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Abbreviations
AS

active surveillance

CRPC

castration-resistant prostate cancer

DHEA

dehydroepiandrosterone

GM-CSF

granulocyte-macrophage colony-stimulating factor

HIFU

high-intensity focused ultrasound

OS

overall survival

PAP

prostatic acid phosphatase

(IM)RT

(intensity-modulated) radiotherapy

INTRODUCTION

  1. Top of page
  2. INTRODUCTION
  3. ACKNOWLEDGEMENTS
  4. CONFLICT OF INTEREST
  5. REFERENCES

Over the past few decades the treatment of prostate cancer has evolved from a primarily hormonal approach, to include open and subsequently minimally invasive radical surgery and radiotherapy (RT) to newer, still unproven, focal methods. In addition, the recent development of effective second-line medical therapies, including docetaxel, cabazitaxel and abiraterone, has resulted in improved survival rates in men with castration-resistant prostate cancer (CRPC) [1]. The debate surrounding screening and early detection using PSA testing continues, but the rising popularity of active surveillance (AS) as a means of managing low-risk disease has gone some way towards allaying the fears surrounding the ‘over-treatment’ of clinically insignificant tumours.

The 1966 Nobel Prize winning observation of Charles Huggins and Clarence Hodges [2] that remission of prostate cancer could be achieved by testosterone deprivation constituted a landmark in the management of this increasingly prevalent disease. The next major breakthrough came when the glycoprotein PSA, secreted by columnar cells within the prostate, which liquefies semen after ejaculation, was discovered. The measurement of PSA levels in the bloodstream, which rise when prostate cancer develops, resulted in a stage shift downward in the detection of prostate cancer, with resultant calls for PSA screening. Unfortunately, PSA proved to be a less than perfect marker for prostate cancer, because of the very large number of men with BPH, with similarly raised PSA values. Nonetheless, the European Randomised Study of Prostate Cancer Screening (ERSPC), initiated in the 1990s, has recently reported a 21% reduction in prostate cancer mortality in the screened arm at 11 years [3], but at the price of a considerable ‘over-diagnosis’ of low-risk, clinically insignificant cancers.

‘Over-diagnosis’ of prostate cancer is only worrisome if it results in ‘over-treatment’. Most reported series of radical prostatectomy and RT treatments for localised prostate cancer undoubtedly contained a proportion of patients with low-risk cancers that may never have progressed within their natural lifespan. Hence the current trend towards AS for men with Gleason pattern 6 cancers present in only a small proportion of biopsy cores, and with no evidence of a large tumour on multi-parametric MRI [4]. Indeed, the recently publicised Prostate Cancer Intervention versus Observation Trial (PIVOT) trial shows no difference in overall survival (OS) for older men with low/intermediate risk disease treated with radical prostatectomy at 10 years compared with those only observed. In contrast the Scandinavian randomised trial of radical prostatectomy vs watchful waiting (SPCG-4) can now provide individualised patient benefit calculations as well as its overall message that surgery can reduce prostate cancer mortality [5]. However, more work needs to be done to reliably detect those men who do have disease progression during AS by defining more clearly the triggers for intervention.

Which treatment then should now be offered to those men with clinically localised intermediate- or high-risk cancer deemed to be at significant risk of progression? Technological advances have transformed both surgery and RT. The development of laparoscopic prostatectomy and more recently robot-assisted radical prostatectomy have reduced hospital stay, complication and transfusion rates, and improved the patients' experience of surgery [6] and seems both oncologically sound with excellent functional outcomes in higher volume centres [7]. The deployment of intensity modulated RT (IMRT) has enhanced targeting of RT treatment. Low-dose brachytherapy is available for those unwilling to consider either surgery or the 7-week daily treatment regime required for IMRT and can be given as a boost to IMRT for those with intermediate/high-risk disease wishing to avoid hormonal ablation. For locally advanced tumours most agree that external-beam RT preceded by 3 months of androgen deprivation is the best alternative.

