weight loss on entering the study. A further 5 patients (4 placebo, 1 megestrol acetate) withdrew from the study between the 6 and 12 week assessment. Withdrawal of these patients was also due to disease progression leading to a reduced performance status and requiring hospital admission. There was no significant change in weight in either group, over the 6 or 12 weeks (see Table 1). Furthermore, there was no significant difference in total body water or total body potassium between the group baseline measurements or over the period of the study (see Table 2). Finally there was no significant difference in the baseline blood biochemistry and haematology of the two groups (see Table 3). 2 patients (1 placebo, 1 megestrol acetate) reported nausea as a side effect of the treatment. Discussion A number of studies have reported weight gain in a proportion of advanced breast cancer patients
Table 2
Body composition
Patient
Total body water (1) Baseline 12 wk gain
PLACEBO I. 2. 7 ;: 5. 6. I. 8. 9. 10. 11. 12. 13. 14. Median Range
27.2 46.6 31.8 23.1 42.0 36.4 34.8 34.0 ‘4.6 33.3 32.6 30.9 34.5 22.6 33.0 21.8 46.4
MEGESTROL ACETATE 1. 42.4 2. 23.3 3 4: 32.1 32.7 5. 31.5 6. 21.5 7. 23.3 8. 34.9 9. 30. I 10. 28.8 II. 25.0 12. 37.1 Median 30.8 Range 21.5 42.4 W = withdrawn.
of weight-losing
cancer patients
Total body potassium (mmol) Baseline 12 wk gain
W W 0.7 W -3.8 -3.5 2.5 W 0.7 NM -0.2 1.5 0.7 -1.6 0.7 -3.8 2.5
1854 2690 1120 1.526 2730 1731 2286 2279 1873 2628 1925 2127 2619 1780 2026 1120 2730
W W 231 W 0 258 -347 W 2 NM 403 62 205 -241 62 -347 403
0 W
2950 1355 2064 2240 2188 1294 1519 2102 1932 1778 1500 2712 1998 1294 2950
0 W -324 -20 NM NM -269 450 0 NM -31 45 26 -324 450
0.7 0.6 NM NM -1.1 a.6 -2.3 NM 0.7 1.9 0.3 -2.3 1.9
X7
NM = not measured.
following administration of megestrol acetate (5-7, 9). However, it is not clear whether this agent has a role in the treatment of weight loss in gastrointestinal cancer patients. Recently, Loprinzi and co-workers (11) performed a randomised, double-blind, placebocontrolled trial of megestrol acetate in patients with cancer associated anorexia and cachexia. 133 eligible patients with advanced incurable cancer (of which approximately 50 had gastrointestinal cancer) received megestrol acetate (800 mg daily) or placebo for approximately 6 weeks. A weight gain of 6 kg or more over baseline was seen in a higher proportion (16%) of patients on megestrol acetate compared to those on placebo (2%). In contrast, Schmoll and co-workers (12) in a smaller randomised placebo controlled study of mainly gastrointestinal cancer patients (n = 34) reported no statistical difference in weight gain at either 480 or 960 mg/d megestrol acetate, for 8 weeks, compared with placebo.
88
MEGESTROL
Table 3
ACETATE
Blood biochemistry
Parameter
IN
CANCER CACHEXIA and haematology
of gastrointestinal
Placebo Baseline (tl = 14)
6wk (n = 14)
2.5 (1.63.4) 19 (< ltSl70) 12.5 (9.8-15.0) 8.5 (3.619.2) 72 (47-92)
(Z-43) 2.5 (1.1-3.4) 30 (< lCr280) 12.3 (7.7-15.8) 8.8 (4.3-38.2) 61 (27-90)
Albumin (gfi) Transferrin
km CRP (mgA) Haemoglobin (g/l) WBC count
(106/ml) % neutrophils % lymphocytes
&3) % monocytes Platelets (106/ml)
i-10) 368 (104-716) median (range)
(Cl) 5 (l-7) 339 (93476) median (range)
cancer patients.
