Prostate Cancer and Prostatic Diseases (2003) 6, 187–189 & 2003 Nature Publishing Group All rights reserved 1365-7852/03 $25.00 www.nature.com/pcan Randomised crossover trial to assess the tolerability of LHRH analogue administration

G Williams1, S Lindsay1 & WG Bowsher1* 1Department of Urology, Royal Gwent Hospital, Newport, UK

Luteinising hormone releasing hormone (LHRH) analogues are routinely used in the treatment of patients with advanced prostate cancer. This randomised crossover trial was conducted to compare patient comfort and tolerability between two commonly used LHRH analogues: goserelin acetate and leuprorelin acetate. A total of 50 patients were randomised into two groups, each receiving 6-monthly injections of leuprorelin acetate (a liquid presentation) and goserelin acetate (a depot pellet) and crossing over between treatments. Patients completed a simple visual analogue score for the discomfort felt from the injections. An analysis of variance model was used, and the results found that patients do tolerate leuprorelin acetate (0.589) better than goserelin acetate (1.343) (Po0.001, CI ¼ 95%). Prostate Cancer and Prostatic Diseases (2003) 6, 187–189. doi:10.1038/sj.pcan.4500625

Keywords: LHRH analogues; tolerability; patient discomfort

Introduction While the efficacy of the preparations is similar, it is the administration of the medication that differs. Prostate cancer is the most common male cancer in Goserelin acetate is given subcutaneously as a depot Western countries and the second most common cause of pellet in the abdomen via a 16 Ch needle, often with the cancer death. The past 20 years have seen a 50% increase need for a local anaesthetic. Leuprorelin acetate, how- in the number of new cases diagnosed each year. With ever, is given as a liquid subcutaneously or intramuscu- the age of the population continuing to rise, it looks larly through a smaller needle (23 Ch or 21 Ch). While certain that the incidence of prostate cancer will both are well-established treatments, patient acceptabil- increase.1 ity of these different forms of administration has not For patients with advanced prostate cancer, luteinising been assessed. This study was undertaken to investigate hormone releasing hormone (LHRH) analogues such as whether there is a difference in patient tolerability leuprorelin acetate or goserelin acetate are most often between the two methods of administration. used. LHRH analogues are recommended by the British Association of Urological Surgeons (BAUS) as an alter- native to orchidectomy in the first-line treatment of metastatic prostate cancer.2 The analogues work by Methods suppressing the action of serum testosterone, and have been shown to produce a temporary remission of tumour Patients who were undergoing LHRH analogue therapy, growth in about 85% of patients. Treatment is given by a for prostate cancer, were recruited from the urology monthly or 3-monthly injection into the skin or abdomen. clinic at The Royal Gwent Hospital, Newport. The Often the treatment is combined with another type of patients were randomised into two groups, both receiv- anti-androgen therapy. Occasionally, other drugs will be ing a run-in period of 8 weeks goserelin acetate. This was used in the treatment, and severe pain in the bones often to allow the patients to normalise to the injection without responds dramatically to treatment with radiotherapy. a local anaesthetic. Four subsequent injections were given to all patients. Group A received two leuprorelin acetate injections followed by two goserelin acetate injections and Group B received two goserelin acetate injections followed by two leuprorelin acetate injections. *Correspondence: Mr WG Bowsher, Department of Urology, Royal Gwent Hospital, Newport NP20 2UB, UK. All the injections were administered monthly/4-weekly E-mail: [email protected] and without a local anaesthetic. The same nurse gave the Received 30 May 2002; revised 12 July 2002; accepted 24 July 2002 injections. Tolerability of LHRH analogue administration G Williams et al 188 At each visit, the patients recorded their experiences on a questionnaire including a simple Visual Analogue Symptom Scale (ranging from 0 ¼ no discomfort to 10 ¼ worst discomfort) to assess the level of discomfort experienced. Their discomfort was recorded both im- mediately after the injection and also 2 h later. An analysis of variance model was used to evaluate any treatment effects, with the between-patient factors of sequence LG (Group A) and GL (Group B) and patient and the within-patient factors of periods 1 and 2 and treatment being fitted. Due to the discrete nature of the data, a supportive nonparametric Wilcoxon matched- pairs rank sum test was also performed.

