Brrrrsh Juurnal u/ Urulugy (19831, 55, 743-146 0 1983 British Association of Urological Surgeons

Prostatic Cancer: Treatment with Long-acting LH RH Analogue

GORDON WILLIAMS, JANET M. ALLEN, J. P. O’SHEA, K. MASHITER, A. DOBLE and S. R. BLOOM

Departments of Surgery and Medicine, Hammersmith Hospital and Royal Postgraduate Medical School, London

Summary-Fifteen patients with advanced carcinoma of the prostate were treated with a luteinising hormone releasing hormone agonist ICI 118 630. Three of 5 patients who had failed conventional hormone therapy have had a marked alleviation of bone pain, though no objective evidence of disease regression. Nine of 10 patients previously untreated have shown objective evidence of disease response. This drug appears to have advantages over conventional hormone therapy.

Following the work of Huggins and Hodges (1941), the treatment of advanced prostatic cancer has relied on lowering of the serum testosterone by oestrogens, antiandrogens or orchiectomy. Pulsa- tile secretion of the luteinising hormone releasing hormone (LHRH) results in the release from the pituitary of luteinising hormone (LH) and follicular stimulating hormone (FSH) and is a prerequisite of normal gonadal function (Yen er a/., 1972). Continuous stimulation of gonadotrophins by the long-acting LHRH agonists results in the paradox- ical fall in LH and FSH (Pinto et a/., 1979) and hence in testosterone (Linde et a/., 1981). The use of one of the analogues ICI 118,630 as a possible treatment of advanced progressive carcinoma of the prostate is reported.

Patients and Methods Fifteen patients aged 54 to 82 years (mean 70.3) gave informed written consent to participate in the study. All had histologically confirmed carcinoma of the prostate stage T3-T4 and 14 of the 15 had evidence of metastatic disease (UICC, 1978). Two patients died early in the study. The mean period of

Read at the 39th Annual Meeting of the British Association of Urological Surgeons in Harrogate, June 1983.

treatment and follow-up for the remainder was 9 months (range 6-14). Five patients had relapsed or failed to respond to conventional endocrine ther- apy (orchiectomy 3, estramustine phosphate (Es- tracyt) 1, cyproterone acetate 1). The remainder were newly diagnosed and had not previously received any form of endocrine therapy.

For the first week of treatment patients were admitted to hospital. Basal levels of serum LH, FSH, prolactin, testosterone, dihydrotestosterone and androstenedione were measured on 2 consecu- tive days before treatment, as were tests of renal function, biochemical multi-channel profile and total serum acid phosphatase and tartrate labile acid phosphatase. All patients received 250 pg bd of the analogue by subcutaneous injection for the first week and then 250 pg daily. Patients were encouraged and taught to give their own injections. Blood was taken for all of the listed investigations at each follow-up visit. On the day of attendance patients were asked to omit their usual dose of the analogue until the blood samples had been taken. The methods used for the hormone analysis have been previously reported (Allen et al., 1983). Objective response has been measured using radio nuclide bone scans, acid phosphatase measure- ments and prostate size. We have also used the patient’s own appraisal of the disease on their activities, and in particular the effect on analgesic

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BRITISH JOURNAL OF UROLOGY

requirements using a scoring system. They were examined by one examiner (GW) prior to starting treatment, at 6 weeks and 3 months and then at 3- monthly intervals. At each visit the patients were questioned concerning possible side effects from the drug, in particular alteration of sexual activity.

Results

Endocrine Response The first dose of the agonist resulted in a prompt sustained rise in the serum LH (Fig. 1) and FSH in all of the patients. This acute response was completely abolished after the first week of treatment and was suppressed below basal levels after 2 weeks of treatment. The serum testosterone (Fig. 2 ) and dihydrotestosterone followed the serum LH, there being a rise in the first week and suppression to orchiectomy levels by the third week. One patient had an abnormally low testoste- rone at the start of the study and did not show this acute rise. There was no overall change in serum prolactin or serum androstenedione in any patient.

