Clinical trials in carcinoma prostate

1. By
Dr. Ayush Garg

2. Life Expectancy Options
< 10years Observation
10 to 20years Active Surveillance
> 20 years Active Surveillance
RT
Surgery
Very Low Risk

3. Life Expectancy Options
< 10years Observation
> 10years Active Surveillance
RT
Surgery
Low Risk

4. Life Expectancy Initial Therapy Adjuvant Therapy
< 10years Observation
RT ADT (short course)
> 10years RT ADT (short course)
Surgery RT if adverse
features ADT
if LN positive
Intermediate Risk

5. Initial Therapy Adjuvant Therapy
RT ADT (long course)
Surgery RT if adversefeatures
ADT (long course) if LN
positive
High Risk

6. Initial Therapy Adjuvant Therapy
RT ADT (long course)
Surgery RT if adversefeatures
ADT (long course) if LN
positive
Treat like metastatic
disease, with ADT alone
(selectedpatients)
Very High Risk

7. ACTIVE SURVEILLANCE (AS) AND
WATCHFUL WAITING (WW)

8. ACTIVE SURVEILLANCE (AS) AND
WATCHFUL WAITING (WW)
• 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.

9. • 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.
• WW may forgo possibility of curative
treatment but symptoms are addressed.

11. • The Prostate Cancer Intervention versus
Observation Trial (PIVOT)253 enrolled 761 US
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).

12. HORMONAL THERAPY

13. Castration
• Surgical orchidectomy
(subcapsular)
• Medical orchidectomy
(LHRH agonists, LHRH antagonists, High Dose
Antiandrogens)
• Testosterone Level :
The standard castrate level was < 50 ng/dL (1.7 nmol/L).
It was defined more than 40 years ago, when testing was
limited.

14. • Male sex hormones (testosterone, androgens) are critical to growth of prostate cancer
• Normalization of PSA < 4ng/ml - 60-70%
• Tumor masses will decrease by half or more in 30-50%
• Improvement in symptoms (bone pain, urinary obstruction)- 60%
• There are four general forms of ADT:
Ablation of
androgen source
Inhibition of
LHRH or LH
Inhibition of androgen
synthesis
Antiandrogens
Orchiectomy DES
Leuprolide
Aminogluthemide Cyprotene acetate
Goserelin Ketoconazole Flutamide
Triptorelin Biclutamide
Histrelin Nilutamide
Cetrorelix
Abarelix

15. HormoneTherapy
• Neoadjuvant Setting
• Adjuvant Setting – Duration of hormone
therapy?
• Metastatic
• Castrate Resistant Prostate Cancer (CRPC)

16. Hormonal Therapy - Options
• Bilateral Orchidectomy
• LHRH agonists and antagonists
• Anti androgens
• Combined Androgen Blockade
• Hormone Therapy for CRPC

17. Combined Androgen Blockade
• Original Rationale : Combine castration-based deprivation
of testicular androgen with physiologic inhibition of adrenal
androgens via an antiandrogen.
• Two populations of cell would survive following surgical or
medical castration: androgen-independent cells (which
may be responding to locally produced androgens) and
androgen-supersensitive cells.
• Addition of an antiandrogen to castration therapy would be
expected to target the androgen-supersensitive cells, thereby
reducing the number of proliferating cancer cells.

18. • Prostate Cancer Trialists’ Collaborative Group (PCTCG)
conducted a metaanalysis 2001
• With Nonsteroidal antiandrogens, significant 8% reduction in
risk of death. With steroidal antiandrogens, significant 13%
increase in risk of death.
• Nonsignificant benefit for CAB over castration alone in terms of
5-yr overall survival (survival 25.4% vs. 23.6%, respectively).
• Difference in steroidal vs non steroidal drugs
Evidence

19. PCTCG meta analysis

20. Evidence
Combined androgen
blockade is predicted to
reduce mortality by
20% compared with
surgical or medical
castration.
Of the available
nonsteroidal
antiandrogens,
Bicalutamide 50 mg is the
best tolerated

21. ADT ALONE OR WITH RT

24. AIMS & OBJECTIVES
1.Feasibility of combining Brachytherapy boost after
EBRT (IMRT)
2. To compare dosimetric parameters for PTV
between IMRT & Brachytherapy arm
3. To compare dosimetric parameters for OAR
(bladder & rectum)

