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Systemic Treatment of Advanced Prostatic Cancer: Development of a New System for Defining Response
0022-534 7/81/1252-0224$02.00/0
THE
Vol. 125, February Printed in U.S.A.
JOURNAL OF UROLOGY
Copyright© 1981 by The Williams & Wilkins Co.
SYSTEMIC TREATMENT OF ADVANCED PROSTATIC CANCER: DEVELOPMENT OF A NEW SYSTEM FOR DEFINING RESPONSE D. L. CITRIN,* A. I. COHEN, J. HARBERG, S. SCHLISE, C. HOUGEN
AND
R. BENSONt
From the Departments of Human Oncology, Medicine and Surgery, University of Wisconsin and Wisconsin Clinical Cancer Center, Madison, Wisconsin
ABSTRACT
The low incidence of measurable or evaluable metastases in patients with prostatic cancer makes evaluation of response difficult. This is particularly true in patients with bone metastases only. With a digital model it is possible to measure quantitatively from the radioisotope bone scan the total area of skeletal involvement by metastatic tumor. Definitions of response in bone have been derived from this model. These response criteria have been compared to response in acid phosphatase determinations and clinical status in a study of 44 patients with advanced prostatic cancer treated with estramustine phosphate. Based on serial quantitative bone scans, serial measurements of acid phosphatase levels and repeat clinical evaluations a system is proposed for defining response to systemic therapy that is applicable to the majority of patients with metastatic prostatic cancer. The majority of patients with metastatic prostatic cancer treated with systemic therapy do not have clinically measurable or evaluable disease by conventional criteria. 1' 2 Distant metastases often occur with good control of local disease. Cutaneous or subcutaneous tumor nodules and superficial lymphadenopathy accessible to clinical examination are uncommon, and lung or other visceral involvement also is seen infrequently. Most commonly (in approximately 85 per cent of all cases) the skeleton is the only clinically obvious area of metastatic involvement. 3 However, directly measurable osteolytic metastases are rare since most lesions in this disease are osteoblastic or mixed lytic/blastic. Consequently, evaluation of response or progression using conventional radiography is difficult. In routine clinical practice this difficulty may not be a major problem-it has been suggested that the clinical performance of the patient (in terms of level of activity and bone pain) may be all that is required for month-to-month assessment, and that length of survival is the ultimate indicator of effectiveness of therapy. 4 However, in the case of phase 2 or 3 studies of chemotherapy in patients with prostatic cancer the inability to define response is a critical deficiency for several reasons. First, and most simply, to identify active drugs it is necessary to be able to identify unequivocal response to therapy (significant decrease in tumor size). 2 Second, to enable studies to be completed successfully a sufficient number of patients must be eligible for and entered into study. Presently, the majority of patients with metastatic prostatic cancer are not eligible for phases 2 and 3 studies owing to the lack of measurable or evaluable disease. This has led to several attempts at defining response based on a combination of objective and subjective factors. 1• 2 • 5- 9 Although these studies do have some validity they have, in general, not provided clear response data. For example, the National Prostatic Cancer Project has reported "objective response rates" of 29 to 37 per cent in 3 recent phases 2 and 3 studies. However, the percentage of patients achieving an objective partial response in these studies was only 2 to 6 per cent, the remaining "responders" demonstrating stable disease only.IO, II Another final and perhaps most important disadvantage of current phases 2 and 3 studies in prostatic cancer with their Accepted for publication May 9, 1980. Supported by grant P30-CA-14520. * Current address: Hematology/Oncology Section (lllE), Veterans Administration Hospital, San Diego, California 92161. t Current address: Department of Urology, Mayo Clinic, Rochester, Minnesota 55901. 224
reliance on patients with only objectively measurable soft tissue and visceral disease, is the fact that those patients who do have measurable disease and are entered into study may not be typical of the general prostatic cancer population. 2 • 12 It has been suggested that patients with non-osseous metastases may have poorer prognosis than those with bone dominant disease, and the information derived from studies of such patients may not be generally applicable.2 For all of these reasons a method of defining and assessing response in the majority of patients with prostatic cancer (that is those with bone dominant disease) is desirable. Radioisotope bone scans are strongly positive in cases of bone involvement by prostatic cancer, irrespective of whether the lesions are radiologically lytic, mixed or pure blastic. 13 The scan is accurate and specific enough for use in the detection and assessment of bone metastases, and can be repeated at regular intervals to provide serial data. 14 We have described recently a digital model that permits accurate measurement of the total area of metastatic involvement in any radioisotope bone scan. 15 This technique allows serial quantitative measurement of the area of bone metastases in repeated studies during the course of treatment. 15 From these quantitative measurements it has been possible to define criteria of response similar to those used currently by cooperative groups for assessment of soft tissue and visceral disease. Our criteria of response for bone metastases have been validated and shown to be of clinical significance in a study of breast cancer patients with bone metastases and measurable or evaluable non-osseous metastatic disease. 15 Others have shown that measurement of serum acid phosphatase levels is a useful indicator of disease activity in prostatic cancer. 1• 16 Additionally, several careful studies have outlined clinical factors that are of definite prognostic significance. These factors include performance status, appetite, maintenance or loss of body weight, and presence or absence of visceral metastases. 16' 17 We herein describe a retrospective study of patients with bone dominant metastatic prostatic cancer treated with estramustine phosphate. The purpose of this study was to document the response of the patient to treatment as measured by quantitative bone scanning. Response in bone then was compared to response in serum acid phosphatase determinations, and both parameters then were compared to changes in clinical status and ultllllate survival. The major goal of the study was not to determine the response rate to estramustine but rather to confirm the accuracy of the bone scan model in prostatic cancer,
