PROSTATE:

STRATEGIES FOR TREATMENT (DE)ESCALATION

Anders Widmark,

Professor, Senior Consultant

Department of Radiation Sciences,

Oncology, CancerCenter

Umeå University

DISCLOSURE

• I have no disclosure

• “The views expressed in this presentation are those of the presenters and do not necessarily reflect the views or policies of Accuray Incorporated or its subsidiaries. No official endorsement by Accuray Incorporated or any of its subsidiaries of any vendor, products or services contained in this presentation is intended or should be inferred.”

• An honorarium is provided by Accuray for this presentation

• Dose-escalation – 2 Gy x 32=64 Gy

• Conventional fractionation o 2 Gy x 39 = 78 Gy

• Moderate HYPO fractionationo 2.4−3.4 Gy, 20 fractions

o 4 randomised trials

o

• ULTRA HYPO fractionation o 5–10 Gy per fraction x 4–7 fractions

o HYPO-RT-PC

• SBRT- Stereotactic Body RadioTherapyo 5–10 Gy per fraction x 4–7 fractions

o non-randomised trials Outcome and Toxicity

AGENDA

Is there a Patient Benefit?

HDR Bracy is common in high risk

in Sweden

Dose Escalation Radiotherapy of

Prostate Cancer

Onk. AW 0204

Randomised Studies

Dose-escalation RadiotherapyMD Andersson (n=304)

– 70 Gy v.s. 78 Gy

Holland ( Rotterdam, Amsterdam)

– 68 Gy v.s. 78 Gy n=650? (Closed)

MRC (England)

– 64 Gy v.s. 74 Gy n=800 Closed

France (Prof Bey, Nancy et al)

– 70 Gy vs. 78 Gy (200 closed)

Berlin (Charite)

– 76 Gy vs. 82 Gy (200??)

NUS, Onk. AW 9811

Dose-escalation

Lancet Oncol 2014; 15: 464–73

Treatment data were obtained on more than 20,000 patients in

the National Oncology Data Alliance®, a, proprietary database of merged

tumor registries, who were treated for prostate cancer with definitive radiotherapy

between 1995 and 2006. M. Follow up 8 Years.

Md. OS

11.4 y.

12.0 y.

12.8 y.

• Convenient to patients

• Competitive to radical prostatectomy

• Cost effective

• A way to increase the biological dose

• Iso-toxic

• More efficient

• May avoid hormones

?

Why hypofractionation?

HYPOFRACTIONATION

ISSUES

• If prostate cancer α/β is low, higher effect is expected, with FEW but higher dose/fraction (Enhanced Tumor Control Probability).

• BUT Small doses per fraction saves late responding (normal) tissue,

• So if large dose/fraction, we must reduce MARGINS WHICH REQUIRES GOOD POSITIONING

• BUT

• Reducing margins really need PRECICION radiotherapy, since missing the tumor is devastating, due to the high dose per fraction

α/β for prostate cancer!

KingWang

Hyper

Valdagni

B&R

NahumDasu A, 2007

Prostate alpha/beta revisited – an analysis of clinical results

from 14 168 patients,

Patients: Conventional Fractionation (CF) 11330 – HYPO 2838

“The analysis of hypofractionation data led to very low a/b values (1–1.7

Gy)”

Dasu A, Toma-Dasu I 2012

α/β < 3.0

Tumour α/β =10.0

Prostate

30 40 50 60 70 80 900

20

40

60

80

100

Fowler, Ritter, Chappell & Brenner "What hypofr protocols..." IJROBP 2003 56(4):1093-1194.

30F

i.e. 69% to 85%

190 x 2 pats

Using 15F x 3.6Gy with no change in physical technique should give

same late complic's but increased bNED as if 72Gy increased to 80Gy,

Assuming prostate

tumor = 1.5 Gy

(3Gy)Constant late BED equiv to 72 Gy NTD

36Fx 2Gy

3F 5F

7.12

Gy

10F

4.69

Gy

15F

3.62

Gy

20F

3.0

Gy

25F

2 Gy fractions

Prostate Ca Intermediate Risk 10-20 ng/ml

Actu

ari

al 5

y

bN

ED

%

Total dose (Gy)

MODERAT-HYPO-FRACTION TRIALS

Dearnaley & Hall 2017

IM

IM + High

IM

LR

2.5-4 Gy / Fraction

Hormones, 6m

Hormones 32m

1 2 3 4 5 6 7 8 9 10 α/β

The “real prostate cancer α/β”

Lukka

Arcangeli

DearnaleyCHHiP

LeeRTOG 0415

IncrocciHYPRO

*

*

*Pollack

Yeoh

ULTRA-HYPOFRACTIONATED VERSUS CONVENTIONALLY FRACTIONATED

RADIOTHERAPY FOR PROSTATE CANCER:

