Hypofractionation in Prostate Cancer: Is Less Enough? 1) The document discusses several studies that have compared hypofractionated radiation therapy (delivering larger doses of radiation in fewer treatments) to standard fractionation for prostate cancer. The PROFIT trial found equivalent 5-year outcomes for intermediate risk prostate cancer patients treated with either 60Gy in 20 fractions over 4 weeks or 78Gy in 39 fractions over 7-8 weeks, with less late gastrointestinal toxicity in the hypofractionated group. 2) The CHHiP trial also found non-inferior 5-year outcomes when comparing 60Gy in 20 fractions to 74Gy in 37 fractions for intermediate risk prostate cancer, with no difference in toxicity.

1. Hypofractionation
in Prostate Cancer
Is Less Enough?
Presenter: Dr. Narayan Adhikari
Moderator: Dr. K.P. Haresh
August 31,2017

2. Epidemiology

3. Epidemiology
• Most common cancer in men in the west
– Incidence- 30.7 per 100000 (Second most incident cancer next to ca lungs)
– Mortality- 7.8 per 100000
– Prevalence = 25.2% (most prevalent)
• Second most common malignancy in Indian men
– Incidence – 4.2 per 100000
– Mortality – 2.7 per 100000
– Prevalence = 9.6% (Second to ca lip and oral cavity)
• Slow growing tumors
• Multiple treatment options
3
Globocan, 2012

4. Anatomy

5. Staging
5

6. 8th AJCC Changes

7. Gleason’s Score

8. NCCN Risk stratification
Risk Category T Stage Gleason
Score
PSA Other
Very Low T1c ≤6 <10 <3 core positive
<50% in each core
PSA density <0.15 ng/mL/g
Low T1-T2a ≤6 <10 -
Intermediate T2b-T2c or 7 or 10-20 -
High T3a or ≥8 or >20 -
Very High T3b-T4 or - - Primary Gleason pattern 5
>4 core with Gleason score 8-10
8

9. Management options
• Active Surveillance
• Radical Prostatectomy ± Pelvic LN dissection
• Brachytherapy
• Radical EBRT
Low Risk
• Radical EBRT + Short term ADT
• EBRT + Brachytherapy boost + Short term ADT
• Radical Prostatectomy ± Pelvic LN dissection ± Adjuvant RT
• Brachytherapy
Intermediate Risk
• Radical EBRT + long term ADT
• EBRT + Brachytherapy boost + long term ADT
• Radical Prostatectomy + Post op RT
High Risk
9

10. Roach formulas
• Partin’s risk nomograms uses pretreatment PSA,
Gleason score, and T category for risk assessment.
• Seminal vesicle involvement - PSA +([GS-6] x 10)
– Cutoff is 13%
– If <13%, risk 7%; if >=13%, risk 37%.
• Lymph node involvement - 2/3 x PSA + ([GS-6] x 10)
– Cutoff is 15%.
– If calculated risk is <15%, actual risk 6%; if >=15%,
actual risk 40%.
• Extracapsular extension - 3/2 x PSA + ([GS-3) x 10)
– Approximates actual risk
10

11. Radiotherapy
• Definitive Radiotherapy
– Radical EBRT
– EBRT + Brachytherapy boost
• Adjuvant Radiotherapy: Patients with unfavorable risk factors
• pT3-prostate cancer-ECE/SV+
• Positive surgical margins
• High Gleason scores /PSA
• Salvage Radiotherapy: In case of a biochemical failure occurs
• EBRT
– 3D-CRT/ IMRT with image guidance
– SBRT
– Particle radiation – Proton, Carbon Ions
• Brachytherapy
– Permanent implant
– Temporary implant
Target Volumes
Low risk: Prostate ± Proximal SV
Intermediate risk: Prostate + SV
High risk: Prostate + SV ± Pelvic
LNs (External and internal iliac,
presacral and obturator LN)
11

12. Journey of RT in Ca Prostate

13. Dose Escalation
Trial n Dose FU BCF OS
Heemsbergen et
al 2014
664 78 Gy vs 68 Gy 110 mo + -
Hoskin et al 2012 216 80 Gy vs 63 Gy 85 mo + -
Dearnaley et al
2011
843 74 Gy vs 64 Gy 120 mo + -
Beckendorf et al
2011
306 80 Gy vs 70 Gy 61 mo + -
Kuban et al 2007 301 78 Gy vs 70 Gy 114 mo + -

