Sunaryo Hardjowijoto

Wahjoe Djatisoesanto
Division Oncology
Department of Urology
Airlangga School of Medicine

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Cancer of The Prostate
Epidemiology :
In American Men :
The most common cancer
The 2nd leading cause death (after lung cancer)

Increases Rapidly with age

The lifetime risk of 50 year old man :
Latent/occult CaP : 40%
Clinically CaP : 9,5%
Death from CaP : 2,9%
The probability of CaP developing :
40 year of age : 1 in 10.000
40 59 : 1 in 103
60 79 : 1 in 8 2
The Risk factors for Ca P
1. Aging Process
2. Positive Family History
3. Dietary of High Fat
4. Exposure to Cadmium

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 Carcinogenesis
Carcinogen

Gen in Chromosom 1 Inactivation of TSG in Chromosomes

(familial Ca P) 8p, 10q, 13q, 16q, 17p and 18q

Mutation of Genes

Produce Abnormal Protein

Ca P
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PATHOLOGY
Adenocarcinoma 95%
TCC
Small Cell Carcinoma 5%
Sarcoma

Microscopic Picture :
Nuclear :
Hyperchromatic
Enlarge
Prominint nucleolus
NC Ratio not Useful
Basal cell Layer Absent
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PATHOLOGY (Continued)

If Dx doubtful :
High molecular weight keratin
immunohistochemical staining stains basal
cells if absent Ca P

Prostatic Intraepithelial Neoplasia (PIN) :

Cytologic features similar to Ca P but the basal cells
layer is present
Low grade PIN 20% become invasive Ca P
High grade PIN 50 80% become invasive CaP

Ca P :
50 70% originate in peripheral zone
10 20% originate in transtition zone
5 10% originate in in central zone 6
GRADING & STAGING
The GLEASON grading system :
Base on the glandular architecture
Grades range from 1 to 5
Primary grade : the most observed
Secondary grade : the second most common
Gleason score : the sum of primary and
secondary grade

GLEASON Score :
24 : well differentiated
57 : moderately differentiated
8 10 : poorly differentiated
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Gleason scoring system for Prostate Cancer

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 STAGING
T-Primary tumor
Tx Cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ (PIN)
T1a 5% of tissue in resection for benign disease has cancer, normal DRE
T1b > 5% of tissue in resection for benign disease has cancer, normal DRE
T1c Detected from elevated PSA alone, normal DRE and TRUS
T2a Tumor palpable by DRE or visible by TRUS on one side only, confined to prostate
T2b Tumor palpable by DRE or visible by TRUS on both sides, confined to prostate
T3a Extracapsular extension on one or both sides
T3b Seminal vesicle involvement
T4 Tumor directly extends into bladder neck, sphincter, rectum, levator muscles, or into
pelvic sidewall
N-Regional lymph nodes (obturator, internal iliac, external iliac, presacral lymph nodes)
Nx Cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a regional lymph node or nodes
M-Distant metastasis
Mx Cannot be assessed
M0 No distant metastasis
M1a Distant metastasis in nonregional lynph nodes
M1b Distant metastasis to bone
M1c Distant metastasis to other sites
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DRE, digital rectal examination; PIN, prostatic intraepithelial neoplasma; PSA, prostatic spesific antigen; TRUS, transrectal ultrasound.
Source : American Joint Committee on Cancer : Cancer Staging Manual, 5 ed. Lippincott-Raven, 1997
th
Whitemore-Jewett staging system for Ca P
A1 3 foci carcinoma and 5% of tissue in resection for benign disease has cancer, Gleason sum < 7
A2 > 3 foci carcinoma and > 5% of tissue in resection for benign disease has cancer, Gleason sum 7
B1 Palpable nodule 1.5 cm, confined to prostate
B2 Palpable nodule > 1.5 cm, confined to prostate
C1 Palpable extracapsular extension
C2 Palpable seminal vesicle involvement
D0 Clinically localized disease, with negative bone scan but elevated serum acid phosphatase
D1 Pelvic lymph node metastases
D2 Bone metastases
D3 Hormone-refractory prostate cancer

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Clinical Manifestation
Early stage Ca P : asymptomatic
Symptom positive

Voiding complaints Bone pain paresthesias

weakness lower extremties
urinary/fecal incontinence
Local growth to
urethra/bladder neck
Bone vertebral
column metastasis

