International Urology and Nephrology 22 (4), pp. 359--362 (1990)
Secondary Treatment of Advanced Cancer of the Prostate with Zoladex P. KLARSKOV, F. LUND, S. E. PETERSEN Departments of Urology, Herlev Hospital and Rigshospitalet, University of Copenhagen; Aarhus County Hospital, University of Aarhus, Denmark (Received July 1, 1989) Twelve patients with advanced prostatic carcinoma and relapse following previous hormone manipulation therapy were treated with Zoladex-depot every 4 weeks. The treatment was well tolerated and the endocrine response was satisfactory. However, no clinically important improvement was obtained.
Zoladex is a LHRH-analogue, which reduces serum testosterone concentrations to castrate levels by preventing synthesis and secretion of the luteinizing hormone (LH) [1 ]. Initially a transient rise in plasma LH occurs resulting in increased testosterone values. Zoladex-depot is a biocompatible, biodegradable cylindrical rod containing 3.6 mg active substance. By injecting Zoladex-depot into the subcutaneous tissue of the abdomen every 4 weeks a constant suppression of the testosterone values can be obtained [2-4]. The present paper reports on the results from a phase II study with Zoladexdepot in patients with advanced carcinoma of the prostate, who were not controlled satisfactorily with other forms of hormone manipulation therapy, The aim was to monitor the safety and efficacy of the Zoladex-depot formulation.
Materials and methods
Twelve patients entered the study. The median age was 66 years (range 51-83 years). The type of previous hormone manipulation therapy is given in Table 1. The median duration of previous therapy was 37 weeks (range 12-146 weeks). Nine patients had a Ta local tumour and 3 had a T 4 tumour growth. Distant metastases were present in i0 patients o n entry to the trial. All 10 patients had bone metastases and in three patients some of these lesions were osteolytic. The lymph nodes were involved in two patients and two others had liver and lung metastases. Inclusion criteria were (1) histological verification of prostatic carcinoma; (2) radiological and/or isotope scan evidence of bone metastases or evidence of soft tissue metastases or extension of the tumour through the prostatic capsule; (3) life expectancy of more than 3 months; (4) failure to respond to prior hormone VSP, Utrecht Akaddmiai Kiad6, Budapest
360
Klarskov et aL : Zoladex in prostatic cancer
Table 1 Details of previous hormonal treatment, best objective response to Zoladex and reason for withdrawal
Previous treatment
Duration of
previous treatrnent (weeks)
Duration Best response to Zoladex
of response (weeks)
Duration of Reason for withdrawal
Zoladex therapy (weeks)
Flutamide Orchidectomy
37
PR
2
Died Ca. prostate
9
Estradurin Orchidectomy
15
SD
43
Objective progression
47
Stilboestrol Orchidectomy
22
SD
1
Died Ca. prostate
5
Flutamide Orchidectomy
99
SD
9
Died Ca. prostate
13
Orchidectomy
37
Died Ca. prostate
1
Died. Pneumonia, Ca. prostate
6
Orchidectomy
21
-SD
-1
Orchidectomy
12
SD
8
Orchidectomy
146
--
--
Oestrogen
121
SD
8
Died Ca. prostate
32
Orchidectomy Flutamide
55
SD
31
Died Ca. prostate
136
Estradurin Oestrogen
35
SD
2
Died Ca. prostate
8
143
PR
4
Objective progression
13
Estradurin
Objective progression Died. Heart failure Ca. prostate
56 3
PR = partial objective response. SD = stable disease.
