Leuprorelin depot injection: patient considerations in the management of prostatic cancer

Figures & data

Table 1 Methods to interrupt the production of and/or block the action of testosterone

Methods	Action	Side effects
Orchiectomy	Surgical suppression of testicular male hormones leading to immediate drop in testosterone (Iversen 1998)	Limitations include its irreversible nature causing erectile dysfunction, occasional post-operative complications, and associated psychological factors (Cassileth 1989)
Estrogens	The negative feedback on the hypothalamus afforded by estrogen. Suppression of LHRH release and subsequent decrease not only of LH but also of FSH (Brawerr 2001)	Cardiovascular complications. gynecomastia is a common complaint
LHRH agonists	Over-stimulation of the LHRH receptors, followed by subsequent drop due to the loss the pulsatile secretion pattern (LSG 1984); the net effect is a reduction of testosterone to castration levels within 2–4 weeks	Testosterone surge and potential for clinical flare
LHRH antagonists	Inhibition of LHRH and subsequent rapid time to testosterone suppression with a higher rate of medical castration (Debruyne 2004)	-Safety of abarelix is comparable to that of LHRH agonists with or without anti-androgen -Cost -Increased liver enzymes
Anti-androgens	Block the binding of DHT to the androgen receptors in the prostate (Iversen 2001)	Gynecomastia, breast pain Diarrhea,visual disturbances
Inhibitors of alfa-reductase	Inhibit 5-alfa reductase conversion of testosterone to DHT in the prostate	Gynecomastia, breast pain, anemia
Ketoconazole	In high dose is able to produce castrate levels of androgens (both testicular and adrenal) within 4–8 h of the first dose (Lowe 1990)	Gastrointestinal disturbances and suppression of cortisol production which resulted in subsequent Addisonian crisis and sudden death (Pont 1987)

Abbreviations: DHT, dihydrotesterone; LH, luteinizing hormone; LHRH, luteinizing hormone-releasing hormone; FSH, follicle-stimulating hormone.

