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Gleason score The Gleason score is the sum of the two most common patterns (grades 1-5) of tumour growth found. The Gleason score ranges between 2 and 10, with 2 being the least aggressive and 10 the most aggressive. In needle biopsies, the worst grade should always be incorporated in the Gleason score, even if comprising < 5% of the cancer. During the past 20 years, there appears to have been a shift towards higher Gleason scoring levels ,even in cases evaluating microscopic foci of PCa. Some tumours previously given a Gleason score of 6 (3 + 3) might be scored today as 7 (3 + 4) or higher.
SCREENING AND EARLY DETECTION Based on the results of these two large, randomised trials, (PLCO) (ERSPC) most if not all of the major urological societies conclude that at present widespread mass screening for PCa is not appropriate. Rather, early detection (opportunistic screening) should be offered to the well-informed man Two key questions remain open: • At what age should early detection start? • What is the screening interval for PSA and DRE?
A baseline PSA determination at age 40 years has been suggested, upon which the subsequent screening interval may then be based (GR: B). A screening interval of 8 years might be enough in men with initial PSA levels <1 ng/mL . PSA testing in men older than 75 years is not recommended because its early detection would not have any clinical impact .
DIAGNOSIS The main diagnostic tools to obtain evidence of PCa include DRE, serum concentration of PSA and transrectal ultrasonography (TRUS). Its definite diagnosis depends on the histopathologic verification of adenocarcinoma Sextant biopsy is no longer considered adequate. At a glandular volume of 30-40 mL, at least eight cores should be sampled. The British Prostate Testing for Cancer and Treatment Study has recommended 10 core biopsies (LE: 2a) More than 12 cores are not significantly more conclusive (LE: 1a)
Endorectal MRI (e-MRI) may allow for more accurate local staging as Image quality and localization improves significantly with e-MRI , When compared with DRE and TRUS.
e-MRI contributes significant incremental value for local PCa staging ,particularly in the pre-operative identification of extraprostatic extension (EPE) and seminal vesicle invasion (SVI). e-MRI could impact on the decision to preserve or resect the neurovascular bundle (NVB) at the time of radical surgery
TREATMENT:DEFERRED TREATMENT There is a great difference between the incidence of PCa and deaths from Pca Several autopsy studies of people dying from different causes have shown that while 60-70% of older men have histological PCa, a large proportion of these tumours will not progress. The incidence of small, localised, well-differentiated PCa is increasing, mainly as a result of prostate-specific antigen (PSA) screening and ‘multicore’ schemes of prostate biopsy
These data suggest that many men with localised PCa would not actually benefit from definitive treatment. With the aim of reducing the risk of overtreatment in this subgroup of patients, two conservative management strategies of ‘watchful waiting’ and ‘active surveillance’ have been proposed.
Watchful waiting (WW)localised PCa (stage T1-T2, Nx-N0, M0) the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) randomised 695 patients with clinical stage T1-T2 to WW (348) or radical prostatectomy (347) . This study began after PSA screening was introduced into clinical practice, but only 5% of men were diagnosed by screening.
After a median follow-up of 12.8 years, this study showed a significant decrease in cancer-specific mortality, overall mortality, metastatic risk progression and local progression in patients treated with radical prostatectomy versus WW (LE: 1b). Subgroup analysis showed that the overall difference was not modified by PSA level (below or above 10 ng/mL) or by the Gleason score (below 7 or above) at the time of diagnosis. However, age at that the time of randomisation had a profound impact, the benefit on overall survival and metastases free survival being only seen for those below 65 years of age.
The Prostate Cancer Intervention Versus Observation Trial: VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT) is an ongoing, controlled, multicentre, randomised clinical trial comparing radical prostatectomy with WW in patients with clinical stage T1-T2 disease. 731 patients with a median age of 67 years were enrolled. approximately 43% of men had low-risk PCa, 36% had medium-risk PCa, and 20% had high-risk PCa. Follow-up is planned for 15 years, and the primary endpoint is the overall mortality.
Preliminary unpublished results have been presented at the latest AUA meeting . The results suggested that overall there was a lack of survival benefit. However, there appeared to be an overall survival benefit in men with an intermediate- and high-risk PCa, as well as a cancer specific survival benefit in men with high-risk PCa or with a PSA above 10 ng/mL. It appears that many small localised well-differentiated PCas will not progress, and radical therapy may lead to substantial overtreatment with resulting effects on the patients’ quality of life and treatments costs.
Active surveillance A variety of additional studies on active surveillance in clinically organ confined disease have now been published.