m a n i p u l a t i o n therapy or progression following initial response to prior h o r m o n e m a n i p u l a t i o n therapy a n d (5) i n f o r m e d consent. E x c l u s i o n criteria were c o n c u r r e n t malignancies other t h a n c a r c i n o m a of the skin a n d lip. A s s e s s m e n t s . The patients were assessed by subjective a n d objective criteria. The subjective criteria included p e r f o r m a n c e score (0-4), b o n e p a i n score (0-4) a n d analgesia use. The presence or absence of libido, erections, h o t flushes a n d International Urology and Nephrology 22, 1990
K l a r s k o v e t aL : Z o l a d e x
in p r o s t a t i c c a n c e r
361
breast swelling and tenderness were also recorded. The objective criteria were T-category, prostatic dimensions (or volume assessed by rectal ultrasound), serum acid phosphatase, bone scan and X-ray of chest, pelvis and vertebral column, details of any other clinically measurable metastases and body weight. Laboratory analyses included serum LH, FSH and testosterone, haemoglobin, total red cell count, total white cell count and platelet count, serum creatinine, calcium, bilirubin, albumin, alkaline phosphatase and ASAT. The patients had all assessments performed prior to initiation of Zoladex therapy and at 3-month intervals thereafter. At 1 and 2 months after entry the patients were assessed with all but X-ray and bone scan. Response criteria were similar to the criteria proposed by the European Organization for Research and Treatment of Cancer (EORTC) [3].
Results
Two patients died within the first month before follow-up assessment leaving only 10 patients for evaluation. Another four patients died within the first three months before the first bone scan and X-ray examination on treatment. The duration of therapy and reason for withdrawal for all patients are shown in Table 1. Objective response. Two patients had a partial objective regression of very short duration (Table 1). One patient had a reduction in dimensions of a metastatic lymph node by 62 ~ and down grading of the local tumour from T~ to T 0. The other patient (with normal pretreatment testosterone values) had a 95 ~o reduction of prostatic acid phosphatase. However, both deteriorated rapidly thereafter and died. For the other eight patients the best response to Zoladex was stable disease for 1-43 weeks. The reasons for progression were local tumour growth in one and increase in metastatic lesions in the others. Subjective response. According to the clinicians' assessment four patients responded subjectively with a reduction of pain and improvement in performance status. Before this response one patient with normal pretreatment serum testosterone value developed severe increase in bone pain accompanied by fever and hot sensation two days after onset of treatment. This lasted for five days. Endocrine response. One patient had testosterone value above the castrate level at entry into the trial (16.9 mmol/1). His testosterone values were reduced to castrate level within the first four weeks of Zoladex treatment and remained low at subsequent assessments. For the other patients the testosterone values were unchanged and in the castrate range, and LH concentrations were either suppressed or unchanged. Pharmacological side effects. Libido and potency were not present before onset of therapy in any of these patients and consequently no decrease was reported in libido and potency. In one patient breast swelling prior to therapy disappeared on commencing Zoladex and in two of three patients breast tenderness disappeared International Urology and Nephroloyy 22, 1990
362
Klarskov et aL : Zoladex in prostatic cancer
during treatment. No new breast swelling or breast tenderness was seen. Two of the ten eligible patients developed hot flushes during Zoladex therapy. Adverse events. No local discomfort was registered and no toxic effect was noted on the laboratory parameters.
Discussion
The monthly depot injections with Zoladex were well tolerated and the endocrine responses were as anticipated. No adverse events were seenlocally or systemati.. cally except for the initial symptomatic flare in one patient with serum testosterone values within the normal range, a complication which has been seen in approximately 5 70 of previously untreated patients [5]. Some symptomatic relief was seen in pain and breast discomfort. However, no clinically important objective improvement occurred. This was also the experience from another study with Zoladex on 17 relapsed progressive prostatic cancer patients [6]. The reason for these poor results is probably that the relapse following hormone manipulation therapy is due mainly to outgrowth of androgen-independent cancer cell lines. No satisfactory second line therapy has yet been developed for these patients. In conclusion, Zoladex-depot does not seem to be advantageous for patients with progression of prostatic cancer disease following previous hormonal therapy, except perhaps for patients with plasma testosterone values outside the castrate range prior to the onset of Zoladex therapy.
