The Need for Improved Therapeutic Strategies for Patients with Metastatic Hormone-Refractory Prostate Cancer

By: John Andersonlowast

European Urology Supplements, Volume 5 Issue 15, September 2006, Pages 811-816

Published online: 01 September 2006

Keywords: Chemotherapy, Docetaxel, Hormone-refractory prostate cancer, HRPC, Multidisciplinary, TAX 327

Abstract Full Text Full Text PDF (153 KB)


Prostate cancer is the second most commonly diagnosed cancer in men in the European Union (EU) and the third most common cause of cancer-related death in men in the Western world. In recent years, prostate-specific antigen (PSA) testing has become an indispensable tool in urological oncology. In addition to allowing risk stratification and prognosis determination, PSA testing also allows the earlier detection of hormone-refractory prostate cancer (HRPC). More patients, therefore, now present with potentially curative disease. For many men, however, disease prognosis is considerably poorer. Prostate cancer often progresses to HRPC with death from widespread metastases. Not only is it important to acknowledge the heterogeneity of patients with HRPC, and thus the need for individualised treatment, but it is also important to stratify patients according to their risk of disease recurrence, a process that can guide treatment decisions. Patients with HRPC present a treatment challenge. Until recently, once a patient started to fail to respond to androgen-deprivation therapy, the options were limited. Second- and third-line hormonal therapies represent the standard of care but are relatively ineffective. Patients with HRPC will therefore require multiple systemic therapies for their disease, ideally within the multidisciplinary team setting. Traditionally, HRPC was considered unresponsive to chemotherapy. This view may need to be refined in light of new data indicating that chemotherapy confers a survival advantage to these poor-prognosis patients.

Take Home Message

Prostate cancer often progresses to hormone-refractory disease with death from widespread metastases. Until recently, treatment options were limited. This view may need to be refined in light of new data revealing a survival advantage of chemotherapy in these patients.

Keywords: Chemotherapy, Docetaxel, Hormone-refractory prostate cancer, HRPC, Multidisciplinary, TAX 327.

1. Introduction to prostate cancer

Prostate cancer is an ever-escalating global health problem that encompasses a wide spectrum of disease [1] and is associated with significant patient morbidity [2] and mortality. It is the third most common cause of cancer-related death in men in the Western world, and, in 2004, 237,800 men in the European Union (EU) were diagnosed with prostate cancer, making it the second most commonly diagnosed cancer in men in the EU, accounting for 15.5% of all cancers in men [3] and [4].

The introduction of prostate-specific antigen (PSA) testing in the mid-1980s has undoubtedly facilitated the earlier detection of prostate cancer [3]. More younger men present with localised disease that is suitable for radical and curative treatment [5] and [6] and the number of patients with more advanced disease is accordingly in decline [5]. PSA testing has also enabled the detection of biochemical failure in patients with early-stage disease before the clinical appearance of symptoms. Radical prostatectomy or external-beam radiotherapy in men with organ-confined prostate cancer has a 10-yr cancer-specific survival of >75% [7] and [8]; however, up to one third of men will develop biochemical recurrence [9]. The 5-yr chance of PSA recurrence increases with increasing clinical stage, Gleason score, and PSA level at diagnosis (Table 1) [10].

Table 1 5-yr chance of PSA recurrence

Risk Stage Gleason score PSA, ng/ml Chance of PSA failure
Low <T2a ≤6 <10 <25%
Intermediate T2b 7 10–20 25–50%
High T2c 8–10 >20 >50%

Reproduced with permission from D’Amico et al. [10].

An estimated 80% of men with high-risk prostate cancer at diagnosis will develop biochemical recurrence and clinical failure within 10 yr [11]; these patients therefore represent a difficult group to treat. These men, and those who present with advanced or metastatic prostate cancer, will require multiple systemic therapies for their disease, and ideally this will be within the multidisciplinary team setting. In the United Kingdom, there is an improving outcomes guidance drive toward better standards of care for patients with prostate cancer and this implicitly involves multidisciplinary team management [12].

