Management of Prostate Cancer Post-Prostatectomy

Ajita Narayan, MD, PhDLafayette Cancer Care

To paraphrase Benjamin Disraeli

“Lies, more lies and then there is statistics…….”

In prostate cancer

“Controversy, more controversy and then there are statistics…”

Relative power struggle!!

Urologists

Medical Oncologists

Radiation

Oncologists

Statistics (cancer)

• A total of 1,529,560 new cancer cases and 569,490 deaths from cancer are projected to occur in the United States in 2010.

Jemal, A., Siegel, R., Xu, J., Ward, E., CA Cancer J Clin 2010;60;277-300; Cancer Statistics, 2010

New cases & Death rates 2010

Jemal, A., Siegel, R., Xu, J., Ward, E., CA Cancer J Clin 2010;60;277-300; Cancer Statistics, 2010

• It is generally accepted that the increase in number of newly diagnosed prostate cancers in US men has resulted from PSA screening that detected many early-stage prostate cancers

• Example: percentage of low risk disease has increased from 29.8% (1989-92) to 45.3% (1999-2001); p<0.001

Ergo……

• The comparatively low death rate suggests that unless prostate cancer itself is becoming biologically less aggressive, increased public awareness with earlier detection and treatment has begun to affect mortality from this prevalent cancer.

The “Manogram”

Since we do not have one of those…..

• Prostate ca often diagnosed while asymptomatic with a PSA. However, screening with serum PSA is controversial

• Either by digital rectal examination (DRE) or due to genitourinary symptoms:

• On DRE, asymmetric areas of induration or frank nodules are suggestive of prostate cancer

• Urinary urgency, nocturia, frequency, and hesitancy are usually limited to patients with relatively advanced prostate cancer.

Pretreatment risk stratification for prostate cancer

Serum PSA elevation• PSA is a prostate-specific marker, and elevations

can be caused by either prostate cancer or benign conditions such as BPH.

• Measure BEFORE biopsy• There is significant overlap in the serum PSA

values that accompany prostate cancer and BPH, but the likelihood of finding cancer on a prostate biopsy increases with higher PSA values

• Normal intra-individual and intra-assay fluctuations in serum PSA

Gleason grade and score• The pathologist assigns a grade to the most

common tumor pattern, and a second grade to the next most common tumor pattern. The two grades are added together to get a Gleason score.

• For example, if the most common tumor pattern was grade 3, and the next most common tumor pattern was grade 4, the Gleason score would be 3+4 = 7.

Gleason Score

• The Gleason grade ranges from 1 to 5, with 5 having the worst prognosis.

• The Gleason score ranges from 2 to 10, with 10 having the worst prognosis.

• For Gleason score 7, a Gleason 4+3 is a more aggressive cancer than a Gleason 3+4.

Estimates of Life Expectancy

• Key determinant in treatment decision-making• Difficult to extrapolate the rates of life

expectancy when calculated for groups of men, to an individual patient

• Minnesota Metropolitan Life Insurance Tables or Social Security Administration Life Insurance Table-examples of tables used to calculate life expectancy

• Should be modified by overall health

Why does it matter?

• Rx recommendations could change drastically if referring to prostate cancer in a young man in poor health or an older man in excellent health

• Normograms can be used to inform treatment decision-making for men contemplating active surveillance, RP, neurovascular bundle preservation, or omission of PLND during RP, brachytherapy or EBRT.

• Biochemical PFS can be reassessed post-operatively using age, diagnostic serum PSA and pathologic grade and stage.

Kattan, M, Eastham J et al, J Urol 2003 170 (5) 1792-7; Stephenson, A, Scardino P et al., J Natl Cancer Inst 2006 98 (10) 715-717; Graefen, M etal., J Urol 2001 165: 857-863; Ohori M et al., J Urol 2004 171: 1844-1849

Partin Tables• Originally developed by urologists Alan W.