Results A total of 50 patients were entered into the study, with 25 patients being randomised into each group. Of the patients, four were staged as having T2 disease, 26 as Figure 1 Discomfort scores for periods 1 and 2 experienced immediately T3, and 20 as T4. The mean age of the patients after the injection and also 2 h later. (Group A ¼ goserelin acetate (G) participating in the trial was 73 years (range 48–89). followed by leuprorelin acetate (L), Group B ¼ leuprorelin acetate (L) The length of time diagnosed with prostate cancer varied followed by goserelin acetate (G)). from 0 to 134 months (mean 20). The PSA levels on entering the study varied from 0.2 to 850 mg/l (mean in the run-in period. For the purposes of the summary 81.8 mg/l). While 40% (20) of the patients had received and analysis, the means of doses 3–4 (period 1) and 5–6 previous treatment for prostate cancer, only 26% (13) had (period 2) were used for each period. The results of these previously received LHRH analogues. scores are summarised in Figure 1. Of the 50 patients randomised, 42 (84%) completed the Of the 25 patients randomised to Group A, 24 patients 6-month study period and were included in the analysis. provided data for period 1 and 20 patients for period 2. Of the eight patients who withdrew, five were from Similarly, of the 25 randomised to Group B, 21 patients Group B and three were from Group A. The reasons for provided data for period 1 and 21 patients for period 2. withdrawal were: wished GP to give injection rather than Table 2 shows a summary of the results of the analysis continue at hospital (3); reluctance to have goserelin of variance. A difference (95% CI) between the treatment acetate without local anaesthetic (2); wanted surgical groups of 0.75 (0.42, 1.09) was observed for the pain castration (1); change in family circumstances, which no discomfort scores immediately after injection, in favour longer enabled continuation (1); and a reluctance to of the leuproprelin acetate group. This difference was change from usual treatment (goserelin acetate) (1). statistically significant (Po0.001). Discomfort scores 2 h The data from doses one and two were not used in the after injection also showed leuprorelin acetate injections analysis but are summarised in Table 1. This shows that to be less painful, but this result was not found to be both groups had similarly matched scores for discomfort statistically significant. The results of the supportive analysis were consistent with those given above. A sub- group analysis confirmed the same trend in all T-stage Table 1 Mean discomfort scores groups.

Run-in period Period 1 Period 2

Group A Goserelin acetate Leuprorelin (L) Goserelin (G) acetate acetate Conclusion 1.57 0.677 1.213 Group B Goserelin acetate Goserelin (G) Leuprorelin (L) The results of the study found that patients do tolerate acetate acetate leuprorelin acetate better than goserelin acetate, with a 1.53 1.33 0.5 statistically significant difference being observed be- tween the patients’ discomfort immediately after the

Table 2 Analysis of variance results

Time point Treatment No. Least square (LS) mean Diff (LÀG) (95% Cl) P-value

Immediately Leuprorelin 45 0.589 Goserelin 41 1.343 À0.754 (Àl.085, À0.424) o0.001 2 h later Leuprorelin 45 0.388 Goserelin 41 0.579 À0.191 (À0.431, 0.048) 0.114

Prostate Cancer and Prostatic Diseases Tolerability of LHRH analogue administration G Williams et al 189 injection. After receiving leuprorelin acetate, patients relin acetate, and this combined with leuprorelin acetate perceived goserelin acetate injections to be more un- being administered with a smaller needle also raises the comfortable than those who had not experienced the possibility of patient self-administration. comfort of the leuprorelin acetate injection. Additionally, the lowest mean score was recorded immediately after the leuprorelin acetate injections in the arm where patients received four consecutive goserelin acetate References injections first. Only one of the 50 patients dropped out of the study because he did not like to switch between 1 Pienta KJ. Etiology epidemiology, and prevention of carcinoma of the prostate. In: Walsh PC, Retik AB, Darracott Vaughan E, Wein the LHRH analogue therapies, showing an overall AJ, (eds). Campbell’s Urology, (7th edn.) WB Saunders Company, acceptability by the patients of interchanging the two Philadelphia, pp 2489–2496. (1998) treatments. There were also no adverse medical con- 2 The RCR COIN/BAUS Prostate Cancer Working Group. sequences observed in switching treatments. These Guidelines on the management of prostate cancer. BJU Int 84: results confirm the patients’ better tolerance of leupro- 987–1014. (1999)

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