Prostate news article, February 2010

PROSTATE CANCER: DEVELOPMENTS IN DIAGNOSIS AND TREATMENT   Article by:   Professor Roger Kirby, Chairman, Prostate UK

Prostate cancer is currently diagnosed in over 34,000 men every year and claims more than 10,000 lives per annum in the British Isles, and many more than that internationally. Men dying from advanced disease often suffer intractable bone pain and debilitating lower urinary tract symptoms and consequently suffer considerable quality of life impairment. In the absence of a breakthrough in the treatment of metastatic disease, earlier diagnosis and more effective eradication of clinically significant disease currently seem to afford the best opportunity of stemming the tide.

Recently, prostate specific antigen (PSA) population screening has been evaluated in two major randomised, controlled studies. The European Randomised Study of Prostate Cancer Screening (ERSPC) reported a 20% reduction in the risk of prostate cancer death with screening¹. By contrast, the US based Prostate, Lung Colorectal and Ovarian (PLCO) screening study showed no significant difference in prostate cancer mortality between the two groups². The latter study was however flawed by the inclusion of almost 50% of individuals in the control “unscreened” group who had in fact been tested for PSA values outside the study – a reflection of the pre–existing high level of public awareness of prostate cancer screening by PSA in the USA.

Even though the more mature European study confirmed that PSA screening is capable of reducing prostate cancer mortality, anxieties still persist, particularly surrounding the issue of over-diagnosis of clinically insignificant cancer, which may never be destined to result in morbidity or mortality.

The above-mentioned limitations of the PSA test as a screening tool has driven research into other potential biomarkers for screening for prostate cancer³. The PCA3 test, which is based on the analysis of a urine sample taken immediately after prostatic massage, looks promising in terms of sensitivity and specificity, and may also preferentially identify less well-differentiated, higher risk cancers, rather than those which are clinically insignificant⁴. More clinical trials are required to increase the evidence-base surrounding this marker however before its widespread introduction.

The very recent identification of 29 genetic variants that predispose towards prostate cancer offer another, more targeted, opportunity to reduce the death toll of this increasingly prevalent disease⁵ (Fig 1). Linkage studies in multiple case families have shown linkage to some regions, but searches for definitive genetic mutations arising from candidate gene screening in such regions have yielded conflicting results. Several research groups are now using candidate gene screening for rare variants and genome-wide association approaches to identify common variants. From the former of these types of studies, rare but high/moderate risk variants have been found in genes in the DNA repair pathway. A recent genome wide association study in DNA samples from prostate cancer cases and controls from the UK and Australia found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk and confirmed previous reports of SNPs associated with prostate cancer risk on chromosomes 8 and 17. These discoveries raise the possibility of the identification of a sub-group of men who are especially susceptible to prostate cancer, in the same way that women who harbour certain genetic mutations are particularly prone to breast cancer. These men could be carefully scrutinised for evidence of prostate cancer by regular PSA measurements, as well as PCA3 testing and template prostate biopsies taken via the trans-perineal route, which would significantly reduce the risk of serious infection.⁶

Once prostate cancer has been detected, usually on the basis of a transrectal ultrasound-guided biopsy of the gland, and secondary spread of the disease excluded, the patient and his family are faced with the difficult decision about which treatment option to select. In lower risk cases, (i.e. a Gleason score of 6 or less, a PSA below 10ng/ml and only a small percentage of biopsy cores infiltrated with cancer) a programme of active surveillance may be sufficient. Regular PSA measurement at 3 monthly intervals and an MRI and repeat biopsy are usually recommended to exclude local progression⁷. In fitter men, with more clinically significant disease, eradication of the cancer by surgical removal of the gland is often involved, indeed this is the only treatment which has been proven in a randomised controlled trial to reduce both the rate of metastases and mortality compared with watchful waiting⁸. The traditional open technique of radical prostatectomy is now increasingly being replaced by the laparoscopic “keyhole” approach, with or without the assistance of the da Vinci robot. This sophisticated piece of apparatus allows 3D visualisation and 10 times magnification making the dissection of the neurovascular bundles and anastomosis of the bladder to the urethra more precise^9-11. Other treatment options for localised prostate cancer include brachytherapy, in which radioactive seeds are implanted into the prostate, and external beam radiotherapy, which is usually delivered over a 6-7 week period. Although both radiotherapeutic options can undoubtedly achieve complete cure, they do leave the patient and clinician in some uncertainty as to whether the tumour has been completely eradicated, as PSA values decline but do not reliably become undetectable (unlike after surgery). The same applies to the new treatment option of high intensity focused ultrasound (HIFU), which unlike radiotherapy can be repeated, but for the present should be regarded as experimental.

In contrast to localized or locally advanced disease, metastatic prostate cancer is associated with high mortality – approximately 70% within 5 years. Androgen deprivation, which has become the mainstay of treatment, effectively reduces intraprostatic DHT concentration by over 80%, resulting in reduced androgen receptor stimulation and increased prostate cancer apoptosis. Androgen deprivation can be achieved by bilateral orchidectomy or treatment with LHRH analogs, and the value of adding an antiandrogen (maximal androgen blockade) is still debated. Pure LHRH antagonists are now available.

