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Robert Bristow MD PhD FRCPC Clinician-Scientist and Professor,
Radiation Oncology and Medical Biophysics,
Princess Margaret Cancer Center & University of Toronto
Lead Investigator, Canadian Prostate Cancer
Gene Sequencing Network (CPC-GENE)
Adjuvant Therapy in High-Risk Prostate Cancer
after Radical Prostatectomy
Conflict of Interest Statement
Structured Research Agreements:
• GenomeDx
• AstraZeneca
1. Use of Adjuvant RT 2. Use of Adjuvant Chemo-hormonal therapy 3. Future Trials and Biomarkers
Content Outline
Surgical Outcomes
MSKCC: 1,389 surgical patients with cT1-3 CaP
Positive surgical margin identified in
• 6.8% with pT2
• 23% with ECE (pT3).
10-yr independent predictors of progression free survival on MVA:
Positive surgical margin (10-year PFP: 58% vs 81%)
Pre-operative PSA
Gleason score
Extra-capsular extension
SV invasion
Nodal positivity Swindle, Scardino et al J Urol 2005
Intraductal Carcinoma-Cribiform Architecture
Kweldam, Mod Path; 2015
Taylor, Nat Comm; 2017
1031 biopsies in ERSPC: IDC-CA was an independent
predictor for distant metastasis-free survival (HR 8.0, 95%
CI 3.0–21; P<0.001) and disease-specific survival (HR 5.4,
95% CI 2.0–15, P=0.001).
Clonal
Adjuvant RT Concepts
• PSA screening leasing to increased use of active surveillance (AS) and therefore
increased aggression in patients subsequently undergoing radical prostatectomy
(RadP)
• At least 30% of men will have high-risk post-operative factors, post-RadP
– Extracapsular extension (ECE), margin positivity, SV invasion, increased
Gleason score, IDC-CA and lymph node positivity (N+)
• The majority of men with biochemical relapse following RadP will have positive
molecular imaging in the prostatic fossa or the pelvis if left untreated
• Local component to pattern of failure: anastamosis, pelvic lymph nodes.
• Risk of systemic failure in high-risk individuals. • Potential role for additional local therapy.
• Potential role for systemic adjuvant therapy for high-risk individuals.
3 Randomized Trials: Adjuvant RT Following Surgery
Gandaglia et al; Eur Urol; 2017
Randomized Trials: Adjuvant RT Following Surgery
Gandaglia et al; Eur Urol; 2017
SWOG 8794
Thompson J Urol 2009
P= 0.023
10-year OS: 74% versus 66%
(NT 1/10)
Bolla et al Lancet 2012
10-year bPFS: 60.6% v 41.1% (NT 5)
10-year OS: 76.9% v 80.7% (nss)
EORTC 22911
Wiegel et al JCO 2009
All patients-intent to treat
ARO 96-02
5-year loco-regional failure:
5.4% v 15.4%
EORTC 22911
Bolla et al Lancet 2005
10-year PFS: 56% vs 35%
(NT 5)
Randomized Trials: Adjuvant RT Following Surgery
Gandaglia et al; Eur Urol; 2017
Meta-Analysis (Daly et al., 2011) of all three trials: improved OS and decreased metastases EORTC/SWOG subset analysis for best responders: positive margins, GS 8-10, LN+, SV+
Lin JNCI 2015
National Cancer Database:
Propensity-matched N+
Figure 2. Failure-Free Survival for Reported Radical Radiotherapy Status, in N0M0 and N+M0 Subcohorts
James et al. Page 15
JAMA Oncol. Author manuscript; available in PMC 2016 March 14.
Europe PM
C Funders A
uthor Manuscripts
Europe PM
C Funders A
uthor Manuscripts
STAMPEDE (M0): N+ vs N- Disease
James et al.,
JAMA Oncology 2016
Gandaglia et al;
Eur Urol; 2017
Retrospective Studies: Adjuvant RT in N+ Patients
Majority of studies support suggest benefit of aRT in Node + patients presumable to optimize local control (PLND and ePLND may both benefit)
Adjuvant vs Salvage RT • Prospective randomized trials support a role for aRT in reducing the risk of biochemical
• recurrence (BCR) by 20-30% and improved MF and OS.
