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Progress In Management Of Prostate Cancer

Each affiliate is responsible for ensuring the subsequent local approvals (medical and regulatory). Progress In Management Of Prostate Cancer. EAU 2010 Barcelona, 16-20 April 2010.

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Progress In Management Of Prostate Cancer

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  1. Each affiliate is responsible for ensuring the subsequent local approvals (medical and regulatory) Progress In ManagementOf Prostate Cancer EAU 2010Barcelona, 16-20 April 2010

  2. Please note that the slides provided within this resource contain all of the information necessary to present on the topic. However the presentation is at your disposal, and can be shortened or lengthened depending on what topics are most relevant at your local level.

  3. Progress in management of prostate cancer Plenary session and posters from EAU 2010 • State of the art lecture: Biomarkers for prostate cancer: J.A. Schalken • Biomarkers and prostate cancer: Posters • Evaluating indolent prostate cancer: Posters • Pathology and predictive factors: Posters • Staging: from local to advanced prostate cancer: Posters • Localised and locally-advanced prostate cancer: Posters • Active surveillance and brachytherapy • Management of high-risk disease • Metastatic disease: first-line therapy Posters

  4. State of the art lecture: Biomarkers for prostate cancer J.A. Schalken

  5. Challenges generated by clinical studies • ERSPC (population based screening for prostate cancer) • Evidence that prostate cancer related mortality can be reduced by 20% • BUT at the cost of significant over-treatment • REDUCE: chemoprevention with a dual 5-ARI can prevent prostate cancer incidence in 4 years by 23% Challenge for translational research • Biomarkers for clinically significant prostate cancer • Biomarkers for patient at risk to whom chemoprevention can be advised and/or to monitor the patient

  6. Challenges generated by clinical studies • Many phases are involved before obtaining a new valid biomarker • Actually, 3 molecular markers developed

  7. PCA3 and prostate cancer • Prostate Cancer Antigen 3 (PCA3) over expressed in >95% of prostate cancer (unlike PSA, highly specific) • 3 different urine tests measuring PCA3 mRNA used in clinical studies: • Quantitative (TRF based quantitative RR- PCR) • Semi-quantitative: uPM3 assay • Quantitative: PROGENSA PCA3 assay • PROGENSA PCA3 assay: simple, non-invasive urine specimen collected post-DRE • Measuring PCA3 mRNA in prostate cells: quantitative PCA3 score • Studies using quantitative PCA3 assay for diagnostic of prostate cancer: consistent • Results • A PCA3 score cut off of 35 provides the greatest diagnostic accuracy for repeat biopsy

  8. PCA3 and prostate cancer • Post DRE urine analysis of PCA3 mRNA to help in predicting prognosis of prostate cancer: preliminary data • PCA3 score in low volume/ low grade prostate cancer is significantly lower than in significant prostate cancer European study: PCA3 repeat biopsy prospective multicentre study: 463 men (28% positive repeat biopsy)

  9. Summary • Molecular diagnosis of prostate cancer is available at the clinic • The higher PCA3, the greater the likelihood of a positive biopsy • The higher the PCA3 score, the greater the risk of significant prostate cancer

  10. Biomarkers and prostate cancer Posters

  11. Content • PCA3 outperforms all other biomarkers; however, this advantage is no longer detectable with increasing biopsy number (Haese, A et al, abstr 970) • PCA3 testing may be useful in further clinical advice (Damiano, R et al, abstr 105) • The PCA3 score is not influenced by tumour volume, shape or localisation in the prostate (Schilling, D et al, abstr 26) • The PCA3 assay improves the prediction of initial biopsy outcome and may be indicative of prostate cancer aggressiveness (De la Taille, A et al, abstr 61) • Initial prostate biopsy: PCA3 outperforms established risk factors of prostate cancer and increases multivariate predictive accuracy (M. Auprich et al, abstr 24) • Post-operative Bcl-2 could be a significant predictor of outcome after radical prostatectomy (RP) (I.C. Cho et al, abstr 28)

  12. PCA3 outperforms all other biomarkers; however, this advantage is no longer detectable with increasing biopsy number • A European study analysing the diagnostic performance of PCA3 in relation to the number of biopsy sessions • Results show that the diagnostic performance of PCA3 is better the lower the number of previous biopsies • PCA3 outperforms all other examined markers and offers significant increase in sensitivity and specificity • This advantage is no longer detectable with increasing biopsy number Haese A. et al, abstr 970