LHRH analogues, such as goserelin acetate, buserelin and leuprolide, are highly potent LHRH agonists (superagonists). After administration, there is a transient initial increase in LH secretion, and hence in testosterone secretion; this is followed by desensitization (down-regulation), resulting in a fall in LH and testosterone secretion. These agents can be delivered via 1-, 3- or 6-monthly depot preparations administered subcutaneously or intramuscularly. A potential side effect is tumor “flare”, which 8–32% of patients experience as a result of the initial transient increase (140–170%) in testosterone¹². This may result in increased bone pain or worsening of symptoms of bladder outflow obstruction; spinal metastases may also be stimulated, increasing a risk of spinal cord compression. Tumor flare can be avoided by prior and concomitant administration of an antiandrogen during the first 6 weeks of treatment. Comparative trials have shown that the response rates obtained with LHRH analogs are equivalent to those obtained after orchidectomy in terms of time to progression and overall survival.

Recently the pure LHRH antagonist Degarelix¹³ has been introduced, and regulatory approval of a similar compound Abarelix¹⁴ is expected soon. These peptides inhibit LHRH release without the initial stimulation seen with LHRH analogues by blocking pituitary receptors and thus they are not associated with a surge in testosterone (flare). This results in a more rapid achievement of the castrate state. More rapid return of testosterone with intermittent application is potentially an additional benefit. Currently they need to be administered by monthly injection.

In most cases, advanced prostate cancers treated with any form of androgen deprivation eventually begin to progress, a phenomenon known as “hormone-refractory” or “androgen-independent” disease. An increase in PSA level after initially successful androgen deprivation almost inevitably indicates impending clinical progression. This group is, however, quite heterogeneous, including men with PSA rises only and no demonstrable metastases, and men who have many bone and visceral metastases, pain and poor functional status; survival can range from only a few months to 4 years. Historically, therapy had little impact beyond modest palliation; however, treatments that may delay the progression of symptoms, as well as prolong survival, are becoming available.

Docetaxel, a chemotherapy agent which is a member of the taxoid family, induces apoptosis in cells through microtubule depolymerization. It has been tested in a randomized trial against mitoxantrone and prednisone in men with androgen-independent prostate cancer. The results of this study (TAX-327)¹⁵ showed docetaxel, given in a 3-week schedule, to be superior to mitoxantrone/prednisone in terms of decreasing disease progression, PSA response and improving pain. In addition, docetaxol significantly improved survival from a median of 16.4 months for mitoxantrone/prednisone to 18.9 months for 3-weekly docetaxel, which correlates to a 24% relative reduction in death. The side effects associated with docetaxel include neutropenia, skin reactions and gastrointestinal problems. In the trial described, the incidence of these side effects was higher in the group receiving docetaxel than in the group receiving the mitoxantrone/prednisone combination. Novel therapies such as endothelin A inhibitors, and a compound known as abiraterone, are in development, but none has been approved for clinical use yet by regulatory authorities.

In conclusion, prostate cancer continues to touch the lives of large numbers of men of middle age and beyond, as well as their families, and increasingly General Practitioners are becoming involved in the care of these patients. As a result of concerted efforts, both nationally and internationally, the evidence-base for diagnosis and treatment is steadily improving and with it the outlook for the very many individuals afflicted¹⁵.

 

References

1. Schroder F, Hugosson J, Roobol M, et al Screening and prostate cancer mortality in a randomized European study N Engl J Med 2009;360:1320-8.
2. Andriole G, Crawford E, Grubb R et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009;360:1310-8.
3. Lin D, Beyond PSA: utility of novel tumour markers in the setting of an elevated PSA. Urol Oncol 2009;27:315-21
4. Kirby RS, Fitzpatrick JM, Irani J. Prostate cancer diagnosis in the new millennium: strengths and weaknesses of prostate-specific antigen and the discovery and clinical evaluation of prostate cancer gene 3 (PCA3) BJU Int 2009;103:441-5.
5. Eeles RA Kote-Jarai Z, Giles GC et al. Multiple loci on 8q24 associated with prostate cancer susceptibility Nat Genet 2009;41:1058-60.
6. Kirby RS, Eeles RA, Kote-Jarai Z et al. Screening for prostate cancer: the way ahead. BJU Int 2010 in press.
7. van As NJ, Parker CC. Active surveillance with selective radical treatment for localized prostate cancer. Cancer J. 2007;13:289-94.
8. Bill-Axelson A, Holmberg L, Ruutu M et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2005;352:1977–84
9. Goldstraw MA, Patil K, Anderson C, Dasgupta P, Kirby RS.A selected review and personal experience with robotic prostatectomy: implications for adoption of this new technology in the United Kingdom. Prostate Cancer Prostatic Dis. 2007;10:242-9.
10. Patil K, Kirby RS, Hicks J and Stolzenberg J-U. Laparoscopy or robotics: where does the future lie. BJU Int 2009; 104:1551-3.
11. Dasgupta PD, Kirby RS, The current status of robot-assisted radical prostatectomy. Asian J Androl 2009;11:90-8.
12. Waxman J, Man A, Hendry WF, et al. The importance of tumour exacerbation in patients treated with long action analogues of gonadotrophin releasing hormone for advanced prostate cancer. BMJ 1985;291:1387–8.
13. Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int 2008;102:1531–8.
14. Kirby RS, Fitzpatrick JM, Clarke N, Abarelix and other gonadotrophin- releasing hormone antagonists in prostate cancer. BJU Int 2009;104:1580-4.
15. Petrylak DP, Tangen CM, Hussain MH et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513–20

Figure 1. Chromosomal locations of the 29 genetic mutations so far identified as conferring prostate cancer susceptibility.