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Effect of long-acting LHRH analog (zoladex) on prostate cancer: Evaluated by transrectal ultrasonography
EFFECT OF LONG-ACTING LHRH ANALOG (ZOLADEX) ON PROSTATE CANCER : EVALUATED BY TRANSRECTAL ULTRASONOGRAPHY JOSEPH R . DRAGO, M .D. JOHN A . NESBITT, M .D. CHRISTOPHER CIRULLI, M .D . From the Department of Surgery, Division of Urology, Ohio State University, Columbus, Ohio
ABSTRACT-Transrectal ultrasonography has proved valuable in assessing the effect of primary treatment modalities for prostate carcinoma . This study shows patients who had a significant reduction in primary tumor volume had a significantly better prognosis and had less local symptoms than did the group of patients that did not have a significant reduction (less than 50 %) in primary volume secondary to therapy . Patients were treated with either castration or Zoladex and all had Stage Dz cancer of the prostate .
Since the discovery of hormonal therapy by Huggins and Hodges' patients with prostatic carcinoma have been treated by surgical castration or high dose administration of estrogens . Recently with the advent of highly potent derivatives of luteinizing hormone releasing hormone (LHRH) a new era perhaps in prostate cancer therapy may have come about .' Stage D 2 patients have been randomized between orchiectomy and Zoladex . Zoladex is a long-acting LHRH analog subcutaneously administered on a once-a-month basis . In this present study we have evaluated the response of this treatment versus castration in a prospective randomized fashion using acid phosphatase, hormonal parameters, prostate volume determined by transrectal ultrasound, bone scan, and computerized tomography (CT) scan, as measurable parameters . For the purpose of this discussion we will comment only on the result of the hormone analysis and the use of ultrasonography in these patients . Material and Methods Eighteen patients with biopsy-confirmed prostate cancer who had not been previously treated with any type of therapy were chosen for this study. Their ages ranged from fifty-six
UROLOGY
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OCTOBER 1988
1
years to seventy-five years (average 72 years) . All patients had Stage D 2 disease as determined by bone scan, CT scan, and acid phosphatase . Prostate carcinomas were Gleason grades IVIX with most patients having Gleason grade VI . Zoladex was administered by subcutaneous injection on a monthly basis . During treatment, prostate volume was estimated frequently with transrectal ultrasonography, and simultaneous serum levels of follicle-stimulating hormone (FSH), LH, and testosterone as well as acid phosphatase were determined . Results Serum hormone levels during treatment with Zoladex
All hormonal parameters responded in a similar manner, i.e., serum testosterone rose during the first three days of treatment and following the third day the value declined (Fig . IA) . It approached the castrate level at day 10 and has continued to be suppressed in patients out as long as twenty-four months, Serum levels of FSH and LH (Fig . 2) were equally suppressed without exception as long as Zoladex was administered (Fig . 1B) . Castrated patients had a prompt fall in testosterone, and this remained suppressed during evaluation period .
VOLUME XXXII, NUMBER 4
285
FIGURE 1 .
Values of (A) testosterone and (B) luteinizing hormone during course of therapy .
7-
5.
E m c
5
w
Z 0 w cc
N0 F w y ~-
3
s
1
7
14
21
28
35
42
49
56
53
175
192
189
TIME (days)
A
E w z 0 M
CC
100
0 x
C7 Z Z
5o
w IJ
3
21
7
so
ISO
TIME (days)
Prostatic volume
All patients examined showed a relative reduction in prostate volume parallel with a decline in serum testosterone during the first month . This was then followed by a gradual decline in some patients and a rapid decline in others . The patients who had the rapid decline (decreased volume of more than 50%) in less 286
TABLF 1 . Pre- and post-prostate volume measurements prior to initiation of Zoladex and castration therapy and post treatment
Therapy
Pre Tx Vol em3
Post Tx Vol coil (Range)
Castration Zoladex
26 ± 34 31 ± 4
16 t 3 (16-40) 14 t 2 (10-37)
UROLOGY
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OCTOBER 1988 / VOLUME XXXII, NUMBER 4
Prostate ultrasound (A) prior to therapy and (B) after several months of therapy. Note reduction in prostate volume is significant . FIGURE 2 .
than four months had a much better prognosis (Fig . 2, Table I) . Eleven patients were treated with Zoladex, and 7 were randomized to castration . Of the patients treated with Zoladex, 8 of the 11 had a marked improvement and decrease in 50 percent of prostate volume by ultrasound and have remained in remission for over twenty-four months . Of the castrate group 4 patients had a similar response . Three patients in the castrate group and 3 in the Zoladex group had progressive disease .