  13. PCA3 testing may be useful in further clinical advice • A European study evaluating the ability of PCA3, added to measurements of serum PSA, to predict cancer detection • Results show that urine PCA3 testing performed well as a laboratory-developed test. Its high specificity of PCA3 was confirmed in this study population • In patients with elevated PSA levels and negative biopsy findings, PCA 3 testing might be useful in further clinical advice Damiano R et al, abstr 105

  14. The PCA3 score is not influenced by tumour volume, shape or localisation in the prostate • The aim of this study was to investigate whether the localisation of tumours within the prostate in relation to the urethral course impacts the value of PCA3 • Tumours localised exclusively in the peripheral zone do not reflect in low PCA3 scores • Only tumours in the immediate proximity of the urethral course or the collicule seem to impact the PCA3 score • Exact reconstructions by means of graphical and mathematical models will further allow clarification of the local conditions and the association to PCA3 D. Schilling et al, abstr 26

  15. The PCA3 assay improves the prediction of initial biopsy outcome and may be indicative of prostate cancer aggressiveness EU Data sensitivity PCA3 Score PSAD Total PSA % Free PSA 1-specificity A. De la Taille et al; abstr 61 • European prospective study: 516 men with serum PSA ≥2,5- 10 ng/ml • The probability of a positive biopsy increases with PCA3 scores • Improves the prediction of initial biopsy • Indicative of cancer aggressiveness • Can aid in the decision which men need an initial biopsy when managed in clinical practice in Europe

  16. In the initial biopsy setting, the PCA3 not only represents an independent risk factor of prostate cancer, but is also capable of increasing the predictive accuracy of multivariable models for prostate cancer detection This suggests the inclusion in nomograms to provide more accurate risk stratification of men at risk of prostate cancer Initial prostate biopsy: PCA3 outperforms established risk factors of prostate cancer and increases multivariate predictive accuracy M. Auprich et al, abstr 24

  17. Post-operative Bcl-2 could be a significant predictor of outcome after radical prostatectomy (RP) • The objective of this prospective study was to investigate Bcl-2 expression in prostate cancer and its potential role as a predicting factor for biochemical recurrence after RP • Bcl-2 expression was immunohistologically confirmed in RP specimens from 24.6% of patients • Bcl-2-negative patients had a significantly longer mean BCR-free survival than Bcl-2-positive patients (p = 0.049) • Multivariate Cox proportional hazards analysis revealed that BCR was significantly associated with seminal vesicle invasion(p < 0.001) and with Bcl-2 expression (p = 0.050) • Bcl-2 expression was associated with a significantly worse outcome, highlighting a potential clinical role for Bcl-2 I.C. Cho et al, abstr 28

  18. Evaluating indolent prostate cancer Posters

  19. Contents • Even a high number of negative systemic random biopsies do not exclude high-grade and high-stage prostate cancer (Loch, T et al; abstr 113) • Independent risk factors for Gleason scores downgrading in patients with extended prostate biopsy (Waldert, M et al, abstr 581)

  20. Even a high number of negative systemic random biopsies do not exclude high-grade and high-stage prostate cancer • This prospective study evaluated prostate cancer in patients with multiple negative systemic random biopsies (SRBs) • 132 patients, who had at least 1 series of negative SRBs in their history, were evaluated • Prostate cancer was identified in 66 of the 132 patients. Only 5 (7.5%) of the 66 patients with a median of 12 negative biopsies had a Gleason score (GS) of 5 • GS 6 and 7 present in the majority of patients (71.2%) • GS of 8 and 9 present in 22% of the patients • Results show that prostate cancer found after multiple negative SRBs are, in the vast majority, significant cancers T. Loch et al; abstr 113

  21. Independent risk factors for Gleason scores down-grading in patients with extended prostate biopsy • Down-grading of biopsy Gleason score in radical prostatectomy specimen is poorly described phenomenon in patients with extended biopsy protocol • Gleason score up-grading is common finding (29-40%) • Gleason score down-grading described as 12% on average (9-19%) Conclusion: Factors predictive of downgrading and multivariate analysis 1) Large prostate volume 2) % of positive biopsy Bx cores 3) High Bx Gleason score M. Waldert et al, abstr 581

  22. Pathology and predictive factors Posters

  23. Contents • Biopsy peri-neural invasion predicts both pathological outcomes (excluding margin status) and biochemical recurrence in RP patients (Chopra, S et al, abstr 21) • Smaller prostate volume is a risk of high-grade prostate cancer detected by three dimensional 26-core biopsy (Yokoyama, M et al, abstr 20) • Focal therapies, an emerging therapeutic options for selected patient with low-risk prostate cancer (Gallina, P et al, abstr 577) • Long term progression-free, overall and cancer-specific survival in familial cancer patients (Herkommer et al, abstr 1006)

