Combination hormonal therapy - Nature

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Combination hormonal therapy: a reassessment within advanced prostate cancer JW Moul1* & G Chodak2 1

Center for Prostate Disease Research, Rockville, Maryland, USA; and 2Midwest Prostate and Urology Health Center, Chicago, Illinois, USA

Combination hormonal therapy, comprising a luteinising hormone-releasing hormone analogue (LHRHa) with an antiandrogen, is widely used in the treatment of advanced prostate cancer. There is ongoing debate regarding the use of combination hormonal therapy as opposed to LHRHa monotherapy. The pivotal consideration is whether there are adequate benefits with combination hormonal therapy in terms of increased survival and decreased disease progression to outweigh the increased risk of adverse events and additional cost. The most recent meta-analysis by the Prostate Cancer Trialists’ Collaborative Group indicates a small but statistically significant survival benefit with combination hormonal therapy using nonsteroidal antiandrogens. It is, however, noteworthy that combined conclusions derived from such meta-analyses may not apply across each of the individual antiandrogens. Individual studies have reported differences between antiandrogens in terms of both tolerability and efficacy—for example, bicalutamide has been shown to be better tolerated than flutamide, and may be associated with improved survival. In addition, it is essential that treatment decisions are taken in consultation with the patient. Owing to an increasing proportion of cases presenting with early-stage disease, combination hormonal therapy is increasingly used in the neoadjuvant or adjuvant setting with radiotherapy and, in cases of prostate-specific antigen recurrence after prior localised therapy. Further data are awaited to optimise the use of combination hormonal therapy in these new settings. Prostate Cancer and Prostatic Diseases (2004) 7, S2–S7. doi:10.1038/sj.pcan.4500741

Keywords: antiandrogens; quality of life; radiotherapy

Introduction Castration has long been used to treat patients with prostate cancer. During the 1940 s, it was found that the reduction in androgen levels following bilateral orchiectomy slowed progression of the disease and increased survival rates.1 The basis for the positive results observed with castration, either medical or surgical, is the dependence of cancer growth upon the presence of androgens: the dihydrotestosterone–androgen receptor complex (DHT–AR) regulates gene expression within the cancer cells and, without androgens, the proliferation of *Correspondence: JW Moul, Center for Prostate Disease Research, 1530 East Jefferson Street, Rockville, MD 20852-1532, USA. E-mail: [email protected] The opinions and assertions contained herein are the private views of the author and are not to be construed as the official views of the US Army or the Department of Defense.

these cells is not possible. Androgen blockade produces a temporary halt in cancer growth in 60% of advanced cases, and the subjective response rate may reach 80%.2 However, an important drawback to surgical castration is the psychological trauma and subsequent potential impairment of quality of life. Androgen blockade by surgical castration decreased in popularity due to the development in the 1980s of luteinising hormone-releasing hormone analogues (LHRHa), as these agents were able to prevent testicular production of androgens without the need for surgery. Convincing evidence soon became available to show that LHRHa therapy was equivalent to both surgical castration and oestrogen therapy in terms of reduced disease progression and survival rates.3,4 LHRHa rapidly won favour among patients due to the avoidance of surgical castration and favourable tolerability. Plasma androgen levels are reduced by approximately 90–95% by LHRHa monotherapy, as the adrenal glands continue to produce

Combination hormonal therapy for prostate cancer JW Moul and G Chodak

Efficacy of combination hormonal therapy

LHRHa only LHRHa + NSAA

80 60 40

20 0

0

1

2 3 Time (years)

4

5

Figure 1 Survival among patients receiving combination hormonal therapy (nonsteroidal antiandrogen plus LHRHa) vs LHRHa alone.10 Treatment difference (5-y survival) 2.9% in favour of LHRHa þ NSAA Logrank; 2P ¼ 0.005. LHRHa ¼ luteinising hormone-releasing hormone analogue; NSAA ¼ nonsteroidal antiandrogen. Reprinted from The Lancet10 with permission from Elsevier.