14. Principle

15. Fractionations

16. Introduction
• Hypo-fractionated RT: RT delivered over a shorter
time than standard RT with larger doses per fraction
• Mostly been studied in intermediate-risk prostate
cancers
ADVANTAGES
• Shorter treatment
• Increased patient convenience
• Lesser costs
• Optimized use of resources
CONCERNS
• ? Increased toxicity
16

17. Linear-quadratic model
• α and β are parameters defining the
radiation dose vs response curve
•  (Gy-1)= irreparable ,linear term- gives initial
slope
•  (Gy-2) = repairable, quadratic term- gives
final slope
17

18. Radiobiology

19. Modeling hypofractionation
19

20. History

21. Modern trials

22. Evidence
Trial Design HF dose Standard dose EQD2 Sample
size
F/up Efficacy Acute
toxicity
Late
Toxicity
PROFIT
(Canada)
Non-inf 60Gy/20#/4w 78Gy/39#/8w 77Gy 1206
Interm
6y 5y DFS
85% v 85%
GU same
≥G2 GI
more in
HF
GU same
≥G2 GI
more in
standard
CHHiP
(UK)
Non-inf 60Gy/20# or
57Gy/19#
74Gy/37#/8w 77Gy/
73.3G
3216
Interm
5y 5y DFS
90.6% v
85.9% v
88.3%
No diff No diff
Italian
(Arcagneli)
Non-inf 62Gy/20#/5w 80Gy/40#/8w 81.5 168
High
9y 10y DFS
72% v 65%
No diff No diff
HYPRO
(Dutch)
Sup. 64.6Gy/19#/6w 78Gy/39#/8w 90.4 820
High
5y 5y DFS
80.5% v
77.1%
GU same
GI more
in HF
≥G2 more
in HF
RTOG 0415
(US)
Non-inf 70Gy/28#/5.6w 73.8Gy/41#/8 80Gy 1115
Low
5.8y 5y DFS
86.3% v
85.3%
No diff G2, G3
more in
HF

23. • Intermediate risk patients
• 608 patients :Shorter
hypofractionated radiation
group: 60Gy/20#/4 weeks
• 598 patients: Standard
radiation group :
78Gy/39#/7-8 weeks
• Primary endpoint BCF
• Non inferiority margin 7.5%
(hazard ratio, <1.32)

24. Biochemical-Clinical Failure
• 109 of 608 pts in short arm
vs
• 117 of 598 in the standard
arm
• Most PSA failures
24

25. Biochemical-clinical
failure (BCF)–free survival
• The 5-year BCF-DFS 85%
(95% CI, 82-88%) in both
arms
• HR (short v standard)
adjusted on stratification
factors 0.96 (90% CI, 0.77 to
1.20, p=0.16).
25

26. Freedom from prostate
cancer–related death
• Total 154 deaths in the
cohort (76 in the short arm
and 78 in the standard arm)
• Overall, 10 deaths as a
result of prostate cancer
observed in the short arm
vs 12 in the standard arm
(HR, 0.76; 95% CI, 0.32 to
1.82)
26

27. GU toxicities
• Similar in both treatment
arms.
Acute (14 weeks)
• only 4% of patients in both
arms had grade ≥ 3 GU
toxicity;
Late period (6 months onward)
• 3.0% of patients in standard
arm vs 2.1% in the short arm
experienced grade ≥ 3 toxicity.
27

28. GI toxicities
• A significant increase in acute
grade ≥ 2 toxicity occurred in the
short arm (16.7% v 10.5% p =
.003)
• Late grade ≥ 2 toxicity, a
significant increase occurred in
the standard arm (8.9% v 13.9% p
= .006)
28

29. Toxicity profile
• Late grade ≥ 3 toxicity was not significantly different between groups, but a trend
toward higher levels in the standard arm was observed.
• Significantly less grade ≥ 2 late GI toxicity in the HF arm
• BED (tumor) : 180 Gy v 182 Gy
• BED (Acute tox) : 78 Gy v 93.6 Gy
• BED (Late tox) : 120 Gy v 130 Gy
• The reduction in late toxicity with the hypofractionated regimen is consistent
with the linear-quadratic model
29

30. CHHiP
30

31. Trial Design
• Between Oct 18, 2002, and June 17, 2011, 3216 men enrolled from 71 centres and
randomly assigned, 74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy
group, 1077 patients
• Median follow-up 62·4 months (IQR 53·9–77·0)
• IRPC, PS 0-1, T1b–T3aN0M0 , GS <8, PSA < 30 ng/mL , Risk of SV invol < 30%
• All patients treated by IMRT with portal imaging/image guidance
• All received 6 months of androgen deprivation therapy before and during RT
• BED(74Gy/37#)= 88.8(early), 123.33(late), 172.67(tumor)
• BED(60Gy/20#)= 78(early), 120(late), 180(tumor)
• BED(57Gy/19#)= 74(early), 114(late), 171(tumor)
31

