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Long term follow-up of patients with advanced prostatic cancer treated with nasal buserelin
Annals of Oncology 2: 303-304, 1991. O 1991 Kluwer Academic Publishers. Printed in the Netherlands.
Short report Long term follow-up of patients with advanced prostatic cancer treated with nasal buserelin
Department of Medical Oncology, University of Pretoria, Pretoria, Rep. of South Africa
Summary. Sixty one men, with advanced prostatic cancer, were entered on a trial using a nasally administered gonadotropin-releasing hormone analogue agonist, buserelin, as first line treatment. This is the first trial to use intranasal buserelin without primary injections and without antiandrogens. No flare' phenomenon was observed. The only side effects were hot flashes (69%) and decreased libido (25%). The response rate of 82%, with a median response duration of 16 months, compares favourably to responses reported with orchidectomy or estrogens. Serum testosterone, FSH and LH were monitored at regular intervals. Mean serum testosterone baseline values of 15 nmol/L decreased to castrate levels, and remained low while patients were on study. It is concluded that intranasal buserelin is an effective, simple and safe method to achieve androgen deprivation and is an alternative to orchidectomy in the treatment of advanced prostatic cancer. Key words: buserelin, LHRH, prostate cancer Introduction
Carcinomatous prostate depends on testosterone for its growth and maintenance. A method of medical castration has been introduced in the form of synthetic gonadotropin releasing factor analogs [1]. We have found intranasal buserelin an effective, simple and safe way to achieve androgen deprivation [2]. This study was undertaken to evaluate longterm therapeutic and side effects when intranasal buserelin is given without primary injections or antiandrogens. This was a unique approach, since in previous studies with LHRH agents, injections or depo-preparations were used. In earlier studies with nasal buserelin, it was given after an initial induction phase with subcutaneous administration.
Material and methods
Sixty one men with histologjcally confirmed advanced prostatic cancer were studied, their characteristics are shown in Table 1. Treatment consisted of buserelin intranasally 2400 meg/day for the first 7 days and then 1200 meg/day. Results
Responses were documented in 45 of 55 evaluable patients (Table 1). Median time to treatment failure was 487 days. Mean serum testosterone decreased to castrate levels after one week of treatment and remained low while patients were on study. A progressive
decrease of phosphatase, FSH and LH levels was observed. The only side effects were hot flashes (38 patients), and decreased libido (14 patients). None of the patients in this study experienced a flare reaction. Prolonged use of nasal buserelin had no undesirable local effects on the nasal mucosa. Discussion An abrupt increase in testosterone, dihydrotestosterone (DHT), LH and FSH has been described in patients receiving GnRHA, while following long-term administration, testosterone and DHT decrease to castration levels [3]. It has been suggested that this initial rise in androgen levels can be responsible for worsening of clinical symptoms, termed a disease flare, that occurs in about 10% of patients treated with injections of GnRHA [4]. Pretreatment with antiandrogens has been given to counteract this increase of testosterone [5,6]. It is of note that in our study with intranasal buserelin, where no subcutaneous or depot injections were used, none of the patients experienced disease flare despite the fact that antiandrogens were not given. This may possibly be due to slightly slower induction effects of the nasal in contrast to subcutaneous administration. The nasal spray provides a method of administration that is more acceptable to most patients than daily subcutaneous injections, however in unreliable patients or patients who are not wellmotivated, a periodic depot-injection may have advantage over the nasal formulation.
Downloaded from https://academic.oup.com/annonc/article-abstract/2/4/303/166277 by Leiden University / LUMC user on 17 January 2019
C. I. Falkson, G. Falkson & H. C. Falkson
304 Table 1. Patient characteristics and response (for 61 patients).
Acknowledgement
A. Characteristics
Supported in part by a Grant from the National Cancer Association of South Africa.