  24. Biopsy peri-neural invasion predicts both pathological outcomes (excluding margin status) and biochemical recurrence in RP patients. • This early predictor may be useful for treatment planning, in addition to conventional clinical variables, particularly in low-risk patients S. Chopra et al, abstr 21

  25. Smaller prostate volume is a risk of high-grade prostate cancer detected by three dimensional 26-core biopsy • This study demonstrates that small prostate volume (PV) is a significant predictor of high-grade cancer in men receiving extended biopsy • PV should always be determined when biopsy indication is considered M. Yokoyama et al, abstr 20

  26. Focal therapies, an emerging therapeutic options for selected patient with low-risk prostate cancer • The objective of this study was to identify predictors of unilateral prostate cancer in patients with low-risk disease submitted to radical prostatectomy • Only 29.4% of patients with unilateral low-risk prostate cancer at biopsy had ipsilateral cancer at radical prostatectomy • The number of cores and of positive cores represented independent predictors of ipsilateral prostate cancer. However, the accuracy of the multivariable model tested was low (59%), thus making prediction of ipsilateral prostate cancer extremely inaccurate • These results need to be taken into account in those cases where focal therapy is considered as a treatment option for prostate cancer P. Gallina et al, abstr 577

  27. Long term progression-free, overall and cancer-specific survival in familial cancer patients • 10,349 prostate cancer patients: hereditary cancer (8.4%) vs familial cancer (24.2%) vs sporadic cancer (67%) • Patients undergone radical retropubic prostatectomy PFS: progression free survival; OS: overall survival; CSS: cancer specific survival • Hereditary prostate cancer may have a slightly more aggressive course than sporadic PC Herkommer et al, abstr 1006

  28. Staging: From local to advanced prostate cancer Posters

  29. Contents • The whole extent of prostate cancer cannot be precisely identified using current standard tools in initial prostate cancer diagnosis- implications for focal therapy (Pfitzenmaier, J et al, abstr 1004) • Routine preoperative prognostic factors cannot predict unilaterality of prostate cancer in patients with localised disease (Alekseev, B et al, abstr 1003) • Absence of residual tumour (pT0 status) at radical prostatectomy: oncological outcomes and predictors (Ahallal, YA et al, abstr 1005)

  30. The whole extent of prostate cancer cannot be precisely identified using current standard tools in initial prostate cancer diagnosis • The sensitivity of current imaging technologies are not sufficient to reliable detect and map prostate cancer within the gland • 825 patients who underwent RP after being diagnosed for PCa using prostatic biopsy (median 9 biopsy cores) and PSA value were identified • Differences in Gleason score and pathologic stage between the prostate biopsy and surgical specimen were evaluated to define upstaging and upgrading/downgrading • 30.8% of patients initially identified with unilateral prostate cancer were upstaged to bilateral or even extracapsular disease, p<0.001. Only 21.7% of patients had initial biopsy proven unifocal/unilateral disease • Physicians should act with caution when considering hemiablative or true focal therapy in these patients J. Pfitzenmaier et al, abstr 1004

  31. Routine preoperative prognostic factors cannot predict unilaterality of prostate cancer in patients with localized disease • The aim of this study was to assess probability of only one prostate lobe involvement in PC patients with clinically localised unilateral tumours and to evaluate the prognostic significance of routine preoperative predictors • Very low coincidence of clinically (preoperative) and morphological unilaterality of PS (29.6%) • No reliable routine clinical or morphological prognostic factors were revealed to predict unilateral localisation of tumour B. Alekseev et al, abstr 1003

  32. Absence of residual tumour (pT0 status) at radical prostatectomy: oncological outcomes and predictors • The objective of this study was to determine the oncologic outcome of patients found to have no residual tumour (pT0 status) at radical prostatectomy (RP) and to determine predictors of pT0 status • 4,592 patients underwent RP with (n=224) or without (n=4,368) neoadjuvant androgen deprivation therapy (ADT) but without prior radiation therapy; 35 (0.8%) were found to have pT0 pathologic stage • The incidence of pT0 status was 3/224 (1.3%) and 32/4,368 (0.7%) in those with or without neoadjuvant ADT, respectively • Predictors of pT0 status on multivariate analysis were biopsy Gleason score ≤6, lower PSA, larger prostate size and pre-RP ADT Y.A. Ahallal et al, abstr 1005

