Prostate cancer , radiotherapy

1. Prostate Cancer
Management
BY : MOHAMMAD ABU ASHOUR
RADIATION ONCOLOGY RESIDENT / RMS
‫الرحيم‬ ‫الرحمن‬ ‫هللا‬ ‫بسم‬

2. Topics covered in this presentation
 Risk stratification .
 Treatment recommendation ( NCCN guidelines ).
 KHCC guidelines .
 AS / WW.
 Surgery ( RP / PLND ).
 ADT.
 Brachytherapy.
 EBRT
 Biochemical failure.
 Follow up
 References

4. Treatment recommendation
 there are numerous strategies for treatment
which depend on patient, tumor and treatment
factors :
 Patient factors: Age, co morbidities, performance status,
fitness for surgery, previous radiotherapy
 Tumor factors: Stage, G.S , PSA level
 Treatment factors: Availability of treatment options (esp.
brachytherapy)

5. NCCN guidelines version 4.2018
Divided pts into two major groups :
 1. patients with life expectancy less or equal to 5 years and
asymptomatic .
 2. with life expectancy more than 5 years or symptomatic .

6. 1. patients with life expectancy less or
equal to 5 years and asymptomatic .
 A. very low , low , and intermediate : no further intervention
until symptomatic
 B. high or very high :
EBRT or ADT or observation .
if metastatic ADT or observation.

7. 2. with life expectancy more than 5
years or symptomatic
 Go for risk stratification and treat according .

8. Very low risk group
 A. Life expectancy >= 20 year life expectancy
AS , EBRT or Brachytherapy or RP +/- PLND
 B . Life expectancy 10 – 20 yr
AS
 C . Life expectancy < 10 Yr
observation

9. Low risk
 Life expectancy ≥10 yrs → EBRT or brachytherapy,
radical prostatectomy (RP) ± pelvic LN dissection
(PLND), or AS
 Life expectancy <10 yrs → active surveillance (AS) or
EBRT or brachytherapy

10. favorable Intermediate risk
 Life expectancy ≥ 10 yrs : AS or EBRT or Brachytherapy alone
or RP +/- PLND
 For life expectancy < 10 years : EBRT or Brachytherapy alone
or observation

11. Unfavorable Intermediate risk
 Life expectancy ≥ 10 yrs → RP +/- PLND or EBRT +
short-term ADT ( 4- 6 months ) or EBRT +
Brachytherapy + ADT
 For life expectancy < 10 years → EBRT + short-term
ADT ( 4- 6 months ) or EBRT + Brachytherapy + ADT
or observation .

12. High risk or very high risk group
 Life expectancy ≥ 5
 EBRT + ADT (2-3 yr ) or EBRT + brachytherapy
+ ADT (1-3 yr )
 Consider RP + PLND for selected patients (
young , healthy without tumor fixation to
pelvic side wall ) .

13. Node positive
 RT + long-term ADT (2–3 yrs) +/- CTX
 ADT alone (e.g. GnRH antagonist /agonist )
 RT + ADT preferred over ADT alone when limited LN
disease.

14. Metastatic
 ADT sensitive:
ADT (≥2 yrs) ± (docetaxel ± prednisone)
 ADT resistant:
Docetaxel or abiraterone or radium-233
 Palliative RT ± bisphosphonates

15. Adjuvant RT
Adjuvant EBRT indications:
Residual local disease
+margin(s), pT3 disease ( ECE, SV )
Timing : after surgery complication
subsided and within one year.

16. KHCC Guidelines

20. Active surveillance and watchful
watching
 AS generally consists of DRE and PSA every 3–6 months with routine
repeat biopsy in 1–2 yrs with definitive treatment given if disease
progresses.
 The goal of AS is t o avoid or defer therapy (and side effects) until
necessary.
 .…Disadvantages of AS include risk of missed opportunity for cure, risk
of progression, and/or distant metastases (DM); deferred treatment
may be more intense with increased morbidity and anxiety with
each new PSA/biopsy.