100

Patients surviving (%)

An early study of men with traditional metastatic (stage M1/D2) prostate cancer comparing combination hormonal therapy (leuprolide plus flutamide) with leuprolide alone indicated a 26% increase in the median duration of survival with combination hormonal therapy (35.6 vs 28.3 months, P ¼ 0.035).6 A further study published in 1993 comparing combination hormonal therapy (goserelin acetate plus flutamide) with bilateral orchiectomy, demonstrated significant benefits in terms of survival and time to progression with combination hormonal therapy.7 Further clinical trials were performed to investigate the benefits of combination hormonal therapy vs LHRHa monotherapy. Not all the data from these studies were as clear as the Crawford et al results, and a meta-analysis was therefore undertaken by the Prostate Cancer Trialists’ Collaborative Group (PCTCG).8 The analysis, published in 1995, included data from 22 studies (3283 deaths among 5710 patients), and trends in favour of combination hormonal therapy were identified in terms of overall mortality (56 vs 58%) and 5-y survival (26.2 vs 22.8%), but statistical significance was not reached. Another meta-analysis including nine studies also indicated improved overall survival with combination hormonal therapy, but the 10% difference was again not statistically significant.9 In 2000, the PCTCG published an update of their 1995 meta-analysis.10 This study included data from five more studies than the original meta-analysis, with more patients (48000) and longer follow-up (almost 6000 deaths were included), thus increasing the statistical sensitivity. The updated publication also provided a new perspective on the debate, by reporting that addition of the steroidal antiandrogen cyproterone to castration had a negative effect on 5-y survival (15.4% with combination hormonal therapy vs 18.1% with androgen suppression alone; log-rank 2P ¼ 0.04), whereas addition of the nonsteroidal agents flutamide and nilutamide increased survival (27.6% with combination therapy vs 24.7% with androgen suppression alone; log-rank 2P ¼ 0.005) (Figure 1). Compared with castration alone, the death rate ratio was 1.13 (s.e. 0.06, 2P ¼ 0.04) for cyproteronebased combination hormonal therapy, 0.92 (s.e. 0.06, 2P ¼ 0.02) for flutamide and 0.92 (s.e. 0.06, 2P ¼ 0.14) for nilutamide. Consistent with these findings, a more recent meta-analysis indicated a statistically significant 5-y survival benefit with combination hormonal therapy vs orchiectomy or LHRHa therapy alone (hazard ratio for 5-y overall survival: 0.871; 95% confidence interval: 0.805–0.942).11 However, this meta-analysis was not based on individual patient data and the outcomes are not

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androgens.5 By preventing the remaining androgens from activating the intraprostate androgen receptors, the addition of an antiandrogen was postulated to improve the efficacy of hormonal therapy for this disease. Consequently, treatment with an LHRHa combined with an antiandrogen was investigated for additional efficacy advantages over LHRHa monotherapy. This ‘combination hormonal therapy’ may also be termed maximal androgen blockade (MAB), or ‘combined’ or ‘complete’ androgen blockade (CAB).

Bicalutamide 50mg + LHRHa Flutamide + LHRHa

80 60 40 20 0 0

1

2 3 Time (years)

4

5

Figure 2 Survival among patients receiving combination hormonal therapy: flutamide plus LHRHa vs bicalutamide plus LHRHa.12 Median follow-up 160 weeks: HR 0.87, 95% CI 0.72, 1.05; P ¼ 0.15. LHRHa ¼ luteinising hormone-releasing hormone analogue. Reprinted from Urology12 with permission from Elsevier.

therefore considered to be as robust as those from the PCTCG.

Assessing the potential role of combination hormonal therapy Several considerations must be taken into account when assessing the potential role for combination hormonal therapy; firstly, not all antiandrogen drugs are the same in terms of their effects on survival. Although the difference appears most marked for steroidal vs nonsteroidal antiandrogens, there are also differences between nonsteroidal antiandrogens. A recent study compared combination hormonal therapy with either bicalutamide or flutamide in combination with LHRHa (either goserelin acetate or leuprolide acetate). While there were no significant differences in overall disease outcome between the two antiandrogens, the median survival time was 180 weeks in the bicalutamide group compared with 148 weeks with flutamide (Figure 2).12 Prostate Cancer and Prostatic Diseases