2. Progression to metastatic hormone-refractory prostate cancer

Prostate cancer is a heterogeneous disease; however, changes in androgen signalling appear to be a common element in both its development and progression [13]. Normal prostate epithelial cells are dependent on a critical level of androgen stimulation for growth and survival [14] and are therefore androgen-dependent [15]. Androgen ablation, through either medical or surgical castration, remains the cornerstone of treatment for patients with symptomatic advanced prostate cancer. Hormonal ablation is an effective palliative treatment in about 80% of patients [16], leading to a reduction in bone pain, improvement in performance status, reduction in urinary obstruction and bleeding, and a reduction in serum PSA levels [17]. However, hormonal ablation therapy is not curative and the duration of the response to treatment is often disappointing, rarely lasting for >2 yr [15] and [17]. Most patients will eventually develop resistance to hormonal therapy [18]. This is the result of a proportion of prostate epithelial cells that appear not to be dependent on androgens for growth and survival; these cells are androgen independent [14]. Androgen-independent prostate cancer is still hormone sensitive and therefore may respond to further hormonal manipulations [15]. Furthermore, other prostate epithelial cells appear to be sensitive to androgen but do not die when androgens are removed; these cells are androgen sensitive [14]. Ultimately, disease progression leads to a dominance of hormone-insensitive and androgen-independent prostate cells, yielding the hormone-refractory state of hormone-refractory prostate cancer (HRPC) [15]. Treatment of prostate cancer containing both androgen-independent and androgen-sensitive cells can therefore often fail to yield a clinically detectable response [19]. Patients with HRPC would not be expected to respond to another hormonal treatment [20] and, until recently, there have been no agreed treatment strategies for these patients.

Prostate cancer can be clinically divided into a spectrum of disease based on the degree of disease progression: incidental or subclinical disease, localised disease, biochemical failure, locally advanced disease, and advanced disease [1]. Scher and Heller have proposed a dynamic model of disease progression; a timeline of a patient with prostate cancer who presents at an early stage of disease (Fig. 1).


Fig. 1 Dynamic model of disease progression. DRE=digital rectal examination; PSA=prostate-specific antigen; QoL=quality of life. Reproduced with permission from Scher and Heller [21].

The first clinical state considered is the patient who presents for a prostate evaluation (digital rectal examination [DRE] and PSA) with no cancer. The next clinical state is that of localised disease; such a patient would remain in this state until treatment fails, as evidenced by a rise in PSA. An increasing proportion of patients with prostate cancer are in this third clinical state: after treatment with a rising PSA. There are numerous routes to the fourth clinical state, the metastatic noncastrate state [21]. About 30–35% of patients with prostate cancer initially present with metastatic disease and a further 25% of patients develop metastases during follow-up after treatment with curative intent [22]. There is a hormone-dependent phase of the disease, but this is finite and patients will at some point become hormone refractory. Progression despite castration leads to the fifth clinical state: metastatic castrate. Patients in this state have hormone-refractory metastatic disease and have a poor, but variable, prognosis [21].

3. Definition and guidelines

HRPC can range from asymptomatic biochemical progression to symptomatic metastatic progression, manifesting clinically as symptoms and findings, such as rising PSA levels, progression of bone scan findings, new or enlarging soft-tissue masses, skeletal pain, weight loss, or urinary obstruction [23]. There is therefore no universally accepted definition for HRPC, although it is widely accepted that it is a state of progressive disease despite hormone therapy [22]. Biochemical and treatment failure can be clinically detected as a rising PSA profile [1]. This definition is based on the observation that disease recurrence is almost always associated with a concomitant PSA rise [24]. The level of PSA at which to define treatment failure depends on whether the patient has been treated with radical prostatectomy or radiation therapy. In the case of the former, recurrent cancer is said to occur when two consecutive PSA values ≥0.2ng/ml are recorded, whereas, in the case of the latter, recurrent cancer is represented by three consecutive increasing PSA values above a previous nadir [25]. Using this definition, a heterogeneous patient population is described and it is therefore useful to further distinguish patients, both in terms of the extent of disease (local or systemic) and the presence or absence of symptoms. There is a growing population of asymptomatic men with a rising PSA receiving hormone therapy for biochemical failure after definitive local treatment but with negative bone scans. These are therefore patients with biochemical recurrence, who have no evidence of metastatic disease. The discussion that follows will not focus on these patients, but on those patients with known metastases, for whom the outlook is much worse and for whom new treatment strategies are therefore clearly required. In these patients, the presence or absence of symptoms also has prognostic significance. An asymptomatic patient with metastatic prostate cancer, with disease progression evidenced by rising PSA, has a median survival of 18 mo. This is compared with a median survival of only 12 mo in symptomatic patients.