21.  WW watches for symptoms that may arise from prostate
cancer rather than regimented PSA, DRE, and biopsy typically
in men not suitable for aggressive treatment.
 Pts with severe comorbidity and/or limited life span .
 Compliant pts with low-risk or favorable intermediate risk
disease motivated toward deferring treatment
 Watchful waiting is used for patients with significant
comorbidities and limited life expectancy. It avoids side effects
of treatment in a patient population that is unlikely to develop
problems from their disease.

22.  Hamdy, UK ProtecT (NEJM 2016, PMID 27626136; QOL Donovan NEJM
2016, PMID27626365): 1,643 pts 50 to 69 years of age with localized
prostate cancer randomized to “active monitoring” (AM, PSA monitoring
only), surgery (RP), or RT with. AM, RP, and RT had 1.5, 0.9, and 0.7
prostate cancer specific deaths per 1,000 person-years, respectively,
without any significant difference among groups (p = .48). More DM and
disease progression in AM groups than RP or RT group.
 Conclusion: Irrespective of treatment arm, PCM remained low at ~1%.
Rate of disease progression and metastatic disease significantly lower for
RP or RT compared to AM.

23. Surgery
 Appropriate for localized disease or salvage for recurrence
after EBRT .
 Radical prostatectomy (RP) approaches include open RP,
retropubic , laparoscopic/Robotic , perineal .
 Removes all tumor/ prostate, relieves obstructive symptoms;
obtains pathologic staging; avoids radiation exposure
 Perioperative complications are rare and include mortality,
rectal injury thromboembolism ,myocardial infarction , wound
infection, blood loss and pelvic pain.

24.  Impotence and incontinence are most common.
 Bilateral nerve sparing procedure is associated with an
estimated ~50% rate of impotence and unilateral nerve
sparing is associated with impotence rate of ~75%.
 An estimated 32% of pts reported total urinary control,
40% with occasional leakage, and 7% frequent leakage,
and 1%–2% reported no urinary control *
 A standard lymph node dissection involves sampling of
the obturator and external iliac lymph nodes alone.
 PLND can be exclude in pt with nodal metastasis risk less than 2%
according to nomogram.

25.  *Stanford JL, Feng Z, Hamilton AS, et al. Urinary and sexual function after
radical prostatectomy for clinically localized prostate cancer: the Prostate
Cancer Outcomes Study. JAMA. 2000;283(3):354–360
 No studies compared surgery to RTX or ADT regarding outcomes

26.  How does the side effect profile compare between
RP, EBRT, and brachytherapy?
 Generally, RP has worse incontinence and
impotence, EBRT has worse bowel/rectal
irritation, and brachytherapy has worse
irritation/obstruction.

27.  Donovan, ProtecT Trial QOL (NEJM 2016, PMID 27626365): Patient-
reported outcomes through questionnaires given before diagnosis,
6 and 12 mos, then annually and reported through 6 yrs. RP had
greatest negative effect on sexual function (erections firm enough
for intercourse at 6 mos: 52% AS, 22% RT, 12% surgery) and urinary
incontinence. RT had a peak negative effect on sexual function at 6
mos but recovered and stabilized (note: all pts received short-term
ADT). RT had little effect on urinary continence but urinary voiding
and nocturia problems peaked at 6 mos, then recovered by 12 mos
to be similar to other groups. RT had worse bowel function at 6 mos
compared to other arms but then recovered (except for frequency
of bloody stools, which remained ~5%) while other groups had
stable bowel function. Sexual function gradually declined in AM
group (erections firm enough for intercourse: 41% yr 3 and 30% at
yr 6) as well as urinary function. No differences among groups for
anxiety, depression, general health-related or cancer-related QOL.