225
SYSTEMIC TREATMENT OF ADVANCED PROSTATIC CANCER
and to attempt to derive a widely applicable set of response criteria for patients with prostatic cancer who do not have measurable or evaluable non-osseous disease. MATERIALS AND METHODS
The clinical records and bone scans of 44 patients were reviewed. All of the patients had histologically proved adenocarcinoma of the prostate gland with metastases documented on a radioisotope bone scan without clinical or laboratory evidence of soft tissue or visceral metastases. All of the patients received estramustine, an investigational drug currently undergoing phases 2 and 3 studies in ::,ur Clinical Science Center. Estramustine was administered as primary therapy to 7 patients and as secondary therapy to 37 who had failed primary hormonal treatment, generally bilateral orchiectomy and/or estrogens. All patients had a 99mtechnetium pyrophosphate or diphosphonate bone scan, using the standard technique described previously, 18 and at least 1 measurement of serum acid phosphatase before entry into the study. Acid phosphatase was measured with the standard indirect substrate method currently used in our clinical laboratory. 19 Serial measurements of acid phosphatase levels generally were obtained every 3 months and repeat bone scans were obtained at approximately 6-month intervals. All patients included in this review had at least 2 bone scans and at least 2 measurements of serum acid phosphatase levels. Clinical 'review of the patients' records was undertaken without knowledge of the results of the bone scans and acid phosphatase measurements. The clinical status of the patients was assessed and recorded at approximately 3-month intervals. Clinical status. Assessment of clinical status was based on factors that have been shown previously to be of prognostic significance, namely performance status, level of bone pain, body weight and hemoglobin level. The scoring system used by the Eastern Cooperative Oncology Group was used to record performance status and level of bone pain. Determination of the bone scan response, acid phosphatase response and clinical status was made on 1 occasion only, at the time of the first bone scan evaluation during treatment (within 3 to 8 months of beginning therapy). In responding patients the duration of response was calculated from the time response was first recognized until a subsequent corresponding study showed evidence of relapse. Survival was calculated from the first evaluation until death. Clinical status. Clinical improvement was defined as a decrease of 1 in performance status or in bone pain, or an increase of >5 per cent in body weight or of >2 gm. per cent in hemoglobin level maintained for at least 12 weeks, all other clinical parameters remaining unchanged. Clinical deterioration was defined as an increase of 1 in performance status or in bone pain, or a decrease of >5 per cent in body weight or of >2 gm. per cent in hemoglobin level, maintained for at least 12 weeks. Clinical stability was defined as no increase or decrease in performance status, bone pain, body weight or hemoglobin level during a minimum study interval of 12 weeks. An additional clinical category was recognized, namely the entirely asymptomatic patient whose only evidence of disease was an abnormal bone scan (with or without elevated acid phosphatase levels) and who remained asymptomatic throughout the period of study. Response criteria. The total area of metastatic involvement was measured and recorded from the bone scan image with a digital model described previously. 15 The model displays anterior and posterior views of the skeleton, each with a 1,000 square matrix. All abnormal areas noted on visual inspections of the scan are recorded on the model and the total area of bone involved by metastatic tumor (A) is then calculated from A = a/2,000 per cent, where a is the sum of involved matrices. The response in bone then was determined from comparison of
the serial bone scans using the following criteria: response-a ~50 per cent decrease in the area of skeletal involvement when compared to initial (pre-treatment) study, no change-a <50 per cent decrease or a <25 per cent increase in the area of skeletal involvement when compared to initial (pre-treatment) study and progression-a ~25 per cent increase in the area of skeletal involvement when compared to initial (pre-treatment) study. The results of serial measurement of serum acid phosphatase levels were assessed independently of the clinical status and bone scan results, using the following criteria of response: response-a ;;;;50 per cent decrease when compared to abnormal pre-treatment level or a return to normal range from abnormal pre-treatment level maintained for at least 3 months, normalan acid phosphatase level persistently within the normal range, no change-an initially abnormal level with a <50 per cent decrease, <25 per cent increase or a failure to return to normal range, maintained for at least 3 months and progression-a ;;;;25 per cent increase when compared to abnormal pre-treatment level or an increase in a normal pre-treatment level to the abnormal range, maintained at least 3 months. The clinical status and results of bone scans and acid phosphatase levels then were compared and correlated to duration of therapy and total survival. RESULTS
We studied 44 patients ranging in age from 40 to 70 years, with a median age of 64 years. Median duration of treatment with estramustine was 10 months, with a range of 3 to 36 months. Of the 44 patients 5 were asymptomatic at the time of entry into the study. All 44 patients had positive bone scans and 30 had elevated acid phosphatase levels. No patient had measurable or evaluable non-osseous metastatic disease. A diffusely enlarged prostate gland or a prostate nodule was not considered evaluable for the purposes of this study. A total of 18 patients remain alive at the time of analysis, with an over-all median duration of survival of 15 months (range 1 to 31 months) TABLE
1. Comparison of clinical status to response as determined
by bone scan and acid phosphatase levels Clinical Status
Response No. Pts.
No Change No. Pts.
Normal No. Pts.
Progression No. Pts.
Total No. Pts.
Bone scan Improved Persistently asymptomatic Stable Deteriorated Totals Median survival (mos.)
6 2
5 2
0 1
11 5
2 0 10 >30
3 8
5 23 44
11
0 15 16 11
18
Acid phosphatase Improved Persistently asymptomatic Stable Deteriorated Totals Median survival (mos.)
TABLE
6
4 2
1 0
0 2
11 5
2 1 10 >30
2 4 12 >14
0 4 5 7
1 14 17
5 23 44
10
2. Comparison of response in patients determined by bone
scan and acid phosphatase Bone Scan Response No. Pts. Acid phosphatase: Response Normal No change Progression Totals
6
3 1 0 10
No Change No. Pts.