Clinical trials of investigative agents for the treatment of patients with HRPC have infrequently defined HRPC and when they do, it is defined inconsistently. In 2005, the European Association of Urology (EAU) proposed a more concise definition of HRPC [26]. The HRPC patient is clinically identified by the following criteria: serum castration levels of testosterone; three consecutive rises of PSA, each 2 wk apart, resulting in two 50% increases over the nadir; antiandrogen withdrawal for at least 4–6 wk; PSA progression despite secondary hormonal manipulations; and progression of osseous or soft-tissue lesions [27]. These eligibility criteria have been rapidly and widely accepted [26].

There are additional methods by which to more accurately stratify patients with HRPC to both guide treatment decisions and predict survival. Shulman and Benaime propose a PSA-based model to identify those patients with biochemical recurrence after androgen-deprivation therapy (ADT) who are at the highest risk of disease progression. It uses the following parameters to describe these patients: PSA nadir and PSA doubling time (Table 2) [28]. This model therefore incorporates three distinctive patterns of disease progression and provides meaningful information to share with the patient about his long-term outlook.

Table 2 Identification of patients with biochemical recurrence using PSA-based model

Risk PSA nadir PSA increase PSA doubling time (months) Median survival (months)
High >0.5 <7 months after hormonal ablation <6 months 14
Intermediate <0.5 >7 months after hormonal ablation <6 months 38.4
Low >6 months 89.1

Reproduced with permission from Shulman and Benaime [28].

Furthermore, Halabi et al. have proposed an alternative prognostic model for predicting survival in men with HRPC. This model includes factors, such as lactate dehydrogenase, PSA, alkaline phosphatase, Gleason sum, and Eastern Cooperative Oncology Group performance status, and allows the accurate prediction of survival probability in patients with HRPC and therefore the stratification of these patients into distinct risk subgroups. Such stratification not only ensures that, in clinical trials, treatment groups are balanced with respect to risk, but it may also allow the clinician to better tailor treatment to the needs of the individual patient [29].

4. The history of treatment for metastatic HRPC

The treatment of metastatic HRPC (mHRPC) is particularly challenging [15]. Patients with HRPC are a heterogeneous population, expressing a wide range of disease prognoses, and therefore treatment needs to be individualised. Furthermore, patients experiencing disease relapse after hormonal therapy are usually in a more advanced stage of disease than their hormone-naïve counterparts and will therefore usually become symptomatic relatively rapidly after onset of the PSA rise [27]. This issue is further complicated by the lack of universal clinical end points by which to evaluate and compare the response of patients with HRPC to different treatment options currently being explored in clinical trials.

Once a patient starts to fail to respond to ADT, the options, until recently, were limited: measure the serum testosterone; add antiandrogen if the patient has had an orchidectomy or luteinising hormone-releasing hormone agonist treatment alone; withdraw antiandrogen if the patient has had maximal androgen blockade; use corticosteroids; and use further hormonal manipulations with an adrenal androgen inhibitor or another antiandrogen. Patients with mHRPC who have failed first-line hormonal therapy cannot be offered curative treatment, and therefore management is focused on maintaining or improving quality of life (QoL) [27]. Some researchers support the use of further hormonal manipulations; however, there are no clear-cut recommendations for their use. This is the result of a notable lack of data from randomised studies [27]. Further hormonal manipulations include adding an antiandrogen to surgical or medical castration (54% of patients obtain a >50% drop in PSA [9]); adding hormonal castration to antiandrogen monotherapy (55% of patients obtain a >20% drop in PSA [9]); and changing the antiandrogen therapy—in patients previously treated with castration plus flutamide, a switch to bicalutamide [30] and [31] or nilutamide [32] and [33] elicits a response in 38–43% of patients [9].

