1. Updates in the Management of Localized Prostate Cancer
Abdul Naser Shunaigat, MD. FACS

2. Cancer Incidence and Mortality Rates age-adjusted, standardized over time
Largely as a result of PSA testing, the mortality rate from prostate cancer today is 45% lower than it was in The best estimates are that 50-70% of this decrease is due to PSA testing and to effective early treatment of potentially lethal cancers.

3. PROSTATE CANCER PREVALENCE AND MORTALITY
Newborn American male has 16% lifetime risk of being diagnosed with prostate cancer – 1 new case every 3 minutes
1/3 of men over age 60 and 1/2 of men over age 70 have prostate cancer
But lifetime risk of death from prostate cancer is only 3%

4. Prostate Cancer Risk Factors Age-median age of diagnosis is 72 years.
Incidence of prostate cancer increases with age so that up to 70-80% of men in their 80-90’s have autopsy evidence of prostate cancer
Smoking
High Fat/ Western diet
Family History-8-9% of all cancers due to inherited gene higher for younger men

5. Prostate Cancer Prostate Cancer Development
Develops from the epithelium
Possibly from the basal cell layer
Requires androgens to develop
Patients castrated before puberty do not develop BPH or Prostate cancer
Increased cell proliferation and decreased apoptosis
BPH is not a risk factor

6. Prostate Cancer Premalignant Lesions
PIN-prostatic intraepithelial neoplasia
May be a precursor lesion to prostate cancer
Characterized by cytologically atypical cells with architecturally benign glands
Approximately 20% of patients with PIN will go on to have a subsequently positive biopsy
ASAP-atypical small acinar proliferation
Atypical glands and cells but can’t quite call it cancer
Up to 50% will have a future positive biopsy

7. Prostate Cancer Screening?? Is PSA Screening for Prostate Cancer Dead?
Is there anything better?

8. Prostate Cancer Screening Trials
American Trial:
76,693 men between 55 and 74 randomized to either annual screening or usual care
After 7-10 years of follow-up, death rate from prostate cancer was very low and did not differ significantly between the two study groups
European Trial:
162,243 men between 55 and 69 randomized to either annual screening or no screening
For first 10 years of follow-up, risk of death from prostate cancer was the same between the two groups, but, after 10 years, there was a 20% decrease in risk of death in the screened group

9. Why the recommendation against screening for prostate cancer?
Screening and consequent treatment, as currently practiced, are often harmful:
Too much screening of elderly men with a short life expectancy
Too liberal criteria for biopsy
Too aggressive treatment of low risk cancers
Inadequate treatment of high risk cancers
Treatment largely administered by low volume providers (higher risks of side effects and lower risks of cure)
We have to recognize that a responsible scientific body, charged with examining all the data, concluded that there is insufficient evidence of benefit and clear evidence of harm with screening for prostate cancer.
As urologists, we should recognize that there have been several problems with the way we do PSA screening. Not to mention here, complications of prostate biopsy
Vickers AJ, Lilja H. Time for another rethink on prostate cancer screening. Nat Rev Clin Oncol. 2011; 9:7-8.

10. 5 treated tp prevent one death
In a follow-up Markov analysis, the European team estimate the benefits of screening over the lifetime of the participants. Now only 98 men needed to be screened and 5 diagnosed (3 were treated; the other 2 were watched) to avoid 1 death from prostate cancer.

11. Screening Smarter: How to Increase the Benefits and Reduce the Risks of Screening for Prostate Cancer
Risk-adjust screening by age and PSA (reduce false positives)
Reduce false positive PSA results by repeating (verifying) positives and by adding additional markers (reduce indications for biopsy)
Active surveillance for low-risk cancers (reduce harms of unnecessary therapy)
Refer patients who need treatment to high-volume physicians or centers (reduce harm of necessary therapy)
Four key strategies for continuing to screen for prostate cancer, but “screening smarter.”
Vickers A, Roobol M, Lilja H. Annu. Rev. Med :161–70.

12. Begin PSA testing at age 45 For men age 45 - 59
Memorial Sloan-Kettering Cancer Center 2010 Guidelines Risk-adjusted Screening for Prostate Cancer
Begin PSA testing at age 45
For men age
PSA ≥ 3 ng/ml : consider biopsy
PSA > 1 but < 3 ng/ml : return for PSA every 2-4 years
PSA <1 ng/ml : return for PSA in 5 years or at age 50 or 60, whichever comes first
For men age 60 – 70
PSA > 1 but < 3 ng/ml : return for PSA every two years
PSA < 1 ng/ml : no further screening
For men age 71 or higher
No further screening
Risk-adjusted screening: If a man’s PSA level is low (<1), do not schedule him to come back annually, risking false-positive results and unnecessary biopsies. Wait 5 years before repeating the test. If the PSA level is intermediate, follow the patient with repeat PSA and DRE every 2-4 years. Remember that the Göteborg trial screened only with PSA every 2 years, and in those patients screened the investigators reduced the risk of dying of prostate cancer by 56%.

