Improving Flexibility and Quality of Life for Your Patients: A Must?

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1 EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) available at journal homepage: Improving Flexibility and Quality of Life for Your Patients: A Must? Axel Heidenreich * Universitätsklinikum der RWTH Aachen, Klinik und Poliklinik für Urologie, Pauwelsstr. 30, Aachen, Germany Article info Keywords: Androgen deprivation therapy Clinical practice Communication Prostate cancer Tolerability Quality of life Abstract Context: Prostate cancer (PCa) and androgen deprivation therapy (ADT) have a significant impact on the quality of life (QoL) of patients. Therefore, QoL is an important factor to be considered before and during ADT, and appropriate measures should be taken to maintain or improve it. Objective: This paper discusses several aspects considered important in the maintenance or improvement of the QoL of PCa patients treated with ADT. Evidence acquisition: During the 2009 European Association of Urology (EAU) Congress in Stockholm, Sweden, a satellite symposium was held on PCa. This paper is based on one of the presentations held at this symposium. Data were retrieved from recent review articles, original articles, and abstracts. Evidence synthesis: Effective, patient-centred communication will ensure that the patient is well informed about the treatment and its potential side-effects, may reduce suffering, and enhances the patient s well-being. ADT may induce side-effects that affect QoL and also cause potentially serious medical problems. Therefore, measures should be taken to prevent or manage these side-effects before and during ADT. Integrating the patient s expectations, preferences, and needs in daily clinical practice, such as during treatment decisions, will ensure well-informed decisions and may minimise future regret and improve treatment satisfaction. A treatment such as the luteinising hormone-releasing hormone agonist Eligard 1, which is available in 1-, 3- and 6-mo depot formulations, enabling administration at different time intervals, offers patients flexibility and is another step in improving QoL. Conclusions: QoL is an important factor to be considered before and during ADT for PCa. Effective and open communication between the patient and physician, prevention and management of ADT-related side-effects, and integration of patient s expectations in clinical practice are measures that can be taken to maintain or improve the QoL of ADT-treated patients. # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Tel. +49 (241) ; Fax: +49 (241) address: aheidenreich@ukaachen.de. 1. Introduction Since the 1940s, when Huggins and Hodges demonstrated that prostate cancer (PCa) is an androgen-dependent cancer, androgen deprivation therapy (ADT) has been the standard treatment for advanced and metastatic PCa [1,2]. In symptomatic patients, ADT aims to palliate symptoms and to reduce the risk of potentially devastating complications of advanced disease, such as spinal cord compression, pathologic fractures, ureteral obstruction, and extraskeletal /$ see front matter # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eursup

2 858 EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) metastasis. In asymptomatic patients, the goal of treatment with ADT is to defer progression to a symptomatic stage and to prevent serious complications related to disease progression [2]. Although ADT clearly has benefits, it may also induce side-effects and adversely affect the patient s quality of life (QoL). A study in 661 men with T1-2 PCa evaluated the impact of 1 yr of treatment with ADT on QoL [3]. A total of 245 of these men received ADT (78% received a luteinising hormone-releasing hormone [LHRH] agonist), and 416 received no treatment. Patients receiving ADT more often reported poor or fair overall health, bother from PCa, limitations in daily activities because of PCa, and physical discomfort because of PCa. However, patients receiving ADT were also more likely to be satisfied with their treatment, worried less about their PCa, and more often believed that they were free of PCa. This study clearly shows that PCa and ADT may affect QoL. Obviously, the benefits and risks of ADT need to be optimally balanced for every patient, which is especially relevant in the setting of noncurative ADT. But how can we make sure that the risks of ADT do not outweigh its benefits? In other words, how can we maintain or even improve the QoL of patients treated with ADT? This quality involves not only the prevention and management of ADTrelated side-effects but also open and effective communication between the patient and his physician as well as integration of the patient s expectations concerning the overall management of PCa [4]. This paper discusses the importance of these measures in maintaining or improving the QoL of PCa patients treated with ADT. 2. Evidence acquisition This paper is based on a presentation given at a satellite symposium on PCa that was held during the 24th annual meeting of the European Association of Urology (EAU) on 18 March 2009 in Stockholm, Sweden. Data were retrieved from recent review articles, original articles, and abstracts. 