Tumour Response Two of the 5 patients who had either failed to respond or had relapsed on conventional hormone therapy also showed no endocrine response to the analogue and both died within 3 months. The other 3 patients have been on treatment for a mean period of 8 months and have had a significant subjective response, in particular the relief of bone pain. All have been able to withdraw from narcotic

-1 serum LH Iu I T

n 1 u

b 2 4 I 'I

Serum LH up to 4 h after first dose of analogue and after

hours

Fig. I I week's treatment.

T

I I 1 I I 14 28

" - 1

I I I 1 0 14

days 28

Fig. 2. The effect on (a) serum LH and (b) serum testosterone of long-term treatment with the analogue.

analgesics and either require none or occasional simple analgesics. These 3 patients have an improved quality of life when assessed on a scoring systt:m, but 2 of them have evidence of progressive disease with a rising acid phosphatase and worsen- ing bone scan. In the other patient the disease remains stable.

Ten patients have received the analogue as primary treatment for a mean period of follow-up of 9.2 months (Fig. 3). The one patient who showed no rise of serum testosterone after the first dose of the analogue showed no objective response to treatment and died after 8 months.

Seven of 9 patients showed objective evidence of disease regression with normalisation of the serum acid phosphatase (5 out of S ) , alkaline phosphatase (2 out of 2) and reduction in the size of the gland (5 out of 5) and improvement in the bone scan ( 2 out of 2). Of the 2 remaining patients 1 showed an

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Patient

G. D.

c. w. W. s. S. B. W. H.

H. K.

R. L. G. M.

H. B.

J. W.

LHRH - Carcinoma of prostate

PROSTATIC CANCER: TREATMENT WITH LONG-ACTING LHRH ANALOGUE

Fig. 3 The clinical response of 10 newly diagnosed patients to the analogue.

New pat ients

Subjective response

0 3 6 9 12 is Months

initial reduction in gland size but developed evidence of progressive metastatic disease after 12 months’ therapy. The other had a reduction in acid phosphatase and alkaline phosphatase at 6 months but these were not in the normal range and are now rising.

Two patients reported an increase in libido, 2 became impotent. No other side effects were noted.

Discussion Approximately 80% of patients with carcinoma of the prostate can be expected to respond to endocrine therapy (Whitehead, 1981). Stilboestrol, even in low dosage, may cause cardiovascular problems and is especially contraindicated in the elderly, those with a previous history of cardiovas- cular disease and after recent surgery (Byar, 1977). Orchiectomy, though safer, is not acceptable to some patients. The development of gonadotrophin releasing hormone agonists provides an alternative means of suppressing serum testosterone to cas- trate levels. Five patients in this study had failed to respond or had disease progression while on other forms of endocrine treatment. None has shown any objective evidence of disease control, though 3 have shown a dramatic alleviation of bone pain- all being able to withdraw completely from

narcotic analgesics for a mean period of 8 months despite a progressive rise in the acid and alkaline phosphatase in 2 of them. Neither of the other 2 patients showed any rise in LH, FSH or testoste- rone after the first dose of analogue. They had no subjective or objective improvement. One of these patients subsequently had a pituitary implant and had considerable relief of bone pain. One other patient had a very low testosterone before the study and also had no response to the analogue. Such hormone assessments after the first dose of the analogue may be a useful method of determining early whether the patients will respond or not. The analogue appears to have additional effects apart from its testosterone-lowering action, particularly in the relief of bone pain.