13. Prostate Cancer Who should I treat? How to treat? When to treat?
When we get a biopsy result of prostate cancer, what should come to our minds as treating physicians?

14. Prostate Cancer
Current guidelines from the AUA, recommend that initial evaluation of, and treatment discussion with a patient with PC focus on the following two factors:
Patient’s overall life expectancy
The biologic characteristics of the tumor, together with its predicted aggressiveness and behavior

15. Prostate Cancer
Whether one of the several different modalities used for treating localized prostate cancer offers survival benefits over others remain controversial.
The choice of definitive therapy has been suggested to make a significant difference in long term survival in less than 10% of patients.
This means that most patients are cured either because the treatment was effective or because they had a non–life-threatening tumor and the treatment was unnecessary. The remainder of patients are not cured, either because they had unsuspected micrometastases or because the local therapy did not eradicate all of the malignant cells.

16. Risk Stratifications
Organizational pre-treatment Prostate Cancer risk stratification
Organization
Low Risk
Intermediate
High Risk
Harvard,AUA, EAU
T1-T2a and GS ≤6 and PSA≤10
T2b and/or GS=7 and/or PSA˃10-20 Not low risk
≥T2c or PSA˃20 or GS 8-10
GUROC, NICE
T1-T2 and/or GS≤7 and/or PSA≤20 NOT low risk
≥T3a or PSA˃20 or GS 8-10
CAPSURE
T2b and/or GS=7 and/or PSA˃10-20 not low risk
T3-4 or PSA˃20 or GS 8-10
NCCN
Not very low risk AND very low risk category
T1c and GS≤6 and PSA˂10 and fewer than 3 biopsy cores positive
T2b or T2c and/or GS=7 and/or PSA˃10-20 not low risk
T3a or PSA˃20 or GS 8-10
ESMO
T1-T2a and GS ≤6 and PSA˂10
Not high and Not low risk (the remainder)
For that reason, some authors and medical bodies have put what is called Risk Stratifications, and categorized patients into different groups to determine which patient to treat and how, which is a bit rough, and not precise enough to get global acceptance.
AUA: American Urological Association; EAU: European Association of Urology; GUROC: GenitoUrinary Radiation Oncologists of Canada; NICE: National Institute for Health and Clinical Excellence; CAPSURE: Cancer of the Prostate Strategic Urologic Research Endeavour; NCCN: National Comprehensive Cancer Network; ESMO: European Society of Medical Oncology

17. Localized Prostate Cancer
Standard treatments for clinically localized Pca includes the following: (Low risk)
Active Surveillance
Watchful Waiting
Radical Prostatectomy
Radiation Therapy
Hormonal Therapy
Cryotherapy. - Proton Beam Radiation. - HIFU
Cryotherapy is also used, but long-term survival studies are lacking. Newer therapies, such as Proton-Beam radiation and HIFU are being used too, but long term survival and complication rates have not been presented in well-done studies.

18. Deferred treatment (active surveillance/watchful waiting)
Active surveillance aims to achieve correct timing for curative treatment, rather than delayed application of palliative treatment
Patients remain under close surveillance, and treatment is prompted by predefined thresholds indicative of potentially life-threatening disease, while considering individual life expectancy.
Many men with localized PCa will not benefit from definitive treatment, and ~45% of men with PSA detected PCa are candidates for deferred management. In men with co-morbidity and limited life expectancy, treatment of localised PCa may be deferred to avoid loss of quality of life (QoL). There are two
distinct strategies for conservative management that aim to reduce overtreatment: active surveillance and watchful waiting.

19. Watchful Waiting Watchful Waiting:
(deferred or symptom-guided treatment). It refers to conservative management, until the development of local or systemic progression.
TURP or other procedures for urinary tract obstruction,
Hormonal therapy or radiotherapy for palliation of metastatic lesions.
No standardized follow-up is recommended.
The rationale behind watchful waiting is that PCa often progresses slowly, and is predominantly diagnosed in
older men with a high incidence of comorbidity and other causes of mortality [286]. Watchful waiting is possible
in patients with localised PCa and limited life expectancy, or older patients with less aggressive cancer.
Bill-Axelson; NEJM, 2005
Iverson P; Scand J Urol Nephrol Suppl, 1995
Wilt, T. J, J Urol, 1994

