The document discusses the role of radiation therapy in treating oligometastatic prostate cancer, noting that radiation can potentially achieve durable responses or even cure in some cases when metastases are limited. It reviews definitions of oligometastatic prostate cancer, the rationale for local and metastasis-directed radiation therapy, clinical evidence from studies on the use of external beam radiation therapy and stereotactic body radiation therapy to treat the primary tumor and metastases, and outcomes from these studies including local control rates, progression-free survival, and overall survival. The document concludes that radiation therapy plays an important role in the treatment of oligometastatic prostate cancer.

1. ROLE OF RADIATION THERAPY IN
OLIGOMETASTATIC PROSTATE CANCER

2. Agenda
Introduction
Definition
Natural History
Clinical evidence
Conclusion

3. Introduction
• oligometastatic state is a limited metastasis burden as an intermediate
state in the malignancy spectrum prior to widespread metastases
• Time point in the malignant process when local therapies can potentially
achieve a durable response to treatment—or even cure
Hellman and Weichselbaum
Ardalan E et al ,Prostate Cancer Oncology Journal Vol 31 201

4. Definitions of Oligometastatic Prostate Cancer Used in the
Published Literature
Study Type Sample Size,
No.
Cutoff for
Oligometastases,
No.
Location of Metastases Imaging Modality
Singh et al;2004 R;NA 369 </= 5 Any 99mTc bone scan
Berkovic et al;2013 P;SA 24 </=3 Bone or Ln 99mTc bone scan, 18F-FDG
PET/CT, 11C-choline
PET/CT
Schick et al;2013 P;SA 50 </=4 NR 99mTcbonescan, 18F-
cholinePET/CT, 11C-acetate
PET/CT
Decaestecker et
al;2014
P;SA 50 </=3 Bone or LN 18F-FDG PET/CT, 18F-
choline PET/CT
Jereczek- Fossa et
al;2014
P;SA 69 </=1 LN 18F-FDG PET/CT, 11C-
choline PET/CT, CT
Ost et al;2016 P;SA 119 </=3 Any 18F-FDG PET/CT, 18F-
choline PET/CT
Ost et al;2018 P;RA 62 </=3 ANY 18F-choline PET/CT
Rao et al genitourinary(prostate) cancer; 2019 ASCO Educational Book.
Abbreviations: FDG, 18-fluorodeoxyglucose; LN, lymph node; NA, not applicable; NR, not reported; P, prospective; R, retrospective; RA,
randomized; SA,single arm.

5. Natural History of Oligometastatic Prostate Cancer
Rao et al genitourinary(prostate) cancer; 2019 ASCO Educational Book

6. Rationale for Local & Metastasis directed therapy
• The primary tumor seems to be responsible for expression of signaling pathways that
activate the epithelial-mesenchymal transition, which facilitates the release of tumor
cells into systemic circulation and initiates the metastatic process. Furthermore, by
producing the necessary chemokines, angiogenic factors, fibronectin, bone marrow
infiltrate cells, and other hormonal factors, the primary tumor appears to play a role
in the development and maintenance of metastases. Local traetment of the primary
tumor inhibits not just initiation of distant disease but also the progression of existing
metastases.
• Notably, the new metastatic foci can also act as a source for additional metastases
while maintaining communication with the primary tumor by releasing tumor cells
into systemic circulation.
Ardalan E et al ,Prostate Cancer Oncology Journal Vol 31 2017
C.C Parker et al, www.thelancet.com 2018

7. Rationale for Local & Metastasis directed therapy
contd.....
• Unlike diffuse systemic disease,established oligometastatic prostate cancer is unique
in that a combination of primary tumor treatment, metastasis-directed therapy, and
systemic therapy (ADT and chemotherapy) can potentially delay disease progression
or in some cases be curative1
• As our experience with molecular imaging (eg, prostate-specific membrane antigen
positron emission tomography/CT scan) improves, disease will be detected at lower
thresholds, resulting in the identification of metastatic lesions when present at lower
quantities and aiding in the stratification of who might most benefit from MDT or
identifying those with higher subclinical disease burden than expected, who might
best be treated with systemic therapies alone2.
1.Ardalan E et al, Prostate Cancer Oncology Journal Vol 31;2017.
2.Deek et al International Journal of Radiation Oncology Biology Physics,2019

8. Points of concern - treating oligometastasis
Few data
Different definition
Limited Retrospective series & randomised control trials
Dynamic concept and No Consensus.
Concern regarding overtreatment of oligometastatic disease.

