CLINICAL
SIGNIFICANCE
PHOSPHATASE
OF SERUM ACID
LEVELS IN ADVANCED
PROSTATIC CARCINOMA* DOUGLAS WILLIAM ROBERT
THE
E. JOHNSON, W.
SCOTT,
P. GIBBONS,
NATIONAL
M.D.+ M.D.
$
M.D.9
PROSTATIC
GEORGE JOSEPH GERALD
CANCER
R. PROUT,
M.D.
D. SCHMIDT,
M.D.?
P. MURPHY,
PROJECT+
1)
M.D.,
D.Sc.**
t
ABSTRACT - This cooperative study was sponsored by the National Prostatic Cancer Project to determine the usefulness of serum acid phosphatase levels as a predictive indicator with regard to perj&-mance status, sites of metastases, response to treatment, and survival in patients with advanced prostatic carcinoma. The results indicate that survival was signijcantly shwter for those patients who had elevation of their on-study (pretreatment) total serum acid phosphatase levels. In addition, a positive correlation was observed between 50 per cent reduction of primary tumor mass, relief of pain, and acid phosphatase activity. No correlation could be demonstrated between serum acid phosphatase and performance status, site of metastases, and other criteria of response to therapy. It is concluded that this test as currently determined spectrophotometrically at this stage of disease and if employed alone is not sufficient to allow fm total evaluation of the response of therapy. It is, however, helpful when used in correlation with the previously mentioned positive factors.
Assays of serum acid phosphatase activity have become a routine and standard examination for the diagnosis and monitoring of patients with prostatic carcinoma. However, its value in these situations has become increasingly controversial,‘s2 since the test generally may lack tissue specificity or may detect a heterogeneous group of many isoenzymes3>4 present in a variety of tissues.‘+ We have, therefore, reviewed our experience utilizing serum acid phosphatase levels as a predictive indicator with regard to performance status, sites of metastases, response to
treatment, and survival in a group of patients with advanced Stage D prostatic carcinoma.
*Supported in part by Public Health Service Grants CA15407, CA-15421, CA-15107, CA-15284, CA-15108, CA15126,and CA-14716from the National Cancer Institutes, National Institutes of Health, Department of Health, Education, and Welfare. t M. D. Anderson Hospital and Tumor Institute, Houston, Texas. $Johns Hopkins Hospital, Baltimore, Maryland.
$Virginia Mason Medical Center, Seattle, Washington. I/Massachusetts General Hospital, Boston. lfuniversity of Iowa Hospitals and Clinics, Iowa City, Iowa. **Roswell Park Memorial Institute, Buffalo, New York. f f Coauthors in this study are T. Ming Chu, Ph. D., John F. Gaeta, M.D., James Joiner, Ph.D., and Jack Saroff, Ph. D., Roswell Park Memorial Institute, Buffalo, New York.
UROLOGY
/ AUGUST 1976 / VOLUME
VIII,
NUMBER 2
Material
and Methods
One hundred twenty-five patients with a histologic diagnosis of prostatic carcinoma who had metastases (Stage D) and had relapsed following orchiectomy and hormonal therapy were entered into the cooperative study to determine the efficacy of single chemotherapeutic agents in the treatment of advanced prostatic carcinoma. g~lo
123
Diagnostic evaluation performed within ten days prior to initiation of therapy included a complete blood count, urinalysis, serum creatinine, urea nitrogen, serum bilirubin, chest x-ray film, skeletal survey, and excretory urogram. Assays of total serum acid phosphatase levels were performed on each patient on entry into the study at the patient’s cooperating institution (Johns Hopkins Hospital, The Mason Clinic, M. D. Anderson Hospital and Tumor Institute, University of Iowa Hospitals and Clinics, and Massachusetts General Hospital), as well as on serum collected and mailed to Roswell Park Memorial Institute for duplicate assays. Performance status was assessed on the day of initiation of treatment based on the Eastern Cooperative Oncology Group performance status scale: [(0) full activity; (1) ambulatory, capable of light work; (2) in bed less than 50 per cent of the time; (3) in bed more than 50 per cent of the time; and (4) completely bedridden]. Clinical data collected at periodic intervals (at least once every six weeks) were forwarded to the central office of the National Prostatic Cancer Project to avoid bias in review.