Median age
(range) 68 years
(44-86)
Performance status' (no. pts) 0 8 1 42 2 6 3 5 15 24 21
Elevated baseline in no. pis Acid phosphatases Prostatic phosphatase
41 34
(4.7-30) (4.6-100) (2.5-150)
B. Response by dominant sites of metastases (no. pts) Degree of responseb CR Bone alone (4) Bone + visceralc (6) Bone + soft tissued (29) Bone marrow (2) Viscera alone' (4) Soft tissue alone' (16)
PR
IMP NC
8
PD
NE
1
2 1 3
1
Performance Status (PS). 0: normal activity, 1: symptoms but ambulatory. 2: in bed <50%of time, 3: in bed >50% of time, 4: 100% bedridden. Response: CR: complete disappearance of evidence of disease. PR: >50% decrease of all tumor and improved PS. IMP: <50% decrease of all tumor and improved PS. NC: stable disease. PD: progressive disease. NE: not evaluable. Lung and/or liver. Pelvic and/or nodes. Lung and/or liver. Lymph nodes, pelvic infiltration and prostate.
1. Schally AV, Redding TW, Comaru-Schally AM. Potential use of analogs of luteinizing hormone-releasing hormones in the treatment of hormone-sensitive neoplasms. Cancer Treat Rep 1984; 86:281-9. 2. Falkson G, Vorobiof DA. Intranasal buserelin in the treatment of advanced prostatic cancer: A phase II trial. J Clin Oncol 1987; 5: 1419-23. 3. Belchetz PE, Plant TM, Nakai Y. Hypophysial responses to continuous and intermittent delivery of hypothalamic gonadotropin releasing hormone. Science 1978; 202:631-3. 4. The Leuprolide Study Group. Leuprolide versus diethylstibestrol for metastatic prostatic cancer. N Engl J Med 1984; 311: 1281-6. 5. Deghenghi R, Misset JL. Disease flare induced by luteinizing hormone releasing hormone analogues in cancer patients. Lancet 1984; 1: 1302-5. 6. Hjertberg H, Varenhorst E, Svensson M, et al. Treatment of prostatic cancer by monthly injections of an LHRH-analogue depot. Acta Oncologica 1988; 27: 361—4. Received 6 August 1990; accepted 31 October 1990. Correspondence to: Prof. G. Falkson Dept. of Medical Oncology Private Bag X169 Pretoria 0001 Rep. of South Africa
Downloaded from https://academic.oup.com/annonc/article-abstract/2/4/303/166277 by Leiden University / LUMC user on 17 January 2019
Median baseline Testosterone nmol/L FSH (IU/L) LH(1U/L)
References
Short report Long term follow-up of patients with advanced prostatic cancer treated with nasal buserelin
Department of Medical Oncology, University of Pretoria, Pretoria, Rep. of South Africa
Summary. Sixty one men, with advanced prostatic cancer, were entered on a trial using a nasally administered gonadotropin-releasing hormone analogue agonist, buserelin, as first line treatment. This is the first trial to use intranasal buserelin without primary injections and without antiandrogens. No flare' phenomenon was observed. The only side effects were hot flashes (69%) and decreased libido (25%). The response rate of 82%, with a median response duration of 16 months, compares favourably to responses reported with orchidectomy or estrogens. Serum testosterone, FSH and LH were monitored at regular intervals. Mean serum testosterone baseline values of 15 nmol/L decreased to castrate levels, and remained low while patients were on study. It is concluded that intranasal buserelin is an effective, simple and safe method to achieve androgen deprivation and is an alternative to orchidectomy in the treatment of advanced prostatic cancer. Key words: buserelin, LHRH, prostate cancer Introduction
Carcinomatous prostate depends on testosterone for its growth and maintenance. A method of medical castration has been introduced in the form of synthetic gonadotropin releasing factor analogs [1]. We have found intranasal buserelin an effective, simple and safe way to achieve androgen deprivation [2]. This study was undertaken to evaluate longterm therapeutic and side effects when intranasal buserelin is given without primary injections or antiandrogens. This was a unique approach, since in previous studies with LHRH agents, injections or depo-preparations were used. In earlier studies with nasal buserelin, it was given after an initial induction phase with subcutaneous administration.
