Expectant Management of Prostate Cancer James A. Eastham, MD and Peter T. Scardino, MD June 23, 2010 Presented by: K. Witzke, DO

Background Histologically apparent cancer can be found in 42% of men older than 50 years who die of other causes, the lifetime risk that an American man will be diagnosed with CaP is 17%, the risk of dying of the disease is 3.6%

PSA Doubling time 2-4 years Biologic potential of histologically detectable cancers is difficult to characterize with certainty. Biopsy may underestimate the extent of cancer

Conservative Management Deferring definitive therapy until evidence that the cancer is sufficiently aggressive to warrant therapy, may be appropriate for many patients with a favorable (low-risk) cancer Identification of such cancers before treatment would be a significant benefit to these patients

Watchful Waiting Traditionally: no active treatment until a patient develops evidence of symptomatic disease progression, at which time androgen deprivation therapy is initiated Limits the morbidity from the disease, not to administer potentially curative treatment. Recently: to delay curative local therapy until the natural history and threat posed by the cancer can be more accurately characterized.

Active Surveillance Selective delayed definitive therapy Distinguish clinically insignificant cancers from life-threatening cancers while they are still localized to the prostate. Risk posed by a given cancer can be assessed with some degree of certainty and that delayed treatment will be as curative as immediate treatment. Avoid over treatment in the majority of patients but also to administer curative therapy

Active Surveillance vs. WW Active SurveillanceWatchful Waiting AimTo individualize treatment To avoid treatment Patient characteristics Fit for radical treatment Age >70 yr or life expectancy <15 yr Age yr Tumor characteristics T1-T2, GS ≤7, initial PSA <15 ng/mL Any T stage, GS ≤7, any PSA MonitoringFrequent PSA testingPSA testing unimportant Repeated biopsiesNo repeated biopsies Indications for treatment Short PSADT Symptomatic progression Higher grade or more extensive cancer on biopsy Treatment timingEarlyDelayed Treatment intentRadicalPalliative

Watchful Waiting For those expected to live less than 5 years, most prostate cancers will grow locally, and some patients will develop metastases, but few will die of the disease. (Chodak, et al 1994) The risk of metastasis at 10 years was 19% for well- differentiated cancers, 42% for moderately differentiated cancers, and 74% for poorly differentiated cancers. If the primary tumor was not controlled, the risk for development of metastases persisted, even accelerated, after 10 years

Although most prostate cancers diagnosed at an early stage have an indolent course, local tumor progression and aggressive metastasis disease may develop in the long term, and early radical treatment should be considered for men with a life expectancy exceeding 15 years. Most cancers had an indolent course during the first 10 to 15 years. 15 to 20 years revealed a substantial decrease in cumulative progression-free survival (from 45% at 15 years to 36% at 20 years) Survival without metastases (from 77% to 51%) Prostate cancer-specific survival (from 79% to 54%) »Johansson and colleagues (2004)Johansson and colleagues (2004)

Impact on Mortality Patients with a well-differentiated cancer (Gleason sum 2 to 4) had a low probability of death from cancer within 20 years; higher grade cancers took a substantial toll even among older men. Gleason sum and patient age at diagnosis

Probability of dying of CaP w/n 15 years of diagnosis in men with clinically localized CaP treated conservatively: Age (years) Gleason Sum %5%6% 7% 56%8%10% 11% 618%23%27% 30% 770%62%53% 42% %81%72% 60%

Scandinavian Trial 695 men clinically localized CaP Randomized to radical prostatectomy or WW with systemic tx deferred until the development of symptomatic progression Endpoint: death from CaP F/u 8.2 years: 50/348 WW died of CaP 30/347 RP Men RP had lower relative risk of distant metastases than did men assigned to watchful waiting

Scandinavian Trial ED and incontinence were higher in men with RP Obstructive voiding and bowel complaints for WW group Retrospective review showed these patients had palliative treatments such as TURP, radiation, or upper urinary tract diversion.

Identifying Men with Low Risk CaP Systematic Biopsy Results Epstein (1994) preop and path features 157 T1C w/radical prostatectomy to find features that could predict “insignificant” tumors No Gleason grade of 4 or 5 PSA density of 0.1 ng/mL per gram or less, fewer than 3 biopsy cores with cancer (six core min), no core with more athn 50% involvement or PSA density of 0.15 ng/mL per gram or less and cancer smaller than 3 mm on only one prostate biopsy sample (min 6 cores) –Model had positive predictive vale 95%, negative value of 66%, predicted that 73% of their cases were insignificant tumors.

Systematic Biopsy Results Goto (1996) predicted 75% probability of indolent cancer in 170 patients. PSA density <0.1, no Gleason 4 or5, and cancer smaller than 2mm in a single core. None of the models have been validated prospectively or on a separate cohort

Indolent Cancer Nomogram Based on 400 patients diagnosed by needle bx, who had low-risk cancer features (clinical T1C or T2a, bx Gleason patterns 2 or3, PSA less than 20) Analysis of RP specimens 80 (20%) had indolent cancer. Using such prognostic information, physicians can identify, with reasonable accuracy, patients with low tumor burden for whom aggressive management may not be indicated initially, especially in men who are older or with significant comorbidity.

(Figure 96-3) Nomogram for predicting an "indolent" prostate cancer Physician: Locates the patients PSA on PRETX PSA axis, draw line upward to the points axis (points toward have indolent cancer). Repeat this process for remaining axes. Add the points locate on Total Points axis. Draw a line down to probability of having indolent cancer.

