hypofractionation in prostate cancer

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.”