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Interestingly, a validated statistical technique has been employed to combine the findings of the Schellhammer study and the PCTCG meta-analysis.13,14 The combined results indicate that combination hormonal therapy using bicalutamide reduces the risk of death by 20% compared with castration alone. In addition, these data showed that there was a 98.5% probability that bicalutamide in combination hormonal therapy was better than castration alone.15 A second consideration is that the benefits of combination hormonal therapy appear to be increased in patients with minimal metastatic disease.16 Interestingly, this effect appears to vary between antiandrogen agents, with an exploratory analysis showing a trend in favour of increased survival with bicalutamide compared with flutamide in these patients.17 A further consideration in clinical practice is the timely withdrawal (or switching) of antiandrogen therapy. For patients receiving combination hormonal therapy and experiencing either disease progression or increasing PSA levels, there is evidence that withdrawal of antiandrogen therapy can produce clinical benefits,18,19 as well as reductions in PSA levels.20 In addition, there is evidence that for patients failing to respond to one antiandrogen, switching to another antiandrogen can be successful, as shown when bicalutamide was used following failure with flutamide.21,22 The basis for these findings may be related to progression of the disease to the hormone-refractory stage19 and/or, the possibility of androgen receptor mutations leading to the antiandrogen agent acting as an agonist rather than an antagonist.2 Thus, inclusion in meta-analyses of patients not withdrawing or switching their antiandrogen therapy appropriately may result in an apparent decrease in the benefits of combination hormonal therapy. A third factor to take into consideration when choosing appropriate treatment is cost.19 Although the cost-effectiveness of combination hormonal therapy compared with monotherapy remains to be established,23 data from a Canadian study indicate that the cost of combination therapy is comparable with new treatments for other common cancers.24 Combination therapy with bicalutamide was reported to cost US$437– 1107 per month of survival benefit.

Holistic approach to the treatment choice There is continuing debate regarding the true value of the additional survival benefit associated with addition of a nonsteroidal antiandrogen to LHRHa therapy. Moreover, we need to consider individual patient preference and any potential increase in the patient’s quality of life associated with combination hormonal therapy. Fundamental to this is the tolerability of combination hormonal therapy and the overall balance of survival benefits vs potential increases in adverse events due to the addition of a second drug. The adverse events most likely to affect the quality of life of patients receiving antiandrogen agents are gynaecomastia and breast pain,25 but these side effects are predictable given the agents’ mode of action. Other adverse events are well documented, with delayed light/ dark adaptation, hepatotoxicity and diarrhoea being Prostate Cancer and Prostatic Diseases

common. Notably, the adverse event profiles vary between the individual antiandrogens. Diarrhoea is one of the most common adverse events with flutamide,26 while there is also a potential risk of hepatotoxicity with this agent.27 Delayed light/dark adaptation and alcohol intolerance have been identified as adverse events with nilutamide,28 and interstitial pneumonitis has also been reported in association with this antiandrogen.29 Bicalutamide appears to be generally better tolerated than both these agents.28 In a study comparing bicalutamide with flutamide, there was a statistically significant reduction in the incidence of diarrhoea with bicalutamide—Table 1 summarises the adverse events that led to withdrawal from both study groups.12 Only the incidence of haematuria was significantly higher with bicalutamide (48 patients, 12% vs 26 patients, 6%; P ¼ 0.007), though this event was related to study medication in only one patient in the bicalutamide group, and two patients in the flutamide group. There is minimal apparent risk of hepatotoxicity with bicalutamide (there has been one report of fatal liver failure in a bicalutamide-treated patient, but this was not attributable to the drug).25 Overall, therefore, bicalutamide may be considered to offer an improved risk : benefit ratio compared with other antiandrogens, either steroidal or nonsteroidal. The question of whether the benefits of combination hormonal therapy (probable increases in time to progression and duration of survival) outweigh the risk of increased adverse events, vs LHRHa monotherapy, can only be answered subjectively. It is therefore crucial to involve the patient in the decision process as early and as much as possible.

Quality of life Few randomised studies have compared quality of life among recipients of combination hormonal therapy compared with castration alone. Perhaps the best available evidence comes from a 6-month comparison of patients undergoing bilateral orchiectomy, treated with either placebo or flutamide.30 Significantly worse emotional function was observed with orchiectomy plus flutamide at 3 and 6 months, compared with orchiectomy alone (Po0.003), together with a higher rate of diarrhoea at 3 months (Po0.0001). Contrary to these findings, a second study reported that prostate cancer patients in remission while treated with combination hormonal

Table 1 Tolerability of bicalutamide vs flutamide: adverse events leading to withdrawal in a total of at least three patients12

Diarrhoea Liver function abnormalities Nausea and/or vomiting Hot flashes Kidney failure Congestive heart failure

Bicalutamide plus LHRHa (n ¼ 401)

Flutamide plus LHRHa (n ¼ 407)

2 6 3 4 1 1

25 10 8 2 2 2

Reprinted from Urology12 with permission from Elsevier. LHRHa, luteinising hormone-releasing hormone analogue.


therapy (LHRHa plus flutamide) experience quality of life that is similar to age-matched, healthy controls.31 While the quality-of-life data for flutamide are somewhat contradictory, recent preliminary data from a Japanese study in approximately 300 patients with previously untreated advanced prostate cancer evaluating quality of life with bicalutamide combination therapy, demonstrated bicalutamide 80 mg (in combination with an LHRHa) improved symptom-related quality of life compared with LHRHa monotherapy.32 Studies comparing quality of life with different antiandrogens are awaited with interest.

