1. Evaluation of biologically equivalent dose escalation, clinical outcome, and toxicity in prostate cancer radiotherapy: A meta-analysis of 12,000 patients from 40 institutions
Nicholas G Zaorsky, MD;
Mark D Hurwitz, MD; Scott W Keith, PhD;
Adam P Dicker, MD, PhD; Robert B Den, MD
Department of Radiation Oncology
Jefferson Medical College and Kimmel Cancer Center
of Thomas Jefferson University
Monday, 23 September 2013
10:45 AM

2. Disclosures
None

3. Background
The role of dose-escalation (DE) to a biologically equivalent dose (BED) of ~180 Gy (at an α/β of 1.5) with conventionally fractionated RT has been established to improve rates of freedom from biochemical failure (FFBF)
Hypofractionated RT and high dose rate brachytherapy (HDR-BT) allow for further BED escalation

4. Background BED = (n) (d) [1 + ] (d) (α/β)
[ ]
(d)
(α/β)
n is the number of radiation fractions
d is the fraction size (Gy)
BED, at α/β of
1.5 = efficacy for eliminating prostate cancer
3 = late toxicity
10 = early toxicity

5. CFRT or HFRT, to a lower total dose (i.e. less fractions)
SBRT
“virtual HDR-BT”
~8 weeks
1.8 – 2.0 Gy
5 days per week
1 fraction, 15 minutes per day
5 days per week
~4 weeks
2.1 – 3.5 Gy
1 fraction, 15 minutes per day
~ 5 fractions
1 fraction, < 45 minutes per day
3.5 – 15.0 Gy
~1-2 weeks
non-DE DE
HDR-BT
~ Gy
per fraction
~ days
1 fraction, ~2 hours per day
CFRT or HFRT, to a lower total dose (i.e. less fractions)
HDR-BT
HDR-BT boost

6. n is the number of radiation fractions;
Higher BED theorized to improve outcome
Lower BED theorized to decrease toxicity
BED = (nd[1 + d/(α/β)])
n is the number of radiation fractions;
d is the fraction size

7. n is the number of radiation fractions;
Higher BED theorized to improve outcome
Lower BED theorized to decrease toxicity
BED = (nd[1 + d/(α/β)])
n is the number of radiation fractions;
d is the fraction size

8. Purpose
To determine if increasing BED > 180 Gy with HDR-BT is correlated with outcomes or late toxicities

9. Methods
Meta-analysis that includes 12,311 prostate cancer patients (n) from 81 studies (N) published from 1970 to 2012 PICOS / PRISMA selection protocol

10. non-DE-CFRT; DE-CFRT; HFRT HDR-BT mono and/or boost
Methods
Patients
Men with localized (T1-T2, N0-Nx, M0) and
locally advanced (T3-T4, N0-Nx, M0) prostate cancer
Intervention
non-DE-CFRT; DE-CFRT; HFRT
HDR-BT mono and/or boost
Control
Either no control group (i.e. intervention as a monotherapy);
or a multi-arm study that contains the intervention
Outcomes
Actuarial 5-years, stratified by risk groups
Late RTOG toxicities, GI and GU
Study design
Large (n > 150), prospective
Small, retrospective studies included to account for variability in fractionation schedules and BEDs

11. non-DE-CFRT; DE-CFRT; HFRT HDR-BT mono and/or boost
Methods
non-DE-CFRT; DE-CFRT; HFRT
HDR-BT mono and/or boost
Studies identified through database searching
(N = 201)
Studies identified through database searching
(N = 270)
Identification
Studies after duplicates and updates removed
(N = 190)
Studies after duplicates and updates removed
(N = 255)
Studies screened
(N = 190)
Studies screened
(N = 255)
Screening
Studies excluded
(N = 130)
Studies excluded
(N = 123)
Full-text studies assessed for eligibility
(N = 60)
Studies assessed for eligibility
(N = 102)
Updates of HFRT trials from national meetings
(N = 1)
Full-text studies excluded, with reasons
retrospective, not a clinical trial, or non-randomized (31)
focus on stereotactic body radiation therapy or high dose rate brachytherapy (9)
report on dosimetry only (8)
report on efficacy or safety only (1)
Full-text studies excluded, with reasons
focus on stereotactic body radiation therapy (6)
report on dosimetry, physics only (12)
report on acute outcomes / toxicity only (14)
report not on primary or definitive HDR-BT (15)
Eligibility
Major trials comparing non-DE-CFRT to DE-CFRT
(N = 6)
Studies included in qualitative synthesis
HFRT vs. non-DE-CFRT or DE-CFRT (N =12)
Major trials comparing non-DE-CFRT to DE-CFRT (N = 6)
Studies included in qualitative synthesis
HDR-BT mono (N = 11 [not exclusive])
HDR-BT boost (N = 44 [not exclusive])
Included
n = 4,028
n = 8,283