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Ca P detection

1. DRE : induration/nodule
2. PSA : cut off point 4 ng%
3. TRUS with systematic biopsy

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DIGITAL RECTAL EXAMINATION
Often neglected or poorly performed by physician
Should be examined using a well lubricated gloved
forefinger through patients rectum
Empty the bladder to avoid overestimate of the
prostatic size
Prostate size is important for urologist to decide on
TURP versus an open prostatectomy in case of BPH
In Ca P it is important to determine the extention of
primary tumor
DRE is also important to determine of clinical
presence of Ca P. Carcinoma prostate are hard,
almost like bone, non tender
50% of carcinomas, especially early stage will miss on
DRE alone
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DIGITAL RECTAL EXAMINATION

On DRE Ca P feel as hard as the base of nose and

BPH should be felt as the tip of the nose
Hard/nodule in the prostate cold be caused by :
Prostate calculose
Previous TURP/operation/biopsy
Granulomatous prostatitis
Prostatitis TB

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PROSTATIC SPECIFIC ANTIGEN

PSA is a serine protease, an enzyme that breaks

down a serine amino acid sequence in a protein
First detected by ABLIN et al in 1970 in prostate
1979 Purification of PSA from prostate tissue by
Wang et al
1987 first mayor clinical paper of PSA by Stamey et al

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PROSTATIC SPECIFIC ANTIGEN
Not specific for Ca P
Elevation of PSA can cause by :
BPH infection, instrumentation
Cut off point : 4 ng %
Refinement of PSA to detec more Ca P :
PSA velocity (change over time) : 0,75 ng/mL/y
PSA density : BPH = 0,12 ng/mL tissue
PSAD > 0,15 Biopsy
Age adjusted PSA (Oesterling, 1993)
Age Normal Range (ng%)
40 49 0 2,5
50 59 0 3,5
60 69 0 4,5
70 79 0 6,5
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TRANS RECTAL ULTRASONOGRAPHY
(TRUS)
Useful in performing prostatic biopsy, local staging
and brachy therapy and cryotherapy
Ca P tends to appear as hypoechoic lesion in the
peripheral zone
More accurate in local staging than does DRE
Also enables to measure prostat volume to calculate
PSAD

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DIFFERENTIAL DIAGNOSIS of Ca P
DRE positive :
Ca P
Chronic granulomatous prostatitis
TB of prostate
Prostatic calculi
Previous TURP/Biopsy

Elevated PSA :
BPH
Infection
Infarction
Instrumentation
Vigorous prostat massage
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TREATMENT of Ca P
A. General Pricnciples
I. Treatment decision depend on :
Grade and stage
LIFE expectancy
Associated morbidity
Patient and physician preferences
II. Modality of treatment :
1. Watchful Waiting :
Old patient
Has concomitant illnesses
Small, well differentiated Ca P

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TREATMENT of Ca P (Continued)