Progression No. Pts.
Total No. Pts.
3 7 2 6 18
1 2 2 11 16
10 12 5 17 44
226
CITRIN AND ASSOCIATES
from the time of the second scan (median 17, range 5 to 39 months from the start of therapy). Total followup for the group was 866 patient months. A total of 135 bone scans was obtained (median 3, range 2 to 8 scans per patient). Analysis of the clinical status during treatment revealed improvement in 11 (25 per cent), while 5 patients (11 per cent) were persistently asymptomatic, 5 (11 per cent) were stable and 23 (52 per cent) deteriorated. With the bone scan response criteria 10 patients had response, 18 had no change and 16 had progression (table 1). Corresponding figures for acid phosphatase were 10 with response, 12 persistently normal, 5 with no change and 17 with progression (table 1). A total of 14 patients showed evidence of response by 1 or both parameters, with a minimum median duration of response of 19 months (range 7 to 36 months). The median survival of responding patients was >30 months, compared to 10 months for patients with progression (p <0.001). There generally was a close accord between the responses noted in the bone scan and acid phosphatase levels (table 2), and there was good correlation between these parameters and the over-all clinical status. Of 10 patients whose scan showed response 9 had either response or normal acid phosphatase levels and none showed clinical deterioration. Of the 10 patients with a responding acid phosphatase level 9 had either response or no change on bone scan, while only 1 had progression (this single patient had clinical deterioration), 6 were improved, 2 were stable and 1 was persistently asymptomatic (table 3). Sixteen patients had progression on bone scan; 11 of these 16 patients had progression confirmed by acid phosphatase, 2 had no change, 2 were normal and 1 had response. Fifteen of 16 patients showed clinical deterioration. In the 17 patients with progression by acid phosphatase 11 showed progression on the scan while 6 showed no change. Clinically, 14 of 17 had deterioration (table 4). When the bone scan or acid phosphatase determination did not show unequivocal response or progression, analysis of the alternate study parameters and clinical status frequently was helpful (table 5). Of 44 patients 18 (41 per cent) had no change on a bone scan. In these patients a responding or normal acid phosphatase level frequently was associated with clinical improvement or stable and improved survival. Additionally, when the acid phosphatase level showed no change or persistently normal patients (17 of 44), response or progression on the bone scan correlated well with clinical status and was predictive of survival. The clinical status of the patients, when considered indeTABLE
pendently of bone scan and acid phosphatase, also was of definite prognostic significance. Median survival of different clinical groups was >30 months in improved patients, 19 months in persistently asymptomatic patients, 13 months in stable patients and 9 months in patients who deteriorated. In the 9 patients in whom neither the scan nor acid phosphatase levels showed any significant change, change in clinical status was the only evaluable significant parameter. A re-analysis of the bone scan data based on more liberal criteria of response (defining response as a ~25 per cent decrease in area of skeletal involvement) showed that if these criteria were accepted an additional 5 of 18 patients originally classified as showing no change would be considered responders. However, the median survival of these 5 patients (11 months) was not statistically different from that of the 13 patients whose bone scan status remained no change even with these less rigid criteria (12 months) (p >0.5). Furthermore, the clinical status and acid phosphatase responses generally were not favorable (table 6). DISCUSSION
The results reported herein are from a retrospective analysis of a relatively small number of patients and, therefore, must be interpreted with caution. However, several conclusions may be drawn from the study: 1) response and progressive disease determined from repeated bone scans do correlate with the clinical status of the patient and are of definite prognostic significance, 2) similar conclusions may be drawn regarding serial measurements of serum acid phosphatase, 3) there generally is a close accord between the results of the bone scan and acid phosphatase determinations in responding and progressing patients and 4) when either the bone scan or acid phosphatase shows no change analysis of the other factor and of clinical status is useful (table 6). The bone scan and acid phosphatase determinations, although complementary, show certain qualitative differences. The bone scan is more sensitive over-all at detecting the presence of metastatic disease in the skeleton; in our study all patients had a positive bone scan, whereas 14 (32 per cent) had a normal acid phosphatase level at entry into the study. In these 14 patients the acid phosphatase level became abnormal in 2 (progression) but remained persistently within normal limits in 12. These figures are in accord with other studies in which approximately 25 per cent of patients with metastatic prostatic cancer had a persistently normal acid phosphatase level. 19
3. Correlation of bone scan, acid phosphatase and clinical
TABLE
,:§,tatus in responding patients
Clinical Status
Acid Phosphatase Results in Bone Scan Responders (10 pts.) Response
Improved Persistently asymptomatic Stable Deteriorated Totals
No Change
Response
0
1 0
5 0
2
status in patients with progressive disease
Bone Scan Results in Acid Phosphatase Responders (10 pts.)
Normal
5 0
4. C?rrelation of bone scan, acid phosphatase and clinical Bone Scan Results in 17 Pts. With Progression on Acid Phosphatase
No ProgresChange sion
No ProgresChange sion
Clinical Status
No Progression Change 1 1
Acid Phosphatase Results in 16 Pts. With Progression on Bone Scan
0 0
Response
Norma!
0
0
0
0
!
0 ~
1
2
0 ~ 2
Persistently asymptomatic Stable Deteriorated Totals
1 0 10 11
1
1
0
1
1
0
Q
Q
Q
Q
Q
!
6
3
1
6
3
1
TABLE
5. Correlation of bone scan, .acid phosphatase and clinical status in patients with no change Acid Phosphatase Results in 18 Pts. With No Change on Bone Scan
Clinical Status Response Improved Persistently asymptomatic Stable Deteriorated Totals Median survival (mos.)
