ASTRO News Brie iefin ing: Refin inin ing Treatment Decis isions - - PowerPoint PPT Presentation

ASTRO News Brie iefin ing: Refin inin ing Treatment Decis isions

Monday, September 26, 8-9am ET Moderator: George Rodrigues, MD, PhD, London Health Sciences Centre

• N107C/CEC.3: A Phase

e II III Tria rial of

• f Pos
• st-Operativ

ive Stereotactic ic Radio iosurgery Com Compared with ith Whol

• le Br

Brain in Radio iotherapy for Res esec ected ed Metastatic Br Brain Dis Disease

Paul D. Brown, MD, Mayo Clinic

• Pos
• st-operativ

ive Stereotactic Radio iosurgery vs. . Observation for Co Comple letely Res esec ected Br Brain in Metastases es: Res esult lts of

• f a Prospective Randomized

ed Stu tudy

Anita Mahajan, MD, MD Anderson Cancer Center

• A Phase III

III Randomized Stu tudy of

• f Im

Image Guid ided Co Conventional l vs Acce ccelerated, Hy Hypofractionated Radia iati tion for

• r Poo
• or Perf

erformance e Statu tus Stage II II and II III NSCLC Patien tients – An In Interim Analy lysis is

Puneeth Iyengar, MD, PhD, University of Texas Southwestern

• Extreme Hy

Hypofractionati tion vs. . Co Conventionall lly Fractionated Radio iotherapy for In Intermedia iate Ris isk Prostate Ca Cancer: Earl rly Toxicity Res esult lts fr from th the e Scandin inavia ian Randomized Phase e II III Tria rial "H "HYP YPO-RT RT-PC PC"

Anders Widmark, MD, PhD, Umeå University, Sweden

N107C/CEC.3: A Phase III III Trial of f Post-Operative Stereotactic Radiosurgery ry (S (SRS) Compared wit ith Whole Brain Radiotherapy (W (WBRT) ) for Resected Metastatic Brain Dis isease

• P. D. Brown1,2, K. V. Ballman3, J. Cerhan1, S. K. Anderson1, X. W. Carrero1, A. C. Whitton4, J.

Greenspoon4, I. F. Parney1, N. N. Laack1, J. B. Ashman5, J. P. Bahary6, C. G. Hadjipanayis7, J. J. Urbanic8,

• F. G. Barker II9, E. Farace10, D. Khuntia11, C. Giannini1, J. C. Buckner1, E. Galanis1, and D. Roberge6

1Mayo Clinic, Rochester, MN, 2The University of Texas MD Anderson Cancer Center, Houston, TX, 3Weill Cornell Medicine, New York, NY, 4Juravinski Cancer Centre, Hamilton, ON, Canada, 5Mayo Clinic, Phoenix, AZ, 6Hopital Notre-Dame du CHUM, Montreal, QC, Canada, 7Winship

Cancer Institute, Emory University, Atlanta, GA, 8University of California, San Diego, La Jolla, CA, 9Massachusetts General Hospital, Boston, MA, 10Penn State University College of Medicine, Hershey, PA, 11Western Radiation Oncology, Mountain View, CA

Background

• WBRT standard of care after resection of brain metastasis to improve

local control

• However WBRT after resection
• No survival benefit
• Side effects (hair loss, fatigue, skin redness)
• Concerns cognitive impact
• Growing practice of SRS to the surgical cavity to reduce risk cognitive

toxicity

• Despite no level I efficacy data Post-Op SRS
• Despite costs of SRS
• Need to prospectively evaluate and compare SRS surgical bed to WBRT,

the standard of care

Method

Resected Brain Met*

S t r a t i f y

 Age (18 to 59 vs. ≥ 60)  Extra-Cranial Disease Controlled (≤ 3 vs. > 3 mo)  Number Pre-Op Brain Mets (1

• vs. 2-4)

 Histology (Lung vs. Radioresistant vs. Other)  Resection Cavity Max Diam (≤ 3cm vs. > 3cm)  Institution