2. Radical Prostatectomy :
Retropubic
Perineal
Laparoscopy
Robotic

3. Radiation therapy :
EBRT : 6.500 7.000 cgy
Brachytherapy

4. Cryosurgery
5. Endocrine/Hormonal therapy
6. Cytotoxic therapy in HRPCA
7. Others (For Painful osseous metastasis)

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 Guidelines for The Primary Treatment of Prostate Cancer
Stage Treatment Comment
T1a Watchful Waiting Standard treatment for well-, and moderately,
differentiated tumours and < 10 year life
expectancy. In patients with > 10 year life
expectancy, restaging with TRUS and biopsy is
advised.
(grade B recommendation)
Radical Prostatectomy Optional in younger patients with a long life
expectancy, especially for poorly differentiated
tumours.
(grade B recommendation)
Radiotherapy Optional in younger patients with a long life
expectancy, especially for poorly differentiated
tumours. Higher complication risk after TURP
especially for interstitial radiation.
(grade B recommendation)
Hormonal Not an option.
(grade A recommendation)
Combination Not an option.
(grade C recommendation)
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 Guidelines for The Primary Treatment of Prostate Cancer
Stage Treatment Comment
T1b Watchful Waiting Asymptomatic patients with well-, and moderately,
T2b differentiated tumours and a life expectancy < 10 years. Patient
who do not accept treatment-related complications.
(grade B recommendation)
Radical Prostatectomy Standard treatment for patients with a life expectancy > 10 years
who accept treatment-related complications.
(grade A recommendation)
Radiotherapy Patients with a life expectancy > 10 years who accept treatment-
related complications. Patients with contraindications for
surgery. Unfit patients with a 5 10 year life expectancy and
poorly differentiated tumours (combination therapy is
recommended; see below).
(grade B recommendation)
Hormonal Symptomatic patients who nedd palliation of symptoms and
who are unfit for curative treatment.
(grade C recommendation).
Antiandrogens are associated with watchful waiting and are not
recommended.
(grade A recommendation)
Combination NHT + radical prostatectomy : no proven benefit (grade A
recommendation).
NHT + radiotherapy : better local control. No proven survival
benefit (grade B recommendation).
Hormonal (2 3 years) + radiotherapy : better than
radiotherapy alone for poorly differentiated tumours.
(grade A recommendation) 22
 Guidelines for The Primary Treatment of Prostate Cancer
Stage Treatment Comment
T3 Watchful Waiting Option in asymptomatic patients with T3, well-
T4 differentiated and moderately differentiated tumours,
and a life expectancy < 10 years.
(grade C recommendation)
Radical Prostatectomy Optional for selected patientsnwith T3 and a life
expectancy > 10 years.
(grade C recommendation)
Radiotherapy T3 with a life expectancy > 5 10 years. Dose escalation
> 70 Gy seems to be of benefit. If this is not available, a
combination with hormonal therapy could be
recommended (see below).
(grade A recommendation)
Hormonal Symptomatic patients, extensive T3 T4, high PSA level
(> 25 ng/mL), unfit patients. Better than watchful
waiting.
(grade A recommendation)
Combination Radiotherapy + hormonal treatment seems better than
radiotherapy alone (grade A recommendation).
NHT + radical prostatectomy : no proven benefit.
(grade B recommendation)
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 Guidelines for The Primary Treatment of Prostate Cancer

Stage Treatment Comment

N+, Watchful Waiting Asymptomatic patients. Patient driven. May have a
M0 negative influence on survival.
(grade C recommendation)
Radical Prostatectomy No standard option.
(grade C recommendation)
Radiotherapy No standard option.
(grade C recommendation)
Hormonal Standard therapy.
(grade A recommendation)
Combination No standard option. Patient driven.
(grade B recommendation)

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Guidelines for Follow-up after Treatment with Curative Intent
1. In asymptomatic patients, a disease-specific history and a serum PSA measurement
supplement by DRE are the recommended test for routine follow-up. These should be
performed at 3, 6 and 12 months after treatment, then every 6 months until 3 years,
and then annually. (grade B recommendation).
2. After radical prostatectomy, a serum PSA level of more than 0.2 ng/mL, can be
associated with residual or recurrent disease (grade B recommendation).
3. After radiation therapy, a rising PSA level, rather than a specific threshold value, is the
most reliable sign of persistent or recuurrent disease (grade B recommendation).
4. Both a palpable nodule and a rising serum PSA level can be signs of local disease
recurrence. (grade B recommendation).
5. Detection of local recurrence by TRUS and biopsy is only recommended if it will affect
the treatment plan.
In most cases, TRUS and biopsy are not necessary before second-line therapy. (grade B
recommendation).
6. Metastasis may be detected by pelvis CT/MRI or bone scan. In asymptomatic patients,
these examinations may be omitted if the serum PSA level is less than 30 ng/mL, but
data on this topic are sparse. (grade C recommendation).
7. Routine bone scans and other imaging studies are not recommended in asymptomatic
patients. If a patients has bone pain, a bone scan should be considered irrespective of
the serum PSA level. (grade B recommendation).
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 Guidelines for The Primary Treatment of Prostate Cancer

Stage Treatment Comment

M+ Watchful Waiting No standard option. May result in worse survival/more
complications than with immediate hormonal therapy.
(grade B recommendation)
Radical Prostatectomy Not an option.
(grade C recommendation)
Radiotherapy Not an option (given for cure)
(grade C recommendation)
Hormonal Standard therapy. Symptomatic patients should not be
denied treatment.
(grade A recommendation)
Combination Not an option.
(grade C recommendation)

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Follow-up of Prostate Cancer Patients

Determination of serum PSA, together with a disease

specific history and supplemented by DRE, are the
cornerstones in the follow-up of prostate cancer
patients. Routine imaging procedures in stable
patients are not recommended and should only be
used in specific situations.