3. Evidence synthesis 3.1. Effective communication between patient and physician PCa is, as other cancers, characterised by high levels of stress, uncertainty, complex information, and life-altering medical decisions [5]. Patient physician communication is especially important in this setting as a means of providing information, ameliorating suffering, enhancing the patient s emotional well-being, and offering practical and social support. The patient s QoL can be improved when clinicians are attentive to the patient s symptoms, functioning, and well-being attentiveness that requires effective communication among the patient, his family members, and the physician. The basic principles of effective communication in cancer care are based on patient-centred care that embraces three core values: (1) consideration of patients needs, perspectives, and individual experiences; (2) provision of opportunities to patients to participate in their care; and (3) enhancement of the patient clinician relationship [6]. These principles lead to patient-centred communication that aims to (1) elicit, understand, and validate the patient s perspective (eg, concerns, feelings, expectations); (2) understand the patient within his own psychological and social context; (3) reach a shared understanding of the patient s problem and its treatment; (4) help a patient share power by offering him meaningful involvement in choices related to his health; and (5) build strong patient clinician relationships characterised by mutual trust, respect, and commitment [6]. To communicate effectively, both clinicians and patients need knowledge, skills, and motivation [5]. The ability of a patient to engage in a dialogue is critical in this regard. In addition, an accessible, well-organised, responsive health care system that facilitates communication is necessary [5]. Patient-centred communication includes, for example, a thorough and careful explanation of the different treatment options, the goals and mechanism of treatment, and their potential side-effects prior to initiation of ADT. This communication will result in a wellinformed patient who also knows about the potential sideeffects of treatment, enabling him to initiate strategies to manage or prevent these side-effects when treatment is started. It also requires that the health care system is easily accessible at all times so that patients can consult physicians and health care providers in case of occurrence of side-effects. Patient involvement in the medical decision-making process should also be an essential part of patient-centred communication. The consideration of values and preferences of patients regarding treatment decisions will result in a well-considered treatment decision, can minimise future regret, and will result in a higher patient satisfaction [4]. When performed carefully, patient-centred communication can thus be a means of enhancing the patient s well-being and reducing the patient s suffering Management of androgen deprivation therapy s side-effects Side-effects of androgen deprivation therapy Although ADT has beneficial effects, it may also induce sideeffects [7]. Until recently, most studies have focused on the short-term symptomatic side-effects such as hot flushes, loss of libido and erectile dysfunction, fatigue, and psychological effects such as emotional instability or depression [8 10]. Recently, however, it has become clear that a substantial part of ADT s related morbidity comes from long-term side-effects that are mostly hidden for the patient [8], including accelerated bone loss leading eventually to osteoporosis and potentially fractures [7]. In addition, ADT may lead to lipid changes, obesity or an increase in fatty tissue, loss of muscle mass, and many of the features of a metabolic syndrome such as increased subcutaneous mass, increased high-density lipoprotein (HDL) cholesterol, and increased adiponectin levels [7,9]. One of the causes of these metabolic changes during ADT is the rapid induction of peripheral resistance to insulin, which may lead to type 2 diabetes mellitus [10,11].