Very recently there has been a flurry of publicity about focal treatment of localised prostate cancer using high-intensity focused ultrasound (HIFU). A recent publication [8] reported data at 1 year in 42 patients treated with minimal impact on either sexual function or continence. However, four patients required re-treatment and others might be anticipated to relapse with further follow-up [9]. A randomised controlled trial comparing HIFU to more conventional therapy is urgently needed to provide better evidence of efficacy.

Androgen ablation therapy remains the mainstay for patients who either present with metastases or develop them in spite of surgery and/or RT. A LHRH analogue, preceded by an antiandrogen to avoid problems with a tumour flare, is the usual treatment of choice. The new LHRH antagonists, such as degarelix, constitute a useful hormonal alternative, and obviate the need for pre-treatment with an antiandrogen.

Eventually, however, in most patients with advanced prostate cancer treated with hormones, the PSA starts to rise. Chemotherapy with a taxane has been shown to be efficacious in this situation. For men with CRPC, the median survival in recent phase III studies has ranged from 12.2 to 21.7 months, with improvements in survival seen mostly with docetaxel-based regimens (8–11). Two studies have firmly established the benefits of this therapy. In the landmark TAX-327 trial, docetaxel 75 mg/m2 every 3 weeks showed a survival advantage compared with weekly docetaxel and mitoxantrone (18.9 vs 16.5 months; P < 0.009). PSA response, pain control and health-related quality of life were also significantly better with docetaxel given every 3 weeks compared with mitoxantrone [10]. An update of the results of the TAX-327 trial from 2007 confirmed an on-going survival benefit with 18.6% of patients alive at 3 years, for the docetaxel group compared with 13.5% with mitoxantrone (P= 0.005) [11].

A study by the Southwest Oncology Group (SWOG) 99-16 also showed survival benefit with docetaxel of 17.5 vs 15.6 months for mitoxantrone (P= 0.02), with a median time to progression (6.3 vs 3.2 months; P < 0.001) and PSA declines of 50% (50% vs 27%; P < 0.001) [12]. These two trials showed a 20–24% reduction in mortality in patients with CRPC treated with docetaxel-based chemotherapy.

There is now new hope for patients who progress after docetaxel-based chemotherapy. A new generation taxane, cabazitaxel, is now available to overcome docetaxel resistance (Fig. 1). Cabazitaxel, like docetaxel, is a semi-synthetic microtubule stabiliser extracted from needles of the European Yew tree. Results of a large phase III trial (TROPIC) involving 755 patients with metastatic CRPC progressing during or after docetaxel treatment have been reported [13,14]. Cabazitaxel significantly reduced the overall risk of death by 30% (P < 0.001) with a median OS of 15.1 vs 12.7 months with mitoxantrone. Progression-free survival, tumour response and PSA response were also significantly improved with cabazitaxel. In this population with very advanced disease and heavily pre-treated with chemotherapy, there were higher rates of neutropenia (81.7% vs 58%), febrile neutropenia (7.5% vs 1.3%) and diarrhoea (6.2% vs 0.3%) with cabazitaxel compared with mitoxantrone. Patients should clearly be carefully monitored for these adverse events.

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Figure 1. Cabazitaxel.

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Recently the CYP inhibitor, abiraterone acetate, has been shown to extend life expectancy in patients with CRPC, but is currently approved only for use after chemotherapy (Fig. 2). Abiraterone inhibits 17 α-hydroxylase/C17,20 lyase (CYP17A1), an enzyme which is expressed in testicular, adrenal, and prostatic tumour tissues. CYP17 catalyses two sequential reactions: (i) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by its 17α-hydroxylase activity, and (ii) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by its C17,20 lyase activity. DHEA and androstenedione are androgens and precursors of testosterone. Inhibition of CYP17 activity by abiraterone thus decreases circulating levels of testosterone. A phase III trial in patients previously treated with docetaxel started in 2008. A placebo-controlled randomised phase III clinical trial in patients with CRPC who are chemotherapy-naive opened to accrual in April 2009. OS was increased by 3.9 months [15]. However, recently presented data suggest that it may also have a role before chemotherapy is deployed [16]. Another emerging agent, MDV3100, is an androgen receptor antagonist, which has recently been shown to improve survival in men with metastatic CRPC previously treated with docetaxel chemotherapy [17].