• Majority of retrospective studies support aRT over sRT (e.g. 10 year rates of metastasis and
BF decreased by aRt over sRT); although many biases (Gandaglia et al; Eur Urol; 2017)
• However, 40% of patients or more managed with initial observation will not recur at 10-yr follow-
up
• Issues with adjuvant RT: over-treatment (40% will not fail at 10 years), associated side-effects
(acute: 15-30%; chronic: 2-8%; meta-analysis shows increased GI tox, strictures, incontiennce,
but not erections; Daly, 2011)), patient inconvenience, health care resources
• Consequently, aRT is administered in approximately 20% of contemporary patients versus sRT
despite lack of Level I evidence; bolstered in era of ultra-sensitive PSA testing
Decision for Post-OP RT Adjuvant or salvage +/-
ADT ?
RADICALS MRC/NCIC-CTG
RANDOMIZE
RT Alone RT + 6 mo ADT
RT + 2 years ADT
Uncertainty about need for Post-Op RT
(High Risk Features)
RANDOMIZE
Immediate RT (within 6 mo)
Early salvage RT (PSA < 0.4)
N= 1350, 2800
Primary endpoint: disease specific survival
RAVES TROG
pT3 or margin positive or SV positive
RANDOMIZE
Immediate RT (within 6 mo)
Early salvage RT
N=470
Primary endpoint: non-inferior to treatment for biochemical failure
Gandaglia et al; Eur Urol; 2017
Prospective Trials: Adjuvant vs Salvage RT
Presented By L. Glode at 2017 Genitourinary Cancers Symposium
Adjuvant ChemoHormonal Therapy SWOG S9921: ADT versus ADT + Mitoxantrone +Prednisone
Presented By Susan Slovin at 2017 Genitourinary Cancers Symposium
TAX-3501 VA Cooperative Study #553
CONCLUSION: Trials failed to accrue and underpowered for their primary endpoints; No hint as to benefit; possible subset in PT3b/African Americans in VA-553 (hypothesis)
ADT- DOC-ESTRA
vs ADT: GETUG 12
Delayed vs Immediate
ADT: N+ (EST 338)
Messing, Lancet Oncol, 2006
p=0·04
Fizazi, Lancet Oncol, 2015
8-year relapse-free survival: 62% versus 50%; [HR] 0·71, p=0·017
RTOG 0521: ADT+DOC +RT vs RT+ADT
Sandler, ASCO, 2015
In the study, the 4-year OS rates were 89% for men who received ADT and RT versus 93% for men treated with ADT, RT, and docetaxel (HR = 0.70; 90% CI, 0.51-0.98; P = .04)
6 | ADVANCE ONLINE PUBLICATION www.nature.com/ nrurol
compared with 6% of DTC-negative patients,17 implying
that a large proportion of DTC-positive patients do not
develop widespread metastatic disease and suggesting
that many of the marrow-associated prostate cancer cells,
if they do have metastatic capacity, remain clinically and
biologically dormant.48
CTCs might also represent an important biomarker
of occult metastases, as concordance has been observed
between the presence of CTCs in blood and DTCs in
bone marrow in patients harbouring tumours defined as
Gleason ≥8.49 Indeed, patients with metastatic castration-
resistant prostate cancer (mCRPC) have significantly
increased levels of CTCs relative to patients with local-
ized high-risk disease.50 The number of CTCs predict the
magnitude and duration of PSA response in patients pre-
senting with de novo metastatic prostate cancer and ADT
is used as the initial primary treatment in these men.51
Furthermore, CTCs are also prognostic for overall sur-
vival in patients with mCRPC receiving chemotherapy.52
Unfortunately, there are few data that support the use of
CTCs to predict metastatic potential in aggressive, high-
