Prostate news article, April 2009

CHANGING TIMES FOR THE MANAGEMENT OF LOCALISED PROSTATE CANCER   Article by:   Professor Roger Kirby, Chairman, Prostate UK

The Prostate cancer is an unusual malignancy in that, although it kills almost 10,000 men annually in the UK, it is also found in an indolent, less dangerous form in the majority of men over 80 years of age. With the steady increase in testing for prostate cancer by prostate specific antigen (PSA) testing and prostate biopsy, and the aging of the population, the number of patients diagnosed with prostate cancer continues to rise. The problem then for clinicians is to distinguish the potentially life-threatening medium to high risk cancers from the less dangerous low risk tumours that pose little or no threat to life, provided that they are carefully followed up in a programme of active surveillance.

Some time ago the parameters of so-called low-risk “insignificant” prostate cancers best managed by active surveillance were defined¹. These include a presenting PSA less than 10 ng/ml, a Gleason score of 6 or less, and no more than 50% of any biopsy core infiltrated by cancer, as well as no disease being palpable on digital rectal examination. Furthermore staging MRI scans should show no evidence of infiltrating disease involving the capsule of the prostate or the seminal vesicles.

A protocol for active surveillance involves three monthly digital rectal examination and PSA determination followed by a repeat ultrasound-guided biopsy of the prostate and MRI at one year. Provided that there is no evidence of progression of the cancer at that stage the surveillance protocol is relaxed to 6 monthly follow ups with a further biopsy at 3 – 5 years^2,3

Recently, guidelines for the management of localised prostate cancer have been issued by the National Institute of Clinical Excellence (NICE) in the UK. http://www.nice.org.uk/guidance/index.jsp?action=byID&o=11924. These have emphasised the role of active surveillance for men with so called “low risk” prostate cancer. But this begs the question of whether can we really define with certainty the men with cancers which have a minimal risk of progression? And can we reliably recognise that progression is occurring at a time when the situation is still remediable?

A note of caution however comes from a paper in the online version of Cancer, Dr Patricia Harnden and colleagues⁴ report a meta-analysis on whether patients with microfocal CaP on biopsy have adverse pathologic findings or any significant risk of PSA recurrence after undergoing radical prostatectomy (RP).

A total of 238 articles were carefully evaluated and in the final review 29 articles addressed the specific question of the correlation between small-volume cancer on biopsy and pathologic findings, biochemical or clinical progression, or mortality. Where possible, outcome data were pooled to estimate the overall risk associated with small-volume cancer at biopsy.

All the studies were retrospective. Studies varied in the maximum number of biopsy cores that were allowed to qualify for the definition of microfocal adenocarcinoma and whether the maximum length of cancer and highest Gleason score were specified. The most common values adopted were a single positive core and a cut-off value of 3mm for the cancer length. Regarding the possibility that no tumour at all would be found in the radical prostatectomy specimen, the occurrence rate was 0.8%. The overall estimate of the risk that patients with microfocal adenocarcinoma would have extracapsular extension (ECE) at RP was 17.6%. The combined estimate for a positive surgical margin among men with microfocal cancer was 12%. The range of PSA recurrences among this population was 0-26%, with an estimated risk of 8.6%. Among watchful waiting studies, the overall number of patients was small, and a rising PSA was reported in 9 of 15 patients who had a microfocus of adenocarcinoma, and 4% experienced clinical progression. Conversion to definitive therapy occurred in 30%. They concluded that a small volume of cancer in prostatic biopsies is not necessarily indicative of a good prognosis. Thus caution is required before the recommendations of NICE are widely adopted. Other anxieties have centred on the psychological effects of telling a man that he has cancer, and then leaving it untreated. One study has evaluated this risk and found it to be minimal, provided that a clear and intelligible explanation is provided and that follow up is meticulous5. Once an active surveillance protocol is initiated the onus falls on the clinician to ensure that progression is properly monitored. An individual who is lost to follow up who subsequently returned with locally advanced disease or metastases would clearly have cause for complaint.