25. EBRT BY IMRT 45GY/
25#/ 5 WEEKS
BOOST BY IMRT
29GY/15# /3 WEEKS
BOOST BY HDR
BRACHYTHERAPY 19GY/2#
EBRT BY IMRT 45
GY/25#/5 WEEKS
Neoadjuvant HT 2 months
RANDOMIZATION
Adjuvant HT:
Intermediate risk: 6 months
High risk: 2 – 3 years
Conc
-
HT
Treatment schema

26. RESULTS
 Total: 30 patients: Median follow up: 8.5 months
 Median age: 68 years: Stage distribution:T2b -T3b
 Median Gleason: 7 (Range 6-8)
 Mean S.PSA :34.9ng/ml
 Intermediate risk – 9 (30%) High risk – 21 (70%)
 The median prostate volume: 49.2mL(26.2-63.5)
 The major symptoms of acute GU toxicity were dysuria,
increase in urinary frequency or nocturia
 The major symptoms of acute GI toxicity were diarrhea
and tenesmus

27. Conclusion
 HDR BT produced a more conformal plan & provides
higher mean dose to prostate
 Doses to the OAR are lower than IMRT
 Brachytherapy is effective in achieving dose
escalation
 No difference in bladder & bowel toxicity
 QOL (bowel symptom scale) better in brachytherapy
 Longer follow-up is needed to evaluate the efficacy

28. RADICAL PROSTATECTOMY (RP)

29. • Pathologic GS 3 + 4 has better prognosis than 4 +
3: 10-yr bRFS (48 vs. 38%), DM (8 vs. 15%), and
CSS (97 vs. 93%) (Tollefson, J Urol 2006).
• Occult LN mets found in 13% of men with pT3
who were pN0 by H&E. Men with occult LN mets
have similar PFS and OS to those with pN+
(Pagliarulo, JCO 2006).
• There is no indisputable evidence that RP is more
effective than RT ± ADT (Roach, IJROBP 2015;
Hamdy, NEJM 2016; Lennernäs, Acta Oncol
2015).

30. RADIOTHERAPY
 Adjuvant
 Radical
 Palliative
Techniques:
• Conventional
• 3D CRT
• IMRT & IGRT
• Proton Therapy
• Brachytherapy

31. • RADICAL RADIOTHERAPY ( MONOTHERAPY)
• SALVAGE RADIOTHERAPY
• PSA recurrence after surgery
• No distant mets
• Few months to yeats after RP
• ADUVANT RADIOTHERAPY
• Immediate post Prostatectomy
• High risk of recurrence
• Adverse pathological features
• PALLIATIVE RADIOTHERAPY
• Most effective in treating symptomatic bone mets

32. Salvage Radiotherapy
• Post RP recurrent
disease
Radical Radiotherapy
• T1, T2, T3, T4a
• Uresectable,
• Elderly , frail, comorbid
condition
• Refusal for surgery
• Prohibitive morbidity
due to surgery
Post op Radiotherapy
• pT3/4
• Close & positive margins
• Extracapsular extension
• Invasion to
• Seminal vesicles
• Extraprostatic extension
• multiple nodes
• R1 resection
• Pre op PSA >10ng/ml
• Pre op PSA velocity >2 ng/
ml/year

33. LANDMARK TRIALS
RTOG 9413 (2003)
Whole Pelvic RT
followed by Prostate
Boost versus Prostate
Only RT
4 months of Neo
Adjuvant Hormone
Therapy + Concurrent
Hormone Therapy or
4 months of Adjuvant
Hormone Therapy
Result
• Whole Pelvic RT + Neo Adjuvant Hormone arm had
59.6% of 4 years PSA relapse free survival better than
other arms.

34. RADIATION DOSE ESCALATION

35. Dose Escalation
A hypofractionated regimen of 70 Gy/2.5 Gy/fx may be
considered. Other hypofractionated schedules include
70.2 Gy/2.7 Gy/fx,
62 Gy/3.1 Gy/fx (4 fx/week), or
51.6 Gy/4.3 Gy/fx.

