1. Management of Prostate Cancer Post-Prostatectomy
Ajita Narayan, MD, PhD
Lafayette Cancer Care

2. To paraphrase Benjamin Disraeli
“Lies, more lies and then there is statistics…….”

3. In prostate cancer
“Controversy, more controversy and then there are statistics…”

4. Relative power struggle!!
Radiation Oncologists
Medical Oncologists
Urologists

5. 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; ; Cancer Statistics, 2010

6. New cases & Death rates 2010
Jemal, A., Siegel, R., Xu, J., Ward, E., CA Cancer J Clin 2010;60; ; Cancer Statistics, 2010

8. 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% ( ) to 45.3% ( ); p<0.001

9. 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.

11. The “Manogram”

12. 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.
The new onset of erectile dysfunction should always raise suspicion for prostate gland pathology since an enlarging gland may encroach upon the periprostatic tissue that contains the neurovascular bundle involved in erectile function. Sexual dysfunction appears to be related to advanced but not early prostate ca

15. Pretreatment risk stratification for prostate cancer

16. 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
. In one series, the positive predictive value (PPV) for detecting prostate cancer on prostate biopsy with serum PSA levels 4 to 10 ng/mL and >10 ng/mL were 21 to 22, and 42 to 64 percent, respectively [10].

17. 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.

18. 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.

19. 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

20. 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

21. 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 et al., J Urol 2003 Men diagnosed with clinically localized prostate cancer have a number of treatment options available, including watchful waiting, radical prostatectomy and radiation therapy. With the widespread use of serum prostate specific antigen (PSA) testing, prostate cancers are being diagnosed earlier in their natural history, with many tumors being small and of little health risk to the patient, at least in the short term. To better counsel men diagnosed with prostate cancer, we developed a statistical model that accurately predicts the presence of small moderately differentiated, confined cancer based on clinical variables (serum PSA, clinical stage, prostate biopsy Gleason grade and ultrasound volume) and variables derived from the analysis of systematic biopsies. The analysis included 409 patients diagnosed by systematic needle biopsy with clinical stages T1c or T2a N0 or NX and M0 or MX prostate cancer who were treated solely with radical prostatectomy at 1 of 2 institutions. Additional biopsy features included number and percentage of biopsy cores involved with cancer and high grade cancer, in addition to total length of biopsy cores involved. Indolent cancer was defined as pathologically organ confined cancer 0.5 cc or less in volume and without poorly differentiated elements. Logistic regression was used to construct several prediction models and the resulting nomograms. Overall 80 (20%) of the patients had indolent cancer. The nomogram predicted the presence of an indolent cancer with discrimination (area under the receiver operating characteristics curves) for various models ranging from 0.64 to Calibration of the models appeared good. Nomograms incorporating pretreatment variables (clinical stage, Gleason grade, PSA and the amount of cancer in a systematic biopsy specimen) can predict the probability that a man with prostate cancer has an indolent tumor. These nomograms have good discriminatory ability and calibration, and may benefit the patient and clinician when the various treatment options for prostate cancer are being considered.
Stephenson, A et al, JNCI
An existing preoperative nomogram predicts the probability of prostate cancer recurrence, defined
by prostate-specific antigen (PSA), at 5 years after radical prostatectomy based on clinical stage,
serum PSA, and biopsy Gleason grade. In an updated and enhanced nomogram, we have extended
the predictions to 10 years, added the prognostic information of systematic biopsy results, and enabled
the predictions to be adjusted for the year of surgery. The
nomogram was externally validated on an independent cohort of 1545 patients with a concordance
index of 0.79 and was well calibrated with respect to observed outcome. The inclusion of the number
of positive and negative biopsy cores enhanced the predictive accuracy of the model. Thus, a new
preoperative nomogram provides robust predictions of prostate cancer recurrence up to 10 years after
radical prostatectomy.
Predictive
Kattan, M, Eastham J et al, J Urol (5) ; Stephenson, A, Scardino P et al., J Natl Cancer Inst (10) ; Graefen, M et
al., J Urol : ; Ohori M et al., J Urol :

22. 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 confined
2. Extracapsular (extraprostatic) extension
3. Seminal Vesicle invasion
4. Lymph node mets

25. Treatment options T1/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

26. 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

27. 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

28. 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

29. 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

30. 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

31. Contraindications to main treatment options for early prostate cancer
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.