Partin, M.D., Ph.D., and Patrick C. Walsh, M.D.• Tables combine clinical stage, Gleason grade,

preop PSA level to predict pathologic stage:1. Organ confined2. Extracapsular (extraprostatic) extension3. Seminal Vesicle invasion4. Lymph node mets

Treatment optionsT1/T2 disease

• The standard approaches for men with organ-confined T1/T2 prostate cancer are– radical prostatectomy (RP)– external beam radiation therapy (EBRT),– brachytherapy, and – active surveillance

For patients receiving definitive treatment for T1/T2 prostate cancer, the choice of therapy is largely a matter of patient preference. There is no evidence that the cure rate is different with RP, EBRT, or brachytherapy when patients are stratified based upon prognostic characteristics

Intermediate- or high-risk T1/T2 prostate cancer

• For these patients definitive treatment rather than active surveillance

• Intermediate-risk disease- EBRT, brachytherapy, or RP

• High-risk disease- ADT plus EBRT or RP plus adjuvant EBRT

Advantages of main treatment for early prostate cancer: EBRT

• Effective long term control with high dose Rx• Low risk of urinary incontinence• Wide range of ages• When combined with hormonal therapy,

offers a chance of cure in high-risk of disease• Treatments can eradicate extension of tumor

beyond the margins of prostate

Advantages of main treatment for early prostate cancer: Brachytherapy• Cancer control rate equal to surgery and EBRT

for organ-confined tumor• Quicker than EBRT (one treatment)• Available for cure in a wide range of ages and

in those with comorbidities

Advantages of main treatment for early prostate cancer: Radical Prostatectomy• Effective long-term cancer control • Prediction of prognosis can be more precise

based on pathologic features in specimen• Pelvic lymph node dissection is possible

through the same incision• PSA failure easy to predict

Advantages of main treatment for early prostate cancer: Active Observation

• Reduces overtreatment• Avoids or postpones treatment-associated

complications• Has no effect on work or social activities

• RP: High operative risk, ‘medical age’ of 70 or more, neurogenic bladder, morbid fear of surgery

• Active observation: High grade tumors, pt preference, expected survival of 10 or more years.

Contraindications to main treatment options for early prostate cancer

Other Approaches

• Include various forms of ablation therapy and systemic hormonal therapy rather than therapy directly to the prostate:– Ablation therapy: • Cryotherapy and high-intensity focused ultrasound

(HIFU) have been used to destroy tissue, either by freezing or by generating local thermal energy. These ablation techniques can be applied focally, subtotally, or to the entire prostate gland

Primary hormone therapy

• Has been used in patients seeking active therapy but wishing to avoid the side effects of RP or RT.

• The available evidence suggests that this approach does NOT have a role in patients with clinically localized disease.

Benefit of early treatment

• Detection of early asymptomatic recurrence following treatment for localized prostate cancer is useful only if it decreases morbidity or mortality. While data directly addressing this issue are lacking, there is some indirect evidence that early detection and treatment of a recurrence can improve outcomes.

• Potential benefits and secondary treatment options are dictated by whether recurrence is systemic or local, and whether the initial treatment was surgery or radiation (EBRT or brachytherapy).

POST PROSTATECOMY OPTIONS

Post prostatecomy options• Post prostatectomy treatment options varies with

the individual patient and needs to be done in a multidisciplinary setting i.e. Medical Oncologist, Radiation Oncologist, Urologist

Options include• Post op Surveillance• Radiation therapy• Hormonal therapy • Chemotherapy

Follow-up surveillance after treatment for prostate cancer

• No widely accepted, evidence-based guidelines that define optimal surveillance for men who have been treated for localized prostate cancer

• Potential benefits and secondary treatment options are dictated by whether recurrence is systemic or local, and whether the initial treatment was surgery or radiation (EBRT or brachytherapy).

Digital Rectal Exam

The lion’s DRE

No fuss, no complaints……..

If there is recurrence…..

