Low risk

1. Dr Naresh Jakhotia
Department of Radiation Oncology
BMCHRC
Department of Radiation Oncology, Duke University Medical Center
5/20/2016

2. Prostate Cancer
Staging
5/20/2016

3. Risk Group
5/20/2016

4. Prostate Cancer
Treatment
 PRINCIPLES OF THERAPY
 May include
 Watchful waiting
 Androgen deprivation
 External beam radiotherapy
 Retropubic or perineal radical prostatectomy
 with or without postoperative radiotherapy to the prostate margins
and pelvis
 Brachytherapy (either permanent or temporary radioactive
seed implants)
 with or without external beam radiotherapy to the prostate
margins and pelvis.
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
5/20/2016

5. Prostate Cancer
Treatment
 Require individualization
 Must take into account
 Patient's comorbidity
 Life expectancy
 Likelihood of cure
 Personal preferences
 Based on an understanding of potential morbidity associated with
each treatment
 A multidisciplinary approach (recommended)
 Integrate
 Surgery
 Radiation therapy
 Androgen deprivation
 Behavioral therapy
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
5/20/2016

6. Prostate Cancer
Treatment
 Surgery
 Traditional
 Robotic
 Radiation
 Brachytherapy
 External beam
 Cryotherapy
 Androgen Deprivation
 Watchful waiting
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
5/20/2016

7. 5/20/2016

8. Prostate Cancer
Treatment - LOW/INTERMEDIATE RISK DISEASE
 LOW/INTERMEDIATE RISK DISEASE
 Randomized trial
 Under the age of 75
 Clinical stage T1b, T1c, or T2 prostate cancer
 Radical prostatectomy
 Reduced the relative risk of death by 50% (a 2% absolute risk
reduction)
 Compared with watchful waiting
 Despite a significant reduction in the risk of metastasis, overall
mortality was unchanged
 Adverse effects on quality of life
 More dysfunction and urinary leakage after radical prostatectomy
 More urinary obstruction with watchful waiting
 Nerve-sparing radical prostatectomy was not routinely performed in this
study
 Less advanced disease with newer surgical techniques are not known
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
5/20/2016

9. Prostate Cancer
Treatment - LOW/INTERMEDIATE RISK DISEASE
 Nonrandomized data
 Suggest that watchful waiting may be judiciously
used
 Gleason score 2, 3, or 4 tumors with life expectancy of
10 years or less
 Watchful waiting is probably not appropriate for young,
otherwise healthy men with high-risk features as
described earlier (PSA > 10, Gleason sum = 7, or
clinical stage T3 or higher).
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
5/20/2016

10. Prostate Cancer
Treatment - LOW/INTERMEDIATE RISK DISEASE
 External beam radiation therapy (EBRT)
 Three-dimensional conformal radiation therapy (3D-CRT)
 IMRT/ IG-IMRT
 Complications of external radiotherapy
 Cystitis
 Proctitis
 Enteritis
 Impotence
 Urinary retention
 Incontinence (7-10%)
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
5/20/2016

11. Prostate Cancer
Treatment - LOW/INTERMEDIATE RISK DISEASE
 Brachytherapy
 Placement of permanent or temporary radioactive
seeds directly into the prostate
 Adequate for
 Intracapsular disease
 No more than minimal transcapsular extension
 It can be combined with external beam radiation therapy.
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
5/20/2016

12. Prostate Cancer
Treatment – High-risk disease
 HIGH-RISK DISEASE.
 Patients with adverse risk features
 (Gleason score 8 to 10, PSA > 10, stage T3)
 Treated with
 Aggressive local therapy or
 Androgen deprivation
 Synergistic with radiation therapy
 Trials
 4 months of androgen deprivation with radiation therapy
 Improve local control and prolong progression-free survival in patients
with intermediate risk features
 Long-term androgen deprivation (up to 3 years)
 Prolongs local control
 Prolongs progression-free survival and overall survival in patients
with high-risk features compared with radiation therapy.
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
5/20/2016

13. Prostate Cancer
Treatment – Recurrent disease
 RECURRENT DISEASE
 ~50% of men treated with radiation therapy or
prostatectomy develop evidence of recurrence
 Defined by a climbing PSA level
 Local salvage therapy
 Selected patients with clear local recurrences
 Surgery for patients previously treated with radiation
 Radiation for patients previously treated with surgery and
androgen deprivation
 Early hormone therapy
 Appears to be better than hormonal salvage therapy
in terms of survival.
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
5/20/2016