20. Active surveillance
Increasingly being recommended for men with low-risk disease
Evolving option, although no randomized studies have yet been conducted
Current NCCN recommendations for active surveillance include the following:
PSA no more often than every 6 mo unless clinically indicated
DRE no more often than every 12 mo unless clinically indicated
Repeat prostate biopsy no more often than every 12 mo unless clinically indicated
With active surveillance, the physician monitors the course of the disease over time and intervenes with treatment if the disease begins to progress.
Active surveillance is increasingly being recommended for men with low-risk disease, which includes T1-2a disease, a Gleason score of 2-6, and a PSA level below 10 ng/mL.
Progression of local disease may be indicated either by increased tumor volume or changes in the Gleason score. PSA doubling times are also being used, although some studies have questioned their reliability for this purpose.
The optimal management of men on active surveillance is evolving, although no randomized studies have yet been conducted. Monitoring typically consists of PSA testing every 3 months and repeat biopsy at 12- to 24-month intervals. Biopsy findings are the most important factor in deciding whether to pursue treatment. A rapid PSA level rise or patient choice can also prompt the physician to proceed to treatment.
Current NCCN recommendations for active surveillance (based on lower-level evidence) include the following :
-PSA no more often than every 6 mo unless clinically indicated
-DRE no more often than every 12 mo unless clinically indicated
-Repeat prostate biopsy no more often than every 12 mo unless clinically indicated
However, the NCCN recommends a repeat biopsy within 6 months of diagnosis if the initial biopsy included fewer than 10 cores. Repeat biopsies are not indicated in patients whose life expectancy is less than 10 years.

21. Klotz L et al. J Clin Onc 2010; 28:126
Active surveillance (AS) works well. In the largest published series, about 30% of men come off AS and are treated within 5 years, and about 40% are treated within 10 years, but 60% remain on AS 10 years after diagnosis, with no appreciable change in their cancer.
Klotz L et al. J Clin Onc 2010; 28:126

22. Nation-wide, population-based cohort. Eur Urol 2012.
All-cause mortality for men with conservatively managed prostate cancer Charlson Comorbidity index 0
In a large population-based study of healthy men (Charlson comorbidity index 0) in Sweden, Rider and his group found no difference in survival over 15 years, whether men with low-risk cancers were treated or watched. The higher risk cancers did cause excess mortality.
J Rider et al. Long-term outcomes according to risk category of prostate cancer.
Nation-wide, population-based cohort. Eur Urol 2012.

23. Radical Prostatectomy
Currently, RP is the only treatment for localized PCa to show a benefit for OS and cancer-specific survival (CSS), compared with conservative management, as shown in one prospective randomized trial.*
RALP is displacing RRP as the gold standard surgical approach for clinically localized PCa in the USA and is being increasingly used in Europe and other parts of the world.
-The benefits in OS and CSS were not reproduced in the overall study population (mean age 67 yr) of another prospective randomised trial. After a median follow-up of 10 years, the PIVOT trial showed that RP did not significantly reduce all-cause mortality or significantly reduce PCa mortality. -
*Bill-Axelson A. N Engl J Med 2014 Mar;370(10):

24. Number of new patients enrolled in active surveillance by year
Pathologic Organ Confined
Number of new patients enrolled in active surveillance by year
At Memorial Sloan-Kettering, they have markedly increased the number of patients on AS over the past 10 years, and they are now following more than 2000 men who were initially referred for surgery.
Biopsy Gleason 6

25. PIVOT: RP v. Observation Overall results: all-cause and prostate cancer-specific mortality N=731
The US PIVOT trial compared radical prostatectomy with watchful waiting and found no difference in overall survival or prostate cancer mortality over years. Most of the patients had low-risk cancer, as defined by the AUA.
Wilt et al. N Engl J Med 2012; 367:203

26. PIVOT: RP v. Observation Patients with high risk cancers
PSA > 10
All cause mortality in patients (n=251)
with PSA > 10 ng/mL (HR 0.36, p<0.02).
AUA High risk
Prostate cancer mortality in patients (n=157) with high-risk cancer (HR 0.40, p=0.05)
However, men with a PSA >10 or a high-risk cancer lived longer after radical prostatectomy than with watchful waiting. So surgery is effective if the patient needs to be treated, but it is unnecessary in as many as half of all men diagnosed today.
Wilt et al. N Engl J Med 2012; 367:

27. PIVOT
The Prostate Intervention Versus Observation Trial (PIVOT), showed no statistically significant difference between radical prostatectomy and watchful waiting with respect to either:
all-cause mortality (47% versus 49.9%, respectively), or
prostate cancer–specific mortality (5.8% versus 8.4%, respectively) after a median follow-up of 10 years.
Unlike the previous reports, the Prostate Intervention Versus Observation Trial (PIVOT), the only such randomized study performed in screened men, showed no statistically significant difference between radical prostatectomy and watchful waiting with respect to either all-cause mortality (47% versus 49.9%, respectively) or prostate cancer–specific mortality (5.8% versus 8.4%, respectively) after a median follow-up of 10 years.

