Hormone therapy in the management of prostate cancer: treating the cancer without hurting the patient

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1 Hormone therapy in the management of prostate cancer: treating the cancer without hurting the patient Authors Key words B. Tombal, A. Stainier Prostate cancer, hormone therapy, LHRH agonists, antiandrogens, side-effects Summary Hormone therapy (HT) is the mainstay systemic treatment of prostate cancer (PCa). Hormone therapy can be delivered by androgen deprivation therapies (surgical castration or LHRH agonists) or by antiandrogens. Conventionally, hormone therapy is considered as a palliative treatment since it rapidly alleviates cancer related symptoms such as pain or urinary obstruction but modestly improves survival. However, recent publications demonstrate that HT improves survival when it is used in adjuvant to external beam radiotherapy or radical prostatectomy in young patients with aggressive disease. However, treating asymptomatic men for long periods of time also raises new concerns on sideeffects. Recent data indicate an increased risk of developing severe complications such as metabolic syndrome, diabetes and cardiovascular events. This implies that physicians have to adapt to these new indications and learn to deliver HT in a more holistic approach in compliance with today s challenges. (BJMO 2008;vol 2;4:205-11) Introduction Despite sixty years of intense use, hormone therapy (HT) basically still is used as described by Charles Huggins in the 1940s. 1 Since then, Luteinising Hormone Releasing Hormone (LHRH) agonists have replaced surgical castration as the main modality of androgen deprivation therapy (ADT) and peripheral antiandrogens have been introduced. With the introduction of prostate specific antigen (PSA) screening, men are often diagnosed when still asymptomatic. HT is rarely prescribed, primarily to alleviate symptoms. Nowadays, HT is more frequently started at diagnosis in every patient who is not eligible for radical treatment or wants to postpone this treatment. However, there is no clear evidence that HT prolongs survival in all settings. Inconclusive recommendations and intense commercial support result in wide variations in indications of HT between urologists, and radiation specialists or medical oncologists. 2 Recent surveys confirm that indications of HT depend more on personal characteristics of the urologist (e.g. board certification, academic affiliation) than on tumour or patient characteristics. Non-academic urologists for example, more frequently prescribe HT for localized PCa, a setting in which the benefits are uncertain. 3 This stresses the need for a better postgraduate education to let physicians keep up with the rapidly evolving evidence and to oppose the intense marketing of LHRH agonists and antiandrogens with validated recommendations. In this review paper the more recent evolutions and the challenges that need to be tackled, will be addressed. Hormone therapy Fewer indications to use HT upfront as single modality, especially in localized prostate cancer Many asymptomatic men receive HT for a localized PCa (T 1-2 N 0 M 0 ), obviously to avoid or postpone 205

2 radical therapy. Kawakami et al reviewed the files of 7,045 men with localized PCa and found that 14.1% were treated primarily with HT. 4 After 5 years, 67.3% of the patients were still receiving HT and only 13.8% had received radical treatment. It is disturbing to know that in localized disease early HT is not only inefficient but can lead to a paradoxical increase in mortality. This was clearly demonstrated by the EPC trial that included 8,113 men with non-metastatic PCa (all M 0 ) to assess the efficacy of early treatment with bicalutamide 150mg. 5 At a median follow-up of 7.4 years, there was a clear trend (Hazard Ratio (HR): 1.16; p=0.07) towards shortened survival in patients with localized disease treated with immediate HT. Moreover, this paradigm does not only apply to localized disease. A recent EORTC trial suggests that HT can also be postponed in patients with locally advanced PCa (T 1-2 N + M 0 or T 3-4 N x M 0 ) who are not eligible for radical treatment. In EORTC trial 30891, 985 patients unfit for radical therapy were randomly assigned to receive immediate HT or were deferred until symptomatic disease progression was observed. 