5-YEAR OUTCOMES OF THE HYPO-RT-PC

RANDOMISED, NON-INFERIORITY, PHASE 3 TRIAL

Anders Widmark, Adalsteinn Gunnlaugsson, Lars Beckman, Camilla Thellenberg-

Karlsson, Morten Hoyer, Magnus Lagerlund, Jon Kindblom, Claes Ginman, Bengt

Johansson, Kirsten Björnlinger, Mihajl Seke, Måns Agrup, Per Fransson, Björn Tavelin,

David Norman, Björn Zackrisson, Harald Anderson, Elisabeth Kjellén,

Lars Franzén, Per Nilsson

Umeå, Lund, Sundsvall, Kalmar, Göteborg, Karlstad, Örebro, Växjö, Jönköping, Linköping, Sweden

and Århus, Denmark

The Lancet Published Online June 18, 2019

• Open, randomised,phase III trial

o Intermediate/high-risk prostate cancer*

o 1200 patients accrued

▪ July 2005-Nov 2015

o No androgen deprivation therapy

MATERIAL AND METHODS − TRIAL DESIGN

RANDOMISE

Conventional fractionation (CF): 39∗2.00 Gy = 78.0 Gyover 8 weeks

Ultrahypofractionation(U-HF): 7∗6.10 Gy = 42.7 Gyover 2.5 weeks

Equieffective for late normal tissue

complication probability (α/β=3 Gy)

*T1c-T3a, PSA ≤20 with one or two of the following risk factors; T3a or Gleason ≥7 or PSA >10

• Primary endpoint

o Time to biochemical* or clinical (local/distant) failure

• Secondary endpoints

o Overall survival

o Cancer specific survival

o Side effects (RTOG scale)

o Quality of Life (QoL)

o Time to change of treatment

o PSA response rate

• Trial design/statistics

o Non-inferiority

o Primary endpoint evaluated with Cox proportional hazards model

o Pre-specified critical HR of1.338 → ∆=4% margin

MATERIAL AND METHODS −

ENDPOINTS/STATISTICS

*PSA nadir + 2.0 ng/ml

• Target volumeso CTV = prostate

▪ SV not included

o PTV=CTV + 7 mm isotropic margino CTV delineated on CT

▪ with MR guidance

• RT techniqueo 3D-CRT (80%)o IMRT/VMAT (20%)

• IGRTo implanted fiducial markers

• OAR constraints/objectiveso Rectum: V90%≤ 15%, V75%≤ 35%,

V65%≤ 45%o Bladder: none

MATERIAL AND METHODS − RADIOTHERAPY

7 mm

BASELINE DEMOGRAPHICS, CLINICAL

CHARACTERISTICS, AND RADIOTHERAPY DETAILS

FOR THE PER-PROTOCOL POPULATION

FAILURE-FREE SURVIVAL

FFS

84%

OVERALL SURVIVAL

SIDE EFFECTS

Physician

Urinary Toxicity

Patient

Physician

Bowel Toxicity

Patient

Physician

Erectal Function

Patient

CUMULATIVE INCIDENCE OF PHYSICIAN-

REPORTED LATE URINARY AND BOWEL TOXICITY

OF GRADE 2 OR WORSE

Urinary Bowel

INTERPRETATION - CONCLUSION

• Ultra-hypofractionated radiotherapy is non-inferior to conventionally fractionated radiotherapy for intermediate-to-high risk prostate cancer regarding failure-free survival.

• Early side-effects, at end of treatment, are more pronounced with ultra-hypofractionation compared with conventional fractionation whereas late toxicity is similar in both treatment groups.

• The results support the use of ultra-hypofractionation for radiotherapy of prostate cancer.

1 2 3 4 5 6 7 8 9 10 α/β

The “real prostate cancer α/β”

Lukka

Arcangeli

DearnaleyCHHiP

LeeRTOG 0415

IncrocciHYPRO

*

*

*Pollack

Yeoh

HYPO-RT-PC

ULTRA-HYPOFRACTIONATION TRIALS

Morgan et. al. JCO 2018

62 Gy in 20fr

FIGURE 2: ACUTE RADIATION THERAPY ONCOLOGY GROUP TOXICITY FOR

GASTROINTESTINAL (A) AND GENITOURINARY (B) SYSTEMS

Incontinence Obstructive subdomain Overall urinary bother

Bowel subdomain Sexual subdomain Hormonal subdomain

QUESTIONS?

COMMENTS?

HYPO ARGUMETS

ACUTE TOX - URINARYRTOG HYPO-RT-PC RTOG – PACE-B PROM HYPO-RT-PC

ACUTE TOX - BOWELPROM HYPO-RT-PCRTOG – PACE-B