The Journal of International Medical Research 1990; 18 (suppl 1): 74 - 78

Clinical Experience with Leuprorelin Acetate Before Radiotherapy for Prostatic Cancer S. Bourdin', G. Karam', P. Clemain", O. Bouchot", P. Peuvrel', J. Lacoste' and J. Auvlgne' 'Centre Rene Gauducheau CRLC de Nantes, France; 2Clinique Urologique CHU de Nantes, France; "Clinique Saint Francois, Nantes, France

A total of 40 patients with stages A2 to C prostatic cancer were treated with leuprorelin acetate depot once a month for 2 months before being treated by pelvic irradiation or radical prostatectomy. In the 32 patients who were evaluable, seven (22% ) were classified as minor responders after leuprorelin treatment and 23 (72%) as major responders when assessed by rectal examination. Prostate-specific antigens also returned to normal concentrations (5 ng/ml) in 26/31 (84%) patients. Leuprorelin acetate depot suppressed plasma testosterone concentrations to castration values during treatment, but concentrations returned to normal 2 months after completion of treatment. Following radical treatment, there were three deaths - one postoperative and two due to recurrent disease - but there was no isolated local relapse. It is concluded that the protocol was locally well tolerated and was etTective in the treatment of stages B2 and C prostatic cancer patients. Quarante malades au total soutTrant de cancer prostatique de stade A2 it C ont ete traites par I'acetate de Ieuproreline sous forme retard une fois par mois pendant 2 mois avant d'etre soumis it une irradiation pelvienne ou it une prostatectomie radicale. Sur les 32 malades evalues, sept (22%) ont ete classes comme manifestant une legere amelioration suite it un traitement par leuproreline et 23 (72% ) comme presentant une amelioration considerable suite it un examen rectal. Les concentrations en antigenes specifiques it la prostate sont egalement revenues it la normale (5 ng/ml) chez 26/31 (84%) des malades. L'acetate de leuproreline retard a diminue les concentrations plasmatiques en testerone pour les amener it des valeurs de castration durant Ie traiteAddress for correspondence: Dr S. Bourdin, Centre Rene Gauducheau, Quai Moncouso, 44035 Nantes Cedex 01, France.

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Leuprorelin acetate before radiotherapy

ment, les concentrations sont toutefois revenues it la normale 2 mois apres la fin du traitement. Suite it un traitement radical, on a deplore trois deces - un deces post-operatif et deux autres dils it une recidive de la maladie - on n'a toutefois pas note de rechute locale lsolee. On en a conelu que Ie protocole avait bien ete tolere du point de vue local et que ce medicament etait efficace dans Ie traitement des cancers prostatiques de stades B2 et C. Un totale di 40 pazienti atTettida cancro prostatico, in stadi di sviluppo da A2 a C, sono stati trattati con leuprorelin acetato, in preparazione "ritardo", somministrato una volta al mese, per un periodo di 2 mesi, prima di essere sottoposti ad irradiazione pelvica od a prostatectomia radicale. Dei 32 pazienti valutabili, in seguito alia valutazione mediante esame rettale, sette (22 %) sono stati cIassificati come soggetti dalla risposta minima al trattamento con leuprorelin e 23 (72 %) sono stati elassificati come soggetti dalla risposta maggiore. Inoltre, gli antigeni prostato- specifici sono ritornati aile normali concentrazioni (5 nglml) in 26/31 pazienti (84%). Illeuprorelin acetato, in preparazione "ritardo", ha soppresso Ie concentrazioni plasmatiche di testosterone a valori analoghi a quelli ottenuti mediante castrazione, nel corso del trattamento; tuttavia, tali concentrazioni sono ritornate ai valori normali entro 2 mesi dal termine del trattamento. A seguito del trattamento radicale, si sono verificati tre decessi - uno postoperatorio e due dovuti a malattia recidiva - tuttavia non si e verificato alcun caso isolato di recidlvlta localizzata. Se ne desume che la terapia e stata ben tollerata a Iivello locale ed e risultata efficace nel trattamento dei pazienti atTetti da cancro prostatico negli stadi B2 e C. KEY WORDS: Leuprorelin acetate depot; prostatic cancer; radiotherapy.