9. Handling Oligometastasis
Radiotherapy

10. Modality of Radiation Therapy
 Radiation therapy plays an important role within the treatment landscape of PCa, ranging
from up-front treatment for localized disease with curative-intent, post-RP adjuvant or
salvage settings, and as a palliative treatment for men with symptomatic metastases.
 Clinical studies on RT used for oligometastatic PCa in improving OS or other clinical
endpoints have focused on both conventional external beam RT (EBRT) and SBRT.
 Studies have suggested that the mechanism of action of SBRT is distinct from EBRT. SBRT
can precisely target the lesion with an intensified radiation dose while minimizing the
radiation exposure to adjacent normal tissues.
 Moreover, the low α/β value of PCa enables hypofractioned SBRT to effectively eradicate
the target lesions.
 Compared to EBRT, which delivers localized cytotoxic effects, SBRT has been shown to
induce immune responses with the potential for additional tumor control.
KC Koo et al Yonsei Medical Journal;2018

11. Clinical Evidence
Local Treatment of Prostate

12. Improved Survival With Prostate Radiation in Addition to ADT
for Men With Newly Diagnosed Metastatic Prostate Cancer
Retrospective study from the National Cancer Database (2004-2012)
Of the 6382 pts ,
5844pts received
ADT alone &
538pts received
ADT+Prostate RT
 The medianfollow up was 5.1years.
 On univariateanalysis,prostate RT+ ADT -longer median OS (53 v 29 months), as well as
improved 3-year (62% v 43%), 5-year (49% v 25%), and 8-year OS estimates (33% v 13%;
[HR, 0.562; P , .001;].
 On multivariate analysis, prostate RT -improved OS (HR, 0.624;P,.001;Table2).
 On subset analysis,both RT to the prostate only and RT to the prostate and pelvis were
associated with improved OS compared with ADT alone
 Propensity matched analysis redemonstrated an association between prostate RT and
improvements in the median (55 v 37 months), 3-year (62% v 51%), 5-year (49% v 33%),
and 8-year OS estimates (33% v 15%; P , .001;).
 On subgroup analyses, the magnitude of the association between prostate RT and improved
survival was greater for patients with Gleason scores <=8(v 9-10) andT1-3 (v T4) tumors.
Men receiving prostate RT plus ADT lived substantially longer than men treated with ADT alone.
Randomized trials to evaluate the impact of local therapy for men with mPCa appear warranted .
C G Rusthoven et al, Journal of clinical oncology; 2016

13. HORRAD Trial-ADT Alone Compared to ADT combined with
concurrent RT to the Prostate in Patients with Primary Bone
Metastatic Prostate Cancer
multicentre prospective randomised cotrol trial in 28 centres across Netherlands
The primary outcome of the trial was overall survival,Secondary oncological endpoint was time to PSA progression
median follow up 47 months(36-68)
432 patients with PSA levels of
more than 20 ng/mL,untreated,
histologically confirmed diagnosis of
adenocarcinoma of the prostate with
any number of bone metastases on
bone scintigraphy.
ADT Alone
n=216
EBRT of
Prostate 70Gy in
35 fractions over
7 weeks +ADT
n=216
No significant difference in
overall survival, although the CI
cannot exclude a substantial
survival benefit.
L M S Bove et al European Urology 2018
Future trials should evaluate the impact of local treatment in patients with oligometastatic disease and by
use of modern imaging modalities.

14. Radiotherapy to the primary tumour for newly diagnosed,
metastatic prostate cancer (STAMPEDE)
Phase III randomised control trial at 117 centres in UK and switzerland
Primary outcome measures: Overall Survival and Failure Free survival
Median Follow-Up: 37 mons (24-48)
2061 pts with newly
diagnosed metastatic
prostate cancer, with
no prior therapies
Standard of care (ADT
w/wo Docetaxel)
n=1029
Standard of Care+ RT
RT dose as 55Gy in 20
fractions / 36 Gy IN 6
fractions. n=1032
 RT improved failure-free survival
compared with standard of care alone
(p< .0001).
 OS was not improved.
 Prespecified subgroup analysis in
patients with a low metastatic burden
(819 patients), RT improved
failurefree survival( p< .0001) and 3-
year OS (81% vs. 73%; HR 0.68; p =
.007)
Prostate radiotherapy improves survival of men with a low metastatic burden and
that it should now be a standard treatment.
C.C Parker et al www.thelancet.com 2018