All have confirmed that, in well-selected patients with very low-risk disease, there was a very low rate of progression and cancer- specific death, with only a few patients required delayed radical intervention. However, an extended follow-up is necessary to obtain definitive results. Thus, active surveillance might mean no treatment at all for patients older than 70 years, while in younger patients, it might mean a possible treatment delayed for years.
Indications Stage T1a: well and moderately differentiated tumours. In younger patients with a life expectancy of more than 10 years, re-evaluation with PSA, TRUS and biopsies of the prostatic remnant is recommended. (LE 2a) Stage T1b-T2b: well and moderately differentiated tumours. In asymptomatic patients with a life expectancy of < 10 years. (LE 2a) In patients with the lowest risk of cancer progression: T1-2a, PSA <10 ng/mL, biopsy Gleason score <6 (at least 10 cores), <2 positive biopsies, minimal biopsy core involvement (<50% cancer per biopsy). (LE 2a)
Active surveillance selection is based on confirmatory biopsies. Follow-up is based on DRE, PSA and repeated biopsies. The optimal timing for follow-up is still unclear (yearly or every 2 years). The trigger for patients being moved off active treatment is based mainly on grade progression on repeated biopsies or at the patient’s request.
ACTIVE MANAGMENT Management decisions should be made after all treatments have been discussed by a multidisciplinary team (including urologists, radiation oncologists, medical oncologists and radiologists), and after the balance of benefits and side effects of each therapy modality has been considered by the patients with regard to their own individual circumstances. Patient must be informed about the likelihood of a multimodal approach. In case of adverse tumour characteristics (positive section margin, extraprostatic extension, or seminal vesicle invasion), adjuvant radiotherapy may reasonably be used after recovery from surgery. When nodal involvement is detected after surgery, adjuvant ADT may be selected.
When it comes to Pca treatment it is a matter of perspective
RADICAL PROSTATECTOMY While it is the recommended choice In patients with low and intermediate risk localised PCa (cT1a-T2b and Gleason score 2-7 and PSA <20 ng/mL) and life expectancy > 10 years. (LE1b) It is optional in Patients with stage T1a disease and a life expectancy >15 years or Gleason score 7. (LE 3) Selected patients with low-volume, high-risk, localised PCa (cT3a or Gleason score 8-10 or PSA > 20 ng/mL). (LE 3) Highly selected patients with very-high-risk, localised PCa (cT3b-T4 N0 or any T N1) in the context of multimodality treatment.
neoadjuvant and adjuvant hormonaltreatment and radical prostatectomy NHT before RP does not provide a significant OS advantage over prostatectomy alone. NHT before RP does not provide a significant advantage in DFS over prostatectomy alone. NHT before RP does substantially improve local pathological variables such as organ-confined rates, pathological down-staging, positive surgical margins, and rate of lymph node involvement. Adjuvant HT following RP shows no survival advantage at 10 years. Adjuvant HT following RP: the overall effect estimate for DFS is highly significantly in favour of the HT arm.
DEFINITIVE RADIATION THERAPY There are no randomised studies comparing radical prostatectomy (RP) with either external beam radiation therapy (EBRT) or brachytherapy for localised PCa. However, the National Institutes of Health (NIH) consensus set up in1988 remains available: external irradiation offers the same long- term survival results as surgery. moreover, EBRT provides a QoL at least as good as that provided by surgery. Intensity modulated radiotherapy (IMRT) +/- image guided (IGRT) is the gold standard .