17 wk (n = 10) 40 (35-43) 2.8 (2.3-3.4) 15 (< 10-170) 13.4 (9.1-15.4) 7.8 (4.4-18.7)
Megestrol acetate Baseline 6wk (n = 12) (n = 12)
12wk (n= 11)
(Z-44)
4S52
$18.7)
$89) 24 (5-39)
(85:24_22.0) 68 (5&83) 24 (7-41)
($89) 24 (6-41)
2.5 (163.2) 16 (< 10-94) 12.0 (9.4-14.0) 9.4 (5.3-24.0) 73 (53-89) 20 (740)
p3-9) 352 (156663) median (range)
:&9) 340 (212-467) median (range)
&8) 379 (263-562) median (range)
p3-7) 390 (213-562) median (range)
In this study we have examined whether megestrol acetate (480 mg/d) can reverse weight loss in gastrointestinal cancer patients using a randomised, double-blind, placebo-controlled design. Almost half of the 38 patients entered into the present study were not evaluable at 12 weeks, most patients withdrawing between the baseline and 6 week evaluation. These findings are comparable to previous reports (11, 12) and reflects the poor condition of patients entering these studies. Clearly, the high attrition rate is a major problem in such longitudinal studies. The patients randomised to the placebo and megestrol acetate were well matched with respect to physical characteristics, weight loss and cancer site. There was no significant difference in weight gain, total body water or total body potassium between the two groups at 6 or 12 weeks. Furthermore, there was no significant difference in the biochemical/ haematological parameters measured over the 12 week period in the placebo or megestrol acetate group. The results of this and previous studies point to the complexity of weight loss in cancer patients. However, it has been proposed that, as well as reduced food intake, the inflammatory response may contribute to weight loss in cancer patients (13, 14). In this context, it is of interest to note that more than half of the evaluable patients had an on-going inflammatory response as evidenced by elevated circulating c-reactive protein concentrations (15, 16).
($3.4) 20 (< l&65) 12.8 (11.1-14.9)
Laboratory reference range
2.6 (1.7-3.2) 15 (< 10-129) 12.2 (10.3-14.4)
2.0-4.0 < 10 11.5-18.0 4.0-l 1.0 60-70 20-25 3-8 15&400
Furthermore, of the 9 patients (3 placebo and 6 megestrol acetate) who lost at least 2 kg in the 12 weeks of the study 8 had evidence of an inflammatory response over this period. In contrast, of the 5 patients who gained at least 2 kg during the study 4 patients had no evidence of an inflammatory response. Therefore, it may be that the presence or absence of an inflammatory response, in patients, was an important factor in determining weight gain in the present study. In summary, the findings of this and previous longitudinal studies with megestrol acetate are likely to have been influenced by the relatively short survival period of advanced gastrointestinal cancer patients with weight loss. The majority of patients in the present study had evidence of an on-going inflammatory response and this may have contributed to weight loss. The results of this study do not indicate that megestrol acetate, at the dose 480 mg/day, is effective in inducing weight gain in advanced gastrointestinal cancer patients with weight loss.
Acknowledgement The authors gratefully acknowledge the interest and encouragement of Professor T. G. Cooke, Dr G. Murray for statistical advice and financial assistance from Bristol-Myers Squibb Pharmaceuticals Ltd. Grateful thanks are also due to the technical staff in the Department of Nuclear Medicine, Southern General Hospital, Glasgow.
CLINICALNUTRITION89
References 1. Warren S. The immediate causes of death in cancer. Am J Med Sci 1932; 184: 610-616. 2. Inagaki J, Rodriguez V, Bodey G P. Causes of death in cancer patients. Cancer 1974; 33: 568-573. 3, Heys S D, Park K G M, Garlick P J, Eremin 0. Nutrition and malignant disease: implications for surgical practice. Br J Surg 1992; 79: 614-623. 4. Cohn H S, Vartsky D, Ashok N et al. Changes in body composition of cancer patients following combined nutritional support. Nutrition and Cancer 1982; 4: 107-l 19. 5. Morgan L R. Megestrol acetate v tamoxifen in advanced breast cancer in postmenopausal patients. Semin Oncol 1985; 12: 4347. 6. Tchekmedian N S, Tait N, Moody M et al. Appetite stimulation with megestrol acetate in cache&c cancer patients. Semin Oncol 1986; 13: 37-43. 7. Aisner J, Tchekmedyian N S, Tait N et al. Studies of high dose megestrol acetate: potential applications in cachexia. Semin Oncol 1988; 15: 68-75. 8. Tchekmedian N S, Tait N, Moody Met al. High dose megestrol acetate: a possible treatment for cachexia. JAMA 1987; 257: 1195-l 198. 9. Pames H L, Abrams J S, Tchekmedyian N S. Tait N, Aisner J.