1 1 1
_Q_ 3
>19
Normal
No Change
Progression
4 0 1 ~ 7 13
0 0 0 ~
0 1 1 4
2
6
11
8
1
1
0
i
10
6
11
Bone Scan Results in 17 Pts. With Normal or Unchanged Acid Phosphatase Levels Response 1 2 1
_Q_ 4 >28
Normal
Progression
4 0 1 4 9 9
0 0 0 4 4 4
SYSTEMIC TREATMENT OF ADVANCED PROSTATIC CANCER TABLE 6.
Details of patients with e;;,25 but <50 per cent decrease in area of bone involvement
Clinical Status Deterioration Stable Improved
'i
I:
Acid Phosphatase
Survival (mos.)
No change Progression Progression Response Normal
7 6
10 16 11
In such cases analysis of the alternative index of metastatic disease, the bone scan, provides the only objective criterion of response to therapy. Although the scan is more sensitive in detecting the presence of metastases it is relatively insensitive in detecting change in these metastases. Significant changes in the acid phosphatase level tend to occur more rapidly than in the bone scan. In 18 patients (41 per cent) serial scans showed no change. In 9 of these 18 patients the acid phosphatase levels showed significant change (either response or progression), which was of prognostic significance. It appears that in patients in whom the bone scan shows no significant change consideration of the acid phosphatase level may be helpful. Although clearly more sensitive than conventional radiography the bone scan only shows relatively major changes in bone involvement by metastatic tumor. One way of increasing the sensitivity of the scan would be simply to rewrite the definitions of response in a more liberal way (~25 per cent decrease in area of involvement as a response). However, we have resisted this temptation. Although the total number of responses is increased these responses apparently are of no clinical significance. We observed a similar effect in our previous study of breast cancer patients and recommend a ~50 per cent decrease as the criterion of response. Clearly, rigid criteria are required for critical identification of antitumor activity. Although not to be considered as an objective response criterion the over-all status of the patient, based on the clinical factors described previously, clearly is of importance in terms of predicting survival, and remains the only clinically useful method of evaluating those patients in whom a bone scan and acid phosphatase levels show no significant change. Because of the unique difficulties with prostatic cancer, most importantly the relative indolence of the disease and the length of time necessary for significant changes in bone metastases to be demonstrable by current techniques, monthly assessment of response is not practicable and we agree with the view that an adequate trial of any single therapy should be considered to be at least 3 months (and possibly even 6). 2 It is of considerable interest that significant response could be identified on the basiH of a single evaluation of bone scan, acid phosphatase and clinical status approximately 3 to 8 months after initiation of estramustine therapy. More clinical information may well be forthcoming from a prospective evaluation of a larger number of patients using these parameters. If this is, indeed, the case then the general acceptance of these response criteria would lead to the eligibility of the majority of patients for phases 2 and 3 studies. We expect that with these criteria approximately 80 per cent of all patients with metastatic prostatic cancer would have objectively evaluable disease, compared to only 20 per cent of patients using current criteria. Additionally, in patients with measurable non-osseous disease a comparison of response in these areas with response in bone scan and acid phosphatase levels using our criteria also would be of considerable interest. A. Jones and R. Hoeft provided technical help.
227
REFERENCES
1. Schmidt, J. D., Gibbons, R. P., Johnson, D. E., Prout, G. R., Scott, W.W., Murphy, G. P. and the National Prostatic Cancer Project: Chemotherapy of advanced prostatic cancer. Evaluation of response parameters. Urology, 7: 602, 1976. 2. Yagoda, A., Watson, R. C., Natale, R. B., Barzell, W., Sogani, P., Grabstald, H. and Whitmore, W. F.: A critical analysis ofresponse criteria in patients with prostatic cancer treated with cis-diamminedichloride platinum II. Cancer, 44: 1553, 1979. 3. Hovsepian, J. A., Byar, D. P. and the Veterans Administration Cooperative Urological Research Group: Carcinoma of prostate. Correlation between radiologic quantitation of metastases and patient survival. Urology, 6: 11, 1975. 4. Hurst, K. S., Byar, D. P. and the Veterans Administration Cooperative Urological Research Group: An analysis of the effects of changes from the assigned treatment in a clinical trial of treatment for prostatic cancer. J. Chron. Dis., 26: 311, 1973. 5. Eagan, R. T., Hahn, R. G. and Myers, R. P.: Adriamycin (NSC123127) versus 5-fluorouracil (NSC-19893) and cyclophosphamide (NSC-26271) in the treatment of metastatic prostate cancer. Cancer Treat. Rep., 60: 115, 1976. 6. Buell, G. V., Saiers, J. H., Saiki, J. H. and Bergreen, P. W.: Chemotherapy trial with comp-F regimen in advanced adenocarcinoma of prostate. Urology, 11: 247, 1978. 7. Merrin, C.: Treatment of advanced carcinoma of the prostate (stage D) with infusion of cis-diamminedichloroplatinum (II NSC 119875): a pilot study. J. Urol., 119: 522, 1978. 8. Merrin, C., Etra, W., Wajsman, Z., Baumgartner, G. and Murphy, G.: Chemotherapy of advanced carcinoma of the prostate with 5fluorouracil, cyclophosphamide and adriamycin. J. Urol., 115: 86, 1976. 9. Kane, R. D., Stocks, L. H. and Paulson, D. F.: Multiple drug chemotherapy regimen for patients with hormonally-unresponsive carcinoma of the prostate: a preliminary report. J. Urol., 117: 467, 1977. 10. Johnson, D. E., Scott, W.W., Gibbons, R. P., Prout, G. R., Schmidt, J. D., Chu, T. M., Gaeta, J., Saroff, J. and Murphy, G. P.: National randomized study of chemotherapeutic agents in advanced prostatic carcinoma: a progress report. Cancer Treat. Rep., 61: 317, 1977. 11. Scott, W.W., Gibbons, R. P., Johnson, D. E., Prout, G. R., Schmidt, J. D., Saroff, J. and Murphy, G. P.: Th continued evaluation of the effects of chemotherapy in patients with advanced carcinoma of the prostate. J. Urol., 116: 211, 1976. 12. DeWys, W. D., Bauer, M., Colsky, J., Cooper, R. A., Creech, R. and Carbone, P. P.: Comparative trial of adriamycin and 5-fluorouracil in advanced prostatic cancer-progress report. Cancer Treat. Rep., 61: 325, 1977. 13. Citrin, D. L. and McKillop, J. H.: Bone tumours. In: Atlas of Technetium Bone Scans. Edited by D. L. Citrin. Philadelphia: W. B. Saunders Co., pp. 67-123, 1977. 