Antiandrogen withdrawal has been shown to be active for all the nonsteroidal antiandrogens. At 2–4 wk following discontinuation of hormonal therapy, between 15% and 20% of patients will exhibit an antiandrogen withdrawal effect that is short-lived, lasting for up to 5 mo [9]. Such antiandrogen withdrawal responses can lead to significant disease improvement [22] and have been observed following the discontinuation of the antiandrogens flutamide, bicalutamide, and flutamide plus aminoglutethimide, as well as oestrogens and progestational agents [34]. Only when both antiandrogen therapy and the antiandrogen withdrawal response have been clinically used should the prostate cancer be considered hormone refractory and other therapeutic strategies considered [15].

The response to secondary hormonal manipulations is variable. Sixty-five percent of patients receiving ketoconazole and hydrocortisone at progression after antiandrogen withdrawal had a >50% decrease in PSA levels [35]. Similarly, a significant PSA response was observed in 59.3% of patients treated with low-dose dexamethasone [36]. Treatment with fosfestrol elicited a ≥50% decrease of PSA levels sustained for longer than 1 mo in 79% (95%CI, 66–92%) of patients [37].

Other treatments have also been developed that play an important role in managing the patient with HRPC. Palliative management is essential to minimise symptoms of disease progression. Bisphosphonates can be offered to patients with skeletal metastases to reduce bone loss and skeletal-related events. In a recent study by Saad et al., zoledronic acid reduced skeletal-related events but had little effect on disease progression, pain, or QoL [38]. Patients with bone metastases will also likely require regular analgesic medication for maximal pain relief, which will, in turn, require careful monitoring for constipation and aggressive management when present [39]. Bone pain can also be managed with radionuclides, such as strontium-89 and samarium-153. Strontium-89 reduces bone pain in 60–70% of patients and gives rise to a PSA response in 30–40% of patients and external-beam radiotherapy [27] and [40]. It is therefore very useful in controlling skeletal-related complications but does nothing to prolong the patient's survival.

Until recently, cytotoxic agents were reported to elicit only palliative effects and not survival benefits in patients with mHRPC [41], and no standard chemotherapy regimen was defined. In a review of 26 clinical trials by Yagoda et al. (n=1001), the overall response rate to chemotherapy was as low as 8.7%, with median survival times within the range of 6−10 mo. HRPC was therefore long considered to be nonresponsive to chemotherapeutics [42], and the urologist has been accordingly reluctant to consult an oncologist about the use of chemotherapy. Data from recent clinical trials suggests, however, that chemotherapy may offer survival benefits in this setting. These data are discussed in detail in Ronald de Wit's article published in this supplement, and offer hope to patients with mHRPC.

5. Conclusions

We know that, in many patients, prostate cancer progresses to HRPC with death caused by widespread metastases. PSA testing has allowed the earlier detection of HRPC, in some cases before metastases develop, and therefore more men now present with potentially curative disease. However, for those men who progress to HRPC, until recently, treatment options were limited. Second- and third-line hormonal therapies represent the standard of care, but are relatively ineffective. Patients with HRPC will therefore require multiple systemic therapies for their disease, ideally within the multidisciplinary team setting. Traditionally, HRPC was considered unresponsive to chemotherapy. This view may need to be refined in light of new data indicating that chemotherapy confers a survival advantage to these poor-prognosis patients.

Conflict of interest

This article was developed from a presentation given at a scientific symposium sponsored by sanofi-aventis at the European Association of Urology (EAU) Annual Congress, Paris, France, 5–8 April 2006.


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Royal Hallamshire Hospital, Sheffield, United Kingdom

lowast Royal Hallamshire Hospital, Department of Urology, Glossop Road, Sheffield S10 2JF, UK. Tel. +44 114 271 34 82; Fax: +44 114 271 34 25.

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