3 EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) increased functioning in verbal memory. It should be noted that although these studies were designed relatively well, they generally only included a small number of patients. Fig. 1 Rate of incident coronary heart disease, myocardial infarction, and sudden cardiac death in prostate cancer patients receiving androgen-deprivation therapy (ADT) or no treatment [12]. The metabolic changes associated with ADT may also have significant consequences for the cardiovascular health of ADT-treated men. Population-based studies have shown that ADT indeed increases the risk of diabetes and cardiovascular morbidity [12 14]. For instance, in an observational study including men with locoregional PCa, it was shown that ADT-treated patients had statistically significantly higher rates of incident coronary heart disease, myocardial infarction (MI), and sudden cardiac death (SCD) than patients receiving no hormone treatment (Fig. 1) [12]. The rate of incident diabetes was also statistically significantly higher in ADT-treated men versus men receiving no ADT (29% vs 20.9%, respectively; p < 0.001). However, a recent analysis of the phase 3 European Organisation for Research and Treatment of Cancer (EORTC) trial, which included 415 patients with locally advanced PCa, suggested that long-term adjuvant ADT to radiation therapy (RT) does not increase cardiovascular toxicity over RT alone [15]. Long-term ADT was given by means of an LHRH agonist over a period of 3 yr; the median follow-up was 9.1 yr. The 10-yr cumulative incidence of cardiovascular mortality was 11.1% for patients treated with RT alone and 8.2% for patients treated with RT and long-term adjuvant ADT (hazard ratio: 1.11; 95% confidence interval, ; p = 0.75). Although the difference in outcome between these two studies may be partly the result of the inclusion of different study populations, further research is needed to determine the effect of ADT on cardiovascular morbidity and to identify men at highest risk of these adverse events. Next to the previously discussed side-effects, ADT may also affect cognitive function. Studies on older or hypogonadal men suggest that testosterone has a significant impact on cognitive performance, such as visuospatial abilities, verbal fluency, memory, and working memory [16]. A systematic literature review, including nine clinical trials evaluating the impact of ADT on cognitive function, showed that, overall, between 47% and 69% of ADT-treated patients declined in at least one cognitive area, most commonly in visuospatial abilities and executive functioning [16]. However, some studies reported contradictory results, with Managing side-effects of androgen deprivation therapy Because the side-effects of ADT can not only be bothersome and seriously affect QoL but also potentially cause serious medical problems, they should be carefully monitored. In addition, appropriate actions need to be taken to prevent and manage side-effects, and in this regard, physicians should adopt a proactive attitude. Before initiation of ADT and also during ADT, the physician should assess the general risk on developing potential consequences of ADT, such as diabetes, cardiovascular disease, or osteoporosis. For example, before and during ADT, the physician should closely monitor the patient s bone mineral density (BMD) in order to assess the risk of osteoporosis and to be able to provide early treatment [17]. Early measurement of BMD can be done by dual energy x-ray absorptiometry. The spine is the preferred site for the serial measurement of bone mass to monitor changes in BMD. The hip can be used as an alternative when the spine is technically inaccessible. Interdisciplinary panels have attempted to provide recommendations for monitoring and treatment of osteoporosis [18]. These expert panels recommend BMD assessment of patients before initiation of ADT and regular follow-up during treatment. As ADT may also induce several endocrinologic and cardiovascular diseases, a colleague endocrinologist or internist can also be consulted to assist in the diagnosis and treatment of these problems. Patients and their family should be informed about the potential side-effects of ADT as early as possible, which may help them recognise, prevent, and manage these effects. For example, explaining to the patient that he may experience problems with his memory may help him cope with this side-effect. Introducing the patient to some moderate, practical, and realistic beneficial dietary and lifestyle changes may promote general health during ADT and may moreover prevent some of the side-effects [17]. For example, dietary advice may help patients adopt a healthy diet to minimise ADT-related metabolic changes, cardiovascular side-effects, and osteoporosis. Physical exercise may prevent or minimise the decrease in BMD and increase in body mass. Furthermore, physical exercise may help fight fatigue, alleviate anxiety and depression, and improve QoL. For patients >65 yr, supplementation with calcium and vitamin D should be discussed to prevent osteoporosis [17]. One side-effect of ADT that may severely bother the patient are hot flushes, also referred to as hot flashes. Hot flushes are one of the most frequent side-effects of ADT, with up to 80% of patients describing it [10]. Mild to moderate hot flushes can in most cases be managed with lifestyle changes such as wearing loose clothing of natural fibres, avoiding food or beverages that trigger hot flushes, and avoiding large temperature changes [17]. However,in moderate-to-severe hot flushes, drug therapy may be required. A number of treatments have been used in the management of hot flushes, such as megestrol acetate, cyproterone acetate, and low-dose diethylstilbestrol.

