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Prostate Cancer
151
• The probability of extracapsular extension and involvement of seminal vesicles is
associated with serum PSA and Gleason score
• Lymph node metastasis is another common mode of spread in prostate cancer
• The probability of regional metastasis can be estimated by a number of predictive
models and is associated with PSA value, gleason score and tumor stage.
• The primary lymphatic vessels from the prostate gland drain into the regional lymph
nodes of the true pelvis (figure-5).
Figure 5. Lymphatic drainage of prostate cancer.
Reference
Swanson GP, Thompson IM, Basler J. Current status of lymph node-positive prostate cancer:
Incidence and predictors of outcome. Cancer. 2006;107(3):439.
Gustavo Arruda Viani
152
Risk groups
Description
NCCN risk categories
Low: T1-2a and GS £6 and PSA <10
Intermediate: T2b–T2c and/or GS 7 and/or PSA 10–20
High: T3a or GS 8-10 or PSA >20 (very high T3b-T4)
Roach formulas
(Based on original Partin data)
ECE = 3/2 × PSA + 10 × (GS-3)
Seminal vesicle involvement = PSA + 10 × (GS-6)
LN involvement = 2/3 × PSA + 10 × (GS-6)
8. Prognostic Factors
• Prediction models can be used to help guide treatment. A number of risk groups and
nomograms have been published to try predicting pathologic stage, biochemical
control, prostate cancer-specific mortality, and developing metastases based on
retrospective review.
• Generally, the majority of risks grouping systems classify patients on the basis of
PSA, Gleason score, TNM stage, and the percent positive biopsy cores.
• The most commonly used risk grouping system is the one proposed by D’Amico et
al. These have been adopted by the NCCN guideline, which divides patients into
low-, intermediate-, high-risk, locally advanced and metastatic groups (Table-5). The
Roach formula can be used to estimate the risk of lymph node involvement (table 6).
Table 6. Risk groups according to D`amico classification
Reference
National Comprehensive Cancer Network. Prostate Cancer treatment recomendation.
V.1.2012. Accessed May 5, 2012.
• Urologists, radiation oncologists and clinical oncologists should to discuss the
natural history of the disease, life expectancy of the patient, treatment outcomes and
its effects on quality of life to help patients to decide on which is the better choice for
their condition.
• The treatment options for men with prostate cancer include radical prostatectomy
(RP), external beam radiation therapy (EBRT), brachytherapy, and active
surveillance. There is no evidence that the cure rate is different with RP, EBRT, or
brachytherapy when patients are stratified based upon prognostic characteristics
(table 7).
9. Treatment
Prostate Cancer
153
Risk group
Description
Low:
T1-2a and GS <=6
and PSA <10
Life expectancy <10 years:
Active surveillance: using PSA and DRE
Definitive therapy using RT
Life expectancy >10 years:
External RT (3DCRT,IMRT, IG-IMRT)
Brachytherapy
Radical prostatectomy (RP)
Intermediate:
T2b–T2c and/or GS 7
and/or PSA 10–20
Life expectancy <10 years:
Active surveillance,
RT ± short term androgen deprivation therapy(ADT)
RP
Life expectancy >10 years:
RT + short-term ADT (4–6 month),
High-dose RT alone
Alternatively RT (3DCRT/IMRT with IGRT) +high dose brachytherapy boost.
RP + pelvic LN dissection
High:
T3a or GS 8-10 or
PSA >20 (very high
T3b-T4)
RT (3DCRT/IMRT with IGRT) with neoadjuvant, concurrent, and adjuvant
ADT (2–3 years).
Whole pelvic RT is an alternative (IMRT).
RP with pelvic LN dissection only for select patients with low-volume disease
and no fixation.
Salvage/adjuvant
Adjuvant RT:
Persistent local disease on imaging or biopsy,
pT3 disease or +margin(s).
Metastatic
ADT ± palliative RT ± bisphosphonates.
hormone-refractory disease, docetaxel and prednisone
Type
Description
Active
surveillance
Advantage:
It avoids side effects of therapy that may be unnecessary.
Disadvantage:
Salvage treatment may be more intense with more side effects.
Increased anxiety for patients.