Radical prostatectomy is the only treatment for localised prostate cancer that has been shown in a randomised controlled trial to reduce cancer specific mortality compared with watchful waiting⁶.  Recently, the morbidity of the procedure has been significantly reduced by the introduction of first laparoscopic, then robotically-assisted radical prostatectomy (RALP).  The initial discovery that the prostate could be safely removed using laparoscopic technology was made in France during the 1990s. It soon became clear that this approach markedly reduced blood loss during surgery because of the raised intra-abdominal pressure resulting from the C02 insufflation, as well as markedly reduced post-operative discomfort and shortened length of hospital stay. The main drawback of the approach is the rather prolonged learning curve which is required to become technically proficient in the dissection and anastomosis, which may result in patients being subjected to the hazards of a prolonged operation and resultant post-operative complications. The first group to apply the da Vinci surgical robot (Figs 1) to radical prostatectomy was that of Dr Menon in Detroit, USA⁷.  Since then many teams including ourselves have adopted the technique⁸. The procedure involves the creation of 6 surgical ports and development of the retropubic space in order to gain access to the prostate. The prostate is then mobilised in the same manner as in open surgery by division of the endopelvic fascia and ligation of the dorsal venous complex. The bladder is then dissected away from the prostate at the vesico-prostatic junction and the seminal vesicles mobilised. The 3D vision and the 10 times magnification as well as the very precise robotic instrumentation (Fig 2) allows extremely accurate preservation of each neurovascular bundle postero-laterally which should eventually translate into a lower incidence of sexual dysfunction. Moreover, the highly refined instrumentation makes the anastomosis between the bladder neck and the transected urethra technically easy and much more accurate and precise. The consequence of this is to make the incidence of troublesome bladder neck stenosis, which used to occur not infrequently after open radical prostatectomy, now extremely rare. The integrity of the anastomosis can be checked under direct vision which allows the duration of catheterisation to be reduced to around a week. An active rehabilitation programme employing phosphodiesterase type 5 inhibitors, such as sildenafil or tadalafil, and the use of a vacuum device is important in terms of restoration of sexual function since there is evidence that a prolonged period without erections can result in fibrosis of the penile corpora cavernosa due to reduced oxygenation.

The chief advantage of radical prostatectomy, achieved by which ever means, as a treatment for localised prostate cancer is the definitive staging and grading that stems from the presence of the pathological specimen that one obtains for analysis. Not infrequently the Gleason score on the biopsy under-reads the definitive score from the resected specimen. Furthermore, the volume of the cancer is usually greater and its proximity to the capsule closer than anticipated pre-operatively. Occasionally however only a very small, low Gleason score cancer is found and it has to be admitted that probably radical prostatectomy did constitute an over-treatment for that individual. The three primary aims of radical prostatectomy are as follows:

• To completely excise all cancer tissue
• To avoid stress urinary incontinence
• To preserve the neurovascular bundles and there permit restoration of sexual function

Eastham et al⁹ have recently reported that the level of surgical experience and the volume of cases performed are key determinants in the successful achievement of these three, sometimes conflicting goals. And with increasing experience the use robotic technology seems certain to help us move closer to the “Holy Grail” of prostate surgery, namely complete excision of the prostate with the minimal perturbation to the patient, both post-operatively and in the longer term in terms of sexual and urinary function.

Other treatment options for men with localised prostate cancer include brachytherapy, high intensity focussed ultrasound (HIFU) and cryotherapy. For higher risk patients with shorter life expectancies external beam radiotherapy preceded by androgen ablation is usually the treatment of choice.

Brachytherapy involves the implantation of radioactive seeds in to the prostate under ultrasound guidance¹⁰. Considerable experience is required to reliably achieve optimal seed distribution. The prostate initially swells in response to the perturbation caused by the implantation and the radioactivity and symptoms of lower urinary tract obstruction are common. For this reason this treatment is contraindicated in men with larger prostates or those with pre-existing lower urinary tract symptoms (LUTS). Long term follow-up confirms good cancer control rates but if recurrence does develop, the only treatment option is hormone therapy because prostatic surgery after brachytherapy does carry a very substantial risk of incontinence or fistula formation.