R a n d

• m

i z e WBRT +SRS unresect mets SRS + SRS unresected mets

Patient Assessments:

• MRI
• Quality of Life (QOL)
• Cognitive Battery

Eligibility Criteria:

• S/P resection 1 lesion
• 0-3 unresected mets
• No chemo during radiation

Primary Endpoints: I: Cognitive Deterioration Free Survival II: Overall Survival *194 patients, 59% Lung Primary Tumor, 77% single metastasis

Results

No Dif ifference in in Surviv ival

SRS WBRT

Worse Cognitive Function wit ith WBRT

However, with WBRT…

• Worse quality of life (QOL)
• More toxicity
• Longer treatment course and

delayed systemic therapy

SRS WBRT

Results

Su Surgic ical l bed control l sim simil ilar, , alt lthough lo long-term better r with ith WBR BRT

Conclusions

Post-Op SRS for patients with resected brain metastases should also be a standard of care with equiv ivale lent survival, better preservation of cognitive function and QOL, and less toxicity than WBRT.

ASTRO News Brie iefin ing: Refin inin ing Treatment Decis isions

Monday, September 26, 8-9am ET Moderator: George Rodrigues, MD, PhD, London Health Sciences Centre

• N107C/CEC.3: A Phase III Trial of Post-Operative Stereotactic Radiosurgery Compared with Whole Brain

Radiotherapy for Resected Metastatic Brain Disease

Paul D. Brown, MD, Mayo Clinic

• Pos
• st-operativ

ive Stereotactic Radio iosurgery vs. . Observation for Co Comple letely Res esec ected Br Brain in Metastases es: Res esult lts of

• f a Prospective Randomized

ed Stu tudy

Anit nita Mah ahajan, MD, , MD D And nderson Can Cancer Cen Center

• A Phase III Randomized Study of Image Guided Conventional vs Accelerated, Hypofractionated

Radiation for Poor Performance Status Stage II and III NSCLC Patients – An Interim Analysis

Puneeth Iyengar, MD, PhD, University of Texas Southwestern

• Extreme Hypofractionation vs. Conventionally Fractionated Radiotherapy for Intermediate Risk Prostate

Cancer: Early Toxicity Results from the Scandinavian Randomized Phase III Trial "HYPO-RT-PC"

Anders Widmark, MD, PhD, Umeå University, Sweden

Post-operative Stereotactic Radiosurgery ry vs. Observ rvation for Completely Resected Brain Metastases: Results of f a Prospective Randomized Stu tudy

• A. Mahajan1, S. Ahmed2, J. Li3, M. F. McAleer1, J. Weinberg4, P. D. Brown3, S. Prabhu4, F. F. Lang4, S. L.

McGovern1, I. E. McCutcheon4, A. Heimberger4, E. P. Sulman3, A. J. Ghia1, S. Ferguson4, K. Hess5, and G. Rao4

1Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 2Department of Neuroradiology, UT

MD Anderson Cancer Center, Houston, TX, 3The University of Texas MD Anderson Cancer Center, Houston, TX, 4Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 5Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX

Background

• Surgical resection and whole brain

radiotherapy (WBRT) independently have been shown to improve local control for brain metastasis

• Whole brain radiation (WBRT) has been

used in the post operative setting but has a deleterious impact on cognition

• Post operative stereotactic radiosurgery

(SRS) may improve local control and allow delay or avoidance of WBRT

Patchell et al JAMA 1998;280(17) 1485-89

Local Failure after surgery alone vs surgery+WBRT

Surgery alone Surgery + WBRT

• Retrospective studies suggest local control rates of 80 to 90% after

post-op SRS

• Surgical techniques have evolved suggesting that en bloc resection

may be a favorable method to removing metastases in order to decrease resection cavity contamination

• Goal: Validate retrospective studies by evaluating SRS to the post-
• perative cavity in a prospective manner

Background and Rationale

Study Objectives

• Primary Objective:
• Determine whether the addition of post-operative SRS to the

resection cavity results in improved local tumor control compared to surgical resection alone

• Secondary Objectives
• Rate of distant brain metastasis, overall survival, WBRT

