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Urological Cancer

Hope Versus Hype: The Treatment Realities for Prostate Cancer

John Anderson, ChM FRCS

Consultant Urological Surgeon, Royal Hallamshire Hospital, Sheffield, UK. Honorary Secretary, British Association of Urological Surgeons. Correspondence to: John Anderson, Department of Urology, The Royal Hallamshire Hospital, Sheffield, S10 2JF, UK. Email: [email protected]

However, recent optimism regarding the development of late-phase pipeline pharmacological products has been somewhat dampened by the publication of negative or over-hyped interpretations of clinical trial data, leaving physicians in a quandary as to how to explain these results to their ever hopeful patients. For existing patients and the 34,302 patients in the UK newly diagnosed with prostate cancer each year [1], it is our responsibility to put this into perspective and sort the hype from the hope. Screening ­ an uncertain benefit or a known harm? Without doubt, prostate-specific antigen (PSA) testing and digital rectal examination (DRE) have contributed to earlier diagnosis, but whether this correlates with reduced mortality rates remains uncertain. Two large ongoing studies - the Prostate, Lung, Colorectal and Ovary (PLCO) trial in the USA and the European Randomised Screening for Prostate Cancer (ERSPC) [2] trial will probably elucidate or compound our current knowledge on the importance of screening and mortality risk. The medical community remains divided in its opinions about the benefits of screening. There are those who advocate early detection through screening, with the prospect of more treatment options and potentially fewer side effects, while those who are less keen on regular screening suggest that the inherent slow growth of prostate cancer means that a patient may be spared debilitating side effects

hilst great strides have been made over the last decade in the research and discovery of new treatments and combined modalities for prostate cancer, effective treatment at all stages of the disease remains a significant clinical challenge. More recently a better understanding of the biology of prostate cancer - the most frequently diagnosed cancer of men in the UK ­ has more clearly defined the regulatory role of male hormone signaling through the androgen receptor. This has been instrumental in the discovery of improved anti-androgen therapies and shaping the future for genetic and biomarker research that may lead to improved screening and customised treatments.

W

Figure 1: a timeline with the key milestones in historical development of treatments.

Treatment history Treatment hist r tory of prostate ca prostate cancer ancer

1940 Huggins demonstrates Huggins regression of prostate prostate carcinoma through endocrine control - advent of orchiectomy orchiectomy and oestrogen treatment treatment

1980s Long-acting synthetic luteinizing hormone-releasing hormone (LH-RH) agonists (LH-RH) 1970s 1970s Steroidal and non-steroidal anti-androgens available

The The future New androgen targeted receptor targeted drugs (eg degarelix), vaccines, biomarkers, genetic research

1904 First radical prostatectomy prostatectom my

2003 First gonadotropin releasing First gonadotropin d n hormone (GnRH) blocker, hor rmone (GnRH) abarelix launched abarelix launched u

1920 1 40 1960 1980 2000 2020 1920 1940 19 960 19 0

1920s Radiation the therapy for prostate prostate erapy cancer using radium g 1867 1867 First perineal prostatectomy performed prostatectomy 1960s and 70s 70s Synthetic oestrogens Synthetic developed, mainly diethylstilbestrol 1960s 1960s Radiotherapy established as importan Rad diotherapy established important nt treatment for prostate cancer prostate treatment 2004 Docetaxel in combination Doceta axel with pr prednisone approved rednisone in Euro as a treatment for Europe ope hormone-refractory metastatic hormone-refractory metastatic prostate cancer prostat te 1995 Cryosurgery accepted as a Cryosurgery treatment option for re recurrent ecurrent cancer after radiation t therapy

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Figure 2: Main currently approved treatment strategies for prostate cancer Treatment EARLY PROSTATE CANCER

Prostatectomy Retropubic Laparoscopic Robot assisted · Reduced risk of local recurrence · Allows for pathological assessment of disease · Any rise in PSA after undetectable PSA suggests local recurrence · Potential for salvage radiotherapy if local recurrence occurs · Potentially curative · Localised radiation over several months ­ more precise than EBR · Outpatient therapy · A return to normal daily activity within a few days · DFS rates at 12-years of 81-93% [7] · No anaesthesia risk and suitable for wide range of patients ­ those not able to tolerate prostatectomy or brachytherapy · Surgical complications such as haemorrhage and infection. · Erectile dysfunction (20-100%), urinary incontinence (0-5%), and stricture (0-12%) [3]