References 1. Allen, J. M., O'Shea, J. P., Mashiter, K., Williams, G., Bloom, S. R. : Advanced carcinoma of the prostate: treatment with a gonadotrophin releasing hormone agonist. Br. Med. J., 286, 1607 (1983). 2. Walker, K. J., Turkes, A. O., Turkes, A., Zwink, R., Beacock, C., Buck, A. C., Peeling, W. B., Griffiths, K. : Treatment of patients with advanced cancer of the prostate using a slow-release (depot) formulation of L H R H agonist ICI 118, 630 ("Zoladex"). J. Endocrinol., 103, R1-R4 (1984). 3. Beacock, C. J., Buck, A. C., Zwinck, R., Peeling, W. B., Rees, R. W. M., Turkes, A., Walker, K., Griffiths, K.: The treatment of metastatic prostatic cancer with the slow release L H - R H analogue Zoladex ICI 118630. Br. J. Urol., 59, 336 (1987). 4. Iversen, P., Rose, C., Stage, J. G., Iversen, H.-G., Hansen, R. I., Hvidt, V., Mogensen, P., Pedersen, T., Hansen, J. B. : LHRH analogue as a depot preparation (Zoladex) in the treatment of advanced carcinoma of the prostate followed by orchidectomy as a second line therapy--A phase II study. Scand. J. Urol. Nephrol. (in press). 5. Donneley, R. J., Milsted, R. A. V.: Zoladex studies in prostatic and breast cancer. In: Vickery, B. H., Nestor, J. J. (eds): LHRH and its Analogs. Contraceptive and Therapeutic Applications. Part 2. MTP Press Limited, Lancaster 1987, pp. 397--409. 6. Kerle, D., Williams, G., Ware, H., Doble, A., Allen, J., Bloom, S. R. : Experience with an L H R H analogue in the management of relapsed progressive prostatic cancer. Br. J. Urol., 56, 495 (1984). International Urology and Nephrology 22, 1990
Secondary Treatment of Advanced Cancer of the Prostate with Zoladex P. KLARSKOV, F. LUND, S. E. PETERSEN Departments of Urology, Herlev Hospital and Rigshospitalet, University of Copenhagen; Aarhus County Hospital, University of Aarhus, Denmark (Received July 1, 1989) Twelve patients with advanced prostatic carcinoma and relapse following previous hormone manipulation therapy were treated with Zoladex-depot every 4 weeks. The treatment was well tolerated and the endocrine response was satisfactory. However, no clinically important improvement was obtained.
Zoladex is a LHRH-analogue, which reduces serum testosterone concentrations to castrate levels by preventing synthesis and secretion of the luteinizing hormone (LH) [1 ]. Initially a transient rise in plasma LH occurs resulting in increased testosterone values. Zoladex-depot is a biocompatible, biodegradable cylindrical rod containing 3.6 mg active substance. By injecting Zoladex-depot into the subcutaneous tissue of the abdomen every 4 weeks a constant suppression of the testosterone values can be obtained [2-4]. The present paper reports on the results from a phase II study with Zoladexdepot in patients with advanced carcinoma of the prostate, who were not controlled satisfactorily with other forms of hormone manipulation therapy, The aim was to monitor the safety and efficacy of the Zoladex-depot formulation.