Table 2 Controversies around hormonal therapy for prostate cancer

HT modality	Argument for	Argument against
Early vs delayed HT	The appropriate time to initiate hormonal therapy for prostate cancer remains a matter of debate. Two recent studies provide convincing clinical evidence supporting the early treatment of advanced prostate cancer (Kirk 2000; Messing 1999). The randomized trial reported by the Medical Research Council (MRC) has shown more rapid local and distant disease progression in the deferred treatment group, increase in serious complications, such as pathologic fractures, spinal cord compression, and there was clear survival advantages associated with early hormone therapy for high risk malignancies (MRC 1997). Also in Eastern Cooperative Oncology Group (ECOG)/SWOG Stage D1 (N+) study (Messing 1999), the survival in the delayed therapy and immediate therapy arms was 65% and 85%, respectively.	Arguments for early hormonal therapy are countered, however, by a number of factors, including: The long natural history for most men of rising PSA levels before clinical metastases and death No randomized controlled clinical trials to confirm the survival advantage or to document the long-term effects of such therapy. The side effects of hormone therapy, particularly for younger men Cost of hormone treatment, particularly if over a long period of time. Studer et al (2006) has shown that there is no benefit in early versus delayed treatment in patients with clinically localized prostate cancer not suitable for radical therapy.
CAB	From 1980 to 1991, approximately 36 prospective, randomized studies were performed, 27 of them being reasonably well designed with at least 1 year of therapy. Of these, only 3 showed a statistically significant improvement in overall survival (Crawford 1989; Denis 1998). Although the overall benefit of MAB may be small, some patients will likely show a more substantial improvement in survival compared with androgen suppression alone. Should remain a reasonable option when discussing treatments for metastatic prostate cancer (Messing 1999). A recent Japanese study showed that first-line combination LHRH-agonists therapy with bicalutamide 80 mg in patients with advanced prostate cancer offered significant benefits over LHRH-A alone, with respect to TTTF,TTP, although the difference in the interim overall survival was not statistically significant (Usami 2007).	The lack of benefit in any of the other 24 studies led to much debate about the overall benefit of MAB in men with metastatic disease. The survival benefit for MAB of only 3% has led many experts to believe that the benefit is overshadowed by the therapy cost and side effects (Chodak 2004, ^Citation2005).
	This option became feasible only when medical castration became available. Advantages include reduction of side effects from therapy such as the physiological changes associated with castration, reduction of cost, and potentially delayed emergence of hormone refractoriness as evidenced by laboratory data (Sandford 1984).	Controversy remains as to which patients might benefit the most from intermittent hormonal therapy, when to start hormonal therapy, how long to treat before stopping, and when to restart subsequent cycles.
Intermittent hormone therapy	The most recent evidence is the mature experience of phase II trial from Ottawa group. Intermittent AS therapy was initiated in prostate-cancer patients to delay hormone resistance and minimize potential side effects of androgen-deprivation therapy (Malone 2007). Intermittent AS has also the potential to reduce side effects, including recovery of hemoglobin level, return of sexual function and absence of weight gain at the end of the study period (Malone 2005). Its use in D1 and D2 prostate cancer patients appears to be safe and feasible. Off treatment periods are >40% and contribute to patients’ quality of life (Miller 2007).
Anti-androgen alone	Monotherapy with bicalutamide 150 mg once daily provides a survival outcome that is not significantly different to that of castration in men with locally advanced, non-metastatic disease, while conferring significant advantages for sexual interest and physical capacity (Boccon-Gibod 1997; Pavone-Macaluso 1994).	The most common side effects of non-steroidal anti-androgen monotherapy are gynecomastia and male breast pain. These events occur more frequently than with castration alone (McLeod 1997; Migliari 1999).
	The administration of low-dose flutamide (125 mg) was clinically effective in treating PSA recurrence after definitive treatments for prostate cancer, and was well tolerated (Barqawi 2003).
Anti-androgen and Inhibition of 5-alfa reductase	The combination of finasteride and flutamide showed a moderate efficacy in patients with PSA-only recurrence after definitive therapy. The efficacy appears to be greater in patients who can achieve a PSA nadir of 0.1 ng/mL or less after the start of treatment (Barqawi 2003). This combination is also regarded as a potency-sparing therapy. It is inevitable that the overwhelming majority of men treated with pharmacologic or surgical castration will develop disease progression due to development and propagation of androgen-independent prostate cancer cells. Although it offers modest activity, it represents an alternative to early use of chemotherapy in patients with androgen independent disease.	Although the side effects are low, combined finaste-ride and flutamide therapy significantly lowers hemoglobin and haematocrit levels in men with advanced prostate cancer (Ornstein 1999).
Secondary HT	The strategy can be summarized as follow either the adjunction second-line non-steroidal anti-androgens or its withdrawal in case of initial CAB, the use of inhibitors of adrenal androgen production such as ketoconazole (Scholz 2005). The future direction would involve the development of molecules that effectively inhibit androgen receptor through changes in the ligand binding complex activating conformational changes or co-factor recruitment (Small 2006). Preclinical evidence supports the hypothesis that FSH signaling contributes to progression of AIPC. Patients on LHRH agonists have modestly reduced but detectable FSH levels, whereas patients treated with orchiectomy have significantly elevated FSH levels. Abarelix suppresses FSH more effectively than LHRH agonists when used as front-line hormonal therapy (Beer 2004).	Longevity following progression has historically been short, with a reported median of 6–9 months, given the lack of efficacious treatment options (Taneja 2003). With the development of potentially efficacious chemotherapeutic regimens, particularly taxane-based chemotherapies, secondary manipulation may delay therapy (Petrylak 2007).
PSA-only Recurence after Radical Prostatectomy	Moul et al in a large retrospective multi-center study, found that delayed hormonal therapy in high-risk disease (GS > 7 and PSA DT < 12 months) was associated with an approximately 2-fold increased risk of metastasis (Moul 2004). Whoever this study has the limitations of retrospective studies and requires validation to reach a meaningful result (Freedland 2005).	Retrospective study, revealed that patients with PSA recurrence who did not undergo hormonal deprivation therapy had a median actuarial time to metastasis of 8 years after PSA rise, only 34% had apparent metastases (Pound 1999). HT provides no benefit or might even harm men with low-risk/local disease (Leibovitz 2001).
Androgen deprivation as monotheraphy for localized prostate cancer	Primary ADT has long been the treatment of choice for localized and locally advanced prostate cancer in Japan and more evidence of its efficacy is accumulating. This trend is also on the rise in clinical practice in the USA (Akaza 2006). More evidence has been accumulating that progression of prostate cancer was retarded by primary hormone therapy in men with localized or locally advanced prostate cancer (Akaza et al 2006). Some authors described that triple androgen blockade (LHRH agonist+anti-androgens) therapy followed by finasteride main-tenance appears to be a promising for management of localized prostate cancer (Labrie 2002), and long-term and continuous CAB offers the possibility of long-term control or possible cure of localized prostate cancer (Janoff 2005).	ADT resulted in poor control of localized prostate cancer. In particular, younger patients and those with Gleason ≥ 6 cancers were at higher risk of treatment failure. And the toxicity, principally in the form of bone fractures, was high (Janoff 2005). Androgen deprivation as a primary therapy for localized prostate cancer provided modest disease control, but toxicity was high. Younger men with tumors of Gleason score ≥6 had a higher risk of biochemical progression (Kirk 2006).
Adjuvant HT	NAS can reduce the number of tumor clonogens prior to radiation, thus increasing the tumor control probability. Also, NAS may sensitize tumor cells to radiation if cell kill by both modalities follows a common pathway. The timing and sequence of NAS and radiation are important, with radiation being most effective if given at the point of maximal tumor regression (Zietman 2000; Hall 2000). Pilepich showed that the incidence of local failure at 10 years was 23% in the adjuvant arm, compared with 38% in the radiation alone The 10-year rate of distant metastases was 24% in the adjuvant arm, compared with 39% in the control arm (p < 0.0001) and concluded that adjuvant androgen suppression reduces disease progression and improves survival in patients with unfavorable-risk, high-grade prostate cancer treated with radiotherapy (Pilepich 2005).	The 5-year bRFS rate for patients with unfavorable tumors who received radiation doses of 72 Gy or greater vs less than 72 Gy was 75% and 41 %, respectively; thus the benefit might not be due to adding hormone to higher radiation dose (Lyons 2000). There appeared to be little if any benefit of adding neoadju-vant AS before high intensity focused ultrasound for men with presumed organ-confined prostate cancer (Uchida 2006). Neo-adjuvant and adjuvant HT before radical prostatectomy showed a significant reduction in the positive surgical margin rate, from 23% to 12% (p = 0.01) for patients who received 3 vs 8 months of neoadjuvant AST, but no cancer control outcomes (Gleave 2001). A recent study to evaluate NHT prior to radical prostatectomy for high-risk prostate cancer, showed that biochemical failure was frequent after this combined treatment, even in a pT0 ca which questions the use of modality in this category of patients (Tabata 2006).