Of the 10 new patients (Fig. 3) one with an abnormally low testosterone did not respond. One patient has shown a partial response during 6 months’ therapy, with improvement in the alkaline and acid phosphatase initially, but these did not return to normal and are now increasing. The remaining 8 patients, all with advanced, local or metastatic disease, have shown objective evidence of response. All have shown reduction in the size of the gland; 2 of 3 have marked improvement in the bone scan and the acid and alkaline phosphatases, when elevated, have all returned to normal. The

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mean period of follow-up is only 10 months and one gonadotrophin-releasing agonist in normal men. New England of these patients has now developed evidence of Jourmf of Medicine, 305, 663-667. metastatic disease 12 months after starting therapy Pinto, H., Wajchenberg, B. L., Linia, F. B., Goldman, J.3

Comnru-SchaUy, A. M. and Schally, A. V. (1979). Evaluation after an good local response to treatment. of the gonadotrophic responsiveness of the pituitary to acute Despite the initial increase in gonadotrophins and and prolonged administration of LH/FSH releasing hormone testosterone no patient has shown any acute (LH-RH) in normal females and males. Acta Endocrinologica, deterioration in symptoms. Four patients have 91, 1-13. reported an alteration in sexual status, 2 with Tolis, IG., Ackman, D., Stellos, A., Mehta, A., Labrie, F.,

Fazekas, A. T. A., Comaru-SchaUy, A. M. and SchaUy, A. V. jncreased libido and have become impotent. Two (l98:!), Tumour growth inhibition in patients with prostatic patients have also noticed hot flushes. The results carcinoma treated with Iuteinising hormone releasing hor- observed in this study compare well with prelimi- mone agonists. Proceedings of rhe National Academy of

UICC. Union Internationale Contre le Cancer (1978). TNM (Borgmann et 1982; er Classification of Malignant Tumours. Third edition. Geneva:

nary reports from other centres using other LHRH Sciet?cex nfthe United stares o?America, 79, 1658-1662.

1982). The use of these analogues may provide a Safe and more effective treatment for carcinoma of

International union against cancer, Whitehead, E. D. (1981). Management of prostate carcinoma.

the prostate than presently available therapy, though longer long-term trials are clearly needed.

References Allen, J. M., O’Shea, J . P., Mashiter, K., Williams, G . and

Bloom, S. R. (1983). Advanced carcinoma of the prostate: treatment with a gonadotrophin releasing hormone agonist. Brirish Medical Journal. 286, 1607- 1609.

Borgmann, V., Hardt, W., Schmidt-Gollwitzer, M., Adenauer, H. and Nagd, R. (1982). Sustained suppression of testosterone production by the luteinising hormone releasing hormone agonist Buserelin in patients with advanced prostate car- cinoma. Loncet. I, 1097-1099.

Byar, D. P. (1977). VACURG studies on prostatic cancer and its treatment. In Urologic Pathology: The Prostate, ed. Tannenbaum, M. Chapter 13, pp. 241-267. New York: Lea and Febiger.

Huggins, C. and Hodges, C. V. (1941). Studies on prostatic cancer I. The effect of castration, of oestrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Research, 1, 293r297.

Lmde, R., Doelle, G. C., Alexander, N., Kirchner, F., Vale, W., Rivier, J. and Rabm, D. (1981). Reversible inhibition of testicular steroidogenesis and spermatogenesis by a potent

New York State Journal oJMedicine, 81, 1481-1485. Yen, 5;. S. C., Tsai, C. C., Naftolin, F., Vandenberg, G. and

Ajahor, L. (1972). Pulsatile patterns of gonadotrophin release in subjects with and without ovarian function. Journal OJ

Clinical Endocrinology and Metabolism, 34, 67 1-615.

The Authors Gordon Williams, FRCS, Consultant Urologist. Janet M. Allen, BSc, MRCP, Research Fellow and Honorary

Registrar, Department of Medicine. J . P. O’Shea, MB, formerly Senior House Officer, Department

of Medicine. Now Medical Registrar, Queen Elizabeth I1 Medical Centre, Perth, Australia.

K. M ashiter, PhD, formerly Endocrinologist and Honorary Senior Lecturer, Medicine and Chemical Pathology. Now Manager-Research and Development Clinical Reagents Division, Amersham PLC, Amersham.

A. Doble, MB, Senior House Officer, Department of Surgery. S. R. Bloom, BSc, FRCP, Professor of Endocrinology,

Department of Medicine.

Requests for reprints to: Gordon Williams, Department of Surgery, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W 12 OHS.