PROGRESS IN MANAGEMENT OF PROSTATE CANCER Presented by Dr. J. Nkusi on the October 2007, 38 th Congress of the Botswana Medical Association.

INTRODUCTION Treatment options

Localised Disease 1.Watchful waiting No randomized study has demonstrated the benefit of radical treatment for early stage cancer of the prostate (T1 and T2)

2. Radical prostatectomy Prognosis (outcome) of patients treated by radical operation correlates with the stage of the disease (involvement of lymph nodes, Gleason score and PSA). Morbidity associated with radical treatment can be significant!

3. Radiotherapy Possible improvement of PSA levels, however improvement of prognosis not proved.

4. Brachytherapy Early data in patients with low volume and low grade cancer of the prostate are encouraging compared to other forms of radiotherapy. Cave: possibility of urine obstruction, seed migration and impotence.

5. Cryotherapy At least at short term cryotherapy can bring to negative prostate biopsy and low or undetectable PSA. Cave: impotence, recto urethral fistula and urinary obstruction!

6.Thermo Ablation An alternative treatment using High Intensity Focused Ultrasound (HIFU) in patient non eligible for a radical prostatectomy.

Locally Advanced Disease At T3 stage the treatment involves External beam radiotherapy (XRT) preceded by complete androgen blockade.

C. Metastatic Disease Androgen ablation therapy and or orchiectomy.

PROGRESS

1. Diagnosis and screening

1.PCa in men with prostate specific antigen <4 ng/ml The widespread use of PSA as a screening tool has led to an increase in PCa patients number.

PSA levels >4ng/ml have been considered an indication for prostate biopsy.There is continuous debate whether the threshold for PCa detection should be lowered to detect more Tm at an organ confined stage.

Contradictory, histopathology results of operated prostates have sometimes come out free of malignancy even with PSA levels well over 10ng/ml. Conclusion: No distinct PSA threshold is suitable for early clinically relevant PCa.

1.2Prostate cancer gene 3 (PCA3) A new test may help : the Prostate CancerGene3 (PCA3) assay. The PCA3 assay uses urine to measure PCA3 and PSA messenger RNA (mRNA) concentrations, of which the ratio is taken to calculate the PCA3 score

The PCA3 assay provides near complete separation of young healthy men vs men with BPH vs men with PCa and those after radical prostatectomy. PCA3 is highly specific for PCa versus BPH and may therefore be used in the diagnosis of PCa.

2.Radical therapy 2.1Surgical skills and PCa recurrence It was established that the surgeons’ skills may influence the outcomes of radical prostatectomy in terms of morbidity and positive margin rates. The number of cases done was not proof of well done procedure.

More and more classical retropubic radical prostatectomy is being replaced by endoscopic procedure and robot assisted prostatectomy.

2. 2. Adaptive radiotherapy Adaptive radiotherapy intends to improve radiation treatment by systematically monitoring treatment variations and incorporating them to re - optimise the treatment early on during the course of treatment.

A recent study (Forsky MS, et all Int. J Radiat Oncol Biol Phys 2006;66) has shown that adaptive radiation therapy may improve biochemical relapse-free survival and reduce the risk of late rectal complications.

2.3. Histopathology At the European Association of Urology 2006 Congress a report mentioned a marked discrepancy between the local pathologists and the review pathologist on the histopathologic evaluation of prostatectomy specimens concerning extracapsular extension and margin status.

Central review of specimens may improve the quality of examinations and play a role in future clinical trials.

2.4. Salvage radiotherapy for biochemical recurrence. In case of recurrence after radical prostatectomy, salvage radiotherapies may be started. The outcomes depend on the pre radiation PSA levels.

Salvage treatment should be started as soon as possible when PSA failure is observed, according to a recent presentation at the AUA 2006 annual meeting. A predictive 5 year progression-free probability model was developed.

3.Hormone Therapy 3.1. Immediate versus deferred treatment There is no consensus whether a hormone therapy( orchidetomy or LHRH agonist) for locally advanced, and asymptomatic metastatic PCa at diagnosis, favorably influences survival and quality of life compared to deferred therapy.

However it is accepted that patients with a PSA 8-50 ng/ml and a PSA doubling within a year are at high risk of disease progression and death, and should be elected for immediate total androgen blockade.

3.2. Androgen-deprivation for biochemical recurrence after prostatectomy Patients with a rising PSA after RP benefit of androgen blockade. It was found that a prolonged response to androgen-deprivation therapy over 12.4 years can be achieved when the immediate response is a PSA at the nadir level of <0.2ng/ml.

3.3. Intermittent versus continuous androgen blockade It is common knowledge that all patients on hormone therapy end up advancing to hormone independence and ultimately to hormone-refractory state.

A recent study showed that intermittent therapy may be a way of delaying hormone resistance while improving quality of life at the same time ( sexual life e.g.).

Survival rate at 5 years was comparable and even better in the intermittent group (53.8% vs 51.0%) compared to the continuous group. Therefore intermittent hormone therapy was adopted by the EAU 2007 guidelines to be an option in regular practice.

3.4. Prevention of mineral loss Patients on hormone therapy for PCa are at risk of decreased bone mineral density and osteoporotic fractures.

The administration of Zoledronic acid 4mg yearly injection has been found effective in preventing the decrease of BMD in a recent randomised study (Michaelson MD, Lee H, Smith MR. J Clin Oncol 2006;24:220 –Abstr no. 4515).

4.Hormone-resistant Prostate Carcinoma Until recently options were limited for the treatment of hormone refractory PCa and no single or combined chemotherapy had proven to prolong survival. Two recent phase3 studies have brought some hope: it appears that Docetaxel- based chemotherapy may prolong survival in patients with hormone refractory PCa.

Although relapse happened after a period of 12 months in 80% of the patients enrolled in the study, who were then restarted on treatment with some success (>50% decrease in PSA), the results suggested that rechallenge with low dose intermittent docetaxel may be effective and well tolerated in patients with hormone refractory PCa and PSA progression after initial treatment.

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