32. Results
• 60 Gy was non-inferior to 74 Gy
with HR 0.84 (90% CI 0.68–1.03),
pNI=0.0018
• Evaluation of the lower 57 Gy was
inconclusive: it cannot be stated to
be non-inferior to the 74 Gy but it
was inferior to the 60 Gy group
• No significant differences in OS
• The proportion of patients,
biochemical or clinical failure free
at 5 years 88·3% (95% CI 86·0–
90·2) in the 74 Gy group, 90·6%
(88·5–92·3) in the 60 Gy group,
and 85·9% (83·4–88·0) in the 57 Gy
group
32

33. Toxicity
• The estimated cumulative 5 year incidence of RTOG grade 2 or worse bowel and
bladder adverse events 13·7% (111 events) and 9·1% (66 events) in the 74 Gy
group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95
events) and 6·6% (57 events) in the 57 Gy group, respectively
• No treatment-related deaths reported
• No difference in bladder s/e except: wave of toxicity occurs earlier in HF arms
• No significant differences in late bowel toxicity
• No significant differences in sexual function domains

34. HYPRO
34

35. HYPRO trial design
• Aluwani, Incrocci et al Lancet Oncology, Mar-Jun 2016 (Dutch)
• Intermediate-risk to high-risk: T1b–T4NX–N0MX–M0 localised prostate cancer,
PSA < 60 μg/L, PS 0-2
• Hypofractionated radiotherapy: 64.6 Gy/19fr of 3.4 Gy, 3fr/week
• Concomitant ADT for 6 months: 67%
• Median f/u 60 mnths
• 95% :IMRT
• The primary endpoint to detect a 10% enhancement in 5-year relapse-free
survival with hypofractionation
• A key additional endpoint non-inferiority of hypofractionation in cumulative
incidence of grade 2 or worse acute and late genitourinary and gastrointestinal
toxicity
• Planned to reject inferiority of hypofractionation for late genitourinary toxicity if
the estimated HR less than 1.11 and for gastrointestinal toxicity was less than
1.13
35

36. Results
• Treatment failure reported in 169 (21%) of 804 patients, 80 (20%) in the
hypofractionation group and 89 (22%) in the conventional fractionation group
• 5-year relapse-free survival 80.5% (95% CI 75.7–84.4) for hypofractionation and
77.1% (71.9–81.5) for conventional fractionation (HR 0.86, 95% CI 0.63–1.16; log-
rank p=0.36)
• No treatment-related deaths
• Not superior

37. Toxicity
Parameter HF Arm (64.6
Gy)
Standard (78
Gy)
Remarks
Treatment Failure 20% 22%
5-yr RFS 80.5% 77.1% Adjusted HR:0.86, (95% CI 0.63–1.16;
p=0.36)
HF-RT was not superior
Acute ≥ 2 GU 60.5% 57.8% p=0.43
Acute ≥ 2 GI 42% 31.2% p=0.0015; non-inferiority not confirmed
≥G2 GU tox (3y) 41.3% 39% HR 1.16
≥G2 GI tox (3y) 21.9% 17.7% HR 1.19 (Significantly more in HFRT)
≥G3 GU toxicity 19% 12.9% p=0.021 (Significantly more in HFRT)
≥G3 GI toxicity 3.3% 2.6% p=0.55
37
BED (hypo#)=
211(tumor),90.4 (EQD2
tumor), 86.56(Early),
137.81(late)
Vs
BED(conv#)= 182(tumor),
93.6(early), 130(late)

38. Arcangeli et al
38

39. Results
• 168 patients with high-risk Ca prostate
• Conventional(80 Gy/40#/8 weeks) vs Hypofractionated (62 Gy/20#/5 weeks)
• Median f/u 9 years
• No differences was observed in late ≥G2 gastro intestinal and genitourinary
toxicity (p=.68 and .57)
• 10-year FFBF rate was 72% in the hypofractionation group and 65% in the
conventional group (HR:1.62, p = .15)
• Ten-year OS rates were 75% in the hypofractionation group and 64% in the
conventional group(HR:1.45 , p= .22)
39
BED (hypo#)= 190.13(tumor),
81(Early), 126.06(late)
Vs
BED(conv#)= 186.67(tumor),
96(early), 133.33(late)