14. Alexander, J. L., Gillespie, P. J. and Edelstyn, G. A.: Serial bone scanning using technetium 99m diphosphonate in patients undergoing cyclical combination chemotherapy for advanced breast cancer. Clin. Nucl. Med., 1: 13, 1976. 15. Citrin, D. L., Hougan, C., Zweibel, W., Schlise, S., Pruitt, B., Ershler, W., Davis, T. E., Harberg, J. and Cohen, A. I.: The use of serial bone scans in assessing response of bone metastases to systemic treatment. Cancer, in press. 16. Byar, D. P., Huse, R., Bailar, J. C., 3rd and the Veterans Administration Cooperative Urological Research Group: An exponential model relating censored data and concomitant information for prostatic cancer patients. J. Natl. Cancer Inst., 52: 321, 1974. 17. DeWys, W. D.: Personal communication. 18. Citrin, D. L., Bessent, R. G., Greig, W.R., McKellar, N. J., Furnival, C. and Blumgart, L. H.: The application of the 99mTc phosphate bone scan to the study of breast cancer. Brit. J. Surg., 62: 201, 1975. 19. Sodeman, T. M. and Batsakis, J. G.: Acid phosphatase. In: Urologic Pathology: The Prostate. Edited by M. Tannenbaum. Philadelphia: Lea & Febiger, chapt. 6, pp. 129-139, 1977.
THE
Vol. 125, February Printed in U.S.A.
JOURNAL OF UROLOGY
Copyright© 1981 by The Williams & Wilkins Co.
SYSTEMIC TREATMENT OF ADVANCED PROSTATIC CANCER: DEVELOPMENT OF A NEW SYSTEM FOR DEFINING RESPONSE D. L. CITRIN,* A. I. COHEN, J. HARBERG, S. SCHLISE, C. HOUGEN
AND
R. BENSONt
From the Departments of Human Oncology, Medicine and Surgery, University of Wisconsin and Wisconsin Clinical Cancer Center, Madison, Wisconsin
ABSTRACT
The low incidence of measurable or evaluable metastases in patients with prostatic cancer makes evaluation of response difficult. This is particularly true in patients with bone metastases only. With a digital model it is possible to measure quantitatively from the radioisotope bone scan the total area of skeletal involvement by metastatic tumor. Definitions of response in bone have been derived from this model. These response criteria have been compared to response in acid phosphatase determinations and clinical status in a study of 44 patients with advanced prostatic cancer treated with estramustine phosphate. Based on serial quantitative bone scans, serial measurements of acid phosphatase levels and repeat clinical evaluations a system is proposed for defining response to systemic therapy that is applicable to the majority of patients with metastatic prostatic cancer. The majority of patients with metastatic prostatic cancer treated with systemic therapy do not have clinically measurable or evaluable disease by conventional criteria. 1' 2 Distant metastases often occur with good control of local disease. Cutaneous or subcutaneous tumor nodules and superficial lymphadenopathy accessible to clinical examination are uncommon, and lung or other visceral involvement also is seen infrequently. Most commonly (in approximately 85 per cent of all cases) the skeleton is the only clinically obvious area of metastatic involvement. 3 However, directly measurable osteolytic metastases are rare since most lesions in this disease are osteoblastic or mixed lytic/blastic. Consequently, evaluation of response or progression using conventional radiography is difficult. In routine clinical practice this difficulty may not be a major problem-it has been suggested that the clinical performance of the patient (in terms of level of activity and bone pain) may be all that is required for month-to-month assessment, and that length of survival is the ultimate indicator of effectiveness of therapy. 4 However, in the case of phase 2 or 3 studies of chemotherapy in patients with prostatic cancer the inability to define response is a critical deficiency for several reasons. First, and most simply, to identify active drugs it is necessary to be able to identify unequivocal response to therapy (significant decrease in tumor size). 2 Second, to enable studies to be completed successfully a sufficient number of patients must be eligible for and entered into study. Presently, the majority of patients with metastatic prostatic cancer are not eligible for phases 2 and 3 studies owing to the lack of measurable or evaluable disease. This has led to several attempts at defining response based on a combination of objective and subjective factors. 1• 2 • 5- 9 Although these studies do have some validity they have, in general, not provided clear response data. For example, the National Prostatic Cancer Project has reported "objective response rates" of 29 to 37 per cent in 3 recent phases 2 and 3 studies. However, the percentage of patients achieving an objective partial response in these studies was only 2 to 6 per cent, the remaining "responders" demonstrating stable disease only.IO, II Another final and perhaps most important disadvantage of current phases 2 and 3 studies in prostatic cancer with their Accepted for publication May 9, 1980. Supported by grant P30-CA-14520. * Current address: Hematology/Oncology Section (lllE), Veterans Administration Hospital, San Diego, California 92161. t Current address: Department of Urology, Mayo Clinic, Rochester, Minnesota 55901. 224
reliance on patients with only objectively measurable soft tissue and visceral disease, is the fact that those patients who do have measurable disease and are entered into study may not be typical of the general prostatic cancer population. 2 • 12 It has been suggested that patients with non-osseous metastases may have poorer prognosis than those with bone dominant disease, and the information derived from studies of such patients may not be generally applicable.2 For all of these reasons a method of defining and assessing response in the majority of patients with prostatic cancer (that is those with bone dominant disease) is desirable. Radioisotope bone scans are strongly positive in cases of bone involvement by prostatic cancer, irrespective of whether the lesions are radiologically lytic, mixed or pure blastic. 13 The scan is accurate and specific enough for use in the detection and assessment of bone metastases, and can be repeated at regular intervals to provide serial data. 14 We have described recently a digital model that permits accurate measurement of the total area of metastatic involvement in any radioisotope bone scan. 15 This technique allows serial quantitative measurement of the area of bone metastases in repeated studies during the course of treatment. 15 From these quantitative measurements it has been possible to define criteria of response similar to those used currently by cooperative groups for assessment of soft tissue and visceral disease. Our criteria of response for bone metastases have been validated and shown to be of clinical significance in a study of breast cancer patients with bone metastases and measurable or evaluable non-osseous metastatic disease. 