14. Prostate Cancer
Treatment – Advanced disease
 ADVANCED DISEASE
 Microscopic involvement of lymph nodes
 Revealed by radical prostatectomy
 Immediate androgen deprivation prolongs survival
 Should not wait until osseous metastases are detected
 Patients at high risk of nodal invasion and who undergo external beam
radiation
 Benefit from concurrent short-term hormonal therapy.
 Newly diagnosed metastatic prostate cancer
 Androgen deprivation is the mainstay of treatment
 Results in symptomatic improvement and disease regression in approximately
80 to 90% of patients
 Androgen deprivation can be achieved by orchiectomy or by medical
castration
 Luteinizing hormone-releasing hormone (LHRH) agonist (leuprolide acetate,
goserelin acetate)
 Safer and as effective as estrogen treatment.
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
5/20/2016

15. Prostate Cancer
Treatment – Advanced disease
 Side effects of LHRH agonist
 LH and testosterone surge within 72 hours
 Transient worsening of signs and symptoms during the first week of therapy
 An antiandrogen (flutamide, bicalutamide, or nilutamide) should be given with the first LHRH
injection to prevent a tumor flare
 Medical castration occurs within 4 weeks
 Hormone sensitivity
 Duration
 5 to 10 years for node-positive or high-risk localized (or recurrent) prostate cancer
 18 to 24 months in patients with overt metastatic disease
 Side effects androgen ablation
 Loss of libido
 Impotence
 Hot flashes
 Weight gain
 Fatigue
 Anemia
 Osteoporosis
 Bisphosphonates reduce bone mineral loss associated with androgen deprivation.
Small, E., Cecil Textbook of Medicine, Prostate Cancer, 2004, WB Saunders, an Elsevier imprint
5/20/2016

16. NRG Oncology RTOG 0415: A
Randomized Phase III Non-Inferiority
Study Comparing Two Fractionation
Schedules in Patients with Low-Risk
Prostate Cancer
W Robert Lee, James J Dignam, Mahul B Amin, Deborah
W Bruner, Daniel Low, Gregory P Swanson, Amit B Shah,
David D'Souza, Jeff M Michalski, Ian S Dayes, Samantha
A Seaward, William A Hall, Paul L Nguyen, Thomas M
Pisansky, Sergio L Faria, Yuhchyau Chen, Bridget
Koontz, Rebecca Paulus, Howard M Sandler
5/20/2016

17.  Processed as a Rapid Communication
manuscript.
 Supported by National Cancer Institute.
 Presented in part at
 57th Annual Meeting of the American Society
for Radiation Oncology, San Antonio, TX,
September 18-21, 2015
2016 American Society of Clinical Oncology,
Genitourinary Symposium, San Francisco,
CA, January 7-9, 2016. 5/20/2016

18. Background
• Conventional radiotherapy involves
40-45 once daily treatments over 8-9
weeks
• Fractionation sensitivity of prostate
cancer may favor hypofractionation
• Contemporary randomized trials have
not demonstrated increased efficacy
with hypofractionation 5/20/2016

19. Purpose of NRG Oncology RTOG 0415
 To determine whether efficacy of hypofractionated
treatment schedule was not worse than a
conventional schedule in men with low-risk prostate
cancer. This is first report of this study.
 Advantage: Potentially increasing efficacy of RT,
smaller number of treatments with hypofractionation
increases convenience for patient and decreases
use and health care costs.
5/20/2016

20. Trial Design & Participants
 Men age >18 years with Prostate Adenocarcinoma
– Eligibility Criteria
 Stage - cT1b to T2c cNo Mo
 Gleason score 2 to 6
 S.PSA < 10
 Zubrod performance status <2
 No prior B/l orchidectomy, chemotherapy, RT,
cryosurgery, or definitive surgery for prostate cancer.
 No h/o another invasive cancer (except localised basal
or squamous cell skin carcinoma), unless continually
free from that cancer for a minimum of 5 years.
5/20/2016

21.  Before entry in study –
 History
 Physical examination, including DRE
 S.PSA (within 180 days before registration)
 Androgen suppression was not allowed, except as a
salvage therapy
 All participants –
 Written informed consent, before registration
 Receive protocol-specified care
 Follow-up at a member site
 Did not receive compensation
 No commercial support
5/20/2016

22. Random Assignment
 Multicenter, stratified, parallel group study with 1:1
random assignment approved and sponsored by the
US National Cancer Institute.
 Patients were stratified according to
 PSA level ( <4 ng/ml v 4 to 10 ng /ml)
 Gleason score (2 to 4 v 5 to 6)
 Radiation modality ( 3D-CRT v IMRT)
 Participants were then randomly assigned by using
the permuted block method to either a C-RT
treatment schedule (73.8 Gy in 41 fractions over 8.2
weeks) or to an H-RT schedule (70 Gy in 28
5/20/2016