28. RANDOMIZED TRIAL OF WATCHFUL WAITING VERSUS RADICAL PROSTATECTOMY
Scandinavian randomized trial of 695 men found absolute risk reduction of 6.1% in prostate cancer deaths at 15 years in men undergoing radical prostatectomy vs watchful waiting
Number needed to treat to prevent 1 prostate cancer death – 15
Benefit more pronounced in men < 65 years of age
Number needed to treat – 7
Men in “low risk” group also derived benefit
4.2% reduction
Bill-Axelson, A, et al, Radical prostatectomy versus watchful waiting in early prostate cancer: NEJM 364:18 ( ), 2011.

29. Indications for nerve-sparing surgery
Nerve-sparing RP can be performed safely in most men with localized PCa undergoing RP. In the past decade, a dramatic shift towards lower-stage tumors has become evident. More importantly, men are younger at the time of diagnosis and more interested in preserving sexual function. Nevertheless, clear contraindications are patients in whom there is a high risk of extra-capsular disease, such as any cT2c or cT3 PCa, any GS > 7 on biopsy, or more than one biopsy > 6 at the ipsi-lateral side.

30. External Beam Radiation therapy
Offers potential for curative treatment of local disease.
3-D conformal Radiation Therapy (3-D CRT)
Intensity Modulated Radiation Therapy. (IMRT)
QoL after 2 years: IMRT is equal to RP *
Early salvage RT is comparable to adjuvant RT with regard to biochem. recurrence. **
Geinitz H; Int J Radiat Oncol Biol Phys. 2011
** Briganti A; Eur Urol. 2012

31. Radiation vs Surgery
No solid evidence to determine whether any type of RT results in fewer deaths or cancer recurrence than RP in low risk patients.
Agency for Healthcare Research and Quality. October 2012

32. Treatment: definitive radiotherapy
Intensity-modulated radiotherapy (IMRT), with or without image-guided radiotherapy (IGRT), is the gold standard for EBRT. All centers that do not yet offer IMRT should plan to introduce it as a routine method for the definitive treatment of PCa.

33. Hormonal Therapy
ADT alone, has not been considered a "standard" treatment option for localized disease
Increased risk of cardiovascular disease and diabetes
In some cases only.

34. Neoadjuvant and adjuvant hormonal therapy and radical prostatectomy
Since PCa is an androgen-dependent tumor, NHT is an appealing concept. A recent review and meta-analysis
studied the role of NHT and prostatectomy. NHT significantly reduced positive margin rates, extra-prostatic extension, and lymph node invasion.
However, this was not associated with improved OS or disease-free survival (DFS).

35. Locally Advanced PCa Radiation Therapy Hormonal Therapy
Radical Prostatectomy
Brachytherapy
For locally advanced prostate cancer, radiation therapy along with androgen ablation is generally recommended, although radical prostatectomy may be an appropriate alternative to radiation therapy in some cases. A combination of external radiation, brachytherapy, and hormone therapy is also being used, but it is unclear whether it offers advantages over hormone therapy and external radiation alone, and it does increase complications.

36. Intermediate risk Active surveillance Brachytherapy Radiotherapy
Radical prostatectomy
Cryotherapy *
In patients with intermediate-risk localized prostate cancer, appropriate treatment options include active surveillance, interstitial prostate brachytherapy, external beam radiation therapy, and radical prostatectomy. Cryotherapy should also be discussed.[63] Treatment should be based in part on the patient’s preferences and functional status. A patient who chooses conventional external beam radiation therapy may have improved survival by combining it with 6 months of hormone therapy.
* Bahn D, et al. Eur Urol. 2012

37. High-risk and locally advanced prostate cancer
At an increased risk of:
PSA failure
Need for secondary therapy
Mets progression
Death.
Radical Prostatectomy & Extended PLND
Patients classified with high-risk PCa are at an increased risk of PSA failure, need for secondary therapy, metastatic progression and death from PCa. Nevertheless, not all high-risk PCa patients have a uniformly poor prognosis after RP.
There is no consensus regarding the optimal treatment of men with high-risk PCa. Provided that the tumour is not fixed to the pelvic wall, or that there is no invasion of the urethral sphincter, RP is a reasonable first step in selected patients with a low tumour volume. Extended LND should be performed in all high-risk PCa cases, because the estimated risk for positive lymph nodes is 15-40% [328]. Limited LND should no longer be performed, because it misses at least half the nodes involved [243]. Management decisions should be made after all treatments have been discussed by a multidisciplinary team

38. Metastatic PCa Rarely curable Directed toward symptomatic relief
Metastatic prostate cancer is rarely curable. Management of these cases typically involves therapy directed at relief of particular symptoms (eg, palliation of pain) and attempts to slow further progression of disease.

39. Prostate Cancer Categorize your patient
Complete work up
General health
Complete and Comprehensive patient counseling.

40. Thank You