Risk of progression and/or metastases
Radical
prostatectomy
(RP)
Advantage:
RP is a local treatment that reduces mortality, local progression and metastasis over
observation.
Reduced treatment time
Pathological stagement
Disadvantage:
Intra-operative bleeding, urinary incontinence, and erectile dysfunction
External beam
radiotherapy
Advantage:
Very low risk of urinary incontinence .
Treatments can eradicate extensions of tumor beyond the margins of the prostate
Disadvantage:
Significant risk of impotence
Risk of later rectal symptoms
temporary bladder or bowel symptoms during treatment
Brachytherapy
Advantage:
Highly conformal dosimetry
Moderate invasiveness
Reduced number of treatment visits
Disadvantage:
Significant risk of impotence
Successful cancer control is operator dependent
Risk of later rectal symptoms
Temporary bladder or bowel symptoms with treatment
Table 7. Sumarizes the treatment options for patients with prostate cancer according
to risk groups
Table 8. Resumes the indications, advantages and disadvantages of each modality
Gustavo Arruda Viani
154
Swedish trial
(2008)
Randomized 695 patients with T1b-T2 to WW vs. RP. With median follow-up 10.8
years, RP reduced 12-year death from prostate cancer (20→14%) and DM
(26→19%), but no longer a difference in OS (p > 0.09).
On subgroup analysis, men younger than 65 years at diagnosis had significant
improvements with RP, while there was no discernible difference among those
above 65 years.
SEER (2006)
Compared almost 32,000 treated patients with age 65–80, T1–2 GS 2–7 vs. ~12,000
patients observed.
Treatment group had 31% lower mortality (HR 0.69). Benefits for specific
subgroups: age 75–80 years 27% benefit, PSA era diagnosis 38% benefit, no
comorbidities 29% benefit, cT1–T2a GS 2–4 21% benefit.
Klotz et al.
(2004)
Phase II study of 299 patients with low-risk or intermediate risk disease (if >70
years) treated with active surveillance with delayed intervention for PSA DT <2
years or grade progression on rebiopsy.
Eight-year DSS and OS were 99 and 85%, respectively.
• RP, EBRT, brachytherapy, and active surveillance are all considered treatment
options for patients with localized, low-risk prostate cancer.
• There are significant differences in toxicity patterns with these treatments. The
advantages, disadvantages, and contraindications with each approach are summarized
in the table (table 8)
9.1. Active Surveillance
• Active surveillance is an option for carefully chosen men with low-risk prostate
cancer.
• Generally active surveillance is made performing DRE and PSA every 3–6 months
with routine repeat biopsy in 1–2 years to rule-out Gleason grade progression (table-
9).
Table 9. Clinical evidence for active surveillance for low rik prostate cancer
References
Bill-Axelson A, Holmberg L, Filen F, et al. Radical prostatectomy versus watchful waiting in
localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial. J
Natl Cancer Inst 2008;100(16):1144-1154.
Wong YN, Mitra N, Hudes G, et al. Survival associated with treatment vs observation of
localized prostate cancer in elderly men. JAMA 2006;296(22):2683-2693.
Klotz L. Active surveillance with selective delayed intervention: using natural history to
guide treatment in good risk prostate cancer. J Urol 2004;172:S48-50; discussion S50-
S41.
Prostate Cancer
155
Institution
Description
Washington
University
(1998)
From 1983 through August 1997, 1 surgeon performed RP in 1,778 men.
Patients were followed with semiannual prostate specific antigen (PSA) tests and
annual digital rectal examinations. Follow up PSA 0.3 ng./ml or greater was
considered evidence of cancer recurrence.
The estimated 7-year prostate cancer specific survival rate was 97% and the all
cause survival rate was 90%.
Johns Hopkins
(1994)
Between April 1982 and March 1991, 955 men with clinically localized prostate
cancer were submitted to RP.
Using actuarial analysis, at 10 years the likelihood of an undetectable prostate
specific antigen (PSA) level was 70%, isolated elevation of PSA 23%, distant
metastases 7% and local recurrence 4%.
Cleveland
Clinic (1998)
1,143 consecutive patients (median age, 64 years; range, 38 to 79 y) who underwent
RP at one institution (mean follow-up time, 9.7 years).