Km r,-.\
*\ - *.‘.\*.\
‘;; 2
’ .. ‘.
-.. ‘\
80-
. .
\
i2 5 5
\
\
\
\
Normal
**.. ....
Abnormal
*.
!S
P
‘\-_
. *.
-.
*.
40-
*a.*
\ \ \
\
*.
\ \ \L---M
*. *. -. ‘.
20-
0
I 8
I
I. 24
SAP
_\
F E 8
SAP
\ ‘\._
60-
m g
\
----
1. 40
I.
*. *. . . . . . . . . . .
1.
56
I,
72
63
WEEKS FIGURE 1. Survival of Protocol 100 patients by normal and abnormal serum acid phosphatase.
Results Although the methods for assay of serum acid phosphatase differed among the five participating institutions, assays of duplicate specimens at Roswell Park Memorial Insitute revealed a high degree of correlation between magnitude of values obtained by individual institutions and Roswell Park Memorial Institute (Table I). Of the 125 patients, serum acid phosphatase activity was elevated in 92 patients (74 per cent) prior to initiation of chemotherapy and was within the normal range in 33 patients (26 per cent). Elevated pretreatment serum acid phosphatase activities had a statistically significant (p cO.05) adverse effect on survival (Fig. 1). Analysis of the
Correlation of serum acid phosphatase values between participating institutions and RPM1 *
TABLE I.
Institution
No. of
Samples
Correlation Coefficient
M. D. Anderson University of Iowa Mason Clinic Massachusetts General Johns Hopkins
451 264 216 99 237
0.90 0.96 0.84 0.82 0.87
*RPMI: Roswell Park Memorial Institute.
124
on-study performance status compared with serum acid phosphatase activities is given in Table II. When patients were studied according to performance status 0 and 1, 2 and 3, and 4, the elevated acid phosphatase activities in these three categories were 72, 75, and 78 per cent, respectively. These results were not statistically significant (p >0.05), indicating a homogeneity between the serum acid phosphatase levels when compared with performance status. The site of metastases at the time the patients entered the study may be seen in Table III. The data suggested that elevated serum acid phosphatase occurred more often in patients with
On-study performance status compared with serum acid phosphatase
TABLE II.
-Performance 0, 1 Normal serum acid 20 (28)* phosphatase Elevated serum acid phosphatase 5372) 73 (100) TOTAL
Status Scale4 2, 3 11 (25)
3275) 43 (100)
2 (22)
1178) 9 (loo)
*Number of patients and (per cent) of patients in each category.
UROLOGY /
AUGUST 1976 I VOLUME VIII, NUMBER 2
TABLE III.
Sites of metastases with respect to on-study serum acid phosphatase (SAP) levels Per Cent with No. with Metastasis Elevated SAP
No. of Evaluable Patients
Site of Metastasis Bone Bone and lung Bone and pleura Bone and liver Bone and lymph node
123 115 108 102
121 14 6 19
74 86 83 84
94
19
84
metastases to lung, pleura, liver, and lymph nodes, in addition to bone. For all treatments, there were positive correlations between the serum acid phosphatase activities and reduction of tumor mass, as well as the relief of pain (Tables IV and V). The pretreatment, as well as subsequent serum acid phosphatase activities did not correlate with other specific objective and subjective response signs. However, a greater percentage of serum acid phosphatase values subsequently fell within normal range in patients undergoing chemotherapy (24 per cent) compared with standard therapies (11 per cent). Comment Failure of the serum acid phosphatase levels to be elevated in 26 per cent of our patients with prostatic carcinoma who had evidence of progressing metastatic disease was not unexpected, since others have reported similar findings.“,12 The reason for normal levels, however, in this situation remains unclear. It has been suggested that normal acid phosphatase levels might be due to (1) tumor cells which were poorly differentiated secreted little acid phosphatase activity, (2) acid phosphatase which was present in the serum but inactivated prior to assay, (3) small quantities of
TABLE IV.
Tumor Mass Reduction+ No reduction
Comparison of serum acid phosphatase and tumor mass* -Acid PhosphatasDecrease to No Normal Change 7
10
2
TOTALS
19
65 72
*Significant correlation (p < 0.05). tReduction of primary mass greater than 50 per cent.