  33. Localized and locally-advanced prostate cancer Posters

  34. Localised and locally-advanced prostate cancer • Active surveillance and brachy/radiotherapy • Management of high-risk prostate disease

  35. Active surveillance and brachytherapy Posters

  36. Contents • Careful selection and close monitoring of low-risk prostate cancer minimizes the need for treatment (Soloway, MS et al, abstr 6070) • Outcomes of surveillance for localised prostate cancer: a Sweden population-based cohort study (Stattin, PE et al, abstr 608) • Endorectal MRI can be helpful in selecting patients for active surveillance (Luyckx F et al, abstr 610) • Histopathological and functional outcomes for active surveillance (AS) candidates who opt for prostatectomy (Brajtbord, JS et al, abstr 578) • Age at prostate cancer diagnosis does not need to be a restriction for treatment with brachytherapy (Hinnen, KA et al, abstr 613)

  37. Careful selection and close monitoring of low-risk prostate cancer minimizes the need for treatment • 212 patients enrolled in an active surveillance (AS) protocol • 88% of patients remained on AS for an average of 41 months • Over the last 3 years, the AS cohort has more than doubled and yet the treatment rate of <12% has been a constant with no known recurrence or deaths due to prostate cancer • In the incidence of low-risk cancer, some suggest 50% cases detected by PSA screening are over-treated M.S. Soloway et al, abstr 607

  38. Outcomes of surveillance for localised prostate cancer: a Sweden population-based cohort study • Population studied • 1,085 men aged 70 years and below, with localised low risk prostate cancer (T1 stage, Gleason score 6 and PSA below 10 ng/ml) and, • 936 men with intermediate risk prostate cancer (T2 stage or Gleason score or PSA 10-20 ng/ml) • With a 10 years prostate cancer specific mortality of 3% among men with low risk, surveillance appears to be a suitable treatment strategy for many men, however longer follow-up time is needed for conclusive evaluation of this treatment strategy P.E. Stattin et al, abstr 608

  39. Endorectal MRI can be useful in selecting patients for active surveillance • In this study, only 20.6% of patients who could have chosen AS had tumour volume < 0.5cc • When adding positive sextants at 1.5 er MRI PPA and/or at biopsy, if the sum is strictly > 1, it could allow the urologist to detect 63% of non-latent prostate cancer F. Luyckx et al, abstr 610

  40. Histopathological and functional outcomes for active surveillance (AS) candidates who opt for prostatectomy • This study evaluated the final histopathologic outcomes of patients with preoperatively low-risk cancer and those who qualify for AS, but opted for robotic assisted laparoscopic prostatectomy (RALP) • Results show that patients who desire curative therapy have a high likelihood of achieving excellent functional and oncologic outcomes following RALP • Patients who elect AS can be reassured that the majority of AS candidates had favourable tumour characteristics at the time of prostatectomy, as only 3% were up-staged J.S. Brajtbord et al, abstr 578

  41. Age at prostate cancer diagnosis does not need to be a restriction for treatment with brachytherapy • The position of prostate brachytherapy in treating patients aged 60 years and younger is unclear, mainly due to a lack of follow-up proving its long-term effectiveness • Retrospective study: 511 patients treated by brachytherapy (mean FU: 100 months) • No significant impact of age on disease free survival • The results 10 years after brachytherapy are excellent for patients aged ≤60 years as well as for patients > 60 years • Only the tumour characteristics predicted for prostate cancer survival K.A. Hinnen et al, abstr 613

  42. Management of high-risk disease Posters

  43. Contents (1) • The definition of high-risk prostate cancer varies and affects the eligibility and sample size when designing surgical clinical trials. The surgical approach should not be a discriminating factor in such trials (Touijer, K et al, abstr 677) • Laparoscopic radical prostatectomy (RP) should be offered to patients with high-risk prostate cancer (Hutton, C et al, abstr 678) • Senior adults ( ≥ 70 years), who have few comorbidities, may still be candidates for surgical management of high-risk prostate cancer (Gontero, P abstr 679) • Elderly patients are at a more elevated risk of pT3 prostate cancer: Results of a European single centre (Budaüs, L et al; abstr 680)

  44. Contents (2) • Nerve sparing radical prostatectomy in properly selected patients with pT3 prostate cancer does not undermine the rates of positive surgical margins (Budäus, L et al, abstr 681) • Role of positive surgical margins in patients with organ confined prostate cancer. Implications for adjuvant treatments (Briganti, A et al, abstr 682) • Positive section margins (PSM) in patients with high-risk prostate cancer treated by radical prostatectomy is an independent predictor of cancer-related death and death from other causes (Spahn, M et al, abstr 683) • Biochemical recurrence after radical prostatectomy: A case of multiplicative interaction between surgical margin status and pathological stage (Isbarn, H et al, abstr 684)