The 10- and 15-year crude survival rates for 1,143 patients were 75% and 60%,
respectively; the cause-specific survival rates were 90% and 83% , respectively;
and the metastasis-free survival rates were 83% and 77%, respectively .
9.2. Prostatectomy Radical
• To date there is not randomized trials comparing modern radiation with
prostatectomy techniques.
• RP is an established option to treat localized prostate cancer, based upon rates of
long-term cancer control, perioperative morbidity and mortality, and side effects
profile. Several institutions have published long-term efficacy data for patients with
prostate cancer treated with retropubic RP.
• Although results vary, approximately 70 % of men undergoing RP for clinically
localized disease have control of disease for at least 10 years based upon this
criterion. Surgical options include the retropubic and perineal approaches, as well as
minimally invasive (robotic or laparoscopic) surgery (table 10).
Table 10. Clinical evidence for prostate cancer treated with retropunic
radical prostatectomy
References
Catalona WJ, Smith DS.Cancer recurrence and survival rates after anatomic radical
retropubic prostatectomy for prostate cancer: intermediate-term results. J Urol.
1998;160(6 Pt 2):2428.
Walsh PC, Partin AW, Epstein JI. Cancer control and quality of life following anatomical
radical retropubic prostatectomy: results at 10 years. J Urol. 1994;152(5 Pt 2):1831.
Zincke H, Bergstralh EJ, Blute ML, Myers RP, Barrett DM, Lieber MM, Martin SK,
Oesterling JE. Radical prostatectomy for clinically localized prostate cancer: long-term
results of 1,143 patients from a single institution. J Clin Oncol. 1994;12(11):2254.
Gustavo Arruda Viani
156
Study
Description
Viani et al.
(2009)
A meta-analysis of randomized, controlled studies comparing HDRT with CDRT for
localized prostate cancer.
7 RCTs with a total patient population of 2812 were identified that met the study criteria.
Pooled results from these RCTs showed a significant reduction in the incidence of
biochemical failure in those patients with prostate cancer treated with HDRT (p<0.0001).
There was no difference in the mortality rate (p = 0.38) and specific prostate cancer
mortality rates (p = 0.45) between the groups receiving HDRT and CDRT. However,
there were more cases of late Grade>2 gastrointestinal toxicity after HDRT than after
CDRT.
In the subgroup analysis, patients classified as being at low (p = 0.007), intermediate
(p<0.0001), and high risk (p<0.0001) of biochemical failure all showed a benefit from
HDRT.
Arcangeli
et al.
(2011)
168 patients were randomized to receive either hypofractionated or conventional
fractionated schedules of three-dimensional conformal radiotherapy to the prostate and
seminal vesicles. All patients received a 9-month course of total androgen deprivation
(TAD), and radiotherapy started 2 months thereafter.
The median (range) follow-up was 32 (8-66) and 35 (7-64) months in the
hypofractionation and conventional fractionation arms, respectively.
No difference was found for late toxicity between the two treatment groups, with 3-year
Grade 2 rates of 17% and 16% for gastrointestinal and 14% and 11% for genitourinary in
the hypofractionation and conventional fractionation groups, respectively.
The 3-year freedom from biochemical failure (FFBF) rates were 87% and 79% in the
hypofractionation and conventional fractionation groups, respectively (p = 0.035).
The 3-year FFBF rates in patients at a very high risk (i.e., pretreatment prostate-specific
antigen (iPSA)>20 ng/mL, Gleason score>or=8, or T>or=2c), were 88% and 76% (p =
0.014) in the former and latter arm, respectively.
9.3. EBRT
• EBRT for localized prostate cancer is used to deliver a therapeutic dose of radiation
to the tumor while minimizing radiation to adjacent normal tissues.
• The results of EBRT appear to be similar to those with radical prostatectomy. The
Phoenix criteria are used in assessing results of RT.
• Although some observational series have suggested that surgery may be more
effective in patients with intermediate or high-risk disease, the improved results may
be related to the differences in time of detection of recurrence and earlier use of
salvage therapy for the surgical patients.
• Outcomes with EBRT have improved significantly due to technical advances and the
combination of ADT to RT. Currently EBRT appears to be as effective as radical
prostatectomy for localized prostate cancer.