23. Schema
S
T
R
A
T
I
F
Y
R
A
N
D
O
M
I
Z
E
Gleason 2-4
Gleason 5-6
PSA <4
PSA 4-<10
3DCRT
IMRT
73.8 Gy/41 fr
of 1.8 Gy over
8.2 weeks
70 Gy/28 fr of
2.5 Gy over
5.6 weeks
No androgen suppression5/20/2016

24. Biologic Effective Dose (BED)
 Biologic effective dose of each treatment arm according to
alpha-beta assumption. This study was designed so that the
two arms would be iso-effective assuming an alpha-beta of
10. If alpha-beta is lower, whether for prostate cancer or
normal tissue, then hypofractionated arm would result in a
higher BED.
0
100
200
300
10 5 3 1.5 1
73.8/41 70/28
BE
D
α/β ratio
5/20/2016

25. Treatment
 RT was initiated within 6 weeks of registration.
 Daily field alignment with intraprostatic fiducial
markers or other means to the prostate was required.
 CTV was prostate as identified on planning CT scan
 A 3D expansion of CTV by 4 to 10 mm was used to
create planning target volume (PTV).
 Participants were assigned either to 73.8 Gy (C-RT)
or to 70 Gy (H-RT) fraction, which was minimum
dose to ≥ 98% of the PTV.
5/20/2016

26.  Maximum dose to PTV could not exceed
prescription dose by > 7%.
 Maximum dose > 7% but < 10% was a
minor, acceptable variation, and ≥ 10% was
a major, unacceptable variation.
 Dose constraints to normal tissues (bladder,
rectum, penile bulb) as listed in the protocol
were followed.
 No attempt was made to treat seminal
vesicles or pelvic lymph nodes.
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27. Results
The study opened in April 2006 and accrual was
closed in December 2009 ahead of schedule with 1115
men enrolled.
5/20/2016

28. Eligibility
1092 men analyzable
73.8 Gy 70.0 Gy
Randomized 558 557
Ineligible 10 3
Not evaluable 6 4
Eligible 542 550
5/20/2016

29. Patient Characterist
Characteristic
73.8 Gy
(n=542)
70.0 Gy
(n=550)
Age ≤ 59 87 (16%) 95 (17%)
60-69 239 (44%) 251 (46%)
≥ 70 216 (40%) 204 (37%)
Race White 430 (79%) 436 (79%)
Black 91 (17%) 99 (18%)
Other 21 (4%) 15 (3%)
Zubrod 0 507 (94%) 504 (92%)
1 35 (6%) 46 (8%)5/20/2016

30. Tumor Characterist
Characteristic
73.8 Gy
(n=542)
70.0 Gy
(n=550)
PSA < 4 106 (20%) 112 (20%)
4 - <10 436 (80%) 438 (80%)
Gleason 2-4 2 (<1%) 0 (0%)
5-6 540 (99%) 550 (100%)
T Stage T1 411 (76%) 442 (80%)
T2 131 (24%) 108 (20%)
5/20/2016

31. DFS Event
73.8 Gy
(n=99)
70.0 Gy
(n=86)
Death w/o failure 49 46
PSA Recurrence 46 36
Non-protocol HT 4 2
Distant Progression 0 2
Primary Endpoint
Median FU 5.8 years5/20/2016

32. HR 0.85 (0.64,1.14)
86%
85%
Disease-free Surviv
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33. Secondary Endpoin
• Biochemical
Recurrence
• Adverse Events
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34. Biochemical Recurre
HR 0.77 (0.51,1.17)
8%
6%
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35. 73.8 Gy
(n=533)
70.0 Gy
(n=542)
73.8 Gy
(n=533)
70.0 Gy
(n=542)
Grade 2 52(9.8%) 54(10.0%) 132(24.8%) 129(23.8%)
Grade 3 3(0.6%) 3(0.6%) 13 (2.4%) 18(3.3%)
Grade 4 0(0%) 1(0.2%) 0 (0%) 0 (0%)
Acute Adverse Events
GI GU
GI p=0.80 GU p=0.665/20/2016

36. 73.8 Gy
(n=533)
70.0 Gy
(n=542)
73.8 Gy
(n=533)
70.0 Gy
(n=542)
Grade 2 61(11.4%) 99(18.3%) 109(20.5%) 142(26.2%)
Grade 3 13(2.4%) 22(4.1%) 11(2.1%) 19(3.5%)
Grade 4 1(0.2%) 0(0%) 1(0.2%) 0(0%)
Late Adverse Events
GI GU
GI p=0.005 GU p=0.0095/20/2016