High Intensity Focused Ultrasound (HIFU) is the newest kid on the block in the treatment armamentarium for localised prostate cancer and holds considerable appeal to patients in that it avoids the need for surgery or irradiation; moreover HIFU treatment can be repeated several times. Preliminary results seem encouraging although there is a small incidence of incontinence due to sphincter damage and fistula formation due to injury to the anterior rectal wall, which can be very challenging to manage¹¹.  The recently published NICE guidelines recommend that HIFU only be used in the context of a clinical trial until more data concerning its safety and efficacy are available.

Cryotherapy has been around for some time as a treatment option for prostate cancer, but the latest so-called third generation technology, is much newer and like HIFU has yet to be endorsed by NICE. The prostate is subjected to temperatures as low as 180 degrees as cooling is delivered though probes inserted via the perineum under ultrasound guidance¹². The rectum is protected from thermal damage by means of two carefully positioned heating probes and the freezing process observed real time by transrectal ultrasonography (TRUS). The tumour is killed by the freeze/thaw process but the prostate itself swell in response to the therapy and for this reason a suprapubic catheter is inserted. As with HIFU, severe side effects such as incontinence and vesico-colic fistulae have been reported, and more safety and outcome data are required before it is widely adopted.

Conclusions
The debate that has surrounded the management of localised prostate cancer is not likely to subside until the results of more randomised trials such as the PIVOT study which has compared radical prostatectomy to watchful waiting are available in 2009. Even then, the protagonists of robotic radical prostatectomy, brachytherapy, HIFU and cryotherapy will still likely be arguing in favour of their own favoured treatment modality. Unfortunately the diversity of opinion and the lack of high quality comparative data do make it difficult for patients to select a given treatment option for themselves. The NICE guidelines have helped to clarify issues in this contentious field, but have themselves been criticised for leaning rather too much towards active surveillance, when the numbers of patients managed by this strategy and reported in the literature are still comparatively small. As the population continues to age and society continues to consume a diet high in unsaturated fats the number of men facing the dilemma of which treatment option to choose for the management of their localised prostate cancer seems certain to grow, and with them, the controversy over the best way to proceed in terms of treatment.

Figures:

Figure 1 - Operating layout for robotic surgery

Figure 2 - Robotic scissors tool

References:
1. Epstein JL, Chan DW, Sokoll LJ, et al. Nonpalpable stage T1c prostate cancer: prediction of insignificant disease using free/total prostate specific antigen levels and needle biopsy findings. J Urol 1998; 160: 2407-11.

2. Klotz L. Active surveillance for prostate cancer: for whom? J Clin Oncol 2005; 23: 8165–9.

3. Klotz L. Low-risk prostate cancer can and should be managed by active surveillance and selected delayed intervention. Nat Clin Pract Urol 2008; 5: 2-3.

4. Harnden P, Naylor B, Shelley MD, et al. The clinical management of patients with a small volume of prostatic cancer on biopsy: what are the risks of progression? A systematic review and meta-analysis. Cancer 2008; 112: 971-81.

5. Burnett KL, Parker C, Dearnaley D, et al. Does active surveillance for prostate cancer carry psychological morbidity? BJU Int 2007; 100: 540-43.

6. 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.

7. Tewari A, Peabody J, Sarle R, et al. Technique of da Vinci robot-assisted anatomic radical prostatectomy. Urology 2002; 60: 569–72.

8. Dasgupta PD, Patil K, Anderson C, Kirby RS. Transition from open to robotic-assisted radical prostatectomy. BJU Int 2008; 101: 667-8

9. Eastham J. 2008 Outcomes etc

10. Blasko JC, Mate T, Sylvester JE, et al. Brachytherapy for carcinoma of the prostate: techniques, patient selection, and clinical outcomes. Semin Radiat Oncol 2002; 12: 81–94.

11.   Gelet A, Chapelon JY, Bouvier R, et al. Transrectal high intensity focused ultrasound for the treatment of localized prostate cancer: factors influencing the outcome. Eur Urol 2001; 40: 124–9.

12. Zisman A, Pantuck AJ, Cohen JK, Belldegrun AS. Prostate cryoablation   using direct transperineal placement of ultra-thin probes through a 17-gauge brachytherapy template - technique and preliminary results. Urology 2001; 58: 988–93.