These results paralleled the study of Kojima et al .a The most striking feature of this study is that there are two distinct groups based on reduction in prostatic volume that parallel their clinical responses . Further studies are obviously necessary to reveal the pathophysiologic significance of kinetic analysis in prostate cancer treated by LHRH analogs .
Comment
1 . Huggins C, and Hodges CV : Studies on prostatic cancer. 1 . The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate, Cancer Res 1 : 293 (1941) . 2 . Sandow J : Clinical applications of LHRH and its analogues, Clin Endocrinol 18 : 571 (1983) . 3. Watanabe H : Measurement of size and weight of prostate by means of transrectal ultrasonotomographv, Ultrasound Med 2 : 193 (1976) . 4 . Watanabe H, Kaiho H, Tanaka M, and Terasawa Y : Diagnostic application of ultrasonography to the prostate, Invest Urol 8 : 548 (1971) . 5 . Ohe H, et a1 : Relationship between the kinetic analysis of prostatic size reduction by treatment in patients with prostatic cancer and the prognosis, in Gill RW, and Dadd MJ (Eds) : Proceedings of the Fourth Meeting of the World Federation for Ultrasound in Medicine and Biology Sydney, Pergamon Press, 1985, p 184 . 6 . Kojima M, et al : Kinetic evaluation of the effect of LIIRH analog on prostatic cancer using transrectal ultrasonotomography Prostate 10 : 11 (1987) .
Columbus, Ohio 43210-1228 (DR . DRACO) References
It has become widely accepted that transrectal ultrasonography can be applied as a reliable procedure to monitor therapeutic effects of prostate cancer.' It is also important to note that this may be a technique that can be used for evaluating and detecting prostatic carcinoma . 15 The results of this study demonstrate the dynamic change in prostate volume related to hormonal manipulation, i .e., castration or Zoladex, and that the regressive curve of prostate volume does corrrelate with clinical remission . Conversely lack of prostatic volume decrease correlates well with progression of disease,
UROLOGY
/
OCTOBER 1088
/
VOLUME XXXII, NUMBER 4
287
ABSTRACT-Transrectal ultrasonography has proved valuable in assessing the effect of primary treatment modalities for prostate carcinoma . This study shows patients who had a significant reduction in primary tumor volume had a significantly better prognosis and had less local symptoms than did the group of patients that did not have a significant reduction (less than 50 %) in primary volume secondary to therapy . Patients were treated with either castration or Zoladex and all had Stage Dz cancer of the prostate .
Since the discovery of hormonal therapy by Huggins and Hodges' patients with prostatic carcinoma have been treated by surgical castration or high dose administration of estrogens . Recently with the advent of highly potent derivatives of luteinizing hormone releasing hormone (LHRH) a new era perhaps in prostate cancer therapy may have come about .' Stage D 2 patients have been randomized between orchiectomy and Zoladex . Zoladex is a long-acting LHRH analog subcutaneously administered on a once-a-month basis . In this present study we have evaluated the response of this treatment versus castration in a prospective randomized fashion using acid phosphatase, hormonal parameters, prostate volume determined by transrectal ultrasound, bone scan, and computerized tomography (CT) scan, as measurable parameters . For the purpose of this discussion we will comment only on the result of the hormone analysis and the use of ultrasonography in these patients . Material and Methods Eighteen patients with biopsy-confirmed prostate cancer who had not been previously treated with any type of therapy were chosen for this study. Their ages ranged from fifty-six
UROLOGY
/
OCTOBER 1988
1
years to seventy-five years (average 72 years) . All patients had Stage D 2 disease as determined by bone scan, CT scan, and acid phosphatase . Prostate carcinomas were Gleason grades IVIX with most patients having Gleason grade VI . Zoladex was administered by subcutaneous injection on a monthly basis . During treatment, prostate volume was estimated frequently with transrectal ultrasonography, and simultaneous serum levels of follicle-stimulating hormone (FSH), LH, and testosterone as well as acid phosphatase were determined . Results Serum hormone levels during treatment with Zoladex
All hormonal parameters responded in a similar manner, i.e., serum testosterone rose during the first three days of treatment and following the third day the value declined (Fig . IA) . It approached the castrate level at day 10 and has continued to be suppressed in patients out as long as twenty-four months, Serum levels of FSH and LH (Fig . 2) were equally suppressed without exception as long as Zoladex was administered (Fig . 1B) . Castrated patients had a prompt fall in testosterone, and this remained suppressed during evaluation period .