32.  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

33. 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.

34. 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).

35. Post prostatecomy options

36. 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

37. 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).

38. Digital Rectal Exam

39. The lion’s DRE
No fuss, no complaints……..

40. 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

41. 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

42. Definition of PSA recurrence
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)

43. 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

44. 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.

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

46. All men: post-prostatectomy baseline PSA at 3 months, then as follows:
Follow-up strategy after radical prostatectomy based on pathologic grade and stage
All men: post-prostatectomy baseline PSA at 3 months, then as follows:

47.  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

48. 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.

49. 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

50. Adjuvant RT
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

51. 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 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:

52. 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.

53. SWOG 8794/PR-2
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)
Thompson IM, et al., JAMA 2006;296:

54. Adjuvant RT
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.

55. 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
Thus rather than unnecessarily subjecting every patient to treatment, one can wait until cancer recurrence is confirmed before proceeding with treatment

56. Overall Survival Benefit
Updated analysis of SWOG 8794, presented in 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

57. 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.

58. 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 and RTOG ) provide additional information about the use of ADT in this situation and in men with a rising PSA following a prior radical prostatectomy
RTOG (ADT is given before and/or during RT (neoadjuvant), or only upon completion of RT (adjuvant) ) PURPOSE: To test the hypothesis that androgen ablation before and during radiotherapy for locally advanced carcinoma of the prostate may, by reducing tumor bulk and enhancing tumor cell kill, improve locoregional control and ultimately survival. METHODS AND MATERIALS: The study was conducted from 1987 to Eligible patients were those with bulky tumors (T2--T4) with or without pelvic lymph node involvement and without evidence of distant metastases. They were randomized to receive goserelin, 3.6 mg every 4 weeks; and flutamide, 250 mg t.i.d. for 2 months before radiation therapy and during radiation therapy (Arm I), or radiation therapy alone (Arm II). Of 471 randomized patients, 456 were evaluable: 226 on Arm I and 230 on Arm II. RESULTS: As of November 1999, the median follow-up has reached 6.7 years for all patients and 8.6 years for alive patients. At 8 years, androgen ablation has been associated with an improvement in local control (42% vs. 30%, p = 0.016), reduction in the incidence of distant metastases (34% vs. 45%, p = 0.04), disease-free survival (33% vs. 21%, p = 0.004), biochemical disease-free survival = PSA<1.5 (24% vs. 10%, p<0.0001), and cause-specific mortality (23% vs. 31%, p = 0.05). However, subset analysis indicates that the beneficial effect of short-term androgen ablation appears preferentially in patients with Gleason score In that population, there is a highly significant improvement in all endpoints, including survival (70% vs. 52%, p = 0.015). In patients with Gleason tumors, the regimen has not resulted in a significant enhancement in either locoregional control or survival. CONCLUSION: In patients with Gleason score 2--6 carcinoma of the prostate, a short course of androgen ablation administered before and during radiotherapy has been associated with a highly significant improvement in local control, reduction in disease progression, and overall survival.
RTOG BACKGROUND: Several studies have shown the efficacy of endocrine therapy in combination with radiotherapy in high-risk prostate cancer. To assess the effect of radiotherapy, we did an open phase III study comparing endocrine therapy with and without local radiotherapy, followed by castration on progression. METHODS: This randomised trial included men from 47 centres in Norway, Sweden, and Denmark. Between February, 1996, and December, 2002, 875 patients with locally advanced prostate cancer (T3; 78%; PSA<70; N0; M0) were centrally randomly assigned by computer to endocrine treatment alone (3 months of total androgen blockade followed by continuous endocrine treatment using flutamide; 439 patients), or to the same endocrine treatment combined with radiotherapy (436 patients). The primary endpoint was prostate-cancer-specific survival, and analysis was by intention to treat. This study is registered as an international standard randomised controlled trial, number ISRCTN FINDINGS: After a median follow-up of 7.6 years, 79 men in the endocrine alone group and 37 men in the endocrine plus radiotherapy group had died of prostate cancer. The cumulative incidence at 10 years for prostate-cancer-specific mortality was 23.9% in the endocrine alone group and 11.9% in the endocrine plus radiotherapy group (difference 12.0%, 95% CI %), for a relative risk of 0.44 ( ). At 10 years, the cumulative incidence for overall mortality was 39.4% in the endocrine alone group and 29.6% inthe endocrine plus radiotherapy group (difference 9.8%, %), for a relative risk of 0.68 ( ). Cumulative incidence at 10 years for PSA recurrence was substantially higher in men in the endocrine-alone group (74.7%vs 25.9%, p<0.0001; HR 0.16; ). After 5 years, urinary, rectal, and sexual problems were slightly more frequent in the endocrine plus radiotherapy group. INTERPRETATION: In patients with locally advanced or high-risk local prostate cancer, addition of local radiotherapy to endocrine treatment halved the 10-year prostate-cancer-specific mortality, and substantially decreased overall mortality with fully acceptable risk of side-effects compared with endocrine treatment alone. In the light of these data, endocrine treatment plus radiotherapy should be the new standard.
Pilepich, M et al., Int J Radiat Oncol Biol Phys 2001 Aug 1;50(5): ;
Widmark A., et al, Lancet Jan 24;373(9660):301-8.