• Patients submitted to EBRT should receive a dose of 74 Gy or higher with
contemporary conformal techniques or IMRT.
• Recently randomized trials have showed that shorter courses of RT using larger
treatment fractions yielded similar results than conventional fractionation, although
longer follow up is necessary (Table-11).
Table 11. Clinical evidence for high dose radiation therapy and hypofractionated EBRT
Prostate Cancer
157
Study
Description
Jones et al.
(2011)
1979 eligible patients with <T2b prostate adenocarcinoma and a prostate-specific
antigen (PSA) level < 20 ng per milliliter were randomized to RT alone (992
patients) or RT with 4 months of total androgen suppression starting 2 months
before RT (RT plus short-term ADT, 987 patients). The median follow-up period
was 9.1 years.
The 10-year rate of overall survival was 62% among patients receiving RT + ADT
as compared with 57% among patients receiving RT (P=0.03). The addition of
short-term ADT was associated with a decrease in the 10-year disease-specific
mortality from 8% to 4% (P=0.001). Biochemical failure, distant metastases, and
the rate of positive findings on repeat prostate biopsy at 2 years were significantly
improved with RT plus short-term ADT.
D`Amico et
al.(2008)
206 men with localized but unfavorable-risk prostate cancer were randomized to
receive RT alone or RT and AST combined.
With a median follow-up of 7.6 (range, 0.5-11.0) years, 74 deaths have occurred.
A significant increase in the risk of all-cause mortality (44 vs 30 deaths; P = .01)
was observed in men randomized to RT compared with RT and AST. However,
the increased risk in all-cause mortality appeared to apply only to men randomized
to RT with no or minimal comorbidity (31 vs 11 deaths; P<.001).
Pilepich et al.
(2005)
Eligible patients were those with palpable primary tumor extending beyond the
prostate (clinical Stage T3) or those with regional lymphatic involvement.
The patients were randomized to both RT and adjuvant goserelin (Arm I) or RT
alone followed by observation and application of goserelin at relapse (Arm II). In
Arm I, the drug was to be started during the last week of RT and was to be
continued indefinitely or until signs of progression.
977 patients were entered: 488 to Arm I and 489 to Arm II. The median follow-up
for all patients was 7.6 years and for living patients was 11 years.
At 10 years, the absolute survival rate was significantly greater for the adjuvant
arm than for the control arm: 49% vs. 39%, respectively (p = 0.002). The 10-year
local failure rate for the adjuvant arm was 23% vs. 38% for the control arm
(p<0.0001).
Roach et al.
(2008)
456 assessable patients (median age, 70 years) were enrolled. Eligible patients had
tumors (T2-4) with or without pelvic lymph node involvement.
Patients received combined ADT that consisted of goserelin 3.6 mg every 4 weeks
and flutamide 250 mg tid for 2 months before and concurrent with EBRT, or they
received EBRT alone. 10-year OS estimates (43% v 34%).
There was a statistically significant improvement in 10-year DSM (23% v 36%; P
= .01), DFS (11% v 3%; P<.0001), and BF (65% v 80%; P<.0001) with the
addition of ADT, but no differences were observed in the risk of fatal cardiac
events.
References
Viani GA, Stefano EJ, Afonso SL. Higher-than-conventional radiation doses in localized
prostate cancer treatment: a meta-analysis of randomized, controlled trials. Int J Radiat
Oncol Biol Phys. 2009;74(5):1405.
Arcangeli G, Saracino B, Gomellini S, Petrongari MG, Arcangeli S, Sentinelli S, Marzi S,
Landoni V, Fowler J, Strigari L. A prospective phase III randomized trial of
hypofractionation versus conventional fractionation in patients with high-risk prostate
cancer. Int J Radiat Oncol Biol Phys. 2010;78(1):11.
Table 12. Clinical evidence for EBRT plus ADT versus EBRT in prostate cancer
Gustavo Arruda Viani
158
Study
Description
RTOG
9413.