10.
11.
12.
13.
14. 15.
16.
Submission dare: 23 June 1993; Accepted after revision: 11 October 1993
A phase I/II study of high-dose megestrol acetate in the treatment of metastatic breast cancer. Breast Cancer Res Treat 1991; 18: 171-177. Watson W S. Total body potassium measurement: The effect of fallout from Chernobyl. Clin Phys Physiol Meas 1987; 8: 337-341. Loprinzi C L. Ellison N M, Schaid D J et al. Controlled trial of megestrol acetate for the treatment of cancer anorexia and cachexia. J Nat1 Cancer Inst 1990; 82: 1127-l 132. S&m011 E, Wilke H, Thole R, Preusser P. Wildfang I, Schmoll H J. Megestrol acetate in cancer cachexia. Semin Oncol 1991; 18(l) (Suppl. 2): 32-34. Preston T, Fearon K C H, Robertson I, East B W, Calman K C. Tissue loss during severe wasting in lung cancer patients. In: Ellis K J, Yasumura S, Morgan W D, eds. In Vivo body composition studies. London: Institute of Physical Sciences in Medicine, 1987: 61-69. Kern K A, Norton J A. Cancer cachexia. JPEN 1988; 12(3): 286298. Pepys M B, Baltz ML. Acute phase proteins with special reference to c-reactive protein and related proteins (pentaxins) and serum amyloid A protein. Adv Immunol 1983; 141-212. Thompson D, Milford-Ward A, Whither J T. The value of acute phase protein measurements in clinical practice. AM Clin Biochem 1992: 29: 123-131.
Ltd 1994
Effect of megestrol acetate on weight loss, body composition and blood screen of gastrointestinal cancer patients D. C. McMILLAN”, J. M. SIMPSON*, T. PRESTON+, W. S. WATSON*, A. SHENKIN++, H. J. G. BURNS*, and C. S. McARDLE*
K. C. H. FEARON”“,
*University Department of Surgery, Royal Infirmary, Glasgow, +Department of Health Physics, SURRC, East Kilbride, *Department of Nuclear Medicine, Southern General Hospital, Glasgow, **University Department of Surgery, Royal Infirmary, Edinburgh, ++Department of Clinical Chemistry, Royal Liverpool Hospital, Liverpool (Correspondence to DCM, University Department of Surgery, Royal Infirmary, Glasgow G31 ZER, UK).
ABSTRACT-Reduced food intake is probably the major cause of continuing weight loss in cancer patients. Therefore, agents which stimulate food intake may be of significant benefit to such patients. To examine this, a randomized double-blind placebo controlled study of megestrol acetate was carried out. 38 gastrointestinal cancer patients with weight loss (8-43% of pre-illness stable weight) were entered into the study. 26 were evaluable at 6 weeks and 21 at 12 weeks. Clinical details, serum biochemistry and haematology were examined at 6 and 12 weeks and total body water, total body potassium at 12 weeks after the baseline assessment. There was no significant weight change in either group over the 6 or 12 weeks. Furthermore, there was no significant difference in total body water, total body potassium, blood biochemistry or haematology between the groups over the study period. It does not appear that megestrol acetate at a dose of 480 mg/day results in weight gain in advanced gastrointestinal cancer patients with weight loss.
Introduction
data on serum biochemistry and haematology in these patients. In order to obtain such data we undertook a study to assess the effect of megesterol acetate on weight loss, body composition and blood parameters of weight-losing gastrointestinal cancer patients.