Materials and methods
Twelve patients entered the study. The median age was 66 years (range 51-83 years). The type of previous hormone manipulation therapy is given in Table 1. The median duration of previous therapy was 37 weeks (range 12-146 weeks). Nine patients had a Ta local tumour and 3 had a T 4 tumour growth. Distant metastases were present in i0 patients o n entry to the trial. All 10 patients had bone metastases and in three patients some of these lesions were osteolytic. The lymph nodes were involved in two patients and two others had liver and lung metastases. Inclusion criteria were (1) histological verification of prostatic carcinoma; (2) radiological and/or isotope scan evidence of bone metastases or evidence of soft tissue metastases or extension of the tumour through the prostatic capsule; (3) life expectancy of more than 3 months; (4) failure to respond to prior hormone VSP, Utrecht Akaddmiai Kiad6, Budapest
360
Klarskov et aL : Zoladex in prostatic cancer
Table 1 Details of previous hormonal treatment, best objective response to Zoladex and reason for withdrawal
Previous treatment
Duration of
previous treatrnent (weeks)
Duration Best response to Zoladex
of response (weeks)
Duration of Reason for withdrawal
Zoladex therapy (weeks)
Flutamide Orchidectomy
37
PR
2
Died Ca. prostate
9
Estradurin Orchidectomy
15
SD
43
Objective progression
47
Stilboestrol Orchidectomy
22
SD
1
Died Ca. prostate
5
Flutamide Orchidectomy
99
SD
9
Died Ca. prostate
13
Orchidectomy
37
Died Ca. prostate
1
Died. Pneumonia, Ca. prostate
6
Orchidectomy
21
-SD
-1
Orchidectomy
12
SD
8
Orchidectomy
146
--
--
Oestrogen
121
SD
8
Died Ca. prostate
32
Orchidectomy Flutamide
55
SD
31
Died Ca. prostate
136
Estradurin Oestrogen
35
SD
2
Died Ca. prostate
8
143
PR
4
Objective progression
13
Estradurin
Objective progression Died. Heart failure Ca. prostate
56 3
PR = partial objective response. SD = stable disease.
m a n i p u l a t i o n therapy or progression following initial response to prior h o r m o n e m a n i p u l a t i o n therapy a n d (5) i n f o r m e d consent. E x c l u s i o n criteria were c o n c u r r e n t malignancies other t h a n c a r c i n o m a of the skin a n d lip. A s s e s s m e n t s . The patients were assessed by subjective a n d objective criteria. The subjective criteria included p e r f o r m a n c e score (0-4), b o n e p a i n score (0-4) a n d analgesia use. The presence or absence of libido, erections, h o t flushes a n d International Urology and Nephrology 22, 1990
K l a r s k o v e t aL : Z o l a d e x
in p r o s t a t i c c a n c e r
361
breast swelling and tenderness were also recorded. The objective criteria were T-category, prostatic dimensions (or volume assessed by rectal ultrasound), serum acid phosphatase, bone scan and X-ray of chest, pelvis and vertebral column, details of any other clinically measurable metastases and body weight. Laboratory analyses included serum LH, FSH and testosterone, haemoglobin, total red cell count, total white cell count and platelet count, serum creatinine, calcium, bilirubin, albumin, alkaline phosphatase and ASAT. The patients had all assessments performed prior to initiation of Zoladex therapy and at 3-month intervals thereafter. At 1 and 2 months after entry the patients were assessed with all but X-ray and bone scan. Response criteria were similar to the criteria proposed by the European Organization for Research and Treatment of Cancer (EORTC) [3].