UROLOGY /
AUGUST 1976 /
VOLUME VIII, NUMBER 2
“prostatic” enzyme which was present but not detected by ordinary spectrophotometric methods employed, and (4) that the prostatic gland contains a “barrier” which may prevent release of acid phosphatase into the circulation.3,13 It is doubtful that the first and last postulate occurred although the biology and biosynthesis of acid phosphatase in prostatic cancer cells is not completely known at present. Inactivation prior to assay was likewise unlikely, since there was a good correlation between the different assays performed on duplicate samples which were collected and handled in entirely different ways. Although small quantities of prostatic acid phosphatase may not have been detected in the serum by calorimetric methods, the question remains unanswered as to why in patients with advanced disease there is such variation in the levels of acid phosphatase.
TABLE V.
Relief from Pain
Comparison of serum acid phosphatase and relief of pain* -Acid PhosphataseDecrease to No Normal Change
Yes No TOTALS
14
26
19
46 72
5
*Significant correlation (p < 0.05).
Although Ishibe, Usui, and Nihera’l,12 recently reported that pretreatment serum acid phosphatase levels are insignificant in regard to fiveyear survival rates, we were able to show, in this national study, a statistically significant adverse effect for elevation of serum acid phosphatase levels on survival. Return of the on-study serum acid phosphatase level to normal range during therapy correlated well with reduction of tumor mass and relief of pain, but it did not correlate with other criteria for objective response or subjective improvement. It is concluded that the test as currently assayed and employed, alone is not sufficient to allow for accurate evaluation of the response to therapy in patients with advanced disease, such as those in the currently conducted National Prostatic Cancer Project clinical chemotherapy trials. 666 Elm Street Buffalo, New York 14203 (DR. MURPHY)
125
References 1. MORGAN, B.: Predictive value of acid phosphatase, Br. J. Cancer 30: 190 (1974). Enzymes in the diagnosis of prostatic 2. A~~ADOR,E.: disease, Postgrad. Med. 47: 51 (1970). Clinical significance of the human acid 3. YAM, L. T.: phosphatase. A review, Am. J. Med. 56: 604 (1974). 4. CHU, T. M., et al. : Tumor antigen and acid phosphatase isoenzymes in prostatic cancer, Cancer Chemother. Rep. 59: 97 (1975). 5. GOMORI, G.: The distribution of phosphatase in normal organs and tissues, J, Cell. Physiol. 17: 71 (1941). 6. WALKER, B. S., LEMON, H. M., DAVISON, M. D., and SCHWARTZ, M. K.: Acidphosphatases. A review, Am. J. Clin. Pathol. 24: 807 (1954). 7. MARBERGER, H., RIEDESEL, R. D., ANDERSON,D. O., and MALEK, L. H.: A comparative study of phosphatase activities of various human tissue, J. Urol. 75: 857 (1956).
126
8. LAM, K. W., LI, O., LI, C. Y., and YAM, L. T.: Biochemical properties of human prostatic acid phosphatases, Clin. Chem. 19: 483 (1973). 9. SCOTT, W. W., et al. : Comparison of 5-fluorouracil (NSC-19893)and cyclophosphamide (NSC-26271) in patients with advanced carcinoma of the prostate, Cancer Chemother. Rep. 59: 195 (1975). 10. SCOTT, W. W., et al. : Chemotherapy of advanced prostatic carcinoma with cyclophosphamide or 5-fluorouracil: results offirst national randomized study, J. Ural. 114: 909 (1975). 11. ISHIBE, T., USUI, T., and NIHERA, H.: Prognostic usefulness of serum acid phosphatase levels in carcinoma of the prostate, ibid. 112:237 (1974). 12. ISHIBE, T.: Serum acid phosphatase level and prognosis of patients with prostatic carcinoma, Jap. J. Urol. 65: 102 (1974). 13. WOODWARD,H. G. : The clinical significance of serum acid phosphatase, Am. J. Med. 27: 902 (1959).