15. Clinical Evidence
Metastasis Directed Radiotherapy

16. Stereotactic Ablative Body Radiotherapy (SABR) for
Oligometastatic Prostate Cancer: POPSTAR
Siva et al; European urology 2018
Clinical outcome measures
• The safety and feasibility of
single fraction SABR for
patients with oligometastatic
prostate cancer.
• Secondary endpoints were
local and distant
progression-free survival,
toxicity, quality of life.
Thirty three patients with 50
oligometastases received the
trial intervention and were
followed for 2 yr
Intervention
Single fraction of 20 Gy
SABR to all visible (1–3)
sites of disease. A margin of
5 mm was given to the gross
visible tumor to define the
planning target volume.
 Thirty two of 33 pts
completed the RX ,
Feasability rate:97%
 Only one grade 3 adverse
event(fracture).
 Among 22 pts who had
HSPC, freedon from ADT
at 24 months was 48%.
Single SABR session was feasible and associated with low morbidity in this cohort. Over one-third of patients
did not progress and were free from ADT at 2-yr. QoL measures were maintained with this treatment strategy.
A Prospective Clinical Trial

17. Prostate brachytherapy and metastasis-directed RT in
newly diagnosed oligometastatic prostate cancer
Retrospective cohort Study
40 patients with bone
metastasis and node positive
prostate cancer were
retrospectively analyzed.
MDT(n=18) No MDT (n=22)
Outcome measures
survival analysis of
CRPC free survival rate
Toxicities
 The 5-year castration-resistant prostate cancer (CRPC)-free survival rate
and cancer-specific survival was 64.4% and 87.9%, respectively.
 Pre or post-treatment predictive value including prostate-specific antigen
(PSA) at diagnosis ≥20 ng/mL, Gleason grade group 5, positive biopsy
core rate ≥51%, PSA nadir level of ≥0.02 ng/mL after the radiotherapy,
and no MDRT were significantly associated with progression to CRPC.
 Patients with MDRT had significantly higher probability of achieving a
PSA level of <0.02 ng/mL than those without the therapy
 (P = 0.0354) and consequently had a better CRPC-free survival than
those without the therapy.
 Comparing PDRT alone, PDRT with MDRT did not significantly
increase the incidences of genitourinary and gastrointestinal toxicities.
Combination of PDRT and MDRT using prostate HDR-BT and EBRT was a feasible approach and had better
CRPC-free survival rates than PDRT alone for patients with newly diagnosed oligometastatic prostate cancer.
Tsumura et al The Prostate 2018;1-9

18. Radiation Therapy in the Definitive Management of
Oligometastatic Prostate Cancer
Inclusion criteria :
men with histologically
confirmed PCa with
imaging features
consistent of metastatic
disease and who
received definitive-
intent RT to the
metastatic lesions.
Stereotactic Ablative
Radiationtherapy
(SABR)
largest retrospective
study 156 men with 354
lesions
Clinical Outcomes
1. Biochemical
progression free
survival(bPFS)
2. Time to next
intervetion(TTNI)
3. Toxicity
• Median follow-up time :24.6 months
• PSA stability or decline after RT -86%
• Local failure at 12 months-3.9% and
24 months-7.4%
• Median bPFS -12.9 months (95%
confidence interval [CI],10.5-17.9
months) and 52% at 1 year
• Median TTNI -21.6 months (95% CI,
17.3-32.5 months)
• Toxicity data available-150 pts ,41%
experienced an acute toxicity,
• CTCAE grade 1- 53pts, CTCAE
grade 2 -8 pts.
Deek et al;International Journal of Radiation Oncology Biology Physics,2019
The Johns Hopkins Experience (2013 -2018)

19. The Johns Hopkins Experience contd....
On stratification and
multivariate analysis,
• Peri-RT ADT, smaller
GTV & HSPC, i.e Low
volume disease were
associated with
improved bPFS.
• Peri-RT ADT& HSPC
were associated with
longer TTNI.
Biochemical progression-
free survival after radiation
therapy
Time to next intervention
after radiation therapy.
Deek et al;International Journal of Radiation Oncology Biology Physics,2019

20. The Johns Hopkins Experience key points
• The optimal time for intervention is with lower-volume disease.
• Although ADT remains the standard of care in men with metastatic disease, a cohort
of patients treated with a course of ADT and MDT appear to have sustained disease
response after testosterone recovery; therefore, indefinite ADT might not be
necessary in all cases, although it is currently not clear how to identify this
population, if it exists.
• MDT using SABR appears feasible in delaying the initiation of systemic therapies
that often have an unfavorable adverse effect profile, especially ADT, while itself
minimizing adverse effects.
Deek et al;International Journal of Radiation Oncology Biology Physics,2019