59. 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 May;179(5):1830-7; discussion 1837.

60. What about adjuvant hormone therapy alone in pT3 disease?
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.
Iversen, P et al., BJUI 2010; 105:1074.

61. What about adjuvant chemotherapy in pT3 disease?
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.
PURPOSE: Southwest Oncology Group (SWOG) study 9921 is a randomized, phase III, intergroup study to define the role of adjuvant chemotherapy in patients with high-risk prostate cancer. PATIENTS AND METHODS: We allocated 983 patients with prostate cancer with high-risk features to receive 2 years of androgen-deprivation therapy (ADT) with or without six cycles of mitoxantrone (12 mg/m(2)) after prostatectomy. RESULTS: In January 2007, SWOG 9921 was closed to further accrual after three cases of acute myelogenous leukemia (AML) were reported of a total of 487 patients in the mitoxantrone treatment arm. The key cytogenetic features of these cases included inv(16) in the first case, t(15;17) in the second, and del(5) in the third case. Time from the start of mitoxantrone to the detection of AML was 13, 48, and 72 months, respectively. Before SWOG 9921, there were no cases of mitoxantrone-induced AML reported in patients treated for prostate cancer. CONCLUSION: The emergence of this possible pattern of secondary malignancy emphasizes the importance of randomized controlled trials in defining safety and efficacy of new approaches for patients in the adjuvant setting.
Flaig, T et al., J Clin Oncol Mar 20;26(9):1532-6