40. RTOG 0415
40

41. • Lee et al, JCO April 2016(US based)
• 1,115 men with low-risk prostate cancer (T1b to T2c,GS 2-6, PSA<10)
• C-RT (73.8 Gy/41#/8.2 wks) 1.8gy/# vs
• H-RT (70 Gy/28#/5.6 wks) 2.5Gy/#
• Median follow-up 5.8 years
• Trial designed to establish (with 90% power and an alpha of .05) that
treatment with H-RT results in 5-year disease-free survival (DFS) that is
not worse than C-RT by more than 7.65% (H-RT/C-RT hazard ratio [HR] ,
1.52
• BED (H-RT): Tumor=186.67, Early = 87.5, Late = 128.33
• BER (C-RT): Tumor= 162.36, Early = 87.08, Late = 118
41
RTOG 0415 Trial design

42. • 5-year DFS was 85.3% (95% CI, 81.9 to 88.1) in the C-RT arm and 86.3%
(95%CI, 83.1 to 89.0) in the H-RT arm
• DFS HR was 0.85 (95% CI, 0.64 to 1.14), and the predefined noninferiority
criterion was met (critical HR <1.52)(p<.001)
• No differences in early GI or GU adverse events were observed
• Late grade 2 and 3 GI and genitourinary adverse events were increased
(HR, 1.31 to 1.59) in patients who were treated with H-RT, but no
differences in severe toxic effects were recorded
42
RTOG 0415 Results

44. Metaanalysis
• 9 studies with 5969 patients
• RevMan 5.3 software
• H-RT group obtained greater improvements in the 5-year biochemical or clinical
failure-free survival (RR = 1.04, 95% CI:1.01–1.08; P = 0.01) and 5-year disease-
free survival(RR = 1.04, 95% CI: 1.01–1.07, P = 0.02) than the C-RT group
• 5-year overall survival rates comparable in the two groups (RR = 1.02, 95% CI:
0.99–1.04; P = 0.18)
• Comparison of multiple secondary parameters, including grade 2-4 acute/late
gastrointestinal toxicity, grade 2–4 acute/late genitourinary toxicity, biochemical
failure, local failure, distant failure and prostate cancer-specific mortality
between the H-RT and the C-RT groups showed no statistical differences
• This meta-analysis thus indicates that in patients with localized prostate cancer,
moderate H-RT exerts a great beneficial effect on the primary parameters than C-
RT without enhancing adverse events
Cao et al. Oncotarget, 2017

45. Metaanalysis
Cao et al. Oncotarget, 2017

46. Metaanalysis
Cao et al. Oncotarget, 2017

47. Metaanalysis
• 6 of 341 studies fulfilled inclusions with 6931 patients
• No significant difference in BCDF between H-RT and C-RT (RR=0.94, 95%
CI: 0.83-1.06, p=0.31), with a moderate heterogeneity I2=36%).
• Dose-escalated H-RT significantly improved BCDF compared with C-RT
(RR=0.86, 95%CI:0.74-0.99, p=0.04)
• Patients who received H-RT showed a lower BF (RR=0.78, 95% CI: 0.63-
0.97, p=0.03), without heterogeneity (I2=0%).
• No significant difference in overall survival (RR=0.89, 95% CI: 0.76-1.03,
p=0.12) between H-RT and C-RT, also no heterogeneity noted ( I2=0%).
• No significant difference in late GI (RR=1.04, 95%CI: 0.88-1.23, p=0.63)
and GU toxicity (RR=1.10, 95% CI: 0.47- 2.40, p=0.26) at 5-years
• Dose-escalated H-RT increased in late GI toxicity (RR=1.80, 95%CI: 1.32-
2.43, p=0.0002) and GU toxicity (RR=1.38, 95%CI: 1.07-1.79, p=0.01)
significantly, while non dose-escalated H-RT (GI: RR=0.82, 95%CI: 0.68-
1.00, p=0.05; GU: RR=0.92, 95%CI: 0.72-1.16, p=0.46)
Yin et al. ESTRO, 2017

48. Adjuvant/Salvage
48

49. Pelvic LN Irradiation
• Prospective, Phase II trial, 2009 to 2012,
• 40 patients of high-risk prostate cancer (increased risk of microscopic lymph node
involvement)
• Helical IMRT (tomotherapy) of the pelvic lymph nodes (51.0 Gy) with HF-SIB (2.25
Gy/#) to the prostate (76.5 Gy) in 34 fractions
• Overall acute toxicity rates were low and no acute grade 3 or 4 GI / GU toxicity.
• No late grade ≥ 2 GI toxicity and 6.4 % late grade 2 GU toxicity.
• At median f/u 2 yrs: 34/37 patients free of a PSA recurrence
49
The combined irradiation
of both prostate and
pelvic lymph nodes
seems to be as well
tolerated as the
irradiation of the prostate
alone