The majority of cancer patients with progressive malignant disease lose weight and a proportion become emaciated to the extent that they appear to die primarily from cachexia (1, 2). Furthermore, cancer cachexia causes distress, loss of independence and is extremely difficult to reverse. Attempts to reverse this weight loss by enteral and parenteral nutrition have not been encouraging (3). Moreover, it would appear from these studies that when weight is gained it usually is due to an increase in body water and fat rather than protein (4). Studies using megestrol acetate, a progestational agent used to treat advanced breast cancer, have shown that a proportion of patients gain weight with few side-effects (5-7) over a range of doses up to 1600 mg daily (8, 9). However, due to the fluid retention induced by progestational agents it is not clear what the nature of the weight gain has been. There is little data on the effect of megestrol acetate on weight gain and body composition in gastrointestinal cancer patients. Furthermore, there is no
Materials and methods Study design 38 patients with histologically proven cancer of the gastrointestinal tract and documented weight loss of greater than 5% (843%) were randomised to receive megesterol acetate (480 mg/d) or placebo for 12 weeks. Each patient was questioned carefully about their pre-illness weight and weight-loss and these were recorded. Patients entered into the study were undergoing only palliative therapy and had a life expectancy of at least 2 months. Patients were excluded from the study if they had undergone surgery, radiotherapy or chemotherapy in the previous 2 months. No patient had physical or functional 85
86
MEGESTROL ACETATE IN CANCER CACHEXIA
obstruction to food intake. In particular, although patients with oesophageal cancer had presented with some degree of dysphagia, at the time of randomisation they had been treated such that they were able to swallow freely. No patient had abnormal liver function tests. Other exclusion criteria included poorly controlled hypertension, congestive heart failure or a history of veno-occlusive disease. The randomisation code was not known to any of the investigators and was only broken at the end of the study. Patients were not given any nutritional advice by dietitians during the study. Baseline measurements of height and weight, blood white cell count, differential white cell count, albumin, transferrin and c-reactive protein as well as routine biochemistry, were carried out. These measurements were repeated at 6 and 12 weeks later. Baseline total body water and total body potassium
Table 1
Characteristics
Patient
PLACEBO 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. Median Range MEGESTROL 1. 2. 3. 4. 5. 6. I. 8. 9. 10. 11. 12. Median Range
of weight-losing
measurements were also carried out on all patients and repeated 12 weeks later. The study was approved by the local hospital ethical committee. All patients gave written informed consent.
Analytical methods Total body water. 3.7 MBq of tritium labelled water taken orally was allowed to equilibrate for 4 h before blood samples were taken. Corrections were made for the fraction of the dose excreted in urine. Total body potassium. This was determined by measuring the amount of the naturally occurring radioisotope, 40K, in each patient using a shielded room scanning whole body counter (10). Albumin and transferrin. They were analysed by immunoturbidometric methods on an Encore centrifugal analyser (Baker Instruments). Antisera for these
cancer patients
Sex
Age
Ht (cm)
wt loss (%)
Baseline Wt (kg)
M M F F M M M M F M M M M F
60 69 75 15 63 60 59 74 70 68 13 75 70 74 70 59 75
170 174 147 154 176 154 163 167 146 170 161 163 171 157 163 146 176
38 13 26 25 18 38 22 15 15 17 9 23 18 11 18 9 38
38.7 68.5 41.6 37.3 67.2 53.1 48.9 53.3 53.1 57.0 63.0 48.8 60.2 45.4 53.1 31.3 68.5
182 159 167 165 172 151 157 173 156 154 150 181 162 150 182
21 29 13 22 18 29 30 43 11 24 18 18 21 11 43
72.8 40.5 60.6 49.1 60.1 38.4 44.0 54.4 55.8 50.1 44.3 62.1 52.3 38.4 72.8
ACETATE M 72 F 15 M 76 M 65 M 61 F 74 F 63 M 16 M 73 F 72 F 17 M 55 73 55 II
Wt gain (kg) 12 wk 6wk
Cancer site
XI.6 -8.5 1.4 -2.3 0.8 -0.1 2.1 -2.3 0.9 -1.0 6.0 -1.8 3.8 -0.4 -0.3 -8.5 6.0
W W -2.0 W -3.2 -1.1 1.1 W -3.6 1.0 7.0 1.2 7.8 3.6 1.1 -3.6 7.8
Oesophagus Colon Stomach Colon Stomach Oesophagus Colon Pancreas Oesophagus Oesophagus Colon Stomach Colon Colon
11.8 0.3 4.6 -3.1 0.9 -2.4 -2.0 -1.4 -0.8 -2.1 1.7 1.3 -1.7 A.8 1.7
-2.8 W -7.6 0.9 -2.1 A.4 4.0 0.6 -2.5 -1.1 2.1 4.4 -2.1 7.6 4.4
Pancreas Colon Colon Stomach Pancreas Oesophagus Colon Stomach Oesophagus Stomach Colon Oesophagus
W = withdrawn, Ht = height, Wt loss = weight loss, Baseline wt = baseline weight Wt gain = weight gain.