38. HYPOFRACTIONATION

42. • Extreme hypofractionation is 6.5–10 Gy/fx for
4–7 fractions, typically using SBRT with intra-
fraction motion management.
• Early data for extreme hypofractionation is
promising, but long-term follow-up data is
limited.

44. Dose Escalation in CA Prostate
Phase III randomized trial from MD Anderson
Hospital (2008)
Arms 8 years
Biochemical
Control
PSA Relapse
Free Survival
I 70 Gy
Conventional
63% 64%
II 78 Gy
Conventional
+ 3D Boost
88% 70%
Kuban DA, Tucker SL, Dong L et al (2008) Long-term results of the MD Anderson randomized
dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys 70:67 –74

45. RTOG 94-06
Dose escalation using 3D CRT
5 Sequential Dose Levels 5 years PSA Relapse free
survival
68.4 Gy @ 1.8Gy/# 68%
73.8 Gy @ 1.8Gy/# 73%
79.2 Gy @ 1.8Gy/# 67%
74 Gy @ 2Gy/# 84%
78 Gy @ 2Gy/# 80%
79.2 Gy given in 1.8 Gy/day was the maximally
well-tolerated dose. Toxicities were significantly higher
with 78 Gy given in 2.0 Gy/day than the 79.2 Gy dose level.

46. Dose Escalation using Proton
Porton Radiation Oncology Group 95-09
(2005,2008)
• 393 patients, T1b-T2b and PSA <15, 58% low, 33%
intermediate risk. No ADT
• 70.2 vs 79.2 Gy with proton boost after 50.4 Gy -
photon to P&SV.
• Median follow up 5.5 years.
• 5-year RFS: Low risk: 84→98%
• Intermediate-risk: 79→91%
• No OS diff

47. Modern Single Arm Trials

48. Hypofractionation offers equal, rates of tumor control in patients with
low and intermediate risk prostate cancers with similar toxicities

49. H-RT group: greater improvement
• 5-year biochemical or clinical failure-free survival (RR = 1.04,
95% CI:1.01–1.08; P = 0.01)
• 5-year disease-free survival(RR = 1.04, 95% CI: 1.01– 1.07,
P = 0.02).
5-year overall survival comparable (RR = 1.02, 95% CI: 0.99–
1.04; P = 0.18).
Grade 2-4 acute/late gastrointestinal toxicity, grade 2–4
acute/late genitourinary toxicity- no statistical differences.
Patients with localized prostate cancer, moderate H-RT

50. SBRT
• King et al reported 35-36.2 Gy in 5# resulted
in 5 years relapse free survival of 93% with
decreased rectal and urinary toxicity.
• MSKCC Phase I randomized trial is
undergoing for SBRT using Image Guided
IMRT.
• 5 mm margin around prostate and 3 mm
margin at rectal junction.

53. SBRT/SABR:The Extreme Hypo-
fractionation

54. • Low-risk prostate cancer
• 67 patients
• 36.25 Gyin 5 fractions with CyberKnifesystem
• Median follow-up of 2.7years
• Low rates of Late rectal and urinary toxicity - >G2in 1 & 5 pts respectively
• The4- year Kaplan-Meier PSArelapse-free survival was94%and is similar
to other definitivetreatments

55. SABR Results
• Multi-institutional pooled data
• N – 1100
• Median dose – 36.25 Gy in 5 fractions (35-40
Gy/4-5#)
• 3 yr median FU, 335 cases with a >4 years
follow-up (median 53 mos)
• Risk group
– Low risk – 59%
– Intermediate risk – 30%
– High risk – 11%
• ADT – 14% King et al Radiother Oncol 2013; 109:217-21

56. SBRT Results
King et al Radiother Oncol 2013;109:217-21

57. SABR Advantage
Conv
- 8 weeks
Moderate Hypo
- 4 weeks
SABR- 5 days
• Safe and Effective treatment
• Short treatment
• Convenient for patient
• Less Hospital visits
• Less waiting times
• Non Invasive
• No Anaesthesia
• No Hospital stay
• May be less cost

59. RT + ADT

60. • There is a large body of evidence supporting
the addition of ADT to EBRT for patients with
intermediate- to high risk prostate cancer.
• Meta-analysis (Nguyen, JAMA 2011). Among
4,141 men on eight randomized trials of
unfavorable-risk prostate cancer, ADT use was
not associated with increased risk of
cardiovascular death but was associated with
lower risk of PCSM and all-cause mortality.