Method

Str tratification

1. 1 vs 2-3 BM 2. Melanoma vs other 3. Pre-operative tumor size <3cm vs > 3cm

Randomizatio ion

• SRS-cav or observation (OBS) of the

surgical cavity (or cavities if >1 lesion was resected)

• Remaining 1-2 metastasis were treated

with SRS

GTR

Register & Randomize

Register & Stratify

• 1. Histology
• 2. Size >3cm, <3cm
• 3. 1 vs 2,3 mets

SRS OBS MRI

FU + MRI q 6-9 wk x 1 y FU + MRI q 3-4 mo x 1 y

RANDOMIZE

Day 0 Day 14- 21 Day 15- 30 5-7 wks

Results: Local Control

ARM RM 6 mo

• LC

12 mo

• LC

95% CI Ha Hazard Ra Ratio OBS 57% 45% 33-61% 0.46 (0.25- 0.85) P=0.01 SRS 83% 72% 60-87%

ARM RM Med ed Tim Time to

• Loc
• c Rec

ec 95% CI OBS 7.6 mo 5.3 - nr SRS Not reached 15.6 - nr

Local Control

Results: DBM & OS

ARM Med OS OS Haz azard Ra Ratio OBS 17 mo

1.22 (0.79-1.87) P=0.37

SRS 17 mo ARM 12 12 mo DB DBM Fr Free Haz azard Ra Ratio OBS 33%

0.79 (0.50-1.24) P=0.29

SRS 43%

Distant Brain Metastasis

v

Overall Survival

v

Variables influencing LC

In Init itial Tumor Dia iameter N LC LC < 2.5 cm 40 91% 2.6-3.5 cm 55 43% >3.5 cm 33 46%

p=0.0004

Months Freedom from Local Recurrence 5 10 15 20 0.0 0.2 0.4 0.6 0.8 1.0 0 - 2.5: N = 40, 3 ev, 12 mon = 91% 2.6 - 3.5: N = 55, 25 ev, 12 mon = 43% > 3.5: N = 33, 17 ev, 12 mon = 46%

Local Recurrence by Tumor Size

Log Rank p = 0.0004

0.0 0.2 0.4 0.6 0.8 1.0

Conclusions

• Post-operative SRS after complete resection significantly improves

local control

• There was no difference in distant brain metastases (DBM) or overall

survival (OS) between the two groups.

• Further analysis will be presented to determine whether specific

patients benefit more from post-operative SRS.

=> Initial Tumor Size may provide guidance on magnitude of benefit => Increasing dose of SRS may allow improved LC on larger tumors

ASTRO News Brie iefin ing: Refin inin ing Treatment Decis isions

Monday, September 26, 8-9am ET Moderator: George Rodrigues, MD, PhD, London Health Sciences Centre

• N107C/CEC.3: A Phase III Trial of Post-Operative Stereotactic Radiosurgery Compared with Whole Brain

Radiotherapy for Resected Metastatic Brain Disease

Paul D. Brown, MD, Mayo Clinic

• Post-operative Stereotactic Radiosurgery vs. Observation for Completely Resected Brain Metastases:

Results of a Prospective Randomized Study

Anita Mahajan, MD, MD Anderson Cancer Center

• A Phase III

III Randomized Stu tudy of

• f Im

Image Guid ided Co Conventional l vs Acce ccelerated, Hy Hypofractionated Radia iati tion for

• r Poo
• or Perf

erformance e Statu tus Stage II II and II III NSCLC Patien tients – An In Interim Analy lysis is

Pun uneeth Iy Iyengar, MD, , PhD PhD, , Un Univ iversit ity of

• f Texas Sou

South thwestern

• Extreme Hypofractionation vs. Conventionally Fractionated Radiotherapy for Intermediate Risk Prostate

Cancer: Early Toxicity Results from the Scandinavian Randomized Phase III Trial "HYPO-RT-PC"

Anders Widmark, MD, PhD, Umeå University, Sweden

A Phase III III Randomized Stu tudy of f Im Image Guid ided Conventional (6 (60Gy/30fx fx) vs Accelerated, Hypofractionated (6 (60Gy/15fx) ) Radiation for Poor Perf rformance Status Stage II II and III III NSCLC Patients – An In Interim Analysis

• P. Iyengar1, K. D. Westover1, L. E. Court2, M. K. Patel3, A. T. Shivnani4, M. W. Saunders5, Y. Li6, J. Y. Chang7, A.