4 860 EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) Fig. 2 The median percent decrease from baseline in hot flush frequency and hot flush score after 4 wk of treatment with placebo or gabapentin 300, 600, or 900 mg/d [19]. Unfortunately, many of these treatments have little evidence supporting their use, and many are based on the treatment of hot flushes in women [10].Aninteresting recent development in the treatment of hot flushes comes from studies evaluating gabapentin, a drug originally developed to treat epilepsy but currently mainly used for the relief of pain. A 4-wk double-blind trial compared gabapentin (at doses of 300, 600, or 900 mg/d) with placebo for treatment of hot flushes in 214 PCa patients on stable ADT experiencing bothersome hot flushes [19]. Frequency and severity of hot flushes were assessed by means of a questionnaire. A hot flush score was computed by assigning points (1, mild; 2, moderate; 3, severe; 4, very severe) to eachhotflushbasedonreportedseverity,summingthe points for each day, and averaging daily scores across each week of the study. Fig. 2 shows the median percent decrease from baseline in hot flush frequency and score after 4 wk of treatment with placebo and gabapentin. The change from baseline in hot flush frequency after 4 wk of treatment with the highest gabapentin dose (900 mg/d) was statistically significantly different from that with placebo ( p = 0.02). The difference between placebo and 900 mg/d of gabapentin in change from baseline in hot flush score approached statistical significance ( p = 0.10). Gabapentin may thus decrease hot flushes, to a moderate degree, in ADT-treated men. Other recent developments in the prevention and treatment of some ADT side-effects are selective oestrogen receptor modulators, such as raloxifene and toremifene. In an ongoing 24-mo double-blind, randomised, placebocontrolled phase 3 trial, Smith et al evaluate whether toremifene (80 mg/d) could prevent incident morphometric vertebral fractures in 1392 ADT-treated PCa patients [20]. An interim analysis of the first 197 subjects after 12 mo of treatment showed that toremifene statistically significantly increased the BMD of the hip and spine (Table 1). Although this conclusion needs to be confirmed by the final results of this trial, these interim results suggest that toremifene may decrease the risk of fractures in ADT-treated men. In the same study, the effect of toremifene on fasting serum lipids was assessed. An interim analysis at 12 mo in 188 patients showed that toremifene (80 mg/d) improved lipid profiles in men receiving ADT compared to placebo. Toremifene statistically significantly decreased mean total cholesterol, low-density lipoprotein cholesterol, and triglycerides and increased HDL cholesterol versus placebo (Table 2) [21]. Although further research is required, toremifene may prevent the loss of bone mass and changes in lipid profile associated with ADT and may therefore prevent osteoporosis and cardiovascular disease Integration of the patient s expectations in clinical practice To improve the QoL of patients treated with ADT, it is not only important to have effective communication between patients and physicians and prevent or manage the ADTrelated side-effects but also to integrate the expectations of Table 1 Toremifene (80 mg/d) statistically significantly increases the bone mineral density of the lumbar spine, total hip, and femoral neck compared to placebo in men treated with androgen-deprivation therapy [20] Change ( SD) from baseline at 12 mo (%) Toremifene (n = 93) Placebo (n = 104) p value Lumbar spine BMD +1.6% 0.4% 0.7% 0.3% <0.001 Total hip BMD +0.7% 0.6% 1.3% 0.3% Femoral neck BMD +0.2% 0.4% 1.3% 0.4% SD = standard deviation; BMD = bone mineral density. Table 2 Toremifene (80 mg/d) statistically significantly improves the lipid profile of men treated with androgen deprivation therapy compared to placebo [21] Change ( SD) from baseline at 12 mo (%) Toremifene (n = 89) Placebo (n = 99) p value Total cholesterol 8.1% 1.4% 1.0% 1.7% LDL cholesterol 8.2% 2.5% +0.8% 2.5% HDL cholesterol +0.5% 2.2% 4.9% 1.2% Triglycerides 13.2% 3.6% +6.9% 4.2% SD = standard deviation; LDL = low-density lipoprotein; HDL = high-density lipoprotein.