• The majority of recurrences following RP or RT for localized prostate cancer are asymptomatic

• Digital rectal examination (DRE)• Serum PSA is the mainstay of surveillance testing

in men who have undergone therapy for localized prostate cancer

• While the use of PSA for cancer screening is controversial, it is an excellent tumor marker in men with an established diagnosis of prostate cancer

Definition of PSA recurrence

• Depends upon the initial treatment• All prostate tissue is removed during a

successful RP. Thus, any detectable PSA in the serum using the standard immunoassay (typical limit of detection is 0.05 ng/ml) theoretically indicates remaining prostate tissue, and presumably represents persistent or recurrent disease

• Biochemical failure following RT is more complicated, since there is benign tissue remaining after RT

• ASTRO (American society for radiation oncology) guidelines on PSA recurrence were revised in 2005 (Phoenix Criteria)

Definition of PSA recurrence

Phoenix criteria

• PSA rise by ≥2 ng/mL above the nadir PSA is considered the standard definition for biochemical failure after external beam RT, regardless of whether or not a patient receives androgen deprivation therapy.

• The date of failure is defined by the time the rise in PSA is noted

PSA bounce

• Serum PSA levels typically fall after RT and can then rise ("bounce") transiently, at a median of 12 to 18 months after treatment.

• Can occur in the absence of recurrent disease and does not necessarily constitute an indication for therapeutic intervention.

American Urological Association Best Practice Policy regarding the use of PSA in the post treatment management of prostate cancer

Follow-up strategy after radical prostatectomy based on pathologic grade and stage

• All men: post-prostatectomy baseline PSA at 3 months, then as follows:

• Bone scan remains a sensitive and reliable test for detecting the presence of skeletal metastases: But role for early detection of asymptomatic recurrence has been largely supplanted by serial PSA testing

• No role for transrectal ultrasound (TRUS) of the prostate or prostatic fossa as a screening test for recurrence of localized prostate cancer

• Routine pelvic CT scans are not indicated because of the limited sensitivity of CT to detect low volume recurrent disease

• The ProstaScint scan is a radiolabeled monoclonal antibody imaging test that is approved in the United States as an aid to determining the site of recurrence (local versus distant) in men with a PSA-only recurrence after RP

• National Comprehensive Cancer Network (NCCN) recommend PSA testing every 6 mths for the first 5 years, then annual testing thereafter. The NCCN also recommends annual DRE.

Adjuvant RT vs. Postop surveillance

• Adj RT decreases the risk of biochemical relapse, but it requires administering RT to some patients who would otherwise never require treatment.

• Postoperative surveillance without treatment followed by salvage RT at the first evidence of a rising serum PSA entails the risk that distant metastases might develop in some men who would have been rendered disease-free with immediate adjuvant treatment

• Extended follow-up from large clinical trials provides evidence that adjuvant RT – is well tolerated – it improves the biochemical and local control rates

in men who are found to have pT3 disease or diffusely positive resection margins at RP

– improves metastasis-free and overall survival

Adjuvant RT

• No randomized trials specifically comparing early adjuvant RT (ART) compared to Salvage RT (SRT)

• 2 published randomized series comparing ART with no ART (various delayed therapies including SRT were employed in the latter group).

• EORTC study 229111 and the SWOG study 8794 (including NCIC [National Cancer Institute of Canada] PR-2), with 1005 and 410 patients, respectively.

Bolla M, et al. Lancet 2005; 366:572-4; Thompson IM, et al., JAMA 2006;296:2329-35.

Adjuvant RT: EORTC trial 22911• Randomly assigned 1005 men with pT3 disease

or positive margins following RP to postoperative EBRT (60 Gy) or observation

• Median follow-up of 5 years • RT group had higher rates of biochemical relapse-

free survival (RFS) (74 versus 53 %, HR 0.48) as well as clinical RFS (85 versus 78 %, HR 0.61)

• The cumulative incidence of locoregional failure at five years was also significantly lower (5.4 versus 15.4 %) but there was no difference in overall survival.