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Guidelines for Follow-up after Hormonal Treatment
1. Patients should be evaluated at 3 and 6 mounths after initiating treatment. Tests
should include at least serum PSA measurement, DRE and careful evaluation of
symptoms in order to assess the tretment response and the side-effects of
treatments given. (grade B recommendation).
2. Follow-up should be tailored to the individual patient, acording to symptoms,
prognostic factors and the treatment given. (grade C recommendation).
3. In patients with stage M0 disease with a good treatment response, follow-up is
scheduled every 6 months, and should include at least a disease-specific history,
DRE and serum PSA determination. (grade C recommendation0.
4. In patients with stage M1 disease with a good treatment response, follow-up is
scheduled for every 3 6 months. A minimal follow-up should include a disease-
specific history, DRE and serum PSA determination, frequently supplemented with
haemoglobin, serum creatinine and alkaline phosphatase measurements.
(grade C recommendation).
5. When disease progression occurs or if the patient does not respond to the
treatment given, the follow-up needs to be individualized.
(grade C recommendation).
6. Routine imaging in stable patients is not recommended.
(grade B recommendation).

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 Guidelines on Second-line Therapy after Curative Treatments
Recommendations :
Presumed local failure Patients with presumed local failure only may be
after RP : candidates for salvage radiotherapy. This should be
given with at least 64 Gy and preferably before PSA has
risen above 1.5 ng/mL. other patients are best offered a
period of watchful waiting (active monitoring) with
possible hormonal therapy later on.
(grade B recommendation)
Presumed local failure Selected patients may be candidates for salvage radical
after RT : prostatectomy (or other curative efforts) although
patients should be informed about the comparatively
high risk of complications. Other patients are best
offered a period of watchful waiting (active monitoring)
with possible hormonal therapy later on.
(grade C recommendation)
Presumed distant +/- There is some evidence that early hormonal therapy
local failure : may be of benefit in delaying progression and possibly
achieve a survival benefit in comparison with delayed
therapy. The results are not without controversy. Local
therapy is not recommended except for palliative
reasons.
(grade B recommendation)
RP = radical prostatectomy
RT = radiotherapy 29
Treatment of Relapse after Hormonal Therapy

Many of these patients are affected by their disease

and maintaining or improving quality of life should
be the main goal.
In most cases the decision to treat, or not to treat, is
made based on counselling of the individual patient,
which limits the role of guidelines.

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Guidelines for Secondary Hormonal Management
1. It is recommended to cease antiandrogen therapy once PSA
progression is documented.
(grade B recommendation).
2. Four to six weeks after discontinuation of flutamide or bicalutamide,
an andtiandrogen withdrawal (AAW) effect might become apparent.
(grade B recommendation).
3. No clear cut recommendation can be made regarding the most
effective drug for secondary hormonal manipulations since data from
randomized trials are scarce.
(grade C recommendation).

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Guidelines for Cytotoxic Therapy in HRPCA
1. In patients with a PSA rise only, 2 consecutive increases of PSA
serum levels above a previous reference level should be
documented.
(grade B recommendation).
2. Prior to treatment, PSA serum levels should be > 5 ng/mL to assure
correct interpretation of therapeutic efficacy.
(grade B recommendation).
3. Potential benefits of cytotoxic therapy and expected side effects
should be discussed with each individual patient.
(grade C recommendation).
4. In patients with metastatic HRPCA, and who are candidates for
cytotoxic therapy, docetaxel at 75 mg/m2 every 3 weeks has shown
a significant survival benefit.
(grade A recommendation).
5. In patietns with symptomatic osseous metastases due to HRPCA,
either docetaxel or mitoxantrone with predisone or hydrocortisone
are viable therapeutic options.
(grade A recommendation).
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Recommendation for Palliative Management of HRPCA
1. Biosphosphonates may be offered to patients with skeletal metastases
(mainly zoledronic acid has been studied) to prevent osseous
complications.
(grade A recommendation).
2. Palliative treatments such as radionuclids, external beam radiotherapy,
and adequate use of analgesics should be considered early on in the
management of painful osseous metastases.
(grade B recommendation).

Summary
Prostate cancer is often a complex disease and one in which many
aspects of the disease and the affected patient must be taken into
consideration before decisions about diagnostic work-up,
treatments, follow-up etc. can be made.

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