61. RT + SHORT-TERM ADT
Randomized trials of stADT vs. no ADT report that
adding 3–6-mo ADT improves bPFS by 10–25% and
CSS by 3–8%.

64. RT + LONG-TERM ADT
For high-risk men, long-term ADT improves DFS, CSS, and OS vs.
no ADT or 4–6-mo ADT.
Current standard for most high-risk men is 2–3 yrs ADT, but 18
months may be reasonable for those with limited high-risk
features or comorbidity.

67. PELVIC NODE RT

68. • Two contemporary Phase III trials (RTOG 9413 and
GETUG-01) reached conflicting results, though smaller
field size, ill-defined nADT use, lower nodal risk, and
smaller number of men in the GETUG-01 trial make the
findings of GETUG-01 difficult to interpret. A number of
retrospective studies report improved biochemical
control with WPRT (Morikawa, IJROBP 2011).
• RTOG 0924 is comparing high-dose RT to prostate and
proximal SV ± WPRT in unfavorable intermediate-risk
and favorable high-risk patients.

69. • RTOG 9413 field size (Roach, IJROBP 2006):
Compared ncADT arms for WP vs. mini-pelvic
vs. prostate-only fields. WP improved 7-yr PFS
(40%) vs. mini-pelvis (35%) or prostate-only RT
(27%).
• No difference in late GU toxicity, small
increase in late Gr 3+ GI toxicity (1 → 4%) with
WPRT.
• Findings support the superior border of the
WP field being at least at the level of L5–S1.

70. • GETUG-01 (Pommier, IJROBP 2016, JCO 2007):
Men with T1b–T3N0 were randomized to
prostate only or “WP.” “WP” field smaller than
RTOG 9413 with superior field border being
S1/S2.
• ~55% men had LN risk <15% by Roach
formula.
• No difference in 10-yr OS or EFS overall.
• Subgroup of men treated without ADT with
risk of LN involvement <15% had improved 10-
yr EFS with pelvic node RT (83% v 50%).

71. CHEMOTHERAPY

72. 1.Docetaxel
2.Mitoxantrone.
TAX 327
1006 patients in 24 countries with HRPC
were randomized to one of three
chemotherapy regimens:
Docetaxel every 3 weeks (with
prednisone10 mg) for 10 cycles
Docetaxel every week (with prednisone
10 mg) for 5 cycles
Mitoxantrone every 3 weeks (with
prednisone 10mg) for 10 cycles
Patients who received Docetaxel every 3 weeks (with prednisone)
experienced:
• Improvement in median survival of 2 months (18.9m vs. 16.5 months)
• Greater PSA decline (45% vs. 32%)
• Improvement in Pain (35% vs. 22%)
• S/E were manageable

73. SWOG 9916
N=770 men
Dose used: Docetaxel (60mg/m2) & estramustine(280 mg orally 3
times daily from days 1 through 5) vs. mitoxantrone(12mg/m2) and
95 mg twice daily)
overall survival favored docetaxel (18.9 months compared with 16
months for mitoxantrone).
20% reduction in mortality in docetaxel &estramustine arm
Median time to progression significantly superior in the same
arm(6.3 vs.3.2 months)
Results Of SWOG & TAX 327 Confirms The Efficacy Of Docetaxel.
But Only Question Is That Only 2 Months Survival Increment IsBy
Use Of Docetaxel.

74. Salvage treatment after first-line docetaxel
All patients who receive docetaxel-based chemotherapy for CRPC will progress, thus,
there
have been many clinical trials investigating the role of salvage chemotherapy.
Several groups have used second-line intermittent docetaxel re-treatment in patients
who had clearly responded to first-line docetaxel.
Newer drugs:
• Cabazitaxel
1. a taxane derivative
2. Positive results have been published from, phase III trial (TROPIC
trial) comparing cabazitaxel + prednisone vs. mitoxantrone +
prednisone in 755 patients with CRPC, who had progressed after or
during docetaxel-based chemotherapy .
3.An OS benefit (15.1 vs. 12.7 months, p < 0.0001) was observed in
the cabazitaxel arm. As well as PFS (2.8 vs. 1.4 months, p < 0.000).
4.Treatment-associated WHO grade 3/4 side effects developed
significantly more often in the cabazitaxel arm, particularly neutropenia
and sepsis.