CLINICAL NUTRITION
proteins were obtained from the Scottish Antibody Production Unit (Carluke, Scotland). C-reactive protein. Serum c-reactive protein was measured by Fluorescence Polarisation Immunoassay using an Abbott TDX analyser and Abbott reagents. The limit of detection of this assay is a C-reactive protein concentration of 10 mg/l. Calculations Data are presented as median and range. Where appropriate, differences between placebo and treatment group data were tested for statistical significance using the Mann-Whitney U test. Data from different time periods within each group were tested for statistical significance using the Freidman test and where appropriate, comparisons of data from different time periods were carried out using the Wilcoxon signed rank test (Minitab Inc., PA, USA).
Results Of the 38 weight-losing gastrointestinal cancer patients entered into the study 12 patients (4 placebo, 8 megestrol acetate) withdrew due to disease progression (2 died, 10 admitted to hospital for supportive care/pain control) leaving 26 patients for assessment at 6 weeks. The clinical and body composition characteristics of the 26 evaluable patients are shown in Table 1. The placebo and megestrol acetate groups were not significantly different (p > 0.05) with reference to height, pre-illness body weight, and percentage weight loss on entering the study. A further 5 patients (4 placebo, 1 megestrol acetate) withdrew from the study between the 6 and 12 week assessment. Withdrawal of these patients was also due to disease progression leading to a reduced performance status and requiring hospital admission. There was no significant change in weight in either group, over the 6 or 12 weeks (see Table 1). Furthermore, there was no significant difference in total body water or total body potassium between the group baseline measurements or over the period of the study (see Table 2). Finally there was no significant difference in the baseline blood biochemistry and haematology of the two groups (see Table 3). 2 patients (1 placebo, 1 megestrol acetate) reported nausea as a side effect of the treatment. Discussion A number of studies have reported weight gain in a proportion of advanced breast cancer patients
Table 2
Body composition
Patient
Total body water (1) Baseline 12 wk gain
PLACEBO I. 2. 7 ;: 5. 6. I. 8. 9. 10. 11. 12. 13. 14. Median Range
27.2 46.6 31.8 23.1 42.0 36.4 34.8 34.0 ‘4.6 33.3 32.6 30.9 34.5 22.6 33.0 21.8 46.4
MEGESTROL ACETATE 1. 42.4 2. 23.3 3 4: 32.1 32.7 5. 31.5 6. 21.5 7. 23.3 8. 34.9 9. 30. I 10. 28.8 II. 25.0 12. 37.1 Median 30.8 Range 21.5 42.4 W = withdrawn.
of weight-losing
cancer patients
Total body potassium (mmol) Baseline 12 wk gain
W W 0.7 W -3.8 -3.5 2.5 W 0.7 NM -0.2 1.5 0.7 -1.6 0.7 -3.8 2.5
1854 2690 1120 1.526 2730 1731 2286 2279 1873 2628 1925 2127 2619 1780 2026 1120 2730
W W 231 W 0 258 -347 W 2 NM 403 62 205 -241 62 -347 403
0 W
2950 1355 2064 2240 2188 1294 1519 2102 1932 1778 1500 2712 1998 1294 2950
0 W -324 -20 NM NM -269 450 0 NM -31 45 26 -324 450
0.7 0.6 NM NM -1.1 a.6 -2.3 NM 0.7 1.9 0.3 -2.3 1.9
X7
NM = not measured.
following administration of megestrol acetate (5-7, 9). However, it is not clear whether this agent has a role in the treatment of weight loss in gastrointestinal cancer patients. Recently, Loprinzi and co-workers (11) performed a randomised, double-blind, placebocontrolled trial of megestrol acetate in patients with cancer associated anorexia and cachexia. 133 eligible patients with advanced incurable cancer (of which approximately 50 had gastrointestinal cancer) received megestrol acetate (800 mg daily) or placebo for approximately 6 weeks. A weight gain of 6 kg or more over baseline was seen in a higher proportion (16%) of patients on megestrol acetate compared to those on placebo (2%). In contrast, Schmoll and co-workers (12) in a smaller randomised placebo controlled study of mainly gastrointestinal cancer patients (n = 34) reported no statistical difference in weight gain at either 480 or 960 mg/d megestrol acetate, for 8 weeks, compared with placebo.