  45. Contents (3) • Nerve-sparing radical prostatectomy in selected high-risk and locally advanced prostate cancers is associated with low positive margin rates using a combination of preoperative MRI, special instrumentation and intra-operative frozen sections (Zlotta, AZ et al, abstr 690) • Pathological findings and PSA outcomes after laparoscopic radical prostatectomy for high-risk prostate cancer (Ploussard, G et al, abstr 691) • Cumulative risk factors in high-risk localised prostate cancer cT≥ 3; PSA≥ 20; GS≥ 8 (Joniau, S et al, abstr 1009)

  46. The definition of high-risk prostate cancer varies and affects the eligibility and sample size when designing surgical clinical trials. The surgical approach should not be a discriminating factor in such trials • The aim of this study was to compare the probability of freedom from recurrence following radical prostatectomy for open (ORP) and laparoscopic (LRP) surgery in high-risk patients • The definition of high-risk patient used is Gleason 8+, PSA >20, clinical stage > T2c or T3 or greater and 5 year preoperative predictor probability of survival • Freedom from biochemical relapse range from 57% to 66% for LRP or 38% to 66% for ORP • The more inclusive definitions of high-risk patients tended to have better recurrence rates than the less inclusive definitions K. Touijer et al, abstr 677

  47. Laparoscopic radical prostatectomy (RP) should be offered to patients with high-risk prostate cancer • Of a total of 1,350 patients accepted for laparoscopic radical prostatectomy (LRP) during a 114 month period from 2000-2009, 250 (19%) had HiRPC • Blood loss, transfusion, complication rates are equal to a non-HRPC patient group • Additionally, a significant proportion of patients (46.5%) had their tumour down-graded on final histology and at a mean follow-up of 30.0 (3-96) months, 95.8% of patients were free of biochemical recurrence and 95.8% were continent • The results serve to encourage urologists to offer prostatectomy to patients with HRPC, reserving radiotherapy and hormonal therapy as later options, if and when residual or recurrent disease is apparent C. Hutton et al. abstr 678

  48. Senior adults ( ≥ 70 years), who have few co morbidities, may still be candidates for surgical management of high-risk prostate cancer. • Senior adults ( ≥ 70 years) are generally not considered candidates for surgery when they present with ≥cT3a OR PSA>20 OR Gleason score ≥8 PCa • This study analysed the cancer-specific (CSS) and overall survival (OS) of patients aged 70 or higher in a European multicentre RP database of patients with high-risk localised prostate cancer • The oncological outcome appears to be highly satisfactory. Even though age ≥70 was significantly correlated to overall mortality, median overall survival time in this age group was well over 10 years, mirroring correct patient selection P. Gontero abstr 679

  49. Elderly patients are at a more elevated risk of pT3 prostate cancer: Results of a European single centre • Surgical management of prostate cancer requires careful consideration of pathological tumour extent to adjust the type and extent of radical prostatectomy. A higher risk of pT3 diagnosis may dictate the need for wider resection and a more extended lymphadenectomy • This study examined the trends of pT3 prostate cancer in the elderly (ages 70 years and older) • Despite adjustment for PSA, clinical stage and pathological Gleason score, elderly patients were more likely to harbour pT3 prostate cancer at final pathology • Therefore, wide resection should be considered in particular men especially in the context of higher rates of pre-existing erectile dysfunction in these individuals L. Budaüs et al, abstr 680

  50. Nerve sparing radical prostatectomy in properly selected patients with pT3 prostate cancer does not undermine the rates of positive surgical margins • Nerve-sparing radical prostatectomy helps preserve sexual function in patients with localised prostate cancer but may increase the positive surgical margin rate (PSM) • This study examined the rates of PSM and biochemical recurrence rates (BCR) in patients with pT3 prostate cancer according to the type of nerve-sparing: None vs. unilateral vs. bilateral • Results show that in properly selected patients, nerve-sparing does not undermine the rate of PSM. Moreover, nerve-sparing does not undermine the rate of BCR • Therefore, a proportion of men with suspected pT3 prostate cancer may continue to be safely considered for nerve-sparing radical prostatectomy • Sexual function data need to complement the validity of this recommendation L. Budäus et al, abstr 681

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