This document discusses the management of intermediate and high risk prostate cancer. It begins by providing background on prostate cancer epidemiology and risk stratification. It then covers various treatment options including observation, active surveillance, radical prostatectomy, radiotherapy, and androgen deprivation therapy. Several studies comparing the efficacy of radiotherapy alone versus radiotherapy with short or long-term ADT are summarized. For intermediate risk prostate cancer, the document recommends 4-6 months of ADT with radiotherapy based on trial results. For high risk prostate cancer, 2-3 years of ADT with radiotherapy is recommended.

1. MANAGEMENT OF
INTERMEDIATE AND HIGH
RISK PROSTATE CANCER
Moderator Prof. Dr. Nazir Ahmad Khan

3. Introduction
• Prostate cancer is the second most common cancer in males
worldwide, according to data from the GLOBOCAN database.
• In developed areas, prostate cancer is increasingly being
diagnosed when the tumour is confined to the prostate, due at
least in part to screening with prostate-specific antigen (PSA).
• However, prostate cancers confined to the gland may become less
frequent than more invasive tumours as PSA screening rates fall.

4. Characteristics of Prostate Cancer
• 95% of prostate cancers are adenocarcinomas.
• 4% of men with prostate cancer have transitional cell morphology
arise from the urothelial lining of the prostatic urethra.
• In rare cases, the tumor has a neuroendocrine morphology.
• Arise from the neuroendocrine stem cells that are normally
present in the prostate.
• 70% arise in the peripheral zone,15-20% arise in the central zone,
and 10-15% arise in the transition zone.

6. • 191,930 Estimated Cases in 2020 in US.
— Median age at diagnosis 66 years.
• 33,330 Estimated Deaths in 2020 in US.
— Median age at death 80 years.
• Approximately 1 in 9 (11%) men will be diagnosed in their
lifetime.
• Approximately 1 in 39 (2 6%) men will die from prostate cancer.
Prostate Cancer Epidemiology

7. According to the
official reports from
the past four years 695
prostate cancer cases
were reported in
Jammu and Kashmir.
In which 242 prostate
cancer cases came to
light in 2014, 273 in
2015, 75 in 2016 and
105 in 2017.

8. Risk Stratification
Many different, but similar ways to stratify risk
• D'Amico
• AUA
• NCCN
• CAPRA

13. GLEASON’S SCORE
• Most commonly used system for classifying the histological characteristics of
Prostate Cancer, which uses glandular architecture within the tumour.
• Each score represents the sum of two grades(patterns).
• Grades are based on the extent to which the epithelium assumes a normal
glandular structure.
• A grade of 1 indicates a near-normal pattern, and grade 5 indicates the
absence of any glandular pattern (less malignant to more malignant).
• This scheme of grading histological features greatly depends on the skills and
experience of the pathologist and is subject to some degree of individual
variation.

15. Grade Groups
• The grouping system was introduced in 2013, and has been adopted by the NCCN.
• The Grade Group is derived from needle-core biopsies in patients with suspected prostate cancer
or analysis of a radical-prostatectomy specimen.
• The Grade Group distinguishes five risk groups based on the core with the worst grade, as
follows:
 Grade Group 1 - Gleason 3+3
 Grade Group 2 - Gleason 3+4
 Grade Group 3 - Gleason 4+3
 Grade Group 4 – Gleason 8
 Grade Group 5 - GS 9-10

18. Signs and symptoms
Patients with prostate cancer report
the following local symptoms:
• No symptoms (47%)
• Urinary frequency (38%)
• Urinary urgency (10%)
• Decreased urine stream (23%)
• Hematuria (1.4%)
• Heamatospermia
• Erectile dysfunction
Metastatic symptoms of prostate
cancer include the following:
• Weight loss and loss of appetite
• Bone pain, with or without
pathologic fracture
• Lower extremity pain and edema
• Uremic symptoms

23. MANAGEMENT
 The optimal management of clinically localized prostate cancer remains
controversial and is often a source of confusion, frustration, and anxiety for
many patients who are compelled to make a decision regarding a treatment
intervention for their disease.
 A recent report based on the SEER–Medicare linked database included
85,088 men with the diagnosis of prostate cancer at age 65 years and
older.
 In this cohort of patients,
 42% were treated with radiation therapy (RT),
 21% were treated with RP,
 17% were treated with primary ADT, and
 20% were followed expectantly.