28. Androgen Deprivation Therapy (ADT):
 The decision to use ADT, and timing, is dependent on
disease characteristics and patient factors. Generally, 2 to 3
yrs of ADT is recommended with high-risk disease treated
with EBRT, and 4 to 6 months of ADT can be considered for
intermediate-risk disease treated with EBRT. Most commonly
used are GnRH agonists alone or with oral antiandrogens
(combined androgen blockade). ADT alone is used for
treatment of metastatic prostate cancer or for select patients
who are not otherwise candidates for definitive local therapy.

32. Side effects include
impotence, decreased libido, fatigue,
weight gain, hot flashes, cognitive changes,
depression, osteoporosis, and potentially
cardiovascular disease.

33.  RTOG 9408 enrolled 1979 pts with T1b-T2b, PSA ≤20,
prostate cancer (54% were intermediate risk). Pts were
randomized to EBRT alone (66.6 Gy) +/– 4-mo ADT
and LHRH agonist) beginning 2 mos prior to EBRT. 12-yr OS
favored the short-course ADT arm (54% vs. 61%). AS also
reduced the rates of + prostate biopsy at 2 years (39% vs.
20%). (Jones CUet al., NEJM 2011)

34.  Bolla, EORTC 22863 (Lancet Oncol 2010, PMID 20933466):
415 pts with T1-2N0 and grade 3 (17%) or T3-T4N0-1 (93%)
randomized to EBRT (50 Gy/25 fx to whole pelvis with 20
Gy/10 fx cone down to prostate and seminal vesicles) + ADT
or EBRT alone. MFU 65.7 months.
 Conclusion: Immediate androgen suppression with GnRH
agonist for 3 yrs with EBRT improves bPFS, DFS, and OS in
pts with high-risk or locally advanced prostate cancer.

35. Brachytherapy
 Can be used as monotherapy for low risk group or combined
to EBRT for dose escalation .
 LDR with
I-125/P-103
or
 HDR with
Ir-192

39. CTX
 When prostate cancer becomes resistant to hormonal
therapies
 Docetaxel is the currently recommended chemotherapy agent
once hormonal therapy has failed.
 Prednisolone has a role too.

40. EBRT
 External beam radiotherapy remains the most
commonly used radiotherapy treatment for prostate
cancer due to widespread availability, familiarity with
the technique, and difficulties with brachytherapy. It
has not been shown to be inferior to radical
prostatectomy or brachytherapy techniques in terms
of cancer control or toxicities .

41. External Beam Radiotherapy
Indications
 ■ Intact prostate alone or combined with
brachytherapy
 ■ Postprostatectomy in the adjuvant or
salvage setting

42. Dose and dose escalation .
Fractionation regimens .
LN +/-
Contouring
OAR and tolerance doses .

44. Dose escalation
 There have been at least five major randomized trials
investigating “dose escalation” with each one showing a
biochemical control benefit t (but no difference in OS) for
higher doses compared to “conventional” lower doses (~70 Gy
at 1.8–2.0 Gy/fx), but also higher rates of toxicities .
 Pollack, MDACC50
 Zietman, MGH51
 Al-Mamgani,Dutch52
 Dearnaley, MRC53
 Michalski, RTOG 0126 (ASCO 2015)

45.  MDACC(2008) 301 men T1–T3N0 No ADT
randomized to 70 vs. 78 Gy
 8-yr bPFS /clinical PFS: Low risk:63 → 88% Int.
risk(PSA > 10): 65 → 94% High risk: 26 → 63% No OS
difference , but more toxicity

47. Hypofractionation
 CHHiP UK (Lancet Oncol 2016, PMID 27339115): three-
arm noninferiority trial. Men randomized to either 74 Gy/37
fx, 60 Gy/20 fx over 4 weeks or 57Gy/19 fx over 3.8 weeks.
Primary endpoint was biochemical or clinical failure. Enrolled
3,216 men, MFU 62 months. 73% were intermediate, 12% were
high risk. 97% received ADT for a median of 24 months. 5-yr
failure-free rates were 88.3% (74 Gy), 90.6% (60 Gy), and
85.9% (57 Gy). The 60 Gy but not the 57 Gy arm was
noninferior to 74 Gy. Side effects were similar. Conclusion: 60
Gy/20 fx non inferior .

