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

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 1992. The best estimates are that 50-70% of this decrease is due to PSA testing and to effective early treatment of potentially lethal cancers. http://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-figures-2012

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%

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

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

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

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

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

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.

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.

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. 2012. 63:161–70.

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 45 - 59 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%.

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?

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

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.

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

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.

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.

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

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.

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

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.

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):932-42.

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

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 12-15 years. Most of the patients had low-risk cancer, as defined by the AUA. Wilt et al. N Engl J Med 2012; 367:203

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; 367:203-213

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.

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 (1708-1717), 2011.

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.

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

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

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.

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.

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).

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.

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

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

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.

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

Thank You