Abbreviations: ADT, androgen deprivation therapy; AIPC, androgen-independent prostate cancer; AS, androgen suppression; DHT, dihydrotesterone; CAB, complete androgen blockade; HT, hormone therapy; LH, luteinizing hormone; LHRH, luteinizing hormone-releasing hormone; FSH, follicle-stimulating hormone; MAB, maximum androgen blockade; NAS, neoadjuvant androgen suppression; NHT, neoadjuvant hormonal therapy; PSA, prostate-specific antigen; TTTF,. time-to-treatment failure; TTP, time-to-disease progression.

Table 3 Leuprorelin: comparative studies to other androgen suppression modalities

	Testosterone lowering/blocking method	Comment	Reference
Leuprorelin	Orchietomy	Equivalent, orchiectomy, cost effective but associated with psychological complications	(Parmar 1985; Cassileth 1989; Iversen 1998; McLeod 2003)
	Estrogens (DES 3 mg) vs 1 mg/day leuprorelin	Equivalent, less cardiovascular side effects with leuprorelin.	(LSG 1984)
	Other LHRH agonists	No meaningful difference among the various approved GnRH agonists.	(Seidenfeld 2000)
	LHRH antagonists (aberalix)	Short time to testosterone suppression.	(McLeod 2001; Debruyne 2004)
		No testosterone surge with aberalix.
		Safety is comparable to that of
		LHRH agonists with or without anti-androgens.

Abbreviation: LHRH, luteinizing hormone-releasing hormone.

Table 4 Leuprorelin formulas and testosterone suppression

Leuprorelin formula	Injection volume (mL)	Testosterone castrate level		Authors
		50 ng/dL	20 ng/dL
7.5 mg monthly	0.250	100.0%	97.5%	Perez-Mareno 2002
22.5 (3 month)	0.375	98%		Berges 2006
		98%	84%	Chu 2002
30 mg (4 month)	0.500	96%		Sharifi1998
45.0 mg (6 month)	0.375	99%	88%	Crawford 2006

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