48. Nodal irradiation
Irradiate or not ????

49.  Roach, RTOG 9413 subset (IJROBP 2006, PMID 17011443):
Secondary analysis of RTOG 9413 to determine if pelvic field
size had an effect on PFS. A “mini-pelvis” (MP) field was
defined as ≥10 x 11 cm, but <11 x 11 cm. 7-yr PFS was 40%,
35%, and 27% for whole pelvis, MP, and prostate only fields,
respectively (p = .02). Increasing field size correlated with late
grade 3–4 GI toxicity, but not grade 3-4 GU toxicity.
Conclusion: RT field size significantly affected PFS and the
results support comprehensive nodal treatment for pts with
≥15% risk of lymph node involvement.

50.  Pommier, GETUG-01 (IJROBP 2016, PMID 27788949): 446 pts
with cT1b-3N0 prostate cancer randomized to whole pelvis
EBRT (46 Gy with boost to prostate 66–70Gy) or prostate
EBRT (66–70 Gy). Pts stratified into low risk (cT1-2, GS 6, and
PSA <3xupper limit normal) versus high risk (cT3 or GS >6 or
PSA >3x upper limit normal). High risk pts received 6-month
ADT. MFU 11.4 yrs. No difference in EFS or OS. subgroup
analysis demonstrated a significant benefit to whole pelvis RT
in pts who did not receive ADT. Conclusion: Pelvic nodal
irradiation did not appear to improve EFS or OS. Comment:
The trial has been criticized for using low doses (median 68
Gy).

51. Contouring
 Pathologic analysis of prostatectomy specimens by Kestin et
al. demonstrated the median length of seminal vesicle
invasion to be 1 cm, with 90% within 2 cm. SV invasion was
found most commonly in patients with PSA ≥10 ng/mL, GS ≥
7, or ≥cT2b. Therefore, the proximal 2 to 2.5 cm of the seminal
vesicles are typically included within the CTV for intermediate
and high-risk patients.

52.  The position of the prostate and SVs varies w/ filling
of the rectum and bladder. Typical prostate variability
is as follows (standard deviation): A-P—2.4 mm, Inf-
Sup—2.1 mm, and Med-Lat—0.4 mm; SV
displacement: A-P—3.5 mm, Inf-Sup—2.1 mm, and
Med-Lat—0.8 mm

53. Localization, Immobilization, and
Simulation
 ■ Patient preparation: full bladder and empty rectum
minimizes dose to critical structures (bladder, small bowel,
rectum).
 ■ Patient position: supine, with arms folded on the chest.
 ■ Immobilization.
 ■ A knee support with the feet banded together provides a
comfortable and reproducible position.
 ■ Simulation: CT scan from mid abdomen to mid femur.

54.  ■ Contrast agents may be considered:
 ■ Intravenous contrast to help delineate major blood vessels,
nearby lymph nodes, and prostate-bladder interface (median
lobe).
 ■ Retrograde urethrogram: 10 cc urethral contrast with penile
clamp to delineate the urethra and penile bulb.
 ■ Oral contrast to delineate the small bowel.

55. Target Volume
Definition for
EBRT: Intact
Prostate

56. Target Volume Definition for EBRT:
Intact Prostate
 ■ Definition of the GTV.
 ■ There is no GTV for prostate cancer with CT-based imaging
because CT is unable to define gross tumor within the gland.
 ■ GTV can sometimes be delineated using MRI.
 ■ Clinically positive nodes (>1.5 cm short axis diameter) seen
on planning CT or on MRI should be included as nodal GTV.