6 Overall survival was modestly increased in patients receiving immediate ADT (HR: 1.25; p>0.1) as a result of fewer non PCa related deaths. The time from randomization to progression of hormone-refractory disease did not differ significantly between immediate versus delayed ADT nor did PCa-specific survival. The median time to start deferred treatment was 7 years and 26% of patients in the delayed ADT group died without ever needing treatment. Further analysis of this EORTC trial suggests that only men with PSA level > 50ng/ ml or with PSA doubling time <12 months are at risk of progression. 7 Taken together, these data suggest that in many patients with asymptomatic locally advanced PCa, HT can be delayed, avoiding adverse effects of longterm treatment. Careful selection of patients based on age, PSA kinetics, imaging and Gleason score could help the identification of patients needing immediate ADT. More arguments to use HT as adjuvant therapy to radical therapies The only randomized trial showing a substantial advantage for immediate HT is the ECOG trial which compared immediate versus deferred HT in patients with positive lymph nodes who underwent radical prostatectomy and pelvic lymph node dissection. 8 At a median follow-up of 11.9 years, immediate ADT significantly improved overall survival (HR: 1.84; p=0.04) and PCa-specific survival (HR: 4.09; p=0.0004). However, the patients in this study had higher tumor burden (e.g. seminal vesicle involvement, positive surgical margins, Gleason score 8-10) than most of the contemporary patients and recent radical prostatectomy series suggest that not all patients with a positive lymph node dissection require immediate HT. 9 The modest benefit obtained when HT is used as monotherapy contrasts with the super-additive results observed when HT is combined with external beam radiotherapy (EBRT). In the EORTC trial, 3-years of adjuvant LHRH agonist added to EBRT in patients with locally advanced PCa decreased the risk of death by 49% vs. EBRT alone. 10 In the RTOG trial, lifelong administration of an LHRH agonist decreased the risk of death by 23% vs. EBRT alone. 11 In the EPC subgroup of 305 patients with locally advanced PCa treated with EBRT, adding bicalutamide 150mg once daily to EBRT reduced the risk of death by 35% compared to EBRT alone (HR: 0.65, p=0.03). 12 The exact duration of adjuvant HT for locally advanced PCa is still unclear, although a recent EORTC trial suggested that it should be prolonged to at least 3 years in order to improve survival. 13 A shorter adjuvant HT treatment is also beneficial for patients with high-risk localized PCa (i.e. Gleason score > 7 or PSA > 20 ng/ml or stage T2c) who are primarily treated with EBRT. In a trial conducted by D Amico et al, 206 patients were randomized to receive EBRT alone or combined with 6-months HT. 14 After a median follow-up of 4.5 years, patients randomized to receive EBRT + HT had a significantly higher survival rate (88%) vs. EBRT alone (78%; p=0.04). Which treatment modality to choose? A shared decision based on the patient s expectations HT can be achieved by lowering testosterone levels (androgen deprivation therapy) or by direct blockage of the androgen receptor by steroidal (SAA; cyproterone acetate) or non-steroidal (NSAA; flutamide and bicalutamide) anti-androgens. Antiandrogens are primarily prescribed to protect the patient against the initial testosterone surge induced by LHRH agonists but they can be prescribed continuously with LHRH agonists to increase the efficacy of medical castration (Maximal Androgen Blockade; MAB). 15 High-dose bicalutamide can also be prescribed alone as an alternative to castration to 206

3 reduce the side-effects of androgen deprivation. 16 The question of which treatment modality is most suited has fuelled passionate debates and produced more reviews than original research articles. There have been very few attempts to match modalities to the expectations of the patient. To do this, patients should receive comprehensive information to decide which treatment modality fits best to their personal philosophy of life. This is a fair and reasonable approach as demonstrated by Nyman et al. 17 When patients are fully informed they can play an active role in the treatment choice and they are usually satisfied with their decision. If we agree that continuous administration of LHRH agonists is the standard of care, then the following information should be given to the patients to investigate whether they prefer an alternative strategy. Maximum androgen blockade (MAB) should be advised to patients who are looking for improving the efficacy of the treatment and who are willing to accept the increased side-effects Several meta-analyses have shown that MAB provides a significant but limited survival advantage (2-3%) when compared to LHRH agonist monotherapy. 