Evolving treatment strategies Typically, combination hormonal therapy has been used for the treatment of advanced prostate cancer, often involving some degree of bone metastasis or lymph node involvement (stage D1 or D2 disease). In recent years, the phenomenon of stage migration has been observed— data from the USA indicate that the proportion of cases presenting with nonpalpable T1a–1c disease more than doubled between 1990 and 2002, with a corresponding reduction in stage D1 and D2 disease.33,34 This is attributable to the introduction of PSA testing and greater awareness of the disease, facilitating earlier diagnosis, and has been accompanied by a large increase in the proportion of patients aged under 55 y. As a result of the beneficial effects of single-agent hormonal therapy in patients with locally advanced prostate cancer, combination hormonal therapy has been investigated for use at earlier stages of disease.

Hormonal therapy after radical prostatectomy LHRHa and antiandrogens have both been investigated as single agents alongside radical prostatectomy in the management of patients with prostate cancer. In a study of patients who have previously undergone radical prostatectomy and subsequently found to have nodal metastases, patients given immediate therapy (either goserelin (n ¼ 33) or bilateral orchiectomy (n ¼ 13); one patient refused either treatment) demonstrated significantly improved overall survival during the median 10-y follow-up, compared with those who received treatment deferred until disease progression (26 of 51 patients in the observation group died, compared with 13 out of 47 in the immediate-therapy group, P ¼ 0.025).35 The ongoing Early Prostate Cancer programme consisting of three randomised, double-blind, placebo-controlled trials (total n ¼ 8113), is investigating the efficacy and tolerability of bicalutamide, 150 mg/day, when given in addition to standard care (ie watchful waiting, radiotherapy or radical prostatectomy) for the treatment of patients with localised or locally advanced prostate cancer.36 At a median 5.4-y follow-up, bicalutamide significantly improved objective progression-free survival (PFS) compared with placebo in the overall population, reducing the risk of objective progression by 27% (HR 0.73; Po0.0001). Patients with locally advanced disease gained most benefit from bicalutamide in terms of PFS, irrespective of the underlying therapy. In the radical prostatectomy subgroup, among patients with

locally advanced disease, bicalutamide significantly reduced the risk of objective progression by 29% compared with placebo (HR 0.71; P ¼ 0.0034). Overall survival was similar in the bicalutamide and placebo groups in the overall population (HR 1.03; P ¼ 0.582) and in the adjuvant therapy subgroups (HR 1.01; P ¼ 0.860). However, it should be noted that, in the watchful waiting subgroup, overall survival appeared to be improved with bicalutamide in those with locally advanced disease (HR 0.81; P ¼ 0.097), whereas overall survival appeared to be reduced with bicalutamide in those with localised disease (HR 1.23; P ¼ 0.050). There is thus clear evidence that hormonal therapy, by LHRHa or bicalutamide, provides benefit as adjuvant therapy to radical prostatectomy in patients with locally advanced disease. However, the current data suggest that early or adjuvant hormonal therapy for patients at low risk of disease progression, such as those with localised disease, may not be appropriate. Following radical prostatectomy, ‘biochemical recurrence’, defined by increasing PSA levels in the absence of known clinical disease, may occur in approximately 40% of cases. We would estimate that up to 50 000 patients per year in the USA alone present with biochemical recurrence.37 Many of these patients are likely to have systemic disease, providing a rationale for treatment with systemic therapy. A follow-up study has been performed to characterise disease progression among patients experiencing biochemical recurrence after radical prostatectomy, and the median time to development of metastases was 8 y after detection of elevated PSA levels.38 Factors associated with increased probability of metastasis development (and a shorter time to metastasis development) were: short time to PSA recurrence (o2 y postprostatectomy), high Gleason score at prostatectomy (8–10) and short PSA doubling time (o10 months). A study to investigate the potential benefit of LHRHa alone or combination hormonal therapy for patients with biochemical recurrence has been performed.39 The results are indicative of prolonged time to metastasis with hormonal therapy vs delayed or no hormonal treatment, although the patients have insufficient follow-up duration to know whether there is any effect on survival. The optimal approach to treating patients with biochemical recurrence, in terms of early vs late hormonal therapy and combination hormonal therapy vs LHRHa monotherapy, remains to be determined.