15 Others have shown that measurement of serum acid phosphatase levels is a useful indicator of disease activity in prostatic cancer. 1• 16 Additionally, several careful studies have outlined clinical factors that are of definite prognostic significance. These factors include performance status, appetite, maintenance or loss of body weight, and presence or absence of visceral metastases. 16' 17 We herein describe a retrospective study of patients with bone dominant metastatic prostatic cancer treated with estramustine phosphate. The purpose of this study was to document the response of the patient to treatment as measured by quantitative bone scanning. Response in bone then was compared to response in serum acid phosphatase determinations, and both parameters then were compared to changes in clinical status and ultllllate survival. The major goal of the study was not to determine the response rate to estramustine but rather to confirm the accuracy of the bone scan model in prostatic cancer,
225
SYSTEMIC TREATMENT OF ADVANCED PROSTATIC CANCER
and to attempt to derive a widely applicable set of response criteria for patients with prostatic cancer who do not have measurable or evaluable non-osseous disease. MATERIALS AND METHODS
The clinical records and bone scans of 44 patients were reviewed. All of the patients had histologically proved adenocarcinoma of the prostate gland with metastases documented on a radioisotope bone scan without clinical or laboratory evidence of soft tissue or visceral metastases. All of the patients received estramustine, an investigational drug currently undergoing phases 2 and 3 studies in ::,ur Clinical Science Center. Estramustine was administered as primary therapy to 7 patients and as secondary therapy to 37 who had failed primary hormonal treatment, generally bilateral orchiectomy and/or estrogens. All patients had a 99mtechnetium pyrophosphate or diphosphonate bone scan, using the standard technique described previously, 18 and at least 1 measurement of serum acid phosphatase before entry into the study. Acid phosphatase was measured with the standard indirect substrate method currently used in our clinical laboratory. 19 Serial measurements of acid phosphatase levels generally were obtained every 3 months and repeat bone scans were obtained at approximately 6-month intervals. All patients included in this review had at least 2 bone scans and at least 2 measurements of serum acid phosphatase levels. Clinical 'review of the patients' records was undertaken without knowledge of the results of the bone scans and acid phosphatase measurements. The clinical status of the patients was assessed and recorded at approximately 3-month intervals. Clinical status. Assessment of clinical status was based on factors that have been shown previously to be of prognostic significance, namely performance status, level of bone pain, body weight and hemoglobin level. The scoring system used by the Eastern Cooperative Oncology Group was used to record performance status and level of bone pain. Determination of the bone scan response, acid phosphatase response and clinical status was made on 1 occasion only, at the time of the first bone scan evaluation during treatment (within 3 to 8 months of beginning therapy). In responding patients the duration of response was calculated from the time response was first recognized until a subsequent corresponding study showed evidence of relapse. Survival was calculated from the first evaluation until death. Clinical status. Clinical improvement was defined as a decrease of 1 in performance status or in bone pain, or an increase of >5 per cent in body weight or of >2 gm. per cent in hemoglobin level maintained for at least 12 weeks, all other clinical parameters remaining unchanged. Clinical deterioration was defined as an increase of 1 in performance status or in bone pain, or a decrease of >5 per cent in body weight or of >2 gm. per cent in hemoglobin level, maintained for at least 12 weeks. Clinical stability was defined as no increase or decrease in performance status, bone pain, body weight or hemoglobin level during a minimum study interval of 12 weeks. An additional clinical category was recognized, namely the entirely asymptomatic patient whose only evidence of disease was an abnormal bone scan (with or without elevated acid phosphatase levels) and who remained asymptomatic throughout the period of study. Response criteria. The total area of metastatic involvement was measured and recorded from the bone scan image with a digital model described previously. 15 The model displays anterior and posterior views of the skeleton, each with a 1,000 square matrix. All abnormal areas noted on visual inspections of the scan are recorded on the model and the total area of bone involved by metastatic tumor (A) is then calculated from A = a/2,000 per cent, where a is the sum of involved matrices. The response in bone then was determined from comparison of
the serial bone scans using the following criteria: response-a ~50 per cent decrease in the area of skeletal involvement when compared to initial (pre-treatment) study, no change-a <50 per cent decrease or a <25 per cent increase in the area of skeletal involvement when compared to initial (pre-treatment) study and progression-a ~25 per cent increase in the area of skeletal involvement when compared to initial (pre-treatment) study. The results of serial measurement of serum acid phosphatase levels were assessed independently of the clinical status and bone scan results, using the following criteria of response: response-a ;;;;50 per cent decrease when compared to abnormal pre-treatment level or a return to normal range from abnormal pre-treatment level maintained for at least 3 months, normalan acid phosphatase level persistently within the normal range, no change-an initially abnormal level with a <50 per cent decrease, <25 per cent increase or a failure to return to normal range, maintained for at least 3 months and progression-a ;;;;25 per cent increase when compared to abnormal pre-treatment level or an increase in a normal pre-treatment level to the abnormal range, maintained at least 3 months. The clinical status and results of bone scans and acid phosphatase levels then were compared and correlated to duration of therapy and total survival. RESULTS
We studied 44 patients ranging in age from 40 to 70 years, with a median age of 64 years. Median duration of treatment with estramustine was 10 months, with a range of 3 to 36 months. Of the 44 patients 5 were asymptomatic at the time of entry into the study. All 44 patients had positive bone scans and 30 had elevated acid phosphatase levels. No patient had measurable or evaluable non-osseous metastatic disease. A diffusely enlarged prostate gland or a prostate nodule was not considered evaluable for the purposes of this study. A total of 18 patients remain alive at the time of analysis, with an over-all median duration of survival of 15 months (range 1 to 31 months) TABLE