(2006)
1323 men with clinically localized disease and an estimated risk of nodal metastases ≥15
percent were randomly assigned to whole pelvis RT (1.8 Gy per fraction, with 50.4 Gy to
the pelvis and 70.2 Gy to the prostate using conventional techniques) or prostate-only RT
(70.2 Gy).
Patients were further randomized, using a 2 x 2 factorial design, to neoadjuvant plus
concurrent ADT administered for two months before and during RT, or adjuvant ADT.
The majority of enrolled men had T2c or higher stage disease, a serum PSA <30 ng/mL,
and a Gleason score of 7 or higher; thus, they would fall into the intermediate-risk and
high-risk categories.
At a median follow-up of 6.6 years, there were no significant differences in PFS or OS
when men treated with whole pelvis RT were compared to those managed with prostateonly RT.
There was a trend toward better PFS and OS with neoadjuvant plus concurrent as
compared to adjuvant only ADT in whole pelvic RT.
GETUG-01
(2007)
444 patients with T1b-T3N0M0 randomized to 66–70 Gy to prostate ± 46 Gy to pelvis
(top border S1/S2): 4–8-month NCHT allowed for “high-risk” patients (T3, GS 7, or PSA
3x normal).
Approximately 55% of patients had LN risk <15% using Roach formula. Median PSA 12,
~25% T3, and ~10% GS 8–10.
With 42-month follow-up, pelvic RT did not improve OS or PFS regardless of LN risk
group, although risk of LN was the most significant prognostic factor on multivariate
analysis. Pelvic RT slightly increased acute mild GI toxicity (p=ns) and late GI grade 2+
toxicity (p=ns), but not acute or late urinary toxicity.
• For men with intermediate-risk, localized prostate cancer who is undergoing EBRT,
the addition of a four to six month course of neoadjuvant and concurrent ADT during
RT improves the RT outcomes.
• Neoadjuvant and concurrent ADT during RT, followed by long-term adjuvant ADT
must be used for men with high-risk localized prostate cancer who will be treated
with EBRT. The optimal duration of adjuvant ADT has not been firmly established,
but, most studies have suggested that the duration should be two to three years
(Table-12).
References
Jones CU, Hunt D, McGowan DG, Amin MB, Chetner MP, Bruner DW, Leibenhaut MH,
Husain SM, Rotman M, Souhami L, Sandler HM, Shipley WU. Radiotherapy and short-
term androgen deprivation for localized prostate cancer. N Engl J Med. 2011;365(2):107.
D'Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen suppression and
radiation vs radiation alone for prostate cancer: a randomized trial.JAMA.
2008;299(3):289.
Pilepich MV, Winter K, Lawton CA, Krisch RE, Wolkov HB, Movsas B, Hug EB, Asbell
SO, Grignon D. Androgen suppression adjuvant to definitive radiotherapy in prostate
carcinoma--long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys.
2005;61(5):1285.
Roach M 3rd, Bae K, Speight J, Wolkov HB, Rubin P, Lee RJ, Lawton C, Valicenti R,
Grignon D, Pilepich MV. Short-term neoadjuvant androgen deprivation therapy and
external-beam radiotherapy for locally advanced prostate cancer: long-term results of
RTOG 8610.J Clin Oncol. 2008;26(4):585.
Table 13. Clinical evidence for whole pelvic radiotherapy compared with prostate only
Prostate Cancer
159
• The role of whole pelvis RT (WPRT) for men with intermediate- or high-risk disease
remains open; some groups advocate WPRT for those with an estimated risk of
regional lymph node involvement of >15 percent,. On the other hand, other authors
suggest that WPRT should be limited to a clinical trial due to controversial results
from two previously published randomized trials. Further studies with longer followup, using the same technique and dose are required before a standard of care can be
recommended (table-13).
References
Roach M III, DeSilvio M, Valicenti R, et al. Whole-pelvis, “mini-pelvis,” or prostate-only
external beam radiotherapy after neoadjuvant and concurrent hormonal therapy in
patients treated in the Radiation Therapy Oncology Group 9413 trial. Int J Radiat Oncol
Biol Phys 2006; 66(3):647-653.
Pommier P, Chabaud S, Lagrange JL, et al. Is there a role for pelvic irradiation in localized
prostate adenocarcinoma? Preliminary results of GETUG-01. J Clin Oncol 2007;25
(34):5366-5373.
