Dr. Rohit Kabre, MD.

1. Locally advanced & Metastatic
Prostatic Cancer- Redefining the role
of Local RT
Dr. Rohit S Kabre.
MD, Radiation Oncology

3. Local radiation & bystander/ abscopal effect

4. • Out-of-field “systemic effects” of RT exerting tumoricidal
control at distant sites- abscopal phenomena- described for
decades
• Contributed by complex interactions –Involving local tumor
ablation, antigen presentation & inflammatory mediators.
• Golden et.al (Lancet Oncol, 2016)- Median survival of patients
demonstrating an abscopal response (defined as ≥30% size
reduction) experienced nearly 3-fold increased survival (21 vs.
8 months)
• Radical local treatment of the primary tumour tested in
several RCTs in metastatic cancer- clear survival benefit
lacking.

5. • Metastatic Prostate cancer typically receive systemic
treatment, local therapy reserved for symptom palliation.
• Primary tumors metastasize by disseminating tumour cells
into circulation and by priming the premetastatic niche.
• Proliferation of tumor cells at distant sites dependent on
compounds secreted by the primary tumor.
• local treatment inhibits initiation of distant disease &
progression of existing metastases.
• Hormone treatment (HT) usually successful at first:
prevents growth & shrinks tumor over period leads to
resistance.
• Newer drugs showing promising activity in prostate cancer
i.e ZA, Docetaxel & Celecoxib.

6. • Retrospective analyses showed association between RT
to primary tumor and improved OS
• HORRAD trial- 432 men with metastatic Ca prostate
ADT with or without prostate RT- no overall survival
benefit but survival might improve in patients with
fewer than five bone metastases.
• Hypothesis-
Radical radiotherapy to the prostate would improve OS in
metastatic prostate cancer and benefit would be greatest
in low metastatic burden disease.

7. STAMPEDE- RT perspective
• If indicated you can also receive radiotherapy (RT) at any
time in the trial. For example, if there is no evidence of
disease outside the pelvic region. Your doctor may offer
you radiotherapy to the prostate gland and nearby lymph
nodes according to local practice in your hospital.
• Intention to give RT (or not) stated at randomisation-
ensuring no bias towards particular combinations of
systemic therapy with radiotherapy.
• To ensure consistency of timing of administration of
radiotherapy in all arms-
RT given around 6-9 months after randomisation & after at least 6
months of HT

8. Trial profile

9. Metastatic burden
• Assessed through whole body scintigraphy and
CT or MRI staging scans.
• Classified according to CHAARTED trial definition
• High metastatic burden- four or more bone
metastases with one or more outside the
vertebral bodies or pelvis, or visceral metastases,
or both
• All other assessable patients- low meta static
burden.
Definition used in LATITUDE trial-absence of visceral
metastases and fewer than three bone metastases

10. • Primary efficacy outcome OS- time from randomisation to death from any
cause.
• Failure free survival- outcome measure for interim analyses - time from
randomisation to at least one of the following:
1. biochemical failure
2. progression either locally, in lymph nodes, or in distant metastases
3. death from prostate cancer
• Biochemical failure- rise above the lowest PSA value reported within 24
weeks after enrolment by 50% and to at least 4 ng/mL
• Patients without a fall of 50% - biochemical failure at time zero.
• Secondary outcomes were PFS - FFS without biochemical events

11. • All patients received lifelong ADT either GnRH agonists/
antagonists or orchidectomy.
• RT to the prostate-
1. 36 Gy in six consecutive weekly fractions of 6 Gy
2. 55 Gy in 20 daily fractions of 2·75 Gy over 4 weeks
• PTV consisted of the prostate only
• Nadir PSA- lowest level of PSA reported within 24 weeks after
randomisation.

12. RESULTS
• Median age 68 years (IQR 63–73)
• Median PSA before ADT - 97 ng/mL (33–315)
• 1630 (79%) patients had a Gleason score of 8–10
• Groups balanced with respect to baseline
characteristics
• Median time to starting radiotherapy- 35 days
(IQR 28–60) after randomisation, and 95 days
(74–120) from starting HT
• Median follow up was 37 months (IQR 24–48)

14. • Overall No survival advantage was noted with radiotherapy (stratified log-rank test
p=0・451; HR 0・92, 95% CI 0・80–1・06; p=0・266)
• OS improved in low metastatic burden disease with radiotherapy (HR 0・68, 95%
CI 0・52–0・90; p=0・007; 3-year survival 73% with control vs 81% with
radiotherapy)
• Overall, FFS improved with radiotherapy (HR 0・76, 95% CI 0・68–0・84; p<0・
0001
• FFS improved in low metastatic burden WITH radiotherapy (HR 0・59, 95% CI 0・
49–0・72; p<0・0001
• prostate cancer-specific survival (Fine and Gray method)- no evidence of an overall
treatment effect (sub-HR 0・94, 95% CI 0・81–1・10; robust p=0・431
• There was evidence of an effect in patients with low metastatic burden
• A significant interaction was seen between treatment effect and metastatic burden
(robustly estimated interaction p=0・007

17. • 1082 patients of daily RT schedule- strong evidence of FFS
advantage with RT (HR 0・69, 95% CI 0・59–0・80; p<0・0001).
• 212 deaths were reported in the control group and 188 in the
radiotherapy group (stratified log rank p=0・123; HR 0・86,
95% CI 0・71–1・05; p=0・128)
• insufficient evidence of a difference for FFS in weekly RT
schedule ( HR 0・85, 95% CI 0・73–0・99; p=0・033) to
report on survival

18. • Adverse effects on RTOG scale during RT- modest over 3 years of follow up.

19. Discussion
• RT to the prostate no improvement in OS in
unselected patients.
• RT did improve overall survival & FFS in those with a
low metastatic burden without compromising on
side effect profile.
• Can be a standard treatment in this subgroup.
• Extrapolating results from these findings-
1. RT may improve survival in pelvic node-positive
disease
2. for prevention of symptomatic local events

20. Probable limitations
• Determination of metastatic burden retrospectively
• Low metastatic burden status determined from scans taken before
randomization.
• Uncertainty regarding the optimum definition of low metastatic burden
(oligometastatic) prostate cancer.
• Definitions based on CT and bone scans- extrapolation to patients imaged
with more sensitive techniques needs caution
• Compliance with allocation to prostate radiotherapy was not complete
(94%)- underestimate the true effect size for radiotherapy.
• Median follow-up (37 months) shorter than median survival (46 months)
particularly relevant to the analysis of symptomatic local events- occur
late and after disease progression
• Most patients in this comparison received androgen deprivation alone
• Up-front systemic treatment of metastatic prostate cancer has evolved.

21. • If the benefit of radiotherapy is mediated by local tumour
eradication- feasibility of radical prostatectomy ?
1. gRAMMP trial (NCT02454543)
2. TROMBONE feasibility study
• Value of prostate RT in men receiving abiraterone tested in
1. PEACE1 trial (NCT01957436)
2. prospectively planned STOPCAP M1 metaanalysis
• Prostate RT does not require regulatory approval and is
readily available at modest cost in most parts of the world.

22. • Prostate RT should be a standard treatment
option for men with a low metastatic burden.
• Local treatment to the primary tumour should
be explored for patients with small volume
metastatic disease from other malignant
diseases.