Results
Two patients died within the first month before follow-up assessment leaving only 10 patients for evaluation. Another four patients died within the first three months before the first bone scan and X-ray examination on treatment. The duration of therapy and reason for withdrawal for all patients are shown in Table 1. Objective response. Two patients had a partial objective regression of very short duration (Table 1). One patient had a reduction in dimensions of a metastatic lymph node by 62 ~ and down grading of the local tumour from T~ to T 0. The other patient (with normal pretreatment testosterone values) had a 95 ~o reduction of prostatic acid phosphatase. However, both deteriorated rapidly thereafter and died. For the other eight patients the best response to Zoladex was stable disease for 1-43 weeks. The reasons for progression were local tumour growth in one and increase in metastatic lesions in the others. Subjective response. According to the clinicians' assessment four patients responded subjectively with a reduction of pain and improvement in performance status. Before this response one patient with normal pretreatment serum testosterone value developed severe increase in bone pain accompanied by fever and hot sensation two days after onset of treatment. This lasted for five days. Endocrine response. One patient had testosterone value above the castrate level at entry into the trial (16.9 mmol/1). His testosterone values were reduced to castrate level within the first four weeks of Zoladex treatment and remained low at subsequent assessments. For the other patients the testosterone values were unchanged and in the castrate range, and LH concentrations were either suppressed or unchanged. Pharmacological side effects. Libido and potency were not present before onset of therapy in any of these patients and consequently no decrease was reported in libido and potency. In one patient breast swelling prior to therapy disappeared on commencing Zoladex and in two of three patients breast tenderness disappeared International Urology and Nephroloyy 22, 1990
362
Klarskov et aL : Zoladex in prostatic cancer
during treatment. No new breast swelling or breast tenderness was seen. Two of the ten eligible patients developed hot flushes during Zoladex therapy. Adverse events. No local discomfort was registered and no toxic effect was noted on the laboratory parameters.
Discussion
The monthly depot injections with Zoladex were well tolerated and the endocrine responses were as anticipated. No adverse events were seenlocally or systemati.. cally except for the initial symptomatic flare in one patient with serum testosterone values within the normal range, a complication which has been seen in approximately 5 70 of previously untreated patients [5]. Some symptomatic relief was seen in pain and breast discomfort. However, no clinically important objective improvement occurred. This was also the experience from another study with Zoladex on 17 relapsed progressive prostatic cancer patients [6]. The reason for these poor results is probably that the relapse following hormone manipulation therapy is due mainly to outgrowth of androgen-independent cancer cell lines. No satisfactory second line therapy has yet been developed for these patients. In conclusion, Zoladex-depot does not seem to be advantageous for patients with progression of prostatic cancer disease following previous hormonal therapy, except perhaps for patients with plasma testosterone values outside the castrate range prior to the onset of Zoladex therapy.
References 1. Allen, J. M., O'Shea, J. P., Mashiter, K., Williams, G., Bloom, S. R. : Advanced carcinoma of the prostate: treatment with a gonadotrophin releasing hormone agonist. Br. Med. J., 286, 1607 (1983). 2. Walker, K. J., Turkes, A. O., Turkes, A., Zwink, R., Beacock, C., Buck, A. C., Peeling, W. B., Griffiths, K. : Treatment of patients with advanced cancer of the prostate using a slow-release (depot) formulation of L H R H agonist ICI 118, 630 ("Zoladex"). J. Endocrinol., 103, R1-R4 (1984). 3. Beacock, C. J., Buck, A. C., Zwinck, R., Peeling, W. B., Rees, R. W. M., Turkes, A., Walker, K., Griffiths, K.: The treatment of metastatic prostatic cancer with the slow release L H - R H analogue Zoladex ICI 118630. Br. J. Urol., 59, 336 (1987). 4. Iversen, P., Rose, C., Stage, J. G., Iversen, H.-G., Hansen, R. I., Hvidt, V., Mogensen, P., Pedersen, T., Hansen, J. B. : LHRH analogue as a depot preparation (Zoladex) in the treatment of advanced carcinoma of the prostate followed by orchidectomy as a second line therapy--A phase II study. Scand. J. Urol. Nephrol. (in press). 5. Donneley, R. J., Milsted, R. A. V.: Zoladex studies in prostatic and breast cancer. In: Vickery, B. H., Nestor, J. J. (eds): LHRH and its Analogs. Contraceptive and Therapeutic Applications. Part 2. MTP Press Limited, Lancaster 1987, pp. 397--409. 6. Kerle, D., Williams, G., Ware, H., Doble, A., Allen, J., Bloom, S. R. : Experience with an L H R H analogue in the management of relapsed progressive prostatic cancer. Br. J. Urol., 56, 495 (1984). International Urology and Nephrology 22, 1990