75. Phase 2 trials of docetaxel + atrasentan/
bevacizumab/bortezomid/capecitabine/calcitriol/thalidomide
have been completed.
 Randomized phase 2 trial of thalidomide/docetaxel
Phase 2 trial of docetaxel/calcitriol (ASCENT) strongly favoring survivalbenefit.
Mature results are anticipated within the next 3 to 5 years.
SPARC: phase III, randomized, placebo-controlled trial uses Satraplatin: novel
oral platinum compound Associated with significant PFS improvements in
chemotherapy-naive patients with hormone-refractory prostate cancer.
Immunologic Therapies
Sipuleucel-T is a product freshly prepared for each treatment course consisting of
leukapheresed mononuclear cells pulsed ex vivo with a GM-CSF/prostatic acid
phosphatase fusion protein. Patients are cytopheresed and dendritic cell precursors
isolated prior to fusion protein exposure. Two small randomized phase 3 trials have
been conducted with Sipuleucel-T, 9901 and 9902A.
Anti CTLA-4 antibody is in clinical trial
PROSTVAC-VF TRICOM VACCINE has reported phase 2 data & further studies will ensue.

76. CHEMOTHERAPY WITH RT

77. • STAMPEDE (James, Lancet 2016): Multiarm randomized trial
of standard of care +/− docetaxel, zoledronic acid, or both.
• Among 2,962 men, 24% were high-risk N0M0 (with at least 2
factors: T3/4, GS 8–10, PSA >40), and 15% N + M0.
• Adding docetaxel improved failure free survival for non-
metastatic and metastatic patients (HR 0.6), but increased
grade 3–5 toxicity (52% vs. 32%).
• RTOG 0521 (Sandler, ASCO 2015): 562 high-risk localized
patients treated with RT 72–75.6 Gy with 28-mo ADT ± 6
cycles of docetaxel and prednisone beginning 28 days after RT
for localized high-risk prostate cancer.
• Docetaxel improved 5-yr PFS 66%–73%.

78. • GETUG 12 (Fizazi, Lancet Oncol 2015): 207 men with
high-risk non-metastatic prostate cancer (71% N0, 29%
N1) treated with 3 yrs ADT with local therapy 3 months
later (87% RT 70–78 Gy, 6% RP) ± 4 cycles of docetaxel.
• Docetaxel improved 8-yr RFS 62% vs. 50% (greatest
benefit for GS 8–10, T3–4, N+, and PSA >20).
• RTOG 9902 (Rosenthal, IJROBP 2015): 397 high-risk
localized prostate cancer patients treated with RT 70.2
Gy + 24-mo ADT ± 4 cycles of paclitaxel, estramustine,
and etoposide. Terminated early for chemo-related
toxicity.
• No difference in 10-yr bF, LF, DFS, or OS.

79. Brachytherapy
It is also a dose escalation method when
combined with EBRT.
Low Risk Disease: Brachy only
High Risk Disease: EBRT + Brachy

80. • LDR Brachy
• As Brachy only: I125 144 Gy, Pd103 125 Gy.
• After EBRT 40-50 Gy: I125 110 Gy, Pd103 90 Gy.
• Goals LDR Toxicity
• V100: 95-99% Acute Urinary Retention
• V150: <70% Rectal Toxicty
• V200: <20% Erectile Dysfunction
• D90: 90-100%

81. • HDR Brachy
• As Brachy only: 9.5Gy twice daily for 2 days or
10.5Gy in 3# over one day.
• After EBRT: 9.5Gy in 2# over one session.
• Goals
• V100: 90-96%
• V150: <40%
• D90: >90%

82. General Inclusion Criteria:
• Clinical Stage T1-T3b and selectedT4
• Gleason score 2-10
• PSA No upper limit, but in almost all cases, patient doesnot
have documented distant metastasis (TxN0M0)
Exclusion Criteria:
 Relative Contraindications
• Severe urinary obstructive symptoms
• Extensive TURP defect or TURP within 6 month
• Collagen vascular disease
 Absolute Contraindications
• Unable to undergo anesthesia (general, spinal, epidural, or local)
• Unable to lay flat