UROLOGY
/ AUGUST 1976 I VOLUME VIII. NUMBER 2
SIGNIFICANCE
PHOSPHATASE
OF SERUM ACID
LEVELS IN ADVANCED
PROSTATIC CARCINOMA* DOUGLAS WILLIAM ROBERT
THE
E. JOHNSON, W.
SCOTT,
P. GIBBONS,
NATIONAL
M.D.+ M.D.
$
M.D.9
PROSTATIC
GEORGE JOSEPH GERALD
CANCER
R. PROUT,
M.D.
D. SCHMIDT,
M.D.?
P. MURPHY,
PROJECT+
1)
M.D.,
D.Sc.**
t
ABSTRACT - This cooperative study was sponsored by the National Prostatic Cancer Project to determine the usefulness of serum acid phosphatase levels as a predictive indicator with regard to perj&-mance status, sites of metastases, response to treatment, and survival in patients with advanced prostatic carcinoma. The results indicate that survival was signijcantly shwter for those patients who had elevation of their on-study (pretreatment) total serum acid phosphatase levels. In addition, a positive correlation was observed between 50 per cent reduction of primary tumor mass, relief of pain, and acid phosphatase activity. No correlation could be demonstrated between serum acid phosphatase and performance status, site of metastases, and other criteria of response to therapy. It is concluded that this test as currently determined spectrophotometrically at this stage of disease and if employed alone is not sufficient to allow fm total evaluation of the response of therapy. It is, however, helpful when used in correlation with the previously mentioned positive factors.
Assays of serum acid phosphatase activity have become a routine and standard examination for the diagnosis and monitoring of patients with prostatic carcinoma. However, its value in these situations has become increasingly controversial,‘s2 since the test generally may lack tissue specificity or may detect a heterogeneous group of many isoenzymes3>4 present in a variety of tissues.‘+ We have, therefore, reviewed our experience utilizing serum acid phosphatase levels as a predictive indicator with regard to performance status, sites of metastases, response to
treatment, and survival in a group of patients with advanced Stage D prostatic carcinoma.
*Supported in part by Public Health Service Grants CA15407, CA-15421, CA-15107, CA-15284, CA-15108, CA15126,and CA-14716from the National Cancer Institutes, National Institutes of Health, Department of Health, Education, and Welfare. t M. D. Anderson Hospital and Tumor Institute, Houston, Texas. $Johns Hopkins Hospital, Baltimore, Maryland.
$Virginia Mason Medical Center, Seattle, Washington. I/Massachusetts General Hospital, Boston. lfuniversity of Iowa Hospitals and Clinics, Iowa City, Iowa. **Roswell Park Memorial Institute, Buffalo, New York. f f Coauthors in this study are T. Ming Chu, Ph. D., John F. Gaeta, M.D., James Joiner, Ph.D., and Jack Saroff, Ph. D., Roswell Park Memorial Institute, Buffalo, New York.
UROLOGY
/ AUGUST 1976 / VOLUME
VIII,
NUMBER 2
Material
and Methods
One hundred twenty-five patients with a histologic diagnosis of prostatic carcinoma who had metastases (Stage D) and had relapsed following orchiectomy and hormonal therapy were entered into the cooperative study to determine the efficacy of single chemotherapeutic agents in the treatment of advanced prostatic carcinoma. g~lo
123
Diagnostic evaluation performed within ten days prior to initiation of therapy included a complete blood count, urinalysis, serum creatinine, urea nitrogen, serum bilirubin, chest x-ray film, skeletal survey, and excretory urogram. Assays of total serum acid phosphatase levels were performed on each patient on entry into the study at the patient’s cooperating institution (Johns Hopkins Hospital, The Mason Clinic, M. D. Anderson Hospital and Tumor Institute, University of Iowa Hospitals and Clinics, and Massachusetts General Hospital), as well as on serum collected and mailed to Roswell Park Memorial Institute for duplicate assays. Performance status was assessed on the day of initiation of treatment based on the Eastern Cooperative Oncology Group performance status scale: [(0) full activity; (1) ambulatory, capable of light work; (2) in bed less than 50 per cent of the time; (3) in bed more than 50 per cent of the time; and (4) completely bedridden]. Clinical data collected at periodic intervals (at least once every six weeks) were forwarded to the central office of the National Prostatic Cancer Project to avoid bias in review.