risk or locally advanced prostate cancer to justify the use
or nonuse of ADT with IGRT.53 Similarly, the use of a
blood-associated ‘liquid biopsy’ for circulating tumour
DNA (ctDNA) or RNA (ctRNA) as a biomarker for
occult metastases in the localized disease setting requires
extensive study and validation before it can influence
clinical management.52,54
Future developments in the area of molecular imaging
could also help to better define patients with occult
metastasis at diagnosis who might benefit from com-
bined ADT–IGRT. Novel MRI strategies using ultrasmall,
superparamagnetic particles of iron oxide could improve
detection of first echelon metastases within pelvic lymph
nodes during staging in patients with prostate cancer. This
capacity would enable the use of appropriate IGRT treat-
ment volumes (for example, treating the prostate alone or
adding a pelvic field) and also provide a means of select-
ing patients with node-positive disease for participation
in novel clinical trials to improve survival.55 Whole-body
MRI, including diffusion-weighted imaging, is being
actively investigated to improve the detection and dis-
crimination of synchronous micrometastases or provide
evidence for limited oligometastatic sites that could be
ablated with SBRT with curative intent.56 Novel PET
tracers for detecting early or lytic bony metastasis might
have additional utility for both initial staging and monitor-
ing of response to systemic therapy.57,58 PET tracers such
as 18F-choline or 11C-choline can be used to detect lymph
node involvement in patients with localized prostate
cancer with a pooled sensitivity of 49.2% (95% CI 39.9–
58.4%) and pooled specificity of 95% (95% CI 92–97.1%),59
and can predict PCSS in patients experiencing biochemi-
cal failure during ADT.60 Novel PET tracers for use in the
setting of prostate cancer include 18F-fluciclovine, which
targets leucine metabolism,61 68Ga-PSMA-ligand,
which targets prostate-specific membrane antigen,62 bom-
besin, which targets the gastrin-releasing peptide recep-
tor (GRPR)63 and 16β-18F-fluoro-5α-dihydrotestosterone
(FDHT).64 Use of these tracers could improve the detec-
tion of extraprostatic metastases at initial diagnosis and
enabling the efficacy of systemic ADT or molecular
t argeted therapies to be tracked.
Importantly, in the era of molecular genomics, several
prognostic signatures based on genome-wide analyses
of RNA and DNA are being studied to assist in decision-
making regarding the use of adjuvant IGRT and/or ADT
after radical prostatectomy.65–72 Future advances in the area
of prognostic genomics could include the development of
a gene signature that could enable clinicians to assign
patients to treatment escalation (for example increas-
ing the dose of IGRT that patients receive or a adding
systemic therapy such as ADT) or de-escalation (with
no requirement for systemic therapy) protocols on the
basis of diagnostic biopsy, thus providing a priori infor-
mation regarding a patient’s likelihood of experiencing
treatment failure.73 The use of these invasive and/or non-
invasive assays might help to better define the fraction of
patients harbouring occult metastases whom could benefit
from combined ADT–IGRT and improve their survival
o utcomes (Box 2).