9.4. Brachytherapy
• Prostate brachytherapy is a treatment modality in which the radiation source is placed
within the gland using a transperineal approach under imaging guidance (generally
transrectal ultrasound [TRUS]), being usually performed under light general or spinal
anesthesia.
• Radiation can be delivered either with permanent low dose rate (LDR) implantable
radioactive sources (seeds) or by temporarily placing high dose rate (HDR) sources
into hollow catheters or needles that have been positioned in the prostate.
• Typically LDR- brachytherapy is an appropriate treatment option for patients with
low-risk, clinically localized prostate cancer. Relative contraindications to prostate
brachytherapy include; a large prostate gland size (>50 to 60 g) or high AUA/IPSS
symptom index (≥15 to 20). Although for large prostate gland size androgen
deprivation therapy may be useful to downsize the prostate prior to brachytherapy,
neoadjuvant hormonal therapy has not been shown to reduce the risk of urinary
morbidity (uropathy).
• EBRT combined or not with brachytherapy or radical prostatectomy are better
treatment options than brachytherapy alone for patients with intermediate-risk or
high-risk prostate cancer (table 14).
Gustavo Arruda Viani
160
Study
Description
Giberti et al
(2009)
200 patients were enrolled and randomized into two groups of 100 patients each to
undergo surgery (group 1) or brachytherapy (group 2). Oncological results were
reported at 5 years, while functional outcomes were reported at 6 months, and 1 and 5
years mean follow-up.
174 completed the 5-year follow-up assessment. With regards to oncological
outcomes, similar 5-year biochemical disease-free survival rates were reported for
RRP (91.0%) or BT (91.7%). At 6 months and 1 year, both techniques produced a
significant decrease in quality of life aspects, while group 2 patients reported a
significantly higher and longer lasting rate of urinary irritative disorders and better
erective function than group 1.
No differences in functional outcomes were encountered after 5 years in either group.
Sathya eta al.
(2005)
T2 and T3 prostate cancer with no evidence of metastatic disease were randomly
assigned to EBRT of 66 Gy in 33 fractions during 6.5 weeks or to BT of 35 Gy
delivered to the prostate during 48 hours plus EBRT of 40 Gy in 20 fractions during
4 weeks.
51 patients were randomly assigned to receive BT plus EBRT, and 53 patients were
randomly assigned to receive EBRT alone.
The median follow-up was 8.2 years. In the BT plus EBRT arm, 17 patients (29%)
experienced BCF compared with 33 patients (61%) in the EBRT arm (P = .0024).
87 patients (84%) had a postradiation biopsy; 10 (24%) of 42 in the BT plus EBRT
arm had biopsy positivity compared with 23 (51%) of 45 in the EBRT arm (P =
.015).
OS was 94% in the IM plus EBRT arm versus 92% in the EBRT arm.
Hoskin et al.
(2007)
220 patients were randomized to standard radiotherapy 55 Gy in 20 fractions treating
or a combined schedule comprising external beam treatment delivering 35.75 Gy in
13 fractions followed by a temporary HDR afterloading implant delivering 17 Gy in
two fractions over 24h.
With a median follow up of 30 months (range 3-91) a significant improvement in
actuarial biochemical relapse-free survival is seen in favour of the combined
brachytherapy schedule (p=0.03).
Table 14. Clinical evidence for LDR or HDR brachytherapy in prostate cancer
References
Giberti C, Chiono L, Gallo F, Schenone M, Gastaldi E. Radical retropubic prostatectomy
versus brachytherapy for low-risk prostatic cancer: a prospective study. World J Urol.
2009;27(5):607.
Sathya JR, Davis IR, Julian JA et al. Randomized trial comparing iridium implant plus
external-beam radiation therapy with external-beam radiation therapy alone in node-
negative locally advanced cancer of the prostate. J Clin Oncol. 2005;23(6):1192.
Hoskin PJ, Motohashi K, Bownes P, Bryant L, Ostler P. High dose rate brachytherapy in
combination with external beam radiotherapy in the radical treatment of prostate cancer:
initial results of a randomised phase three trial. Radiother Oncol. 2007;84(2):114.