Km r,-.\
*\ - *.‘.\*.\
‘;; 2
’ .. ‘.
-.. ‘\
80-
. .
\
i2 5 5
\
\
\
\
Normal
**.. ....
Abnormal
*.
!S
P
‘\-_
. *.
-.
*.
40-
*a.*
\ \ \
\
*.
\ \ \L---M
*. *. -. ‘.
20-
0
I 8
I
I. 24
SAP
_\
F E 8
SAP
\ ‘\._
60-
m g
\
----
1. 40
I.
*. *. . . . . . . . . . .
1.
56
I,
72
63
WEEKS FIGURE 1. Survival of Protocol 100 patients by normal and abnormal serum acid phosphatase.
Results Although the methods for assay of serum acid phosphatase differed among the five participating institutions, assays of duplicate specimens at Roswell Park Memorial Insitute revealed a high degree of correlation between magnitude of values obtained by individual institutions and Roswell Park Memorial Institute (Table I). Of the 125 patients, serum acid phosphatase activity was elevated in 92 patients (74 per cent) prior to initiation of chemotherapy and was within the normal range in 33 patients (26 per cent). Elevated pretreatment serum acid phosphatase activities had a statistically significant (p cO.05) adverse effect on survival (Fig. 1). Analysis of the
Correlation of serum acid phosphatase values between participating institutions and RPM1 *
TABLE I.
Institution
No. of
Samples
Correlation Coefficient
M. D. Anderson University of Iowa Mason Clinic Massachusetts General Johns Hopkins
451 264 216 99 237
0.90 0.96 0.84 0.82 0.87
*RPMI: Roswell Park Memorial Institute.
124
on-study performance status compared with serum acid phosphatase activities is given in Table II. When patients were studied according to performance status 0 and 1, 2 and 3, and 4, the elevated acid phosphatase activities in these three categories were 72, 75, and 78 per cent, respectively. These results were not statistically significant (p >0.05), indicating a homogeneity between the serum acid phosphatase levels when compared with performance status. The site of metastases at the time the patients entered the study may be seen in Table III. The data suggested that elevated serum acid phosphatase occurred more often in patients with
On-study performance status compared with serum acid phosphatase
TABLE II.
-Performance 0, 1 Normal serum acid 20 (28)* phosphatase Elevated serum acid phosphatase 5372) 73 (100) TOTAL
Status Scale4 2, 3 11 (25)
3275) 43 (100)
2 (22)
1178) 9 (loo)
*Number of patients and (per cent) of patients in each category.
UROLOGY /
AUGUST 1976 I VOLUME VIII, NUMBER 2
TABLE III.
Sites of metastases with respect to on-study serum acid phosphatase (SAP) levels Per Cent with No. with Metastasis Elevated SAP
No. of Evaluable Patients
Site of Metastasis Bone Bone and lung Bone and pleura Bone and liver Bone and lymph node
123 115 108 102
121 14 6 19
74 86 83 84
94
19
84
metastases to lung, pleura, liver, and lymph nodes, in addition to bone. For all treatments, there were positive correlations between the serum acid phosphatase activities and reduction of tumor mass, as well as the relief of pain (Tables IV and V). The pretreatment, as well as subsequent serum acid phosphatase activities did not correlate with other specific objective and subjective response signs. However, a greater percentage of serum acid phosphatase values subsequently fell within normal range in patients undergoing chemotherapy (24 per cent) compared with standard therapies (11 per cent). Comment Failure of the serum acid phosphatase levels to be elevated in 26 per cent of our patients with prostatic carcinoma who had evidence of progressing metastatic disease was not unexpected, since others have reported similar findings.“,12 The reason for normal levels, however, in this situation remains unclear. It has been suggested that normal acid phosphatase levels might be due to (1) tumor cells which were poorly differentiated secreted little acid phosphatase activity, (2) acid phosphatase which was present in the serum but inactivated prior to assay, (3) small quantities of
TABLE IV.
Tumor Mass Reduction+ No reduction
Comparison of serum acid phosphatase and tumor mass* -Acid PhosphatasDecrease to No Normal Change 7
10
2
TOTALS
19
65 72
*Significant correlation (p < 0.05). tReduction of primary mass greater than 50 per cent.