Cancer metabolism and hypoxia have been linked
to differential androgen signalling and radiotherapy
response. Ranasinghe et al.74 demonstrated that patients
whose tumours express HIF1-α (hypoxia-inducible
factor 1α) have significantly decreased metastasis-free
survival compared with patients with no HIF1-α tumour
expression. On multivariate analysis, HIF1-α expression
was an independent risk factor for metastasis (HR = 9.8,
P = 0.017). Furthermore, nonspecific HIF1-α inhibitors
seem to increase PFS and reduce the risk of developing
metastases in patients receiving ADT.75 These observa-
tions indicate that HIF1-α could be a marker of disease
progression. Al-Ubaidi et al.76 demonstrated that down-
regulation of HIF1-α occurred after castration in five
out of 14 patients with high-risk, locally advanced pros-
tate cancer, all 14 of whom had strong HIF1-α expres-
sion before castration. Yapp et al.77 utilized the Shionogi
tumour model to demonstrate, using flow cytometry
and PET imaging with a radiolabelled tracer for hypoxia
(18F-EF5), significantly higher levels of hypoxia in CRPC
Box 2 | Potential biomarkers for residual or recurrent prostate cancer or metastasis
■ Disseminated tumour cells
■ Circulating tumour cells
■ Intratumoural hypoxia78
■ Molecular imaging
■ Whole-body MRI
■ PET
Genomic (DNA, RNA) signatures
■ Cell-cycle progression score (Prolaris® test [Myriad Genetics, USA])
■ Oncotype Dx® test (Genomic Health, USA)
■ Decipher® test (GenomeDx, USA)
■ Prostarix™ test (Metabolon, USA)
■ Signature of genes regulated by NF-κB
■ PGA100
Selected genes, based on copy number alteration, RNA or protein expression
■ TP53, MDM2, MYC, NKX3-1, NBN, PTEN, SCHLAP199
Abbreviations: NF-KB, nuclear factor κ-light-chain-enhancer of activated B cells; PGA, percent
genome alteration.
REVIEWS
© 2015 Macmillan Publishers Limited. All rights reserved
Adjuvant Biomarkers for RT-ADT-CHEMO Treatment
Locke, Dal Pra, Bristow; Nat Rev Urol; 2015
High PORTOS Low PORTOS
High PORTOS group (1/4 patients): 4% in the radiotherapy group vs 35% in the no radiotherapy group; HR 0·15 [95% CI 0·04–0·60], p=0·0020; Low PORTOS group: 32% in both Caveat: PSA kinetics/Margin status missing; variable RT and ADT and only 12% patients received aRT
Needs validation
“PORTOS: 24-gene predictor of response to postoperative radiotherapy in prostate cancer: a matched,
retrospective analysis” (Zhao et al; Lancet Oncology, 2016)
PORTOS and DECIPHER SIGNATURES
• Post-operative RT is a valuable adjunct to surgery and well-tolerated
• Optimal timing of adjuvant RT and role of ADT not yet established [cf. sRT (GETUG-
AFU-16 (6 months) vs. RTOG 9601 (2 years)]
• Need to optimize RT dose/volume/delivery/nodal technique to maximize control and
minimize RT-related toxicity; IGRT 60-66 Gy
• No published data supporting general use of Adj. chemo-ADT and OS;
– Possible subsets of patients who benefit (pT3/T4; African American, high PSA)
– Needs further trials and longer follow-up in GETUG and NRG/RTOG trials
• In my own practice with high-risk patients:
– Enroll in multimodal clinical trials (PUNCH-CALGB 90203)
– If aRT: 50/25Gy to pelvis (if no ePLND) and 66/33 Gy to prostate in margin-positive,
N+ or IDC-CA+
– 6-24 months of adjuvant ADT depending on reassessment-tolerance
Summary
• Neoadjuvant chemohormonal therapy; mostly Phase II trials
– Silberstein, JCO, 2014: Paclitaxel, Carboplatin, Estramustine-no difference in outcome when
compared to RadP comparator group
– Taplin, JCO, 2014: Abi plus LHRH to effectively suppress T; very few pT0/MRD
– Montgomery, CCR, 2016: Enza +/- LHRH/DUT; only 4/48 achieved MRD, pT0
– Note neoadjuvant chemohormonal therapy-treated FFPE biopsies can yield information AR status and NE/EMT genes to identify molecular outliers (Beltran et al., JCO, 2017)
• Increasing use of genomics and imaging will re-define sub-groups
– Use of genomic assays: DECIPHER, PORTOS, Germline DNA repair
– Molecular imaging (PET; wbMRI) to rule out metastatic disease in clinically-staged patients
• Need to support ongoing RCT’s to answer outstanding questions using modern
molecular imaging, genomics, and state-of-the-art androgen deprivation and blockade
(ABI/ENZA)
Summary-Future