1. Comparison of clinical status to response as determined
by bone scan and acid phosphatase levels Clinical Status
Response No. Pts.
No Change No. Pts.
Normal No. Pts.
Progression No. Pts.
Total No. Pts.
Bone scan Improved Persistently asymptomatic Stable Deteriorated Totals Median survival (mos.)
6 2
5 2
0 1
11 5
2 0 10 >30
3 8
5 23 44
11
0 15 16 11
18
Acid phosphatase Improved Persistently asymptomatic Stable Deteriorated Totals Median survival (mos.)
TABLE
6
4 2
1 0
0 2
11 5
2 1 10 >30
2 4 12 >14
0 4 5 7
1 14 17
5 23 44
10
2. Comparison of response in patients determined by bone
scan and acid phosphatase Bone Scan Response No. Pts. Acid phosphatase: Response Normal No change Progression Totals
6
3 1 0 10
No Change No. Pts.
Progression No. Pts.
Total No. Pts.
3 7 2 6 18
1 2 2 11 16
10 12 5 17 44
226
CITRIN AND ASSOCIATES
from the time of the second scan (median 17, range 5 to 39 months from the start of therapy). Total followup for the group was 866 patient months. A total of 135 bone scans was obtained (median 3, range 2 to 8 scans per patient). Analysis of the clinical status during treatment revealed improvement in 11 (25 per cent), while 5 patients (11 per cent) were persistently asymptomatic, 5 (11 per cent) were stable and 23 (52 per cent) deteriorated. With the bone scan response criteria 10 patients had response, 18 had no change and 16 had progression (table 1). Corresponding figures for acid phosphatase were 10 with response, 12 persistently normal, 5 with no change and 17 with progression (table 1). A total of 14 patients showed evidence of response by 1 or both parameters, with a minimum median duration of response of 19 months (range 7 to 36 months). The median survival of responding patients was >30 months, compared to 10 months for patients with progression (p <0.001). There generally was a close accord between the responses noted in the bone scan and acid phosphatase levels (table 2), and there was good correlation between these parameters and the over-all clinical status. Of 10 patients whose scan showed response 9 had either response or normal acid phosphatase levels and none showed clinical deterioration. Of the 10 patients with a responding acid phosphatase level 9 had either response or no change on bone scan, while only 1 had progression (this single patient had clinical deterioration), 6 were improved, 2 were stable and 1 was persistently asymptomatic (table 3). Sixteen patients had progression on bone scan; 11 of these 16 patients had progression confirmed by acid phosphatase, 2 had no change, 2 were normal and 1 had response. Fifteen of 16 patients showed clinical deterioration. In the 17 patients with progression by acid phosphatase 11 showed progression on the scan while 6 showed no change. Clinically, 14 of 17 had deterioration (table 4). When the bone scan or acid phosphatase determination did not show unequivocal response or progression, analysis of the alternate study parameters and clinical status frequently was helpful (table 5). Of 44 patients 18 (41 per cent) had no change on a bone scan. In these patients a responding or normal acid phosphatase level frequently was associated with clinical improvement or stable and improved survival. Additionally, when the acid phosphatase level showed no change or persistently normal patients (17 of 44), response or progression on the bone scan correlated well with clinical status and was predictive of survival. The clinical status of the patients, when considered indeTABLE
pendently of bone scan and acid phosphatase, also was of definite prognostic significance. Median survival of different clinical groups was >30 months in improved patients, 19 months in persistently asymptomatic patients, 13 months in stable patients and 9 months in patients who deteriorated. In the 9 patients in whom neither the scan nor acid phosphatase levels showed any significant change, change in clinical status was the only evaluable significant parameter. A re-analysis of the bone scan data based on more liberal criteria of response (defining response as a ~25 per cent decrease in area of skeletal involvement) showed that if these criteria were accepted an additional 5 of 18 patients originally classified as showing no change would be considered responders. However, the median survival of these 5 patients (11 months) was not statistically different from that of the 13 patients whose bone scan status remained no change even with these less rigid criteria (12 months) (p >0.5). Furthermore, the clinical status and acid phosphatase responses generally were not favorable (table 6). DISCUSSION
The results reported herein are from a retrospective analysis of a relatively small number of patients and, therefore, must be interpreted with caution. However, several conclusions may be drawn from the study: 1) response and progressive disease determined from repeated bone scans do correlate with the clinical status of the patient and are of definite prognostic significance, 2) similar conclusions may be drawn regarding serial measurements of serum acid phosphatase, 3) there generally is a close accord between the results of the bone scan and acid phosphatase determinations in responding and progressing patients and 4) when either the bone scan or acid phosphatase shows no change analysis of the other factor and of clinical status is useful (table 6). The bone scan and acid phosphatase determinations, although complementary, show certain qualitative differences. The bone scan is more sensitive over-all at detecting the presence of metastatic disease in the skeleton; in our study all patients had a positive bone scan, whereas 14 (32 per cent) had a normal acid phosphatase level at entry into the study. In these 14 patients the acid phosphatase level became abnormal in 2 (progression) but remained persistently within normal limits in 12. These figures are in accord with other studies in which approximately 25 per cent of patients with metastatic prostatic cancer had a persistently normal acid phosphatase level. 19
3. Correlation of bone scan, acid phosphatase and clinical
TABLE
,:§,tatus in responding patients
Clinical Status
Acid Phosphatase Results in Bone Scan Responders (10 pts.) Response
Improved Persistently asymptomatic Stable Deteriorated Totals
No Change
Response
0
1 0
5 0
2
status in patients with progressive disease
Bone Scan Results in Acid Phosphatase Responders (10 pts.)