Material and methods
Sixty one men with histologjcally confirmed advanced prostatic cancer were studied, their characteristics are shown in Table 1. Treatment consisted of buserelin intranasally 2400 meg/day for the first 7 days and then 1200 meg/day. Results
Responses were documented in 45 of 55 evaluable patients (Table 1). Median time to treatment failure was 487 days. Mean serum testosterone decreased to castrate levels after one week of treatment and remained low while patients were on study. A progressive
decrease of phosphatase, FSH and LH levels was observed. The only side effects were hot flashes (38 patients), and decreased libido (14 patients). None of the patients in this study experienced a flare reaction. Prolonged use of nasal buserelin had no undesirable local effects on the nasal mucosa. Discussion An abrupt increase in testosterone, dihydrotestosterone (DHT), LH and FSH has been described in patients receiving GnRHA, while following long-term administration, testosterone and DHT decrease to castration levels [3]. It has been suggested that this initial rise in androgen levels can be responsible for worsening of clinical symptoms, termed a disease flare, that occurs in about 10% of patients treated with injections of GnRHA [4]. Pretreatment with antiandrogens has been given to counteract this increase of testosterone [5,6]. It is of note that in our study with intranasal buserelin, where no subcutaneous or depot injections were used, none of the patients experienced disease flare despite the fact that antiandrogens were not given. This may possibly be due to slightly slower induction effects of the nasal in contrast to subcutaneous administration. The nasal spray provides a method of administration that is more acceptable to most patients than daily subcutaneous injections, however in unreliable patients or patients who are not wellmotivated, a periodic depot-injection may have advantage over the nasal formulation.
Downloaded from https://academic.oup.com/annonc/article-abstract/2/4/303/166277 by Leiden University / LUMC user on 17 January 2019
C. I. Falkson, G. Falkson & H. C. Falkson
304 Table 1. Patient characteristics and response (for 61 patients).
Acknowledgement
A. Characteristics
Supported in part by a Grant from the National Cancer Association of South Africa.
Median age
(range) 68 years
(44-86)
Performance status' (no. pts) 0 8 1 42 2 6 3 5 15 24 21
Elevated baseline in no. pis Acid phosphatases Prostatic phosphatase
41 34
(4.7-30) (4.6-100) (2.5-150)
B. Response by dominant sites of metastases (no. pts) Degree of responseb CR Bone alone (4) Bone + visceralc (6) Bone + soft tissued (29) Bone marrow (2) Viscera alone' (4) Soft tissue alone' (16)
PR
IMP NC
8
PD
NE
1
2 1 3
1
Performance Status (PS). 0: normal activity, 1: symptoms but ambulatory. 2: in bed <50%of time, 3: in bed >50% of time, 4: 100% bedridden. Response: CR: complete disappearance of evidence of disease. PR: >50% decrease of all tumor and improved PS. IMP: <50% decrease of all tumor and improved PS. NC: stable disease. PD: progressive disease. NE: not evaluable. Lung and/or liver. Pelvic and/or nodes. Lung and/or liver. Lymph nodes, pelvic infiltration and prostate.
1. Schally AV, Redding TW, Comaru-Schally AM. Potential use of analogs of luteinizing hormone-releasing hormones in the treatment of hormone-sensitive neoplasms. Cancer Treat Rep 1984; 86:281-9. 2. Falkson G, Vorobiof DA. Intranasal buserelin in the treatment of advanced prostatic cancer: A phase II trial. J Clin Oncol 1987; 5: 1419-23. 3. Belchetz PE, Plant TM, Nakai Y. Hypophysial responses to continuous and intermittent delivery of hypothalamic gonadotropin releasing hormone. Science 1978; 202:631-3. 4. The Leuprolide Study Group. Leuprolide versus diethylstibestrol for metastatic prostatic cancer. N Engl J Med 1984; 311: 1281-6. 5. Deghenghi R, Misset JL. Disease flare induced by luteinizing hormone releasing hormone analogues in cancer patients. Lancet 1984; 1: 1302-5. 6. Hjertberg H, Varenhorst E, Svensson M, et al. Treatment of prostatic cancer by monthly injections of an LHRH-analogue depot. Acta Oncologica 1988; 27: 361—4. Received 6 August 1990; accepted 31 October 1990. Correspondence to: Prof. G. Falkson Dept. of Medical Oncology Private Bag X169 Pretoria 0001 Rep. of South Africa
Downloaded from https://academic.oup.com/annonc/article-abstract/2/4/303/166277 by Leiden University / LUMC user on 17 January 2019
Median baseline Testosterone nmol/L FSH (IU/L) LH(1U/L)
References