Advantages

Disadvantages

Brachytherapy

· Urinary side effects due to procedure-induced oedema ­ urinary frequency, hesitancy or retention · PSA rebound of unknown cause ­ occurs 1-2 years after brachytherapy · Dose variables ­ can differ greatly between planned implantation and actual implantation ­ seed anisotropy and migration · No histology to guide treatment · Surgery more difficult after radiotherapy · Relies on clinical staging and may therefore include patients with higher stage disease not detected by clinical and imaging workup · Rectal complications as dose may be delivered to surrounding rectal tissue ­ bleeding, local irritation, diarrhoea may result · Erectile dysfunction due to local nerve damage · No consensus on patient population to be observed · Relies on disease status, patient status, and patient compliance for follow-up

External beam radiotherapy (EBR)

Active surveillance

· Patients with low risk, low Gleason grade disease, spared side-effects of interventional treatments · May be suitable for older patients and considered in the context of the patient's life expectancy

ADVANCED PROSTATE CANCER Orchidectomy Mostly replaced by chemical castration Anti-androgens Non-steroidal: Flutamide, bicalutamide, nilutaminde Steroidal: Megestrol acetate Medroxyprogesterone Cyproterone acetate LH-RH/GnRH agonists Goserelin Leuprolide Buserelin Triptorelin · Rapid suppression of serum testosterone and decreases in PSA · Prevent or inhibit effects of androgens · Non-steroidal anti-androgens act on androgenic receptors and have minimal progestational side-effects (preserves libido and potency). · Oral administration · Alternative to surgical castration. · Achieves castrate levels of testosterone. · Psychological effects

· Side-effects that may affect quality of life include diarrhoea, nausea, loss of appetite, gynaecomastia.

· Early increase or surge in serum testosterone in first two weeks and possible tumour flare. Castrate levels achieved by four weeks. [8] · Possible testosterone microsurges (`breakthrough' testosterone) while on therapy. Evidence suggests that GnRH agonists do not achieve the same level of testosterone suppression as with orchiectomy, or as rapidly. [9] · Extended treatment with LH-RH/GnRH agonists may result in a decrease in bone mineral density. · Injectable administration. · Loss of libido, impotence, and hot flushes. · Possible cost implications due to high repeat administration.

METASTATIC PROSTATE CANCER Chemotherapy

(hormone-refractory) · Palliation of symptoms · Survival gain for some patients · Cytotoxic side-effects include alopecia, fatigue, nausea, and myelosuppression

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of treatment when the cancer is at a stage where intervention may not yet be indicated. Certainly, we know that the lower the PSA, the lower the detection rate of cancer [3]. According to the British Association of Urological Surgeons (BAUS) Cancer Registry [4], which keeps a database on the stage of disease at presentation, a quarter of patients have locally advanced or metastatic disease at diagnosis. This evidently high rate of advanced disease at diagnosis underlines the importance of early detection where there is greater potential for curative treatment when the cancer is localised to the prostate. Treatment today ­ how far have we progressed since the days of Huggins and Hodges? Since the pioneering work of Huggins and Hodges in 1941 [5] when a direct link was made between testosterone and the growth of prostate cancer cells, the ensuing six decades have seen androgen deprivation as the standard of care for advanced prostate cancer. Despite the advent of new treatments after 1941, when orchidectomy or oestrogen treatment was the standard of care for prostate cancer, the therapeutic goal remains essentially the same, i.e. suppression of testosterone. They include steroidal or non-steroidal anti-androgens, luteinising hormone-releasing hormone agonists (LH-RH), and, most recently gonadotropin-releasing hormone blockers (GnRH). A timeline of key milestones in historical development of treatments is shown in Figure 1. While acknowledging these advances, the long-term survival of patients with advanced prostate cancer remains poor and better treatment options are needed. Current treatment approaches Treatment strategies for early prostate cancer (organ confined) with intent to cure are primarily surgery (prostatectomy) and radiation therapy (brachytherapy with or without external-beam radiotherapy). Active surveillance is appropriate for some patients with low risk, low Gleason-grade disease. Hormone therapy (chemical castration) consists of GnRH analogues and anti-androgens. Hormone therapy may be prescribed in the neoadjuvant setting, adjuvant setting, or as salvage therapy (for biochemical or clinical failure after local therapy). It is the mainstay of treatment for advanced prostate cancer. While androgen deprivation leads to symptomatic improvement and reduction in serum PSA, the disease eventually becomes refractory to hormone therapy. Treatment options for patients with metastatic prostate cancer that is refractory to hormone intervention include chemotherapy, second-line hormonal manipulations, radiation/radioisotope therapy, and bisphosphonates. Chemotherapy has significant palliative benefits, and most recently docetaxel plus prednisone has given improved survival and response rates (pain, serum PSA level, and quality of life) compared to mitoxantrone plus prednisone [6]. For the future, new hope may come from research exploring several novel treatments, including improved hormone therapies that reduce the risk of testosterone flare, vaccines and vitamin D analogues, inhibitors of angiogenesis, and immunomodulators. Challenges in androgen deprivation therapy of prostate cancer Controversial issues regarding hormonal treatment of prostate cancer continue to be debated, including the benefits of complete androgen blockade versus monotherapy androgen suppression, the optimal timing of treatment, the importance of clinical flare, treatment breaks, resistance to hormone treatment, the value of new therapies at late stage clinical development, and new therapeutic strategies. An area that continues to generate much discussion is that of clinical flare associated with GnRH agonists; is this avoidable or a necessary evil? A surge in testosterone may cause subclinical tumour stimulation that can result in increased pain, ureteric obstruction, and paralysis due to spinal cord compression in patients with spinal column metastases. In contrast to orchiectomy, where rapid suppression of serum testosterone is observed, the administration of a GnRH agonist results in an initial rise in serum testosterone (1.5 to 2 times greater than baseline testosterone) for seven days and reaches castration levels three weeks after the first dose [9].