12. non-DE-CFRT; DE-CFRT; HFRT HDR-BT mono and/or boost
Methods
non-DE-CFRT; DE-CFRT; HFRT
HDR-BT mono and/or boost
(n)
(d)
[ ]
(d)
(α/β)
CALCULATE
BEDs
Mixed effects regression models used to estimate weighted linear relationships between BED and:
Outcomes (i.e. 5-year FFBF)
Late toxicity

13. Outcomes 5-year FFBF vs. BED at α/β of 1.5 low-risk intermediate-risk
high-risk

14. Low-risk non-DE-CFRT; DE-CFRT; HFRT HDR-BT mono and boost
5-year FFBF (%)
BED with α/β of 1.5 (Gy)
non-DE-CFRT; DE-CFRT; HFRT
HDR-BT mono and boost

15. Intermediate-risk non-DE-CFRT; DE-CFRT; HFRT HDR-BT mono and boost
5-year FFBF (%)
BED with α/β of 1.5 (Gy)
non-DE-CFRT; DE-CFRT; HFRT
HDR-BT mono and boost

16. High-risk non-DE-CFRT; DE-CFRT; HFRT HDR-BT mono and boost
5-year FFBF (%)
BED with α/β of 1.5 (Gy)
non-DE-CFRT; DE-CFRT; HFRT
HDR-BT mono and boost

17. Toxicity Late RTOG toxicity vs. BED at α/β of 3.0 Sites: Grades:
Gastrointestinal (GI)
Genitourinary (GU)
Grades:
0: none
1: mild
2: moderate
3: severe
4: extreme

18. Toxicity non-DE-CFRT; DE-CFRT; HFRT HDR-BT mono and boost
incidence (%)
BED with α/β of 3.0 (Gy)
non-DE-CFRT; DE-CFRT; HFRT
HDR-BT mono and boost

19. Results in perspective
Outcomes and toxicities of increasing BED for prostate cancer radiotherapy
Study type
N (n)
BED (Gy) ranges at α/β
Risk group
5-year FFBFs at BED range with α/β of 1.5
Late RTOG grade 3-4 toxicity at BED range with α/β of 3.0
1.5
3.0
% range
Slope
GU % range
GI % range
non-DE-CFRT; DE-CFRT; HFRT
15 (4,028)
98-133 L
75-100 †
0-7
0.61
0-13
1.54* I
60-100
4.94** H
55-85
HDR-BT monotherapy or boost 81
(8,283)
90-100
- 0.14
0-12
0.57
0-4
0.10
85-100
- 0.01
50-85
0.20
Note:
* denotes p-value < 0.05
** denotes p-value < 0.01
† denotes insufficient data reported

20. Results in perspective
CFRT / HFRT
5-year FFBF (%)
non-dose escalated
dose-escalated
risk group
HDR-BT 90 80 70
100 60
low
intermediate
high 20
toxicity
insert
incidence
(%)
100
BED at α/β of 5
150
100
140
200
300
BED at α/β of 1.5

21. Conclusions: tumor perspective
Increasing BED (at α/β of 1.5) from 140 to 200 Gy is associated with improvements in percent FFBF, specifically in intermediate-risk patients
Further increments of BED above 200 Gy are not significantly associated with improved FFBF among any risk groups

22. Conclusions: normal tissue perspective
Increasing BED (at α/β of 3.0) from 98 to 133 Gy is associated with increased toxicity
Increasing from 107 to 188 Gy is not associated with a change in toxicity

23. END