24. PRINCIPLES OF LIFE EXPECTANCY ESTIMATION
Life expectancy estimation is critical to informed decision-making in prostate
cancer early detection and treatment.
Estimation of life expectancy is possible for groups of patients but challenging
for individuals.
Life expectancy can be estimated using:
• The Social Security Administration tables
• The WHO’s Life Tables by country
• The Memorial Sloan Kettering Male Life Expectancy tool
If using a life expectancy table, life expectancy should be adjusted using the
clinician’s assessment of overall health as follows:
• Best quartile of health - add 50%
• Worst quartile of health - subtract 50%
• Middle two quartiles of health - no adjustment

25. LIFE EXPECTANCY ESTIMATION Example.
The Social Security Administration Life Expectancy for a 65-year- old man is
17.7 years. If judged to be in the upper quartile of health, a life expectancy of
26.5 years is assigned. If judged to be in the lower quartile of health, a life
expectancy of 8.8 years is assigned. Thus, treatment recommendations could
change dramatically using the NCCN Guidelines if a 65-year-old man was
judged to be in either poor or excellent health.

26. • Observation
• Active Surveillance
• Radical prostatectomy
• Radical radiotherapy
• ADT

27. Observation
 Observation involves monitoring with a history and physical exam no more
often than every 12 months (without surveillance biopsies) until symptoms
develop or are thought to be imminent.
Advantages
Patients will avoid possible side effects of unnecessary confirmatory testing
and definitive therapy.
Limitation
There may be a risk of local or systemic symptoms (eg, urinary retention,
pathologic fracture), without prior symptoms or concerning PSA levels.

28. Active Surveillance
Active surveillance involves actively monitoring the course of disease
with the expectation to intervene with curative intent if the cancer
progresses.
Patients who choose active surveillance should have regular follow-up,
and key principles include:
 PSA no more often than every 6 months unless clinically indicated.
 DRE no more often than every 12 months unless clinically indicated.
 Repeat prostate biopsy no more often than every 12 months unless
clinically indicated.

29.  Repeat mpMRI (multiparametric MRI) no more often than every
12 months unless clinically indicated.
 In patients with a suspicious lesion on mpMRI, MRI-US fusion
biopsy improves the detection of higher grade cancers.
 Patients should be transitioned to observation when life expectancy
is <10 years.
 Repeat molecular tumor analysis is discouraged.
 The intensity of surveillance may be tailored based on patient life
expectancy and risk of reclassification.

30. Advantages
 Between 50% and 68% of those eligible for active surveillance may safely avoid
treatment for at least 10 years.
 Patients will avoid possible side effects of definitive therapy that may be
unnecessary while on active surveillance.
 Quality of life/normal activities will be less affected while on active surveillance.
 Risk of unnecessary treatment of small, indolent cancers will be reduced.
Limitations
 Between 32% and 50% of patients will undergo treatment by 10 years, although
treatment delays do not seem to impact cure rate.
 Although the risk is very low (<0.5% in most series), it is possible for a cancer to
progress to a regional or metastatic stage.

31. Radical Prostatectomy
 Is a therapeutic option in selected patients, when the tumor is
confined to the prostate.
 Two approaches for the classic RP are used: retropubic and
perineal.
 Latest approaches include laparoscopic RP and robotic RARP.
Robotic assisted radical prostatectomy

32. ProtecT Study (NEJM, September 2016)
• Cohort of 82,000 male patients.
• 2664 diagnosed with prostate cancer.
• 1643 patients randomized to AS(545), RP(553), EBRT(545).
• The trial showed no difference in prostate cancer mortality (P = .48) or
all-cause mortality (P = .87) among all three groups.
• However, disease progression as defined by metastatic disease, clinical
T3 or T4 disease, or initiation of lifelong ADT was higher in the active
surveillance group (P < .001).

33. PIVOT (Prostate Cancer Intervention Versus Observation)
 Enrolled 761 patients diagnosed by PSA screening.
 At 12-year follow-up, prostatectomy did not significantly reduce all-cause or
prostate cancer–specific mortality compared with observation for localized
prostate cancer in selected patients (T1-T2NxM0 with PSA <50 ng/mL, life
expectancy of at least 10 years, negative bone scan for metastatic disease,
and age no >75 years).