18 The PCTCG meta-analysis demonstrates that MAB increases 5-year survival by 1.8% (p=0.11) compared to LHRH agonists alone, depending on the class of anti-androgen used. MAB with nilutamide and flutamide decreases the risk of death over castration alone by 8%, which translates into a 2.9% increase in 5-year survival. In contrast, MAB with cyproterone acetate significantly increases the risk of death by 13%, therefore reducing 5-year survival by 2.8%. Although this inferiority is clearly stated in the practice guidelines, 35% of the patients treated with MAB in Belgium still receive cyproterone acetate as antiandrogen. NSAAs increase the rate of several side-effects vs. castration alone: diarrhoea (10% vs. 2%), gastrointestinal pain (7% vs. 2%), and non-specific ophthalmologic events (29% vs. 5%). None of the meta-analyses performed so far have incorporated studies with bicalutamide 50mg, which is the most frequently used antiandrogen because of its daily dosing and low gastrointestinal and ophthalmologic adverse effects. Klotz et al calculated that bicalutamide in MAB improves survival by 20% over castration alone. 19 They calculated that for a patient with a hypothetical survival of 5 years, adding bicalutamide 50mg to a LHRH agonist could increase his survival by 1.5 years. Patients worrying about the side-effects of androgen deprivation therapy and valuing quality of life (QoL) over survival should be informed about monotherapy with highdose bicalutamide One meta-analysis has demonstrated that monotherapy with an NSAA was equivalent to castration in terms of survival, but led to less toxicity, particularly with respect to loss of libido and physical capacity. However, this doesn t hold true for cyproterone acetate which is inferior to castration in terms of time to disease progression. 20 Bicalutamide, at the higher dose of 150mg, has been extensively compared to castration in patients with locally advanced T 3 /T 4 non-metastatic disease (M 0 ) or metastatic disease (M 1 ). 16,21 The first analysis was performed at a median follow-up of 100 weeks and showed that the median survival of metastatic (M 1 ) patients treated with bicalutamide 150mg was 6 weeks shorter than the median survival of patients treated by castration (HR: 1.30). Based on these earlier results, bicalutamide 150mg is not an EMEA or Belgian recognized therapy for metastatic PCa. The definitive analysis for non-metastatic patients (M 0 ) was performed after a median follow-up of 6.3 years. 16 In that setting, the study showed that there was no difference between bicalutamide 150mg and castration in overall survival (HR: 1.05; p=0.70) or time to progression (HR: 1.20; p=0.11). In contrast, there was a statistically significant benefit in the bicalutamide monotherapy group with respect to sexual interest (p=0.029) and physical capacity (p=0.046). Bicalutamide 150mg was well tolerated, with breast pain and gynecomastia being the most frequent side effects. Further studies confirmed that bicalutamide 150mg induces fewer bothersome side effects than LHRH agonists and in addition does not decrease bone mineral density and has less impact on lipid metabolism Is it safe to suspend temporarily androgen deprivation therapy in patients complaining of side-effects? Another alternative for men who are not candidate for anti-androgen monotherapy is intermittent androgen deprivation (IAD). Several phase II trials have demonstrated the feasibility of alternating onand off-therapy periods. 24 Prospective phase III trials are still underway and data on survival endpoints and QoL are not yet fully available. However, it appears that with regard to survival, continuous ADT and IAD are equivalent. 25 Awaiting data from the 207