83. IODINE125 PALLADIUM103
T1/2 (days) 59.4 16.97
Energy(keV) 27.4 21
Form Seeds Seeds
Implant type Permanent Permanent
Dose rate 7 19
Mean 0.42 1.3
activity/seed
Monotherapy 145Gy mPD 125Gy mPD
dose
+EBRT dose 110Gy mPD 100Gy mPD
TVL(mm) Pb 0.01 0.03
• A randomized trial
shows no different
between two arms
using two different
isotopes.
• Pd induced radiation
prostatitis is higher
than I 125 but it also
recover sooner than
that.

84. Advantages of EBRT + Brachy
• Better BED than IMRT
• Less dose to nearby critical structures
• Overall treatment time is less than 8 weeks,
hence patient is more compliant
• No issue of prostate motion

85. LDR BRACHYTHERAPY

86. • RTOG 0232 (Prestidge, ASTRO 2016): 588
intermediate risk men with T1c–T2b and either GS 2–
6 PSA 10–20 or GS 7 PSA <10 treated with LDR
implant alone or with 45 Gy EBRT.
• No difference in 5-yr PFS (85–86%).
• Increased grade ≥3 toxicity with EBRT added (GU 7%
vs. 3%, GI 3% vs. 2%).

87. • ASCENDE-RT (Morris, ASCO GU 2015; Rodda, ASTRO
2015): 276 high-risk and 122 intermediate-risk men
treated with 46 Gy whole-pelvic RT and 1-yr ADT
randomized to 32 Gy EBRT boost vs. 115 Gy I-125
boost.
• I-125 boost improved 7-yr RFS 86% vs. 71% but
increased 5-yr grade 3 GU toxicity (19% vs. 5%) with
trend for increased grade 3 GI toxicity (9% vs. 4%).

88. • Zelefsky (IJROBP 2007a, b): Reviewed 2,693 men
with T1–T2 disease treated with LDR
monotherapy (68% I-125, 32% Pd-103).
• 8-yr bRFS 93% if D90 ≥ 130 Gy vs. 76% if <130 Gy;
92% if PSA nadir <0.5, 86% if PSA nadir 0.5 to <1,
79% if PSA nadir 1 to <2, 67% if PSA nadir >2.
• Kittel (IJROBP 2015): 1,989 men with low risk
(61%), intermediate (30%), high-int. (5%), and
high risk (4%) treated with I-125 monotherapy.
• 5-yr bPFS low risk 95%, low-intermediate 90%,
high-intermediate 81%, high risk68%.
• Late grade 3/4 toxicity GU 7/<1%, GI <1/<1%.

89. • Stone (J Urol 2014): 1,669 men with localized
prostate cancer treated with LDR brachytherapy ±
ADT ± EBRT.
• 15-yr CSS: low risk 96%, int. risk 97%, high risk
85%.
• Potters (J Urol 2008): 1,449 men with localized
prostate cancer treated with LDR brachytherapy ±
ADT ± EBRT.
• 12-yr bPFS low risk 89%, int. risk 78%, high risk
63%.
• Overall, biochemical PFS appears to be at least as
good with brachytherapy compared to other
modalities, perhaps better (Grimm, BJUI 2012).

90. HDR BRACHYTHERAPY

91. HDR Monotherapy
• Yoshioka (IJROBP 2016): 190 men (42% int. risk, 58% high
risk, 73% got ADT) treated with HDR monotherapy (48
Gy/8, 54 Gy/9, or 45.5 Gy/7). Median f/u 92 mo.
• 8-yr bPFS intermediate risk 91%, high risk 77%. 8-yr late
grade 3 GU toxicity 1%, GI toxicity 2%.
• Hauswald (IJROBP 2016): 448 men (64% low risk, 36%
int. risk, 9% got ADT) treated with HDR monotherapy
(42–43.5 Gy in 7–7.25 Gy fractions in 2 implants 1 week
apart). Median f/u 6.5 yrs.
• 10-yr bPFS low risk 99%, int. risk 95%. Grade 3–4 GU
toxicity 5%, 0% GI.