INTRODUCTION

ocalized prostatic cancer is usually treated by surgery or radiotherapy. As far as radiotherapy is concerned, the position of the prostate in the pelvis makes it necessary to use relatively moderate irradiation doses in order to avoid complications in the rectum and bladder due to radiation-induced damage. Such doses, however, may prove to be insufficient in neutralizing tumours with a large volume, i.e. stages B2 and C. It would be useful, therefore, to be able to reduce the volume of the tumour medically before any radical treatment is carried out. An initial reversible and transient hormone therapy was proposed which

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consisted of using luteinizing hormone releasing hormone (leuprorelin) as medical treatment. This hormonal therapy was intended to avoid any unfavourable evolution due to a delay in implementing radical therapy, to overcome the final hormonesuppressive effect and to prevent any development of metastases once hormone therapy had been withdrawn. PATIENTS AND METHODS

Patients A total of 40 patients with localized epithelioma of the prostate (stages A2 to C) and a mean age of?l years (range 58 - 81 years) was included in the study conducted between April 1986 and May 1989 (Table 1). 75

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S. Bourdin, G. Karam, P. Clemain et al.

Table 1 Number of patients with various stages of cancer who were given leuprorelin acetate depot and subsequent therapy

Cancer stage

Leuprorelin acetate

Pelvic irradiation

7

5

2

10

6 9

A2 Bl B2

Radical prostatectomy

C

15 8

8

4 6 0

Total

40

28

12

Treatment protocol Patients received an injection of 3.75 mg leuprorelin acetate depot given once monthly subcutaneously after initial assessment had confirmed prostatic cancer. An anti-androgen (750 mg /day flutamide) was also administered for the first 14 days. During the third month of leuprorelin acetate treatment, radical therapy was implemented; the therapy applied had been decided before the start of agonist treatment and was not modified on the basis of the response to leuprorelin acetate depot. External radiotherapy was performed in 28 patients using a 25 MV particle accelerator giving a total dose of 45 Gy over 5 weeks (1.8 Gy per sessions, five sessions per week) delivered to the pelvis, including the prostate, seminal vesicles, and the internal and external iliac lymph nodes, using both anterior and posterior approaches. A scanner was used for localization and dosimetry, and an overdose of 20 Gy was applied over 2.5 weeks to a volume strictly localized to the prostate and seminal vesicles. Radical prostatectomy was performed in the remaining 12 leuprorelin acetatetreated patients. Postoperative radiotherapy was carried out if, after histological examination, there was histological resection at the lower limit, local extension to the capsule, histological evidence of inva-

sion of the seminal vesicle or prostatespecific antigen was higher than 0.5 at 4 weeks after surgery.

Clinical assessment Initial assessment involved rectal examination, a prostate biopsy assay ofserum prostatic acid phosphatase, prostate-specific antigen and testosterone, and a bone scan. Endorectal echography, pelvic scanning and intravenous urography were also performed in some patients. An intermediate assessment was carried out at the end of the first month's treatment in most cases and a further examination was performed at the end of the second month. This involved an evaluation of the percentage response to leuprorelin acetate depot measured by rectal examination and assays for prostatic acid phosphatase, prostate-specific antigen and plasma testosterone. Efficacy of local/regional treatment was assessed after 6 - 24 months. RESULTS

Clinical efficacy ofleuprorelin acetate depot therapy was assessed by rectal examination in 32 patients; this was not possible in the remaining six, who were all classified as stage A2 and could not satisfy evaluation requirements. Of the 32 successfully evaluated, two (6%) displayed no response, seven (22%) a minor response and 23 (72%) a

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Leuprorelin acetate before radiotherapy major response, with an almost complete response in 20 of these patients. Of the 31 patients assayed for prostatespecific antigen both before and after leuprorelin acetate depot treatment, 26 (84%) had prostate-specific antigen concentrations of greater than 5 ng/ml. Concentrations remained high in six patients after leuprorelin acetate treatment for 2 months and two of these patients later developed bone metastases. Initial prostatic acid phosphatase levels were 3 ng/ml or more in seven patients and remained high in two patients after treatment with leuprorelin acetate, who developed metastases after local treatment. Plasma testosterone concentrations fell to castration levels «3 ng/ml) in 39 patients after 2 months' leuprorelin acetate depot treatment. In the remaining patient, plasma testosterone concentrations were above the castration value 3 weeks after the second injection of leuprorelin acetate. Plasma testosterone concentrations remained at castration values in one patient when assayed at least 2 months after the completion of leuprorelin acetate therapy. In 24 patients, plasma testosterone concentrations increased to above 3 ng/ml when assayed 17 - 25 months after completion of therapy. Following local/regional treatment, one patient died postoperatively on day 15 and there were two deaths from intercurrent disease, one due to carcinoma of the colon and the other due to stroke. There was a total of four failures in the 40 patients: one, which occurred 14 months after the completion of radiotherapy, was a local relapse with the appearance of metastases, and in the other three there was no local relapse but in one metastases developed and in two prostate-specific antigen concentrations rose to above 200 ng/ml although there were no signs of bone abnormalities. Following leuprorelin acetate administration hot flushes were commonly experi-