4 phase III trials, IAD is widely offered to patients with PCa in various clinical settings. However, its status should still be regarded as investigational. Side effects of ADT: when the treatment becomes a silent killer Because testosterone is the principal male hormone, its withdrawal is associated with a series of side effects. 26 Until recently, most studies on ADT have focused on the symptomatic toxicity of testosterone withdrawal, such as hot flushes, loss of libido, emotional instability, or fatigue. The morbidity of ADT, however, mainly results from devious toxicities such as the induction of the metabolic syndrome leading to increased cardiovascular risk and osteoporosis. In a cross-sectional study with 58 men, Braga-Brasaria et al have demonstrated that a metabolic syndrome was present in > 50% of the men treated with longterm ADT, predisposing them to an increased cardiovascular risk. 27 In an observational populationbased cohort study including 73,196 men, Keating et al showed that ADT increased the risk of diabetes by 44%, coronary heart disease by 16%, myocardial infarction by 11%, and sudden cardiac death by 16%. 28 This increased risk of developing co-morbidities seems to be higher in patients with localized disease and in those with advanced disease and moderate to severe co-morbidities. 29,30 Loss of bone mineral density is another complication induced by ADT. Significant loss of bone mineral density occurs within 12 months of therapy initiation. 31 ADT significantly increases the risk of any clinical bone fracture, hip fractures, and vertebral fractures in men with PCa. 32 Physicians should take care that appropriate calcium and vitamin D supplements are administered, and that the development of bone loss is monitored by means of osteodensitometry and bisphosphonates are prescribed when bone loss is documented. 33 Promoting wellness and proactive management of side effects in patients receiving ADT Although the side effects of ADT are well recognised, no proactive management of these side effects has been recommended so far. A physician prescribing ADT should spend sufficient time explaining the side effects of ADT to the patient, for example in clarifying the reasons why libido decreases and emotions change. The physician should be aware of early signs of depression and look for advice of a specialized colleague if needed. Sexual side effects are the best-recognized adverse effects of ADT and include loss of libido and erectile dysfunction (ED). Loss of libido is distressing for many men. Urologists often present it as an ineluctable consequence of androgen suppression, so that men normally potent before treatment seldom request specific treatment. However, ancient and modern history contains sufficient evidence that a sexual life is still possible for men deprived from testosterone. 34 Hot flushes are another side effect of ADT. These are perceived as very bothersome but can be reduced by simple lifestyle changes such as wearing light clothes, avoiding abrupt temperature changes and spicy food. The physician should point out these simple tricks to the patient. When the hot flushes are becoming too much of a bother they can be treated with a variety of therapies, including phytotherapy (sage extracts, alfala), clonidine, velaxafine or a small dose of estrogens. 35 In any case, the physician should encourage patients to adopt a lifestyle that is adapted to ADT. Osteoporosis and metabolic syndrome are classical features of other frequent conditions, such as menopause or diabetes. Adopting a better diet and increasing the level of physical activity can minimise the side-effects of ADT. 36,37 In addition, regular exercise may help fighting against fatigue, muscular weakness, and to a certain extent, help restoring a better mood. Physical activity should be tailored to the pre-existing physical activity of the patient, should include regular resistance exercise, and should be associated with correct supplementation of calcium and vitamin D. 38 Finally, specific recommendations should be directed towards the patient s general practitioner so that he/she can adapt his/her practice to patients treated with ADT and monitor on a regular base blood pressure, serum lipid, haemoglobin, and fasting serum glucose. 37 Conclusions Despite sixty years of intensive use, ADT is still the reference systemic therapy for advanced PCa. However, the situation has changed over the years. Indications for ADT are shifting to earlier stage PCa, especially in combination with EBRT, where it results in the largest survival benefit. In the future, new treatment modalities might emerge and new combinations will probably be evaluated. Moreover, the patient s choice and expectations regarding QoL are more than ever considered of vital importance in the management of PCa. 208