37. Overall Survival
 Estimated 5-year overall survival
 C-RT arm – 93.2 %
 H-RT arm – 92.5 %
 HR comparing OS between two arms – 0.95
 Protocol specified noninferiority criteria was
met (HR>1.54 rejected, p= 0.008).
 Most frequent cause of death –
 Cardiovascular disease
 Second cancers
5/20/2016

38.  Additional protocol-specified clinical end points
 As a result of low frequency of these events,
additional analyses are not presented.
C-RT ARM H-RT ARM
LOCAL
PROGRESSION
7 2
Prostate cancer-
specific survival
(deaths)
2 1
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39. Discussion
 Many RCTs were started based on hypothesis that
higher dose per treatment, that is, hypofractionated
external RT, would increase efficacy of RT compared
with conventionally delivered external RT.
 Results reported to date have not confirmed that
hypothesis
 This trial was designed to demonstrate that a shorter,
more convenient treatment schedule could be
accomplished without compromising cure or causing
additional adverse effects.
 Results indicate that shorter course provides similar
efficacy, albeit with an increase in late GI and GU
5/20/2016

40.  This trial is unique in that it focused exclusively on
patients with low-risk prostate cancer, using RT
alone—androgen suppression was not allowed.
 As such, this trial complements other research yet
provides unique findings with generalizability and
immediate relevance.
 Coincidentally designed with a debate about use of
early intervention compared with active
surveillance for this group of patients.
5/20/2016

41.  Noninferiority design was a prudent use of
resources.
 A noninferiority trial is typically warranted when
an investigational treatment is hypothesized to
have efficacy that is comparable to standard
treatment, but with safety, convenience, cost,
and/or other advantages.
5/20/2016

42.  These findings have important implications for men
with low-risk prostate cancer who are considered for
external beam RT.
 If disease control is similar, reducing number of
treatments from 41 to 28 and reducing duration of
therapy by 2.5 weeks (a nearly one-third reduction)
provides greater patient convenience and reduced
cost.
 Observed increase in late GI and GU adverse events
in H-RT arm suggests that increased convenience
5/20/2016

43.  Several patient-reported outcomes, including
health-related quality of life, anxiety, and
depression, were collected as a component of
this study but have not been analyzed to date.
 It will be of great interest to determine whether
patients themselves report differences
according to assigned treatment.
5/20/2016

44.  RTOG 9406 – Dose increase from 1.8 to 2 Gy may
increase toxicity.
 This trial analyze –
 Dose-volume relationships exist when fraction size is
further increased to 2.5 Gy
 IMRT has any effect on late toxicity compared with 3D-
CRT
 Pollack trial –
 only study that reported excess toxicity with
hypofractionation
 Only observed for GU toxicity in 5/20/2016

45.  Most important criticism is that many of these
men with low-risk prostate may not need any
treatment at all.
 Active surveillance is an appropriate initial
strategy for men with low-risk disease and has
increased in use during the last 5 years.
 This trial includes men with low-risk disease
only; therefore, these results should not be
extrapolated to men with intermediate or high-
risk disease.
5/20/2016
Criticism

46.  PTV included prostate only; seminal vesicles and
pelvic lymph nodes were not irradiated.
 Two other noninferiority trials that have
completed accrual include men with intermediate-
and high-risk disease treating larger volumes,
and results are expected soon.
 It is also important to note that all participants had
low-risk disease and were allocated to immediate
intervention. It may not be appropriate to extend
these results to men who progress beyond low-
risk disease after a period of active surveillance
5/20/2016

47. Conclusion
 In low-risk prostate cancer-
 Efficacy of 70 Gy delivered in 28 fractions over 5.5
weeks is not inferior to 73.8 Gy delivered in 41
fractions over 8.25 weeks
 Although an increase in late grade 2 and 3 GI and
GU adverse events was observed.
5/20/2016

48. 5/20/2016
 There is a growing body of evidence suggesting
that prostate cancer has a low α/β-level of 1.4 Gy
and therefore lower than that of surrounding organs
at risk, such as rectum or bladder.
 This poses a therapeutic rationale for
hypofractionation with the possible result of a better
tumor control at a lower toxicity rate.
 Vital for a safe appliance of hypofractionated
schemes are IMRT and IGRT

49. 5/20/2016
 So far, there are encouraging results for
moderately as well as for higher hypofractionated
schemes regardless of prostate cancer risk
group.
 Nevertheless there are still pending questions
and ongoing trials, before hypofractionated
radiotherapy can be generally recommended.
 Therefore so far patients who are intended to be
treated with a hypofractionated scheme should
be enrolled in clinical trials.

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53. THANK YOU5/20/2016