92. HDR Boost
• Hoskin (Radioth Oncol 2012): 220 men with T1–
T3, PSA < 50 (76% ADT) randomized to EBRT 55
Gy/20 alone vs. 35.75 Gy/13 + HDR boost of 17
Gy/2. Median f/u of 30 mo.
• Mean bRFS 5.1 yrs HDR arm vs. 4.3 yrs (SS).
• Acute GI toxicity better with HDR arm. QOL better
with HDR arm.
• Sathya (JCO 2005): 104 int.-risk (40%) and high-
risk (60%) men randomized to 66 Gy EBRT vs. 40
Gy EBRT + 35 Gy HDR boost.
• HDR boost improved 5-yr bF 61%–29% with no
difference in long-term toxicity.

93. • Deutsch (Brachytherapy 2010). Compared
86.4 Gy IMRT (n = 470) vs. 50.4 Gy IMRT +21
Gy HDR boost (n = 160).
• HDR boost improved 5-yr bPFS for int. risk
(98% vs. 84%) and high risk (93% vs. 71%).
• Marina (Brachytherapy 2014). Compared int.-
risk patients treated with 77.4 Gy 3D/IMRT
with IGRT (n = 734) vs. 46 Gy WPRT + 19–21
Gy HDR boost (n = 282).
• HDR boost improved 5-yr bPFS 96% vs. 87%
for T2b-c, PNI, or % positive cores >50%.

94. • Khor (IJROBP 2013): 344 men with int.-high
risk treated with 46 Gy EBRT + 19.5 Gy HDR
boost in three fractions compared to matched
cohort treated with 74 Gy EBRT.
• HDR boost improved 5-yr bPFS 80% vs. 71%
but increased grade 3 urethral stricture 12%
vs. 0.3%.

95. ADJUVANT RADIOTHERAPY
AFTER RP

97. SALVAGE RADIOTHERAPY

98. • PSA failure occurs in 15–40% of patients after RP.
• Men with rising PSA after RP have up to 60% risk of
developing DM and 20% risk of prostate cancer
mortality within 10 yrs if untreated.
• Median time from PSA failure to DM is 8 yrs but only
3 yrs for high GS or PSA doubling time <3 mo.
• Median time from DM to death is <5 yrs
• Salvage RT can improve bPFS and CSS. Multiple
nomograms exist to predict post-RP.
(Pound, JAMA 1999; Freedland, JAMA 2005).

100. ROLE OF ADT WITH SALVAGE OR
ADJUVANT RADIOTHERAPY

101. • The “Phoenix Definition” (current ASTRO/RTOG
definition) of PSA failure after EBRT, with or
without ADT, is defined as
• A rise by ≥2 ng/mL above the nadir PSA (defined
as the lowest PSA achieved), with the date of
failure “at call” and not backdated.
• Among men who undergo any salvage therapy,
failure is declared at the time of + biopsy or
salvage administration (whichever is first).

102. • RTOG 9601 (Shipley, NEJM 2017): 760 men post-
RP for pT3pN0 or pT2pN0 with +margins who had
bF (PSA 0.2–4 ng/ml) randomized to RT ±
bicalutamide (24 mo, 150 mg daily).
• Adding bicalutamide improved 12-yr OS (76% vs.
71%), prostate cancer mortality (6% vs. 13%), DM
(15% vs. 23%), and 10-yr bPFS (46% vs. 30%).
• Greatest DM benefit for GS 8–10, PSA 1.5–4,
+margin.
• Greatest OS benefit for GS 7, PSA 0.7–4, +margin.
Bicalutamide 70% gynecomastia, <1% grade 3
liver toxicity.

103. • GETUG-AFU 16 (Carrie, Lancet Oncol 2016):
• 743 men with pT2–4a and rising PSA 0.2 to <2
received 66 Gy salvage RT ± 6 months
goserelin.
• Goserelin improved 5-yr bPFS 80% vs. 62%.