Active Surveillance with Selective Delayed Definitive Therapy AS for a healthy man with a life expectancy longer than 10 years risks permitting a curable cancer to become metastatic Initial evaluation seriously underestimates the grade and extent of the present cancer Indolent cancer grows undetected and becomes metastatic before it is treated. The initial evaluation of a candidate for AS aims to reduce the chance that a large, aggressive cancer has been missed. Subsequent evaluations aim to detect progression before the cancer metastasizes. AS patients must accept frequent, regular detailed evaluations of the status of their cancer for as long as they are healthy and young enough to be a candidate for definitive therapy.

Authors recommendation for low- risk patients: Complete reevaluation at baseline DRE, free and total PSA determinations Imaging study of the prostate (endorectal magnetic resonance imaging with spectroscopy) And Ultrasound-guided systematic needle biopsy If confirm a low-risk cancer, patient chooses AS: Recommend a check-up every 6 months with DRE and PSA determinations indefinitely Repeated imaging and biopsy 12 to 18 months after the baseline evaluation Every 2 to 3 years. The goal is to detect progression of the cancer while cure is still possible

Biopsy on follow up vs. PSA Annual surveillance biopsies are necessary for men on AS, since PSA criteria are not likely to reveal disease progression accurately. (Study of 81 men thought to have small vol CaP T1c) Although PSA criteria were significant predictors of cancer progression, extensive overlap in PSA density and percentage free PSA values in men with and without progression, suggesting that accurate prediction of progression would be difficult by these criteria 39 men in whom every follow-up biopsy specimen showed cancer, 22 (56%) had disease progression, compared with 3 of 42 men (7%) with normal findings on one or more follow-up biopsies (P <.001).

AS feasible alternative to initial curative treatment Select patients with favorable, localized prostate cancer. About half of these patients remain free of progression at 10 years, and definitive treatment appeared effective in those with progression. Consistent with the study by Carter and associates (2002), authors found that absence of cancer on repeated needle biopsy early after initial diagnosis identified cases unlikely to progress during 10 years.Carter and associates (2002)

Point system of evaluating progression in pts treated with deferred therapy: 1 Point2 Points3 Points Gleason score increase1>1Any new Gleason pattern 4 or 5 PSA velocity (ng/mL/yr) >0.75 during 12 months >0.75/yr during 24 months DRE/transrectal ultrasonography Increasing old lesion New lesion not biopsy proven New biopsy- proven lesion Biopsy specimens Bilateral or multifocal cancer >4 cores with cancer

University of Toronto (Klotz 2004) 299 patients with good-risk prostate cancer or intermediate- risk prostate cancer in men older than 70 years PSA level was less than 15 ng/mL, Gleason sum 7 or lower, and clinical stage T2b or lower Observed until they met specific criteria: PSA progression (defined by all of three conditions): PSA doubling time (PSADT) of 2 years or less, final PSA level of more than 8 ng/mL, and P <.05 from a regression analysis of ln(PSA) on time; Clinical progression (defined by meeting any of four conditions): more than a doubling of the product of the maximum perpendicular diameters of the primary lesion as measured by DRE, local progression of prostate cancer requiring transurethral resection of the prostate, development of ureteral obstruction, and radiologic or clinical evidence of distant metastasis; and histologic progression: Gleason sum 8 or higher on repeated biopsy of the prostate at 12 to 18 months.

University of Toronto Patients with progression offered RP Median PSA DT was 7 years, 35% had 10 years or more. Follow up at 55 months 60% patients remained on AS 12% biochemical progression 8% clinical progression 4% histological progression 16% patient preference At 8 years: 85% actuarial survival, 99% disease specific survival

For Men on AS, What are the Factors Predicting Progression? Although PSADT is a predictor of cancer progression for men on AS, “the exact trigger point at which to recommend treatment requires further investigation.” One study suggested that the definition of progression for men on AS include a PSADT of less than 2 years on the basis of at least three separate measurements during a minimum of 6 months

What are the Factors Predicting Progression? Although all AS studies have included periodic DRE as part of routine follow-up, none has found this to be an independent predictor of cancer progression It remains important, however, as an indicator that a repeated prostate biopsy is warranted during AS and in clinical staging and the prediction of outcome if active treatment is recommended.

What are the Factors Predicting Progression? Serial imaging studies have also proved to be of limited value in the AS population. Study of 136 men who underwent two or more serial transrectal ultrasound examinations, there was no correlation between changes in either gland volume or the number of peripheral zone hypoechoic lesions and the rate of change of PSA. The role of serial pelvic imaging (CT or endorectal MRI) has not been investigated but is likely to be limited. These men are at low risk for macroscopic extraprostatic disease, so interval changes in any of these examinations are unlikely. Bone scans are not useful, especially if PSA <15

What are the Factors Predicting Progression? Repeated prostate biopsies are considered an important aspect of continued evaluation of men managed with AS, not only to identify men with cancer progression but also to identify men unlikely to progress. Author’s cohort of 88 men on AS, an abnormal finding on second biopsy was the most significant prognostic factor for progression Progression in 5 of the 43 men (11%) who had a first repeated biopsy that was negative for cancer, compared with 12 of 27 (40%) with an abnormal finding on first repeated biopsy (P =.004). Actuarial progression-free probability at 5 years was 83% in patients with normal findings on repeated biopsy compared with 43% in those with abnormal findings on repeated biopsy. –Increase in Gleason sum noted in 59% of repeat biopsy

Summary Patients with a life expectancy (based on age and comorbidities) of less than 10 years and cancer with Gleason score of 6 or lower may be suitable for watchful waiting, especially if clinical stage and PSA values are favorable. Intervention is palliative and delayed until symptoms develop. AS may be a safe alternative to immediate treatment in compliant men with a low risk of cancer progression

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