88
MEGESTROL
Table 3
ACETATE
Blood biochemistry
Parameter
IN
CANCER CACHEXIA and haematology
of gastrointestinal
Placebo Baseline (tl = 14)
6wk (n = 14)
2.5 (1.63.4) 19 (< ltSl70) 12.5 (9.8-15.0) 8.5 (3.619.2) 72 (47-92)
(Z-43) 2.5 (1.1-3.4) 30 (< lCr280) 12.3 (7.7-15.8) 8.8 (4.3-38.2) 61 (27-90)
Albumin (gfi) Transferrin
km CRP (mgA) Haemoglobin (g/l) WBC count
(106/ml) % neutrophils % lymphocytes
&3) % monocytes Platelets (106/ml)
i-10) 368 (104-716) median (range)
(Cl) 5 (l-7) 339 (93476) median (range)
cancer patients.
17 wk (n = 10) 40 (35-43) 2.8 (2.3-3.4) 15 (< 10-170) 13.4 (9.1-15.4) 7.8 (4.4-18.7)
Megestrol acetate Baseline 6wk (n = 12) (n = 12)
12wk (n= 11)
(Z-44)
4S52
$18.7)
$89) 24 (5-39)
(85:24_22.0) 68 (5&83) 24 (7-41)
($89) 24 (6-41)
2.5 (163.2) 16 (< 10-94) 12.0 (9.4-14.0) 9.4 (5.3-24.0) 73 (53-89) 20 (740)
p3-9) 352 (156663) median (range)
:&9) 340 (212-467) median (range)
&8) 379 (263-562) median (range)
p3-7) 390 (213-562) median (range)
In this study we have examined whether megestrol acetate (480 mg/d) can reverse weight loss in gastrointestinal cancer patients using a randomised, double-blind, placebo-controlled design. Almost half of the 38 patients entered into the present study were not evaluable at 12 weeks, most patients withdrawing between the baseline and 6 week evaluation. These findings are comparable to previous reports (11, 12) and reflects the poor condition of patients entering these studies. Clearly, the high attrition rate is a major problem in such longitudinal studies. The patients randomised to the placebo and megestrol acetate were well matched with respect to physical characteristics, weight loss and cancer site. There was no significant difference in weight gain, total body water or total body potassium between the two groups at 6 or 12 weeks. Furthermore, there was no significant difference in the biochemical/ haematological parameters measured over the 12 week period in the placebo or megestrol acetate group. The results of this and previous studies point to the complexity of weight loss in cancer patients. However, it has been proposed that, as well as reduced food intake, the inflammatory response may contribute to weight loss in cancer patients (13, 14). In this context, it is of interest to note that more than half of the evaluable patients had an on-going inflammatory response as evidenced by elevated circulating c-reactive protein concentrations (15, 16).
($3.4) 20 (< l&65) 12.8 (11.1-14.9)
Laboratory reference range
2.6 (1.7-3.2) 15 (< 10-129) 12.2 (10.3-14.4)
2.0-4.0 < 10 11.5-18.0 4.0-l 1.0 60-70 20-25 3-8 15&400
Furthermore, of the 9 patients (3 placebo and 6 megestrol acetate) who lost at least 2 kg in the 12 weeks of the study 8 had evidence of an inflammatory response over this period. In contrast, of the 5 patients who gained at least 2 kg during the study 4 patients had no evidence of an inflammatory response. Therefore, it may be that the presence or absence of an inflammatory response, in patients, was an important factor in determining weight gain in the present study. In summary, the findings of this and previous longitudinal studies with megestrol acetate are likely to have been influenced by the relatively short survival period of advanced gastrointestinal cancer patients with weight loss. The majority of patients in the present study had evidence of an on-going inflammatory response and this may have contributed to weight loss. The results of this study do not indicate that megestrol acetate, at the dose 480 mg/day, is effective in inducing weight gain in advanced gastrointestinal cancer patients with weight loss.
Acknowledgement The authors gratefully acknowledge the interest and encouragement of Professor T. G. Cooke, Dr G. Murray for statistical advice and financial assistance from Bristol-Myers Squibb Pharmaceuticals Ltd. Grateful thanks are also due to the technical staff in the Department of Nuclear Medicine, Southern General Hospital, Glasgow.
CLINICALNUTRITION89
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Submission dare: 23 June 1993; Accepted after revision: 11 October 1993
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