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Hormonal therapy after radiotherapy A number of randomised trials have demonstrated that the use of hormonal therapy together with radiotherapy can lead to improved survival rates compared with radiotherapy alone in patients with locally advanced disease. This approach to treatment may yield further benefits owing to the belief that treating smaller prostates may lower the morbidity of radiotherapy.40 Results of the Early Prostate Cancer programme are consistent with this notion—in the radiotherapy subgroup, among patients with locally advanced disease, bicalutamide 150 mg/day significantly reduced the risk of objective progression by 42% compared with placebo (HR 0.58; P ¼ 0.0035).36 Prostate Cancer and Prostatic Diseases


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A comparison of radiotherapy administered alone or with an LHRHa (concurrent and 3-y adjuvant goserelin) was performed in patients with locally advanced disease.41 Disease-free survival during the 5-y followup period was 40% in the radiotherapy alone group, compared to 74% with multimodal therapy (P ¼ 0.0001). Significant improvements were also noted in overall and prostate-cancer-specific survival. Similarly, a study by Pilepich et al42 compared adjuvant LHRHa therapy with radiotherapy alone: absolute survival at 5 and 10 y was reported as 71 and 38% in the radiotherapy alone group, compared with 76 and 53% for multimodal therapy (Po0.0043). A similar benefit was observed in diseasespecific mortality: 5-y and 10-y rates of 13 and 22% were observed with radiotherapy alone, compared with 9 and 17% in the mutimodal therapy group (P ¼ 0.0053). The use of combination hormonal therapy with radiotherapy has also been investigated. Radiotherapy with neoadjuvant and concurrent combination hormonal therapy was associated with improved 4-y PFS, compared to radiotherapy with adjuvant combination hormonal therapy.43 Multimodal therapy is presently more likely to be used in the USA, owing to the general support for this approach among US oncologists. There are, as yet, no data to suggest whether combination hormonal therapy may be superior to LHRHa monotherapy when used together with radiotherapy.

Conclusion In conclusion, combination hormonal therapy with an antiandrogen and an LHRHa is widely used to treat patients with advanced (stage D1/D2) prostate cancer. There has been some debate concerning the benefits of this approach compared with LHRHa monotherapy, and the cost-effectiveness of combination hormonal therapy. Nevertheless, the clinical data are supportive of combination hormonal therapy with an associated increase in duration of survival. The choice of antiandrogen has an important bearing on the treatment decision. Nonsteroidal agents offer improved survival compared with steroidal agents (cf PCTCG data), while bicalutamide offers improved tolerability compared with other nonsteroidal agents. Owing to stage migration (larger proportion of cases presenting with early-stage prostate cancer) there is increasing tendency for combination hormonal therapy to be used as neoadjuvant and adjuvant therapy, as well as in patients demonstrating biochemical (PSA) recurrence. Further data are required to establish whether there are benefits of using combination hormonal therapy as opposed to LHRHa monotherapy in these settings.

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35 Messing EM et al. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer: results at 10 years of EST 3886. Presented at AUA 2003, abstract no. 1480. Chicago, IL, USA. 36 Wirth MP, See WA, McLeod DG. Bicalutamide ‘Casodex’ 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer: results from the second analysis of the Early Prostate Cancer program at 5.4 years’ median follow-up. J Urol 2004; in press. 37 Moul JW. Prostate specific antigen only progression of prostate cancer. J Urol 2000; 163: 1632–1642. 38 Pound CR et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999; 281: 1591–1597. 39 Moul JW et al. Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy. J Urol 2004; 171: 1141–1147. 40 European Association of Urology. EAU guidelines on prostate cancer. Available from: http://www.uroweb.org/files/uploaded_files/prostatecancer.pdf (accessed 14 May 2004). 41 Bolla M et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002; 360: 103–106. 42 Pilepich MV et al. Phase III trial of androgen suppression adjuvant to definitive radiotherapy. Long term results of RTOG study 85-31. Proc Am Soc Clin Oncol 2003; 22: 381. 43 Roach III M et al. Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol 2003; 21: 1904–1911.

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