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Figure 2. Abiraterone.

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Recent evidence has also indicated a role for vaccine-based immunotherapy in CRPC. Sipuleucel-T (Provenge) consists of autologous peripheral blood mononuclear cells, including antigen-presenting cells, which have been activated during a defined culture period with a recombinant fusion protein consisting of prostatic acid phosphatase (PAP), an antigen expressed in prostate cancer tissue, linked to granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune cell activator. The patient's peripheral blood mononuclear cells are obtained via a standard leukapheresis procedure ≈3 days before the infusion date. The active components are autologous antigen-presenting cells and human PAP-GM-CSF fusion protein. During culture, the recombinant antigen can bind to and be processed by antigen-presenting cells into smaller protein fragments. The recombinant antigen is designed to target antigen-presenting cells, and may help direct the immune response to PAP. Minimal residual levels of the intact human PAP-GM-CSF fusion protein are detectable in the final sipuleucel-T product. The cellular composition of sipuleucel-T is dependent on the composition of cells obtained from the patient's leukapheresis. The activated, antigen-loaded antigen-presenting cells are then infused into the patient, where they can potentially stimulate a T cell response against prostate cancer cells. The process is performed three times over the course of a 4-week period. The vaccine has been studied in three phase III clinical trials. In the first phase III study, D9901, consisting of 127 men with asymptomatic, metastatic CRPC, compared sipuleucel-T every 2 weeks for three cycles with placebo in a 2:1 ratio. The final 3-year follow-up of the D9901 phase III study showed a median survival benefit of 4.5 months and a three-fold improvement in survival at 36 months for patients who were randomised to receive Provenge [18]. In another trial, 98 men with asymptomatic, metastatic CRPC had a 21.4% improvement in OS for patients randomised to sipuleucel-T. In both studies, the vaccine was well tolerated, and the most common adverse events were chills and fatigue. The third phase III trial, D9902B, also known as the IMPACT trial (Immunotherapy for Prostate Adenocarcinoma Treatment) was a randomised, double-blind, placebo-controlled study comparing Provenge with placebo in 512 men with CRPC randomised in 2:1 ratio. The median OS favoured the vaccine arm with a 4.1-month increase in OS for patients treated with sipuleucel-T (25.8 vs 21.7 months; P= 0.032). Also, the 36-month survival probability was 31.7% in the sipuleucel-T group vs 23.0% in the placebo group. Therapy with sipuleucel-T was also associated with a positive OS effect in an analysis that included 18 additional deaths observed between the data-cutoff and study-completion dates, with a median of 36.5 months of follow-up (hazard ratio, 0.76; 95% CI 0.61–0.95; P= 0.02) [19]. Sipuleucel-T is the first active immunotherapy to show an improvement in OS for advanced prostate cancer. Given the short duration of the therapy (1 month) and its favourable benefit-to-risk ratio, sipuleucel-T provides an interesting, albeit expensive, new option for the management of advanced prostate cancer.

In conclusion, there can be few tumours that have been associated with more controversy than prostate cancer, or in which treatment options have changed so radically over recent years. Much work remains to be done to evaluate in randomised controlled trials the comparative risks and benefits of the various emerging therapies. However, in these changing times, it is heartening that the prospects for the very many men presenting with either localised or advanced, and even castration-resistant, prostate cancer have never been better than they are now.

ACKNOWLEDGEMENTS

  1. Top of page
  2. INTRODUCTION
  3. ACKNOWLEDGEMENTS
  4. CONFLICT OF INTEREST
  5. REFERENCES

Professor Prokar Dasgupta acknowledges support from the MRC Centre for Transplantation and the Comprehensive Biomedical Research Centre, King's Health Partners.

REFERENCES

  1. Top of page
  2. INTRODUCTION
  3. ACKNOWLEDGEMENTS
  4. CONFLICT OF INTEREST
  5. REFERENCES
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