UROLOGY /
AUGUST 1976 /
VOLUME VIII, NUMBER 2
“prostatic” enzyme which was present but not detected by ordinary spectrophotometric methods employed, and (4) that the prostatic gland contains a “barrier” which may prevent release of acid phosphatase into the circulation.3,13 It is doubtful that the first and last postulate occurred although the biology and biosynthesis of acid phosphatase in prostatic cancer cells is not completely known at present. Inactivation prior to assay was likewise unlikely, since there was a good correlation between the different assays performed on duplicate samples which were collected and handled in entirely different ways. Although small quantities of prostatic acid phosphatase may not have been detected in the serum by calorimetric methods, the question remains unanswered as to why in patients with advanced disease there is such variation in the levels of acid phosphatase.
TABLE V.
Relief from Pain
Comparison of serum acid phosphatase and relief of pain* -Acid PhosphataseDecrease to No Normal Change
Yes No TOTALS
14
26
19
46 72
5
*Significant correlation (p < 0.05).
Although Ishibe, Usui, and Nihera’l,12 recently reported that pretreatment serum acid phosphatase levels are insignificant in regard to fiveyear survival rates, we were able to show, in this national study, a statistically significant adverse effect for elevation of serum acid phosphatase levels on survival. Return of the on-study serum acid phosphatase level to normal range during therapy correlated well with reduction of tumor mass and relief of pain, but it did not correlate with other criteria for objective response or subjective improvement. It is concluded that the test as currently assayed and employed, alone is not sufficient to allow for accurate evaluation of the response to therapy in patients with advanced disease, such as those in the currently conducted National Prostatic Cancer Project clinical chemotherapy trials. 666 Elm Street Buffalo, New York 14203 (DR. MURPHY)
125
References 1. MORGAN, B.: Predictive value of acid phosphatase, Br. J. Cancer 30: 190 (1974). Enzymes in the diagnosis of prostatic 2. A~~ADOR,E.: disease, Postgrad. Med. 47: 51 (1970). Clinical significance of the human acid 3. YAM, L. T.: phosphatase. A review, Am. J. Med. 56: 604 (1974). 4. CHU, T. M., et al. : Tumor antigen and acid phosphatase isoenzymes in prostatic cancer, Cancer Chemother. Rep. 59: 97 (1975). 5. GOMORI, G.: The distribution of phosphatase in normal organs and tissues, J, Cell. Physiol. 17: 71 (1941). 6. WALKER, B. S., LEMON, H. M., DAVISON, M. D., and SCHWARTZ, M. K.: Acidphosphatases. A review, Am. J. Clin. Pathol. 24: 807 (1954). 7. MARBERGER, H., RIEDESEL, R. D., ANDERSON,D. O., and MALEK, L. H.: A comparative study of phosphatase activities of various human tissue, J. Urol. 75: 857 (1956).
126
8. LAM, K. W., LI, O., LI, C. Y., and YAM, L. T.: Biochemical properties of human prostatic acid phosphatases, Clin. Chem. 19: 483 (1973). 9. SCOTT, W. W., et al. : Comparison of 5-fluorouracil (NSC-19893)and cyclophosphamide (NSC-26271) in patients with advanced carcinoma of the prostate, Cancer Chemother. Rep. 59: 195 (1975). 10. SCOTT, W. W., et al. : Chemotherapy of advanced prostatic carcinoma with cyclophosphamide or 5-fluorouracil: results offirst national randomized study, J. Ural. 114: 909 (1975). 11. ISHIBE, T., USUI, T., and NIHERA, H.: Prognostic usefulness of serum acid phosphatase levels in carcinoma of the prostate, ibid. 112:237 (1974). 12. ISHIBE, T.: Serum acid phosphatase level and prognosis of patients with prostatic carcinoma, Jap. J. Urol. 65: 102 (1974). 13. WOODWARD,H. G. : The clinical significance of serum acid phosphatase, Am. J. Med. 27: 902 (1959).
UROLOGY
/ AUGUST 1976 I VOLUME VIII. NUMBER 2