enced, but they varied in intensity and only one patient found them distressing. Impotence was also commonly reported during leuprorelin acetate depot treatment. No moderate or severe gastro-intestinal or micturition disturbances were experienced by patients following radiotherapy. Following surgery, in addition to the one patient who died, two patients experienced severe incontinence. DISCUSSION

It is too early to evaluate leuprorelin ace-

tate depot for the long-term improvement in local control of prostatic cancer. Improved overall survival may be achieved by better local control; the aim of short-term hormonetherapy,therefore,wasnottocontrol micro-metastasis. There are three objections to the use of leuprorelin acetate prior to radical therapy - delay in radical treatment, defmitive hormone repression, the possibility of rebound effects after hormone therapy - which have been avoided. The delay in implementing radical therapy was balanced by the use of hormone therapy. Following treatment with leuprorelin acetate all patients experienced a decline in prostate-specific antigen and prostatic acid phosphatase levels. In addition, 72% of patients showed a decrease in tumour volume and none of the patients progressed under initialleuprorelin acetate therapy. After the discontinuation of initialleuprorelin acetate therapy all patients in whom serum testosterone concentrations were determined, with the exception of one, showed levels greater than castration values within 2 months of the completion of the overall course of treatment. No rebound was noted after the discontinuation of hormone therapy and only one patient presented with a local and general elevation of testosterone, but then only 16 months after the end of treatment. The two patients who experienced bone metastases 77

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S. Bourdin, G. Karam, P. Clemain et al.

were diagnosed 1 and 2 years after the completion of treatment. These patients were exceptional as they initially had elevated levels of the tumour markers: prostate-specific antigen was 110 ng/ml for one patient and prostate-specific antigen was 59 ng/ml and prostatic acid phosphatase was 17 ng/ml for the other patient. It, therefore, appears that initial hormone therapy had a favourable effect on the clinical and biochemical parameters, although the results when pathological samples were studied were more disappointing. It is concluded that clinical responses were favourable if initial reversible and transient hormone therapy was given prior to local/regionaltreatmentofprostatic cancer. Following radical treatment there was a high incidence of major responders, with a return of prostatic serum antigens to near normal values. In addition, the morbidity was not increased if leuprorelin acetate was administered before radical treatment. A further advantage of leuprorelin acetate was that there were no late complications when treatment with the luteinizing hormone releasing hormone was stopped. It is con-

eluded that this treatment protocol is particularly useful for patients with stage B2 or stage C prostatic cancer before undergoing radiotherapy. BIBLIOGRAPHY Bagshaw MA: Potential for radiotherapy alone in prostatic cancer. Cancer 1985; 55: 2079 - 2085. Bagshaw MA: Current conflicts in the management of prostatic cancer. lnt J Radiat Oneal Bioi Phys 1986: 12: 1721-1727. Leuprolide Study Group: Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N Engl Med J 1984; 311: 1281. Oesterling JR, Chan OW, Epstein JL, et al: Prostate specific antigen in the preoperative and postoperative evaluation of localized prostatic cancer treated with radical prostectomy. JUral 1988; 139: 766 - 772. Paulson OF, Lin GH, Hinshaw W, et al: Radical surgery vs. radiotherapy for stage A2 and stage B (Tl - 2 MO NO) adenocarcinoma of the prostate. J Ural 1982; 128: 502 - 504. Walsh PC, Lepor H, Eggleston JC: Radical prostatectomy with preservation of sexual function: anatomical and pathological considerations. Prostate 1983; 4: 473 - 485. Zagers GK, von Eschenbach AC, Johnson DE, et al: The role of radiation therapy in stages A2 and B adenocarcinoma of the prostate. Int J Radiat Oneal Bioi Phys 1988; 14: 701 - 709.

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Clinical experience with leuprorelin acetate before radiotherapy for prostatic cancer.

A total of 40 patients with stages A2 to C prostatic cancer were treated with leuprorelin acetate depot once a month for 2 months before being treated...
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