50. Hypo# with Pelvic LN irradiation
50

51. Extreme Hypofractionation
51

52. Extreme Radiobiology

53. SBRT- Low Risk
• Low-risk prostate cancer
• 67 patients
• 36.25 Gy in 5 fractions with CyberKnife system
• Median follow-up of 2.7 years
• Low rates of Late rectal and urinary toxicity - >G2 in 1 & 5 pts respectively
• The 4- year Kaplan-Meier PSA relapse-free survival was 94% and is similar to other
definitive treatments 53

54. • 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
54
King et al

55. 55
King et al

56. ASTRO 2016
56

57. Design
• Prostate given 5 doses of 8 Gy each
• RT dose to bladder, rectum, testes &
penile bulb rigorously constrained
• Pts followed an average of 5.1 yrs
57

58. Results
Safety
• No grade 4-5 toxicities
• Grade 3 side effects occurred in 4 pts:
• Two low-risk pts (1.2%)
• Two interm-risk pts (1.5%),
p<0.001
Efficacy
Based on Nadir + 2 definition:
• 97.1% of pts free from recurrence at 5 yrs
58

59. Results
59

60. Late Urinary Toxicity: Gr 2+
60

61. Late Bowel Toxicity: Gr 2+
61

62. Patient reported outcomes
62

63. QoL
63

64. ASTRO opinion
• Cost of treatment
– Higher for IMRT
• GU toxicity at 24
months
– SBRT – 43.9 %
– IMRT – 36.3 % (p =
0.001)
64

65. Image Guidance
• Prostate motion
– Inter-fraction
– Intra-fraction
• Bony Anatomy as surrogate
for prostate location
– Not reliable
– Significant variation
• Advantage
– Tight margin
– Better sparing
– Improved treatment
delivery

66. Image guidance
• Electronic Portal
Imaging
• Cone Beam CT
• Ultrasound (CLARITY)
• Orthogonal X rays
• Tomotherapy

67. Brachytherapy
• n= 218
• T1-T3 and PSA <50 ng/mL
• Radiotherapy
– EBRT alone – 55 Gy/20#
– EBRT 35.75 Gy/13#  HDR Brachytherapy 8.5 Gy x 2#
• ADT – 76%
• Primary end point - bRFS
Hoskin et al Radiother Oncol 2012; 103:217-22

68. Results
• 10 yr bRFS
– EBRT only – 39 %
– EBRT + Brachy boost – 46%
(p=0.04)
• 10 yr OS
– EBRT only – 79%
– EBRT + Brachy boost – 67%
(p=0.2)
• GU and GI toxicity
– Similar
• Risk of relapse
– Treatment arm
– Risk category
– ADT
BED (EBRT)= 155.83(tumor),
EQD2= 66.78 Gy
Vs
BED(EBRT+Brachy)=
(101.29+113.33)=
214.62(tumor), EQD2=
43.41+48.57=91.98 Gy

69. Widmark
(HYPO)
RTOG 0938
PACE
7.25 Gy*5#
36.25 Gy
7.25 Gy*5#
36.25 Gy
6.1 Gy*7#
42.7 Gy
2 Gy*39#
78 Gy
4.3 Gy*12#
51.6 Gy
2 Gy*39#
78 Gy
Future prospects
69
Extreme forms of
hypofractionated
radiotherapy
Tighter PTV
margins with
IMRT/IGRT and
Cyberknife

70. PACE
70

71. PRIAMOS
Hypofractionated helical intensity-modulated radiotherapy of the
prostate bed after prostatectomy with or without the pelvic lymph
nodes - the PRIAMOS trial
71

72. UCLA HR SBRT Trial
8 Gy x 5 (40 Gy) to prostate PTV
5 Gy x 5 (25 Gy) to pelvic LN
72

73. Conclusion
• RT dose is important to control prostate cancer, even in low risk disease
• Hypofractionation offers an equal, if not superior rates of tumor control in
patients with low and intermediate risk prostate cancers
• The toxicity rates are similar if appropriate dose and patient selection criterias
are used
• IMRT and IGRT are pre-requisite tools for administering high doses
• Prostate SBRT is a faster, cheaper and better way of treating localized prostate
cancers
• Further follow-up of already conducted trials need to be awaited, before hypo-
fractionated radiotherapy can be generally recommended for high risk patients
and adjuvant settings
73

74. Thank You
“It is rare that nature hands us a cancer situation
where an improved treatment goes hand in hand with
a shorter and more convenient one.”