Gao8, C. Ahn1, H. Choy9, and R. D. Timmerman1

1University of Texas Southwestern Medical Center, Dallas, TX, 2Department of Radiation Physics, The University of Texas MD Anderson

Cancer Center, Houston, TX, 3Baylor Scott & White Texas A&M Radiation Oncology, Temple, TX, 4Texas Oncology, Dallas, TX, 5US Oncology, Tyler, TX, 6The University of Texas Health Science Center San Antonio, San Antonio, TX, 7Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 8UT Southwestern Medical Center, Dallas, TX, 9Princess Margaret Cancer Centre, Toronto, ON, Canada

• Patients with stage II and III NSCLC who cannot receive standard of

care surgery or chemotherapy + radiation due to co-existing medical comorbidities or poor performance status have limited outcomes with conventionally fractionated radiation alone.

• We previously completed a phase I dose escalation study that

demonstrated no increased toxicity in treating this patient population to doses reaching 60Gy in 15 fractions, which is half the number of radiation treatments as a standard course.

Background/Rationale

Trial Design/Objective

+ QoL

Fun Fundamentall lly, we e aim aim to

• de

determin ine if f ac accelerated, hypo pofractio ionated radi adiatio ion the therapy can impr prove sur surviv ival l whi hile le hal halving tr trea eatm tment tim time in n poo poor pe perform rmin ing stage II II/I /III NSCLC pa patie ients who ho cannot rec eceiv ive sur surgery ry or

• r radi

adiatio ion + + ch chemoth therapy.

• Patients with stage II NSCLC not candidates for surgery or stage III NSCLC not

candidates for chemoradiation due to diminished PS (Zubrod PS 2 or greater)

• Randomization to conventional RT regimes of 60-66Gy/30-33fx or accelerated,

hypofractionated RT of 60Gy/15 fx.

• Overall survival (OS) was the primary endpoint. Secondary endpoints included toxicity

assessment, progression free survival (PFS), quality of life and cost effectiveness.

• Chemotherapy was permissible sequentially either as induction or in the adjuvant

setting.

• The study was open at 15 institutions across the state of Texas and funded by the

Cancer Prevention and Research Institute of Texas.

Method

Results

• 60 patients have been enrolled on the study (28 to Arm A and 32 to

Arm B), with a median age of 68y in both cohorts.

• 53/60 patients presented with stage III disease, 7/60 with stage II.
• 48/60 patients were evaluable due to adequate length of follow-up (24

months). 56% of patients (27/48) were alive at last follow-up.

Results

• By Kaplan-Meier analysis, median OS for the 48 patients evaluable was

14 months, with no statistical difference between conventional vs hypofractionated radiation treatment arms.

• PFS was 11.5 months with again no statistical difference between

treatment arms.

• Grade 3 or higher toxicity was less in the experimental arm at this

time.

Conclusions

• A curative approach with accelerated, hypofractionated radiation

alone with similar OS and PFS to conventional radiation in a population

• f poor PS patients, with limited grade 3-5 toxicity, and a treatment

course of half the time.

• Completion of this study will potentially change the paradigm of

treatment of poor PS stage III NSCLC patients who cannot receive chemoradiation.