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For many high-risk (advanced disease) patients it is now standard practice to co-administer anti-androgen therapy with the first dose of a GnRH agonist to counteract the associated testosterone flare. It is assumed that the increase in testosterone during subsequent injections of GnRH agonists is much lower during continuous therapy, negating the need for further anti-androgen therapy. However, with regard to intermittent therapy, testosterone flare may be evident after initiation of each GnRH agonist treatment, which might adversely affect survival. In this case, it may be necessary to consider each treatment as a first dose, in which case anti-androgens may be necessary. This approach is inevitably associated with increased costs and side effects. The side effects of treatment, such as impotence and hot flushes, may resolve during intermittent therapy, offering better quality of life for patients. Furthermore, treatment breaks reduce the risk of developing hormone-independent growth characteristics, allowing for apoptosis to resume and a slower progression to the androgenindependent state. It is possible to withhold androgen deprivation therapy until PSA rises to a predetermined level indicative of reactivation of the tumour. [8] Complete androgen blockade (CAB), also referred to as combined androgen blockade or maximum androgen blockade, is a therapeutic strategy intended to provide more complete suppression of androgen production by the testes and adrenal glands. Androgen synthesis in the testes is eliminated by chemical castration with GnRH agonists, and low plasma concentrations of the hormone found after suppression are primarily of adrenal origin, which can be targeted with anti-androgen therapy. Some physicians remain sceptical about the value of complete blockade, suggesting that the minimal benefits do not merit the increased cost and risk of side effects attributed to the addition of anti-androgens that can significantly reduce the quality of life.

Trials have shown that degarelix causes a rapid, profound, and sustained reduction in testosterone without the initial surge

A meta-analysis [10] of randomised trials in advanced prostate cancer carried out by the Prostate Cancer Trialists' Collaborative Group concluded that the addition of an anti-androgen to androgen suppression improved the absolute 5-year survival by 2% or 3% (depending upon the type of anti-androgen used), with a range of uncertainty of 0% to 5%. The clinical significance of these findings remains debatable, but the group pointed out that the number of patients in the trials was small. A trial randomising several thousand patients would help minimise the risk of a false-negative result. Another area of contention is when to initiate treatment, whether at the time of diagnosis with the aim of halting disease progression or to delay hormone therapy until symptoms develop. The jury is still out on this matter, but further research should show whether early initiation slows progression with potential survival benefits, or whether delayed treatment reduces the likelihood of resistance to therapy. While considerable research continues on the hormonal pathways and the mechanisms behind refractory disease, resistance to treatment is a major clinical challenge. For patients who have failed hormone therapy, few options remain. The established first-line treatment for HRPC is docetaxel-based chemotherapy, but toxicity issues exclude many patients from this regimen. The search for an effective second-line treatment continues for patients with advanced prostate cancer whose disease has progressed while on androgen deprivation therapy. New treatments on the horizon ­ hope or hype? Evidently treatments are needed that mimic surgical castration without the debilitating testosterone surge. A new agent awaiting