57. Definition of the CTV
 CTV = entire prostate +/- seminal vesicles +/- LN.
 ■ Low-risk prostate cancer CTV = entire prostate
only.
 ■ Intermediate-risk prostate cancer CTV = prostate +
proximal 1 cm of the bilateral seminal vesicles.
 ■ High-risk prostate cancer CTV = prostate +
proximal 2 cm of the bilateral seminal vesicles
(consider entire seminal vesicles if grossly involved)
+/- LN regions

58. LN CTV
 LNI is not standard for low- or intermediate-risk
prostate cancer. LNI is controversial for high-risk
prostate cancer.
 ■ LN CTV = 7 mm expansion around internal/external
iliac vessels, obturators, and presacral regions.

59. PTV
 RTOG 0126 and RTOG 0815 specify
 5-10mm for margin from CTV to PTV.
 This is often institutional, and depends on immobilization and daily
imaging (for example, kv X-rays would require a bigger margin than CBCT).
 posterior margin on the rectum is less to reduce risk of toxicity, so we used
7mm except 5mm posteriorly.

68. postprostatectomy
 NCCN: (64-72Gy),
 RT coverage* (per RTOG Consensus Guideline 2010 and RTOG 0534)
 CTV Fossa:
 Inferior: top penile bulb or last slice urine is visible (~8–12mm below vesicourethral
anastomosis/VUA)
 Anterior: posterior aspect of pubic symphysis to cover bladder neck; above
symphysis, gradually come off bladder (over 3-4 CT slices), ensuring that 1-2cm of
posterior bladder wall is included
 Superior: ≥2 cm above pubic symphysis (max 3-4cm); include surgical clips and SV
remnants (esp if SV involved)
 Lateral: obturator internus
 Posterior: anterior rectal wall
 PTV = CTV + 8-15mm (except posteriorly 6mm acceptable)

69.  Bladder: V80 <15%, V75 <25%, V70 <35%, V65 <25–50%,
V55 <50%, V40 <50%
 Rectum: V75 <15%, V70 <20–25%, V65 <17–35%, V60 <40–
50%, V50 <50%, V40 <35–40%
 Femoral heads: V50 <5%
 Small bowel: max less than 50 , <150 cc >45 Gy
 Penile bulb: mean dose <52.5 Gy

70. Toxicities
 Early toxicities include skin reaction, fatigue, dysuria, frequency, diarrhea
and rectal bleeding
 Late effects include:
 Skin changes (tone, texture, telangiectasia)
 Hair loss
 Reduced bladder volume < 5%
 Incontinence < 5%
 Impotence (50%)
 Radiation proctitis (10-20%, most commonly rectal bleeding and increased
bowel frequency, rarely ~ 1% have severe debilitating complications)
 Hip fracture < 1%
 Second malignancies

71. Future
 Other treatments such as high frequency
ultrasound (HIFU) and cryotherapy are
emerging techniques but are not
recommended as first-line options per NCCN
guidelines.

72. Biochemical failure
 Definitions :
 Post Definitive Radiotherapy : ( 2 + Nadir ) is
considered to be biochemical failure ( 3 consecutive
PSA rises ) .
 PSA nadir usually at 18 months post RTX.
 PSA pounce occur 12-18 post RTX difficult to
differentiate from biochemical failure .

73.  Definition of biochemical failure after RP: AUA
definition is detectable or rising PSA value after
surgery ≥0.2 ng/mL with a second confirmatory level
≥0.2 ng/mL.
 Rising PSA after RP:
 •1/3 will develop DM at median of 8 years
 •17% will die of prostate cancer within 15 years

74.  Treatment of biochemical failure post radiotherapy or
surgery
 Post Radiotherapy : Hormonal therapy.
 Post Radical Prostatectomy: Radiotherapy ± Short
course of Hormonal therapy if no evidence of distant
disease .
 Surveillance is an option in selected patients

75. Follow up
 At 2 weeks
 At 3 months
 At 6 months
 At 12 months
 Then 6 months for 3 years
 Then yearly

76. References
 NCCN guidelines version 4 / 2018 .
 KHCC guidelines .
 Hand book of evidence based radiation oncology ( Mac Roach ) 3rd edition
.
 Econtour.org
 Handbook in treatment planning on radiation oncology 2nd edition .

78. Thank you