Bolla, M., et al., Lancet 2005 Aug 13-19;366(9485):572-8.

• 425 men with pT3 or margin-positive prostate cancer were randomly assigned to immediate RT (60 to 64 Gy) or observation

• Median follow-up of 12.6 years• Progression-free survival advantage with early

radiotherapy: – 67% versus 48% (p < 0.001) for the SWOG/NCIC study

with an HR of 0.52• Metastatic-free survival (SWOG 8794/PR-2): – 84% versus 69% at 5 years, and 68% versus 49% at 10

years with an HR of 0.62 (confidence interval 0.46–0.82, p = 0.001)

SWOG 8794/PR-2

Thompson IM, et al., JAMA 2006;296:2329-35

• Meta-analysis of 1743 patients from the 3 randomized trials

• ART resulted in improved biochemical PFS (HR = 0.47, p < 0.001) and deferred requirement for adjuvant therapies (radiation and androgen ablation) with their associated adverse effects

Morgan SC, et al., Urol Oncol 2009;27:87-8.

Adjuvant RT

Opponents of ART

• Only a certain percentage of “high-risk” patients have local failure and SRT is probably just as effective.

• Systemic failures, which may occur with or without local recurrence, cannot be addressed by ART

• Toxicity from ART may outweigh potential benefits.

• ? lack of OS benefit for ART

Overall Survival Benefit

• Updated analysis of SWOG 8794, presented in 2008 shows increased metastatic-free survival (p = 0.021) and increased overall survival (median 15.2 yr compared with 13.5 yr, p = 0.031), in addition to increased biochemical control (p < 0.001) for the ART group

• Unequivocal benefit for ART with level I evidence

What if seminal vesicle invasion (SVI)?

• Even those with SVI who received ART compared with those who were initially observed had an improved 10 years freedom from biochemical failure (FFBF) survival from 12% to 36% (p = 0.001) and 10-year OS from 51% to 71%.6

• Thus, even with SVI, some patients appear to benefit from adjuvant local radiotherapy.

What about concurrent ADT with adjuvant RT in pT3 disease?

• Less certain, although some retrospective series suggest that this approach is beneficial , the role of ADT has not been established in randomized trials.

• Two trials from the RTOG (RTOG 86-01 and RTOG 85-31 ) provide additional information about the use of ADT in this situation and in men with a rising PSA following a prior radical prostatectomy

Pilepich, M et al., Int J Radiat Oncol Biol Phys 2001 Aug 1;50(5):1243-52; Widmark A., et al, Lancet. 2009 Jan 24;373(9660):301-8.

What about adjuvant hormone therapy without RT in pT3 disease?

• Extremely uncertain! • Retrospective, nonrandomized cohort of men s/p RP,

node negative; 580 men received adjuvant ADT while 1160 were managed expectantly without adjuvant ADT

• 30 % pts on observation arm subsequently received ADT for either a biochemical or systemic recurrence

• Adjuvant ADT was associated with statistically significant improved rates of 10-year biochemical and systemic PFS compared to delayed treatment (95 versus 90 and 98 versus 95 percent, respectively).

• No improvement in overall survival (84 versus 83 percent)

Siddiqui, S et al., J Urol. 2008 May;179(5):1830-7; discussion 1837.

• Early Prostate Cancer program: 8113 men with localized (T1, T2) or locally advanced (T3, T4) nonmetastatic prostate cancer – high-dose bicalutamide monotherapy (150 mg daily)

added to standard care (watchful waiting, RP, RT) – Median f/u of 10 years– Rx with bicalutamide was associated with a statistically

significant improvement in PFS in men with locally advanced (T3, T4) disease regardless of the initial management approach.

– No statistically significant difference in overall survival in these patients.

What about adjuvant hormone therapy alone in pT3 disease?