62. 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.
 The optimal duration of ADT in men undergoing RT has been addressed in at least four trials, all of which suggest benefit from prolonged therapy [45-50].
In the largest trial, RTOG 92-02, 1554 men with T2c-T4 disease received four months of goserelin and flutamide (two months before and during EBRT), and were then randomly assigned to no further therapy or 24 months of additional goserelin [46,48]. At the most recent follow-up, long-term ADT significantly reduced 10-year rates of biochemical failure, local recurrence, and distant metastases (52 versus 68, 12 versus 22, and 15 versus 23 percent, respectively, compared to short-term ADT) [48]. Similarly, long-term ADT significantly improved the 10-year disease-free and disease-specific survival rates (23 versus 13 and 88 versus 84 percent) but not overall survival (54 versus 52 percent). In a post-randomization analysis, overall 10-year survival was significantly increased with long-term ADT in the subset of men with a Gleason score of 8 to 10 (45 versus 32 percent).
In contrast, an overall survival benefit with a longer duration ADT was observed in EORTC trial [49]. In this trial, 970 men undergoing RT for locally advanced or node-positive disease (T1-2, N1-2, or T2c-4, N0-2, (table 1A-B) received six months of complete androgen blockade and were then randomly assigned to observation or 2.5 years of additional treatment with a gonadotropin releasing hormone agonist. At a median follow-up of 6.4 years, the prolonged course of ADT was associated with a significant decrease in overall mortality compared to the six month course of treatment (five-year mortality rate 15.2 versus 19.0 percent, hazard ratio 0.70, 95% CI ).
The main drawback of longer duration ADT is the higher incidence of clinically important side effects, such as impotence, loss of libido, osteoporosis, and cardiovascular disease [51]. These side effects are discussed in detail separately. (See "Managing the side effects of androgen deprivation therapy".)
The optimal timing of RT in men who undergo neoadjuvant ADT is uncertain. In most studies, RT was started two months after institution of ADT. The benefit of delaying the start of RT until a maximal response to ADT is achieved is under study [52]. Another trial, RTOG (NCT ), compares two months versus seven months of neoadjuvant ADT prior to RT in men with intermediate risk prostate cancer. Enrollment is complete and results are pending.
Glode L., et al., J Clin Oncol 2009; 27:237s

63. 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:

64. 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.

65. 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.

66. 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.
Fifteen-year PCSM and all-cause mortality were 12% and 38%, respectively. The estimated PCSM
ranged from 5% to 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. A nomogram predicting the 15-year risk of PCSM was
developed, and the externally validated concordance index was Neither preoperative PSA velocity nor body mass index improved the model’s accuracy. Only 4% of contemporary patients had a predicted 15-year PCSM of greater than 5%.
Andrew J. Stephenson, Michael W. Kattan, et al., J Clin Oncol 27:

67. 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

68. 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

69. 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.

70. 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)
Abiraterone: The first study run at the Royal Marsden Hospital, London, in patients who had not received chemotherapy reported in 2007 that abiraterone acetate induced decline in prostate specific antigen (PSA) in up to 70% of patients as well as radiological shrinkage of tumors, symptom improvement, normalization of lactate dehydrogenase.[5] However others cautioned in 2008 that it was too early to know whether abiraterone treatment will have long term benefit.[6][7]
Results of two Phase II trials indicate that abiraterone may reduce prostate specific antigen (PSA) levels, as well as shrink tumors.[8] Many of the 21 men in the Phase II trial reported significant improvements in their quality of life and several were able to stop taking morphine, used to control the pain caused after the cancer spread into their bones.[9] On average, progression-free survival (PFS) was prolonged by 161 days in patients which had been treated with chemotherapy, and by 236 days in chemotherapy naive patients.[10]
A Phase III trial in subjects previously treated with docetaxel started in 2008.[11] A placebo-controlled randomized phase III clincal trial in patients with castration-refractory prostate cancer who are chemotherapy-naive opened to accrual in April 2009.[12] Encouraging results to be presented in Oct 2010.[13]
In September 2010, an independent panel found that the interim results of the phase three clinical trial were so successful that it would have been immoral to keep half the trial participants on placebo, and all patients began receiving the drug.[1] Additionally, J&J will be allowed to make abiraterone available to some prostate cancer patients before the FDA approves the drug.[1]
A Phase I/II clinical trial evaluating abiraterone acetate in advanced breast cancer patients is also underway.[13]

71. Thank you!
Questions?