5 EUROPEAN UROLOGY SUPPLEMENTS 8 (2009) the patient regarding his treatment in daily clinical practice. A recent survey examining the attitude of 200 PCa patients from five European countries regarding their needs and expectations during ADT showed that although these men want an effective treatment, the majority also wants to maintain their lifestyle during therapy (83% of respondents) and to be involved in the decision-making process (69% of respondents) [22,23]. About two-thirds of these men indeed found it important that the physician considers their lifestyle during treatment decisions, which agrees with the importance of patient-centred care discussed above. With regard to their ADT, two-thirds of patients also indicated that the convenience of a simple, easy injection is important. Over the past years, there have been several developments in ADT, particularly with regard to LHRH agonist depot injections. Although in the beginning only 1-mo injections were available, now 3-mo and 6-mo formulations are at the patient s disposal, with the main purpose of improving flexibility for both the patient and the physician while maintaining similar efficacy. For example, Eligard 1, a novel, extended-release formulation of leuprolide acetate using the polymeric delivery system Atrigel 1,is available in 1-, 3-, and 6-mo depot formulations. In three multicentre, open-label studies, 99% of patients achieved a testosterone level 50 ng/dl with the 6-mo formulation of Eligard, while this level was 100% for the 1- and 3-mo formulations [24 26]. However, it is increasingly being recognised that the appropriate castration level of testosterone should refer to that achieved after the gold standard bilateral orchidectomy (ie, 20 ng/dl) [22]. In this regard, it is important to note that with the 1-, 3-, and 6-mo depot formulations of Eligard, testosterone levels 20 ng/dl were achieved in 98%, 94%, and 88% of the patients, respectively [24 26]. Mean testosterone levels plus or minus standard deviation at the end of the studies were ng/dl, ng/dl, and ng/dl on the Eligard 1-, 3-, and 6-mo depot formulations, respectively. The rate of testosterone escapes was very low with all three formulations. No patients experienced injection-related testosterone escapes (mini-flares), and the subset of patients experiencing breakthrough testosterone escapes was 1% with the 3- and 6-mo formulations of Eligard, while 0% with the 1-mo formulation. As the different Eligard formulations are equally effective in suppressing testosterone to a level comparable to that achieved with bilateral orchidectomy, patients are free to choose the treatment that fits best their lifestyle. Patients who travel frequently or who have transportation difficulties or patients who experience visits to the physician as a severe emotional distress may benefit from prolonged treatment with the 6-mo Eligard formulation [22]. In contrast, patients who prefer close follow-up by a physician might choose a 1- or 3-mo formulation. From the European survey of ADT-treated PCa patients, it appears that 68% of respondents would prefer injections once every 6 mo rather than every 3 mo or every month [23]. Mainly younger (<70 yr of age) patients prefer fewer injections. The idea of less discomfort and pain, improved QoL, fewer reminders of the disease, and less restrictions in undertaking activities were indicated as the main reasons to prefer fewer injections. The development of depot LHRH formulations that require fewer injections is another step in improving the QoL of ADT-treated PCa patients. However, even if the treatment is flexible and therefore the frequency of physician visits and injections can be determined by the patient, regular visits to the physician for overall management of PCa (eg, for the measurement of testosterone levels and management of side-effects) are still important [22]. 4. Conclusions It is evident that the patient s QoL is an important factor to be considered before initiating ADT and during ADT. Appropriate measures should be taken to maintain or improve the patient s QoL during ADT. Effective patientcentred communication will ensure that the patient is well informed about treatment and its side-effects and may additionally enhance the patient s well-being. As ADT may induce side-effects that can not only be bothersome and seriously affect QoL but also potentially cause serious medical problems, measures should be taken to prevent or minimise these effects. It is also clear that nowadays, in modern urologic oncology, we should involve the patient and consider their expectations and needs in the treatment decision process. The consideration of values and preferences will result in a well-considered treatment decision that can minimise future regret and result in higher patient satisfaction. The availability of the three different Eligard depot formulations, which can be administered at different time intervals, offers patients more flexibility and is another step in improving their QoL. Conflicts of interest Prof. Heidenreich is a consultant for Astellas, Ipsen Pharma, Ferring Gmbh Germany, Sanofi-Aventis, Bayer Ag, Pfizer, and Centocor. Funding support The publication of this review was supported by Astellas Pharma Europe Ltd. Acknowledgements The author is grateful to Ismar Healthcare NV for assistance with writing the manuscript. References [1] Huggins C, Stevens R, Hodges CV. Studies on prostatic cancer. II. 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