three-dimensional conformal radiotherapy (3D-CRT) Anatomical data, acquired by scanning the patient in a treatment position, are transferred to the 3D treatment planning system, which visualises the clinical target volume and then adds a (surrounding) safety margin. At the time of irradiation, Intensity modulated radiotherapy(IMRT) enables radiation oncologists to increase radiation doses, up to as much as 86 Gy within the target volume, while respecting the tolerance doses in organs at risk. Certainly, IMRT is the only safe means of treatment delivery for dose escalation beyond 75 Gy
Immediate and delayed post-operativeexternal irradiation after radical prostatectomy Three prospective randomised trials have assessed the role of immediate post-operative radiotherapy The EORTC study 22911 The study concludes that immediate post-operative radiotherapy after surgery significantly improved 5-year clinical or biological survival: 72.2% versus 51.8% (p < 0.0001) Also the ARO trial 96-02 and the SWOG 8794 trial with similar conclusion
Either immediate radiotherapy (ART) to the surgical bed upon recovery of urinary function ; or clinical and biological monitoring followed by salvage radiotherapy (SRT) before the PSA exceeds 0.5 ng/mL . Early salvage radiotherapy provides the possibility of cure to patients with an increasing or persisting PSA after RP. More than 60% of patients who are treated before the PSA level rises to more than 0.5 ng/mL will achieve an undetectable PSA level again
Recommendations regardingradiation therapy In localized prostate cancer T1c-T2c N0 M0, 3D-CRT with or without IMRT is recommended, even for young patients who refuse surgical intervention. (LE 2) For high-risk patients, long-term ADT prior to and during radiotherapy is recommended because it results in increased overall survival.(LE 2) In patients with pathological tumour stage T3 N0 M0, immediate post-operative external irradiation after RP may improve overall survival and biochemical and clinical disease-free survival with the highest impact in cases of positive margins. (LE 1)
In patients with pathological tumour stage T2-3N0M0, salvage irradiation is indicated in case of persisting PSA or biochemical failure, but before the PSA level rises above 0.5 ng/mL. (LE 3) In locally advanced prostate cancer T3-4 N0 M0, concomitant and adjuvant hormonal therapy for a total duration of 3 years, with external beam irradiation, is recommended because it improves overall survival. (LE 1)
Experimental therapeutic options totreat clinically localized PCa All other minimally invasive treatment options - such as HIFU microwave and electrosurgery - are still experimental or investigational. For all of these procedures, a longer follow-up is mandatory to assess their true role in the management of PCa.
Intermittent versus continuous ADT Overall, eight randomized trials are underway the largest trial available so far(still unpublished)has been presented at several meetings. A total of 1,386 patients relapsing after radiotherapy, given as either primary treatment or for relapsing patients after surgery, were randomized to continuous ADT or intermittent ADT. Continuous treatment was for a fixed 8-month period. Intermittent ADT was stopped when PSA < 4 ng/mL and resumed when above 10 ng/mL. After a median 7 years of follow-up, the median OS was 9.1 years in the continuous arm and 8.8 years in the intermittent arm
This finding suggests that, even if continuous treatment provides a specific survival difference compared to IAD, the survival difference is completely counterbalanced by the increased specific toxicity of continuous ADT which therefore results in a lack of difference in OS survival, the increasing of which remains the main objective
BIOCHEMICAL FAILURE AFTERTREATMENT WITH CURATIVE INTENT A recurrence of Ca P can be defined as: •Following RP,PSA values > 0.2 ng/mL confirmed by two consecutive measures. •Following radiotherapy, a PSA value of 2 ng/mL above the nadir after radiotherapy.
Diagnostic procedures for PSArelapse following RP bone scintigraphy and CT scans are of no additional diagnostic value, unless the PSA serum levels are higher than 20 ng/mL or the PSA velocity is more than 20 ng/mL/year. Endorectal coil imaging is a useful technique to detect local recurrences after RP .In a series of 48 patients, local recurrence was correctly identified in 81%, with the mean PSA being 2 ng/mL at diagnosis Although eMRI appears to be very sensitive and predictive in identifying local recurrences following RP, it is currently not a routine imaging modality to be performed in every case, as local versus systemic relapse must be differentiated at PSA levels < 0.5 ng/mL At this PSA level, eMRI is not sufficiently sensitive or accurate.
Local recurrences are best treated by salvage radiation therapy with 64-66 Gy at a PSA serum level < 0.5 ng/mL. For patients with presumed local recurrence who are too unfit or unwilling to undergo radiation therapy, expectant management can be offered. PSA recurrence indicative of systemic relapse is best treated by early ADT resulting in decreased frequency of clinical metastases.
Castration resistant prostate cancer Cancer of the prostate is a heterogeneous disease. Our knowledge of the mechanisms involved in androgen independence, which is now known as castration-resistant prostate cancer (CRPC), remains incomplete but is starting to become clearer . It is thought that androgen independence (now called castration resistance) is mediated through two main, overlapping, mechanisms, which are androgen-receptor (AR)-independent and AR-dependent.
It is recommended to stop anti-androgen therapy once PSA progression is documented. No clear-cut recommendation can be made for the most effective drug for secondary hormonal. According to the positive results of this prospective randomised clinical phase III trial (LE: 1), cabazitaxel should be considered in the management of progressive CRPCA following docetaxel therapy. Based on this second positive trial, in patients with relapse following first-line docetaxel chemotherapy both Cabazitaxel and Abiraterone are regarded as first-choice options for second-line treatment