5 Key messages for clinical practice 1. Modern indications of hormone therapy of PCa are following: - Immediate treatment of symptomatic patients - Immediate treatment of metastatic disease - Immediate treatment of locally-advanced disease with PSA > 50ng/ml or PSA doubling-time < 12 months - Treatment of PSA recurrences after radical treatment if PSA doubling time < 12 months - Long-term adjuvant treatment (2-3 years) to external beam radiation for locally advanced PCa - Immediate treatment of patients with bulky positive lymph nodes after radical prostatectomy 2. Summary of treatment modalities: - Androgen deprivation therapy by surgical castration or LHRH agonist is the Gold Standard treatment. - Maximal Androgen Blockade with a non-steroidal antiandrogen increases survival by 5 to 20% and should be recommended to patients looking for maximum efficacy. - Bicalutamide 150mg monotherapy is equivalent in term of survival to castration in patients with M0 disease, with a better tolerability profile. 3. Patients receiving androgen deprivation therapy must be stimulated to adapt their diet and increase daily exercise to minimize the effects of changes in lipid metabolism and osteoporose. Doctors must monitor lipid profile, fasting serum glucose and bone mass density in addition to oncological parameters. References 1. Huggins C, Hodges C. Studies on prostatic cancer I. The effects of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941(1): Payne HA, Gillatt DA. Differences and commonalities in the management of locally advanced prostate cancer: results from a survey of oncologists and urologists in the UK. BJU Int. 2007;99(3): Shahinian VB, Kuo YF, Freeman JL, Orihuela E, Goodwin JS. Characteristics of urologists predict the use of androgen deprivation therapy for prostate cancer. J Clin Oncol. 2007;25(34): Kawakami J, Cowan JE, Elkin EP, Latini DM, DuChane J, Carroll PR. Androgen-deprivation therapy as primary treatment for localized prostate cancer: data from Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE). Cancer. 2006;106(8): McLeod DG, Iversen P, See WA, Morris T, Armstrong J, Wirth MP. Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU Int. 2006;97(2): Studer UE, Whelan P, Albrecht W, Casselman J, de Reijke T, Hauri D, et al. Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) Trial J Clin Oncol. 2006;24(12): Studer UE, Collette L, Whelan P, Albrecht W, Casselman J, De Reijke T, et al. Which subgroups of patients with newly diagnosed T0-4 N0-2 M0 prostate cancer not suitable for local treatment with curative intent (EORTC 30891) are at risk to die from prostate cancer and benefit from immediate androgen deprivation? European urology supplements. 2007;6(2):A19, Messing EM, Manola J, Yao J, Kiernan M, Crawford D, Wilding G, et al. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. The lancet oncology. 2006;7(6): Palapattu GS, Allaf ME, Trock BJ, Epstein JI, Walsh PC. Prostate specific antigen progression in men with lymph node metastases following radical prostatectomy: results of long-term followup. J Urol. 2004;172(5 Pt 1): Bolla M, Collette L, Blank L, Warde P, Dubois JB, Mirimanoff RO, et al. Long-term results with immediate an- 209

6 drogen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet. 2002;360(9327): Pilepich MV, Winter K, Lawton CA, Krisch RE, Wolkov HB, Movsas B, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma-long-term results of phase III RTOG Int J Radiat Oncol Biol Phys. 2005;61(5): See WA, Tyrrell CJ. The addition of bicalutamide 150 mg to radiotherapy significantly improves overall survival in men with locally advanced prostate cancer. Journal of cancer research and clinical oncology. 2006;132 Suppl 1:S Bolla M, van Tienhoven G, de Reijke TM, van den Bergh AC, van der Meijden AP, Poortmans PM, et al. 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7 36. Gomella LG. Contemporary use of hormonal therapy in prostate cancer: managing complications and addressing quality-of-life issues. BJU Int. 2007;99 Suppl 1:25-9; discussion Moyad MA. Promoting general health during androgen deprivation therapy (ADT): a rapid 10-step review for your patients. Urol Oncol. 2005;23(1): Ott C, Fulton MK. Osteoporosis risk and interest in strength training in men receiving androgen ablation therapy for locally advanced prostate cancer. J Am Acad Nurse Pract. 2005;17(3): Correspondence address Authors: B. Tombal, A. Stainier Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium Please send all correspondence to: Prof. B. Tombal Cliniques Universitaires Saint-Luc Université Catholique de Louvain Avenue Hippocrate Brussels Belgium Tel: 0032 (0) Fax: 0032 (0) bertrand.tombal@uclouvain.be Conflicts of interest: Bertrand Tombal is an investigator and consultant for Astellas, AstraZeneca, Sanofi- Synthélabo and Cougar. 211