35. Addition/Duration of ADT to Radiation RCTs
Intermediate Risk: 4-6 months
— Jones CU, Hunt D. McGowan DG et al: Radiotherapy and short-term androgen
deprivation for localized prostate cancer. N Engl J Med 2011; 365:107.
— D'Amico AV, Chen MH. Renshaw A et al: Androgen suppression and radiation vs
radiation alone for prostate cancer: A randomized trial. JAMA 2008; 299: 289
High Risk: 2-3 years
— Bolla M. Collette L. Blank L et al: Long-term results with immediate androgen
suppression and external irradiation in patients with locally advanced prostate cancer
(an EORTC study): a phase III randomised trial. Lancet 2002: 360: 103
— Horwitz EM, Bae K. Hanks GE at al: Ten-year follow-up of radiation therapy oncology
group protocol 92-02: a phase III trial of the duration of elective androgen deprivation
in locally advanced prostate cancer. J Clin Oncol 2008; 26: 2497

36. RTOG 94-08 (Intermediate Risk)
• Clinical stage T1-T2b, PSA < 20 ng/ml
• Radiation alone (n = 992)
• Radiation plus 4 months ADT (n = 987)
• ~60% Gleason 6, ~30% Gleason 7, ~10%Gleason 8-10
• Low Risk 35%, Intermediate Risk 55%, High Risk 10%

37. RTOG 94-08 (Intermediate Risk)
• Median follow-up 9.1 years
• OS: 57% RT vs. 62% RT+ADT (p = 0.03)
• DSS: 8% RT vs. 4% RT+ADT (p=0.001)
• PSA RFS: 59% RT vs. 74% RT+ADT (p<0.001)
• MFS: 92% RT vs. 94% RT+ADT (p=0.4)

38. Boston Trial
• Clinical stage T1-T2bNOMO + 1 unfavorable risk factor
— PSA> 10 (but < 40)
— Gleason 7-10
— EPE or SVI on MRI
• Radiation alone (n = 104)
• Radiation plus 6 months ADT (n = 102)
• ~27% Gleason 6, ~58% Gleason 7, ~15% Gleason 8-10

39. Boston Trial
• Median follow-up 7.6 years
• OS: 42.3% RT vs. 29.4% RT+ADT (p =0.003)
• DSS: 13.5% RT vs. 3.9% RT+ADT (p=0.01)

40. Summary
4-6 months ADT recommended in addition to RT for
intermediate risk prostate cancer.

41. EORTC (high risk)
• T1-2 WHO Grade 3 OR T3-4 any grade
• Patients with distant mets (including common iliac or
para-aortic nodes) excluded
• Radiation alone = 198
• Radiation + 3 years ADT = 203
• ~30% Gleason 6, ~35-40% Gleason 7-10
• 80-90% T3-T4
• PSA> 20 in 55-60%

42. EORTC (high risk)
• Median follow-up 5.5 years
• OS: 62% RT vs. 78% RT+ADT (p<0.01)
• DSS: 79% RT vs. 94% RT+ADT (p<0.01)
• PSA REFS: 45% RT vs 76% RT+ADT (p<0.01)
• MEFS: 80.8% RT vs. 90.2% RT+ADT (p<0.01)

43. RTOG 92-02 (high risk)
• T2c-T4NO
• Radiation + 3-4 months ADT = 763
• Radiation + 2 years ADT = 758
• ~40% Gleason 6, ~30 Gleason 7, ~25% Gleason 8-10
• ~50% T2, ~50%1T3-4
• PSA > 30 in 33%

44. RTOG 92-02 (high risk)
• Median follow-up 11.3 years
• OS: 51.6% vs. 53.9% (p=0.359)
• DSS: 83.9% vs. 88.7% (p=0.004)
• PSA REFS: 31.9% vs. 48.1% (p<0.001 )
• MES: 77.2% vs. 85.2% (p<0.001

45. Summary
2-3 years ADT recommended in addition to RT for
high risk prostate cancer.

60. MANAGEMENT GUIDELINES

64. Case Scenario
• 55 year Male,
• No underlying comorbidity,
• localized intermediate risk,
• Acinar Adenocarcinoma prostate.

69. CONCLUSION

70. CONCLUSION

71. THANK YOU