Normal
5 0
4. C?rrelation of bone scan, acid phosphatase and clinical Bone Scan Results in 17 Pts. With Progression on Acid Phosphatase
No ProgresChange sion
No ProgresChange sion
Clinical Status
No Progression Change 1 1
Acid Phosphatase Results in 16 Pts. With Progression on Bone Scan
0 0
Response
Norma!
0
0
0
0
!
0 ~
1
2
0 ~ 2
Persistently asymptomatic Stable Deteriorated Totals
1 0 10 11
1
1
0
1
1
0
Q
Q
Q
Q
Q
!
6
3
1
6
3
1
TABLE
5. Correlation of bone scan, .acid phosphatase and clinical status in patients with no change Acid Phosphatase Results in 18 Pts. With No Change on Bone Scan
Clinical Status Response Improved Persistently asymptomatic Stable Deteriorated Totals Median survival (mos.)
1 1 1
_Q_ 3
>19
Normal
No Change
Progression
4 0 1 ~ 7 13
0 0 0 ~
0 1 1 4
2
6
11
8
1
1
0
i
10
6
11
Bone Scan Results in 17 Pts. With Normal or Unchanged Acid Phosphatase Levels Response 1 2 1
_Q_ 4 >28
Normal
Progression
4 0 1 4 9 9
0 0 0 4 4 4
SYSTEMIC TREATMENT OF ADVANCED PROSTATIC CANCER TABLE 6.
Details of patients with e;;,25 but <50 per cent decrease in area of bone involvement
Clinical Status Deterioration Stable Improved
'i
I:
Acid Phosphatase
Survival (mos.)
No change Progression Progression Response Normal
7 6
10 16 11
In such cases analysis of the alternative index of metastatic disease, the bone scan, provides the only objective criterion of response to therapy. Although the scan is more sensitive in detecting the presence of metastases it is relatively insensitive in detecting change in these metastases. Significant changes in the acid phosphatase level tend to occur more rapidly than in the bone scan. In 18 patients (41 per cent) serial scans showed no change. In 9 of these 18 patients the acid phosphatase levels showed significant change (either response or progression), which was of prognostic significance. It appears that in patients in whom the bone scan shows no significant change consideration of the acid phosphatase level may be helpful. Although clearly more sensitive than conventional radiography the bone scan only shows relatively major changes in bone involvement by metastatic tumor. One way of increasing the sensitivity of the scan would be simply to rewrite the definitions of response in a more liberal way (~25 per cent decrease in area of involvement as a response). However, we have resisted this temptation. Although the total number of responses is increased these responses apparently are of no clinical significance. We observed a similar effect in our previous study of breast cancer patients and recommend a ~50 per cent decrease as the criterion of response. Clearly, rigid criteria are required for critical identification of antitumor activity. Although not to be considered as an objective response criterion the over-all status of the patient, based on the clinical factors described previously, clearly is of importance in terms of predicting survival, and remains the only clinically useful method of evaluating those patients in whom a bone scan and acid phosphatase levels show no significant change. Because of the unique difficulties with prostatic cancer, most importantly the relative indolence of the disease and the length of time necessary for significant changes in bone metastases to be demonstrable by current techniques, monthly assessment of response is not practicable and we agree with the view that an adequate trial of any single therapy should be considered to be at least 3 months (and possibly even 6). 2 It is of considerable interest that significant response could be identified on the basiH of a single evaluation of bone scan, acid phosphatase and clinical status approximately 3 to 8 months after initiation of estramustine therapy. More clinical information may well be forthcoming from a prospective evaluation of a larger number of patients using these parameters. If this is, indeed, the case then the general acceptance of these response criteria would lead to the eligibility of the majority of patients for phases 2 and 3 studies. We expect that with these criteria approximately 80 per cent of all patients with metastatic prostatic cancer would have objectively evaluable disease, compared to only 20 per cent of patients using current criteria. Additionally, in patients with measurable non-osseous disease a comparison of response in these areas with response in bone scan and acid phosphatase levels using our criteria also would be of considerable interest. A. Jones and R. Hoeft provided technical help.
227
REFERENCES
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