104. • Ramey (ASTRO 2016): Multi-institutional review of
1,861 post-op GS ≥7 patients.
• For GS 8–10, the combination of WPRT + ADT
improved 5-yr bPFS (prostate bed without ADT 34% vs.
• WPRT without ADT 44% vs. prostate bed with ADT 45%
vs. WPRT with ADT 64%);
• WPRT improved bPFS for GS 7 (67% vs. 53%), but ADT
did not.
• RTOG 0534 is randomizing patients with pT2-3N0 and
PSA ≥0.1 and <2 to salvage prostate bed RT alone
(64.8– 70.2 Gy) ± 4–6 months ADT ± 45 Gy pelvic LN RT.

105. LYMPH NODE INVOLVEMENT

106. • Messing (Lancet Oncol 2006). 98 pN+ men
after RP + PLND were randomized to
immediate ADT vs. observation.
• At 12 yrs, immediate ADT improved MS (11.3
→ 13.9 yrs) and MPFS (2.4 → 13.9 yrs).
• All but three men died of prostate cancer in
observation arm.
• SEER (Tward, Pract Radiat Oncol 2013). 1100
men with cN+ had improved 10-yr CSS with RT
63% vs. no definitive therapy 50%.

107. • SEER (Rusthoven, IJROBP 2014). 796 cN+ and 2,991
pN+ patients.
• Adding RT for cN+ improved 10-yr OS (45% vs. 29%).
• Adding local therapy for pN+ improved 10-yr OS (65%
vs. 42%).
• NCDB (Wong, Urol Oncol 2016). 7,225 pN+ patients. On
multivariate analysis, ADT and adjuvant RT improved
survival vs. no adjuvant therapy, but ADT alone and
adjuvant RT alone did not.
• Abdollah (JCO 2014). 1,107 pN1 patients treated with
ADT (65%) or ADT + adjuvant RT (35%). Adding
adjuvant RT improved 8-yr CSS for pT3b/4 or +margins
(93% vs. 84%) and for those with 3–4 involved nodes
(97% vs. 79%).

108. • RTOG 8531 (Lawton, JCO 2005): 173 men biopsy N+
randomized to RT vs. RT + goserelin indefinitely.
• Goserelin improved 9-yr OS (38 → 62%), bPFS (4 →
10%), and DM (48 → 33%).
• Zagars (Urology 2001): Reviewed 255 pN+ men
treated with early ADT ± 70 Gy to prostate.
• RT improved 10-yr OS (46 → 67%) and PFS.

109. METASTATIC DISEASE

110. • LHRH agonist (medical castration) and bilateral
orchiectomy (surgical castration) appear to be equally
effective.
• Antiandrogen therapy should precede or be
coadministered with LHRH agonist and be continued in
combination for at least 7–14 days to reduce risk of
developing symptoms associated with the flare in
testosterone with initial LHRH agonist alone.
• Antiandrogen monotherapy appears to be less effective
than medical or surgical castration and should not be
recommended.

111. • STAMPEDE (James, NEJM 2017). Adding abiraterone
and prednisolone to at least 2 years androgen
deprivation for men with locally-advanced (at least 2:
T3–4, GS 8–10, PSA >40), node positive, and metastatic
disease significantly improves OS (HR 0.63) and failure-
free survival (HR 0.29).
• For men with metastatic androgen-sensitive disease,
adding chemo appears to have benefit.
– Sweeny (NEJM 2015): 790 men with metastatic, hormone-
sensitive prostate cancer randomized to ADT alone or ADT
+ docetaxel. MS 44 mo with ADT alone vs. 58 mo with
docetaxel.

112. • For castrate-resistant prostate cancer, options
include abiraterone with prednisone, docetaxel
with prednisone, enzalutamide, Ra-223 for
symptomatic bone metastases, or secondary
hormone therapy.
• Expression of androgen-receptor splice variant
seven on circulating tumor cell (CTC) may be
predictive of response to systemic therapy in
castrate-resistant prostate cancer (CRPC) (Scher,
JAMA Oncol 2016).

113. • Retrospective population-based analyses suggest possible
survival benefit of local treatment of the prostate (Rusthoven,
JCO 2016; Satkunasivam, J Urol 2015). Randomized trials are
ongoing to evaluate the impact of local therapy for M1
disease (e.g., NCT01751438 best systemic therapy +/− local
therapy).

114. THANK YOU