21. Author(year) Study
Type
Modality metastasis criteria no.pts
(no.mets)
Treated sites local control
rate
PFS Overall
survival
Rades, et al.
(2007)
R EBRT <= 3 vertebrae 103 Bone 93% at 6
months
and 66% at 3
yr
NR 71% at 1 yr
and
54% at 3 yr
Jereczek-
Fossa, et al.
(2009)
R SBRT isolated LN 14(14) Pelvic LN 100% at 18.6
months
Mean 12.7
months
NR
Ahmed, et al.
(2013)
P SBRT <=5 17(21) Bone,LN,Liv
er
100% at 6
months
74% at 6
months and
40% at 1 yr
100% at 1 yr
Tabata, et al.
(2012)
R EBRT <=5 vertebra 35(38) Bone NR Pain
PFS=64.8%
at 1 yr
77.2% at 3 yr
Jereczek-
Fossa, et al.
(2012)
R SBRT single pelvic LN
and/or single distant
lesion
34(38) Bone , Local
recurrence,
Liver
88% at 16.9
months
42.6% at 30
months
NR
EBRT, external beam radiation therapy; LN, lymph node; NR, not reported; PFS, progression-free survival; SBRT, stereotactic body radiation therapy; R,
Retrospective;P,Prospective.
Summary of other Studies Using Radiation Therapy as a Metastasis-Directed
Therapy for Oligometastatic Prostate Cancer
KC Koo et al Yonsei Medical Journal;2018

22. Author(year) Study Type Modality metastasis
criteria
no.pts
(no.mets)
Treated sites local control
rate
PFS Overall
survival
Berkovic, et
al. (2013)
R SBRT <=3 Bone
and/or LN
24(29) Bone, LN 100% at 2 yr 72% at 1 yr
and 42% at 2
yr
NR
Schick, et al.
(2013)
R EBRT <=4 50(79) Bone,LN,Vis
cera
NR Biochemical
PFS=54.5%
at 3 yr
and clinical
PFS 58.6% at
3 yr
91.7% at 3 yr
Muacevic, et
al. (2013)
P SBRT <=2 40(64) Bone 95.5% at 2 yr NR 75% at 17.5
months
Decaestecker,
et al. (2014)
P SBRT <=3 Bone
and/or LN
50(70) Bone, LN 100% at 2 yr 64% at 1 yr
and 35% at 2
yr
NR
Ost, et al.
(2016)
R SBRT <=3 119(163) Bone,LN,Vis
cera
93% at 3 yr
and 92%
at 5 yr
13% at 3 yr
and 15% at 5
yr
95% at 3 yr
and
88% at 5 yr
Summary of other Studies Using Radiation Therapy as a Metastasis-Directed
Therapy for Oligometastatic Prostate Cancer contd...
EBRT, external beam radiation therapy; LN, lymph node; NR, not reported; PFS, progression-free survival; SBRT, stereotactic body radiation therapy; R,
Retrospective;P,Prospective. KC Koo et al Yonsei Medical Journal;2018

23. Summary of Clinical Trials Investigating Radiotherapy for
Oligometastatic Prostate Cancer
KC Koo et al Yonsei Medical Journal;2018
LN, lymph node; NR, not reported.

24. Conclusion
 Radiotherapy in Low volume Oligometastasis disease is a promising treatment as shown by the
various clinical studies.
 Molecular imaging represents a major development and an essential tool in the staging of patients
with oligometastatic PCa. In particular, 68Ga PSMA is a promising tracer that can accurately assess
disease burden, and can be utilized to select optimal candidates and tailor treatments.
 SBRT demonstrates excellent local control,with delay in both biochemical and clinical progression.
The tolerability of SBRT seems to be acceptable. The use of SBRT to delay ADT confers the benefit
of maintaining a good quality of life.
 In order to define the potential benefits of SBRT on long-term oncological outcomes and to
establish a standard of care, larger studies with homogeneous cohorts will be required.
 Considering the scope of the ongoing trials, it is safe to predict that a combination of primary tumor
treatment (surgery and/or radiation), metastasis-directed therapy (surgery and/or radiation), and
systemic therapy (hormonal and chemotherapy) will delay disease progression or even provide the
possibility of cure to patients with oligometastatic prostate cancer.
Ardalan E et al, Prostate Cancer Oncology Journal Vol 31; 2017
KC Koo et al Yonsei Medical Journal;2018