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regulatory approval that shows promise as an alternative to GnRH agonist therapy is degarelix, classed as a GnRH blocker. GnRH blockers are synthetic peptides that bind to the GnRH receptor, blocking its action, which blocks the pituitary secretion of FSH and LH. Trials have shown that degarelix causes a rapid, profound, and sustained reduction in testosterone without the initial surge [9]. Recently, new data [11] from an ongoing phase-III study of 610 men with prostate carcinoma that compared two doses of degarelix to the GnRH agonist leuprolide depot over 12 months, showed that degarelix provided more rapid and profound testosterone suppression than the conventional treatment. Both doses of degarelix (80mg or 160mg/month) were at least as effective as leuprolide (7.5mg/month) in achieving a rapid treatment response. By day three, 96.1% of patients receiving the 80mg dose and 95.5% receiving the 160mg dose of degarelix had testosterone levels of 0.5ng/mL versus none in the leuprolide arm. This was sustained at day 14 (100% and 99%, respectively) versus 18.2% in the leuprolide arm. There were no incidences of testosterone surge or microsurge with degarelix. Treatment was well tolerated and no serious adverse effects were seen. The data suggest that this treatment offers real hope as an alternative to orchidectomy, [12] with rapid reductions in testosterone levels approaching the immediacy of surgery, but without the psychological effects. In general, degarelix is well tolerated and most side effects are related to androgen deprivation. [12] We await final results from this ongoing phase-III study in the hope that the data will clarify the potential advantages of degarelix over the agonists. In contrast to reviewing these late-phase clinical data, it is important to heed the pitfalls of interpreting early data into clinical benefit. Recently, a great deal of media publicity surrounded the publication [13] of results from a phase-I clinical trial of abiraterone acetate, an inhibitor of the CYP17 enzyme, critical for the synthesis of DHEA and androstenedione. Claims that this experimental drug is a breakthrough that could treat as many as 80% of men with aggressive and drug-resistant prostate cancer have been disputed by the medical profession [13,14]. These results were preliminary, and only further data from an ongoing phase-III trial of 1180 patients will determine whether it is beneficial. Whilst there is hope for this new treatment, one must be wary of the overstated hype regarding recent phase-I trials, which causes much concern for patients and unnecessary consultations with their physicians.

Although these data offer significant new evidence that castrateresistant prostate cancer (CRPC) remains dependent on hormones, extrapolation into clinical benefit is too early and remains a rocky path to tread. This is an important lesson to learn; raising the hopes of patients too early, however promising the data, is doing them a disservice and generates doubts amongst the medical community that may be detrimental to the future of new treatments that could save lives. This highlights the importance of clear, accurate, and realistic communications to the media and our patients. n

References 1. Cancer Research UK. The number of new cases and rates of prostate cancer in the UK, 2005. http://info.cancerresearchuk.org/cancerstats/types/prostate/incidence/. . 2. De Koning HJ, Liem MK, Baan CA et al. Prostate cancer mortality reduction by screening: power and time frame with complete enrolment in the European Randomized Screening for Prostate Cancer (ERSPC) trial. Int J Cancer 2002;98:268-73. 3. Damber E, Aus Gunnar. Seminar: Prostate Cancer. Lancet 2008; 371: 1710-21. 4. British Association of Urological Surgeons website. http://www.baus.org.uk/baus_subspecialty_sections/baus_cancer_registry_ sections_audit.phtml 5. Huggins C, Hodges CU. Studies on prostate cancer. The effect of castration, of estrogen and of androgen injection on serum phosphatises in metastatic carcinoma of the prostate. Cancer Res 1941;293-7. 6. Tannock I, de Wit R, Berry W et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-12. 7. Potters L et al. 12-year outcomes following permanent prostate brachytherapy in patients with clinically localized prostate cancer. Urology 2005;173:1562-6. 8. Crawford ED. Hormonal therapy in prostate cancer: historical approaches. Rev Urol 2004;6(Suppl 7):S3-S11. 9. Anderson J et al. Management of advanced prostate cancer: can we improve on androgen deprivation therapy? BJU International 2008; 101 (12): 1497-1501. 10. Prostate Cancer Trialists' Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Lancet 2000;355:1491-8. 11. Boccon-Gibod L, Klotz L, Schröder FH, et al. Degarelix compared to leuprolide depot 7.5 mg in a 12-month randomised, open-label, parallel-group phase III study in prostate cancer patients. Abstract 537 presented at the 23rd EAU Congress, Milan, Italy, 2008. 12. Nielsen S, Connolly M, Persson B. Variation between countries in the perceived use of antiandrogens to prevent flare symptoms: results of a comprehensive survey. Abstract 539 presented at the 23rd EAU Congress, Milan, Italy, 2008 13. Andrew Cole for BMJ news. Cancer expert doubts claims about prostate cancer trial. http://www.bmj.com/cgi/content/extract/337/jul24_3/a979. BMJ 2008; 337: a979. 14. Gerhardt Attard. Rapid response. Prostate cancer's day in the sun. http://www.bmj.com/cgi/content/full/337/aug11_2/a1249

...this treatment offers real hope as an alternative to orchidectomy, with rapid reductions in testosterone levels approaching the immediacy of surgery, but without the psychological effects

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