VOLUME XXXII, NUMBER 4
285
FIGURE 1 .
Values of (A) testosterone and (B) luteinizing hormone during course of therapy .
7-
5.
E m c
5
w
Z 0 w cc
N0 F w y ~-
3
s
1
7
14
21
28
35
42
49
56
53
175
192
189
TIME (days)
A
E w z 0 M
CC
100
0 x
C7 Z Z
5o
w IJ
3
21
7
so
ISO
TIME (days)
Prostatic volume
All patients examined showed a relative reduction in prostate volume parallel with a decline in serum testosterone during the first month . This was then followed by a gradual decline in some patients and a rapid decline in others . The patients who had the rapid decline (decreased volume of more than 50%) in less 286
TABLF 1 . Pre- and post-prostate volume measurements prior to initiation of Zoladex and castration therapy and post treatment
Therapy
Pre Tx Vol em3
Post Tx Vol coil (Range)
Castration Zoladex
26 ± 34 31 ± 4
16 t 3 (16-40) 14 t 2 (10-37)
UROLOGY
/
OCTOBER 1988 / VOLUME XXXII, NUMBER 4
Prostate ultrasound (A) prior to therapy and (B) after several months of therapy. Note reduction in prostate volume is significant . FIGURE 2 .
than four months had a much better prognosis (Fig . 2, Table I) . Eleven patients were treated with Zoladex, and 7 were randomized to castration . Of the patients treated with Zoladex, 8 of the 11 had a marked improvement and decrease in 50 percent of prostate volume by ultrasound and have remained in remission for over twenty-four months . Of the castrate group 4 patients had a similar response . Three patients in the castrate group and 3 in the Zoladex group had progressive disease .
These results paralleled the study of Kojima et al .a The most striking feature of this study is that there are two distinct groups based on reduction in prostatic volume that parallel their clinical responses . Further studies are obviously necessary to reveal the pathophysiologic significance of kinetic analysis in prostate cancer treated by LHRH analogs .
Comment
1 . Huggins C, and Hodges CV : Studies on prostatic cancer. 1 . The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate, Cancer Res 1 : 293 (1941) . 2 . Sandow J : Clinical applications of LHRH and its analogues, Clin Endocrinol 18 : 571 (1983) . 3. Watanabe H : Measurement of size and weight of prostate by means of transrectal ultrasonotomographv, Ultrasound Med 2 : 193 (1976) . 4 . Watanabe H, Kaiho H, Tanaka M, and Terasawa Y : Diagnostic application of ultrasonography to the prostate, Invest Urol 8 : 548 (1971) . 5 . Ohe H, et a1 : Relationship between the kinetic analysis of prostatic size reduction by treatment in patients with prostatic cancer and the prognosis, in Gill RW, and Dadd MJ (Eds) : Proceedings of the Fourth Meeting of the World Federation for Ultrasound in Medicine and Biology Sydney, Pergamon Press, 1985, p 184 . 6 . Kojima M, et al : Kinetic evaluation of the effect of LIIRH analog on prostatic cancer using transrectal ultrasonotomography Prostate 10 : 11 (1987) .
Columbus, Ohio 43210-1228 (DR . DRACO) References
It has become widely accepted that transrectal ultrasonography can be applied as a reliable procedure to monitor therapeutic effects of prostate cancer.' It is also important to note that this may be a technique that can be used for evaluating and detecting prostatic carcinoma . 15 The results of this study demonstrate the dynamic change in prostate volume related to hormonal manipulation, i .e., castration or Zoladex, and that the regressive curve of prostate volume does corrrelate with clinical remission . Conversely lack of prostatic volume decrease correlates well with progression of disease,
UROLOGY
/
OCTOBER 1088
/
VOLUME XXXII, NUMBER 4
287