Iversen, P et al., BJUI 2010; 105:1074.

• SWOG trial 9921: patients with high-risk prostate cancer s/p RP were randomly assigned to two years of combined androgen deprivation therapy (goserelin plus bicalutamidee), with or without six cycles of mitoxantrone plus prednisone.

• The trial was terminated after 983 of the planned 1360 patients were enrolled, when AML was observed in 3 patients who had received mitoxantrone.

What about adjuvant chemotherapy in pT3 disease?

Flaig, T et al., J Clin Oncol. 2008 Mar 20;26(9):1532-6

SWOG trial 9921• 5-yr PSA relapse-free survival rate was 93 % for the

two treatment arms, and there was no significant difference between those arms

• The SWOG considered a follow-up trial in which patients would be randomly assigned to either one or two years of adjuvant hormone therapy. However, the trial would require nearly 20,000 patients and a follow-up of 23 years to detect a 10 percent difference in the two arms.

• Such a trial is not feasible, and 2 yrs of adjuvant hormone therapy after definitive surgery with or without adjuvant RT remains the de facto standard of care.

Glode L., et al., J Clin Oncol 2009; 27:237s

Prostate Cancer–Specific Mortality After Radical Prostatectomy for Patients Treated in the Prostate-

Specific Antigen Era

Andrew J. Stephenson, Michael W. Kattan, et al., J Clin Oncol 27:4300-4305. 2009

• The long-term risk of prostate cancer–specific mortality (PCSM) after radical prostatectomy is poorly defined for patients treated in the era of widespread PSA screening

• A multi-institutional cohort of 12,677 patients treated with radical prostatectomy between 1987 and 2005 was analyzed for the risk of PCSM.

• Fifteen-year PCSM and all-cause mortality were 12% and 38%, respectively.

• Estimated PCSM : 5% - 38% for patients in the lowest and highest quartiles of predicted risk of PSA-defined recurrence, based on a popular nomogram. Biopsy Gleason grade, PSA, and year of surgery were associated with PCSM.

• Neither preoperative PSA velocity nor body mass index improved the model’s accuracy.

The A-ha! moment…….

• Few patients will die from prostate cancer within 15 years of radical prostatectomy, despite the presence of adverse clinical features.

• Favorable prognosis may be related to the effectiveness of RP (with or without secondary therapy) or the low lethality of screen-detected cancers.

• Given the limited ability to identify contemporary patients at substantially elevated risk of PCSM on the basis of clinical features alone, the need for novel markers specifically associated with the biology of lethal prostate cancer is evident.

Andrew J. Stephenson, Michael W. Kattan, et al., J Clin Oncol 27:4300-4305. 2009

Local recurrence following RP - Summary

• RT may represent a reasonable option for men who are candidates for salvage therapy following a localized recurrence after RP.

• Salvage RT is most successful when the disease burden is low and when the relapse-free interval is 12 months or longer

• Effect of salvage RT on life expectancy in this setting is unclear

Local recurrence following RT - Summary

• RP may provide effective salvage therapy for some men with recurrence following definitive RT

• Cryotherapy has been proposed as a potentially less morbid alternative to salvage RP in men who recur locally after RT, especially in those who with clinical T3 disease

PSA only Recurrence - Summary• Routine serum PSA monitoring after treatment of

localized prostate cancer leads to the identification of men with a PSA-only (biochemical) recurrence.

• A rising PSA may not be accompanied by any other

evidence of recurrent or metastatic disease.

• Biochemical failure by itself is not necessarily a predictor of death from prostate cancer. Overt metastatic disease may not become evident for many years in men who develop a biochemical failure.

Newer agents in advanced disease

• Docetaxel• Cabazitaxel• Sipulicel-T (Provenge)• Abiraterone: currently under investigation for

use in castration-resistant prostate cancer (formerly hormone-resistant or hormone-refractory prostate cancer)

Thank you!

Questions?