ASTRO News Brie iefin ing: Refin inin ing Treatment Decis isions

Monday, September 26, 8-9am ET Moderator: George Rodrigues, MD, PhD, London Health Sciences Centre

• N107C/CEC.3: A Phase III Trial of Post-Operative Stereotactic Radiosurgery Compared with Whole Brain

Radiotherapy for Resected Metastatic Brain Disease

Paul D. Brown, MD, Mayo Clinic

• Post-operative Stereotactic Radiosurgery vs. Observation for Completely Resected Brain Metastases:

Results of a Prospective Randomized Study

Anita Mahajan, MD, MD Anderson Cancer Center

• A Phase III Randomized Study of Image Guided Conventional vs Accelerated, Hypofractionated

Radiation for Poor Performance Status Stage II and III NSCLC Patients – An Interim Analysis

Puneeth Iyengar, MD, PhD, University of Texas Southwestern

• Extreme Hy

Hypofractionati tion vs. . Co Conventionall lly Fractionated Radio iotherapy for In Intermedia iate Ris isk Prostate Ca Cancer: Earl rly Toxicity Res esult lts fr from th the e Scandin inavia ian Randomized Phase e II III Tria rial "H "HYP YPO-RT RT-PC PC"

And nders Wid idmark, , MD, PhD PhD, Um Umeå Un Univ iversit ity, Sweden

Ext xtreme Hypofractionation vs. Conventionally Fractionated Radiotherapy for In Intermediate Risk Prostate Cancer: Early Toxicity Results fr from th the Scandinavian Randomized Phase III III Trial "HYPO-RT RT-PC"

• A. Widmark1, A. Gunnlaugsson2, L. Beckman3, C. Thellenberg-Karlsson1, M. Hoyer4, M. Lagerlund5, P.

Fransson6, J. Kindblom7, C. Ginman8, B. Johansson9, M. Seke10, K. Björnlinger11, E. Kjellén2, L. Franzen1, and

• P. Nilsson2

1Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden, 2Department of Oncology and Radiation Physics,

Skåne University Hospital, Lund University, Lund, Sweden, 3Department of Oncology, Sundsvall Hospital, Sundsvall, Sweden,

4Department of Oncology, Aarhus University Hospital, Aarhus, Denmark, 5Kalmar Hospital, Kalmar, Sweden, 6Department of Nursing,

Umeå University, Umeå, Sweden, 7Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, 8Department of Oncology, Karlstad Central Hospital, Karlstad, Sweden, 9Department of Oncology, Örebro University Hospital, Örebro University, Örebro, Sweden, 10Centrallasarettet Växjö, Växjö, Sweden, 11Ryhov Hospital, Jönköping, Sweden

Background

• Prostate cancer is postulated to have high radiation-fractionation

sensitivity  potential therapeutic benefit for hypofractionated (HF) radiotherapy (RT)

• Results from randomized studies investigating efficacy and side-

effects of moderately hypofractionated (M-HF HF) schedules have recently been reported (CHHiP, HYPRO, RTOG 0415)

• Data from randomized trials with ext

xtreme hypofractionation (E- HF HF) are lacking at this point, however

Patients and Method

• Open randomized phase III trial

‒ Non-inferiority design ‒ 1200 patients accrued

• July 2005-Nov 2015

‒ Intermediate risk PCa

• T1c-T3a, PSA ≤ 20, Gl ≥7,

1-2 of these risk factors were required

• No androgen deprivation therapy

as allowed

• Equieffective for late normal

tissue complication probability (α/β=3 Gy)

R A N D O M I Z E Conventional fractionation (CF): 39∗2.00 Gy = 78.0 Gy

• ver 8 weeks

Extreme hypofractionation (E-HF): 7∗6.10 Gy = 42.7 Gy

• ver 2.5 weeks

Radiation Therapy

• IGRT based 3D-CRT or VMAT/IMRT

90% (80%) 3D-CRT 10% (20%) VMAT

Urin rinary ry toxicit ity ≥ grade 2

10 10 20 20 30 30 40 40 50 50 60 60 70 70 80 80 90 90 100 100

pre R RT RT e end 3m 3m 6m 6m 12m 18m 24m

Prevale lence of f gr grad ade ≥ 2 ur urinary to toxic icity ty (%)

CF CF E-HF

Bowel toxicit ity ≥ grade 2

10 10 20 20 30 30 40 40 50 50 60 60 70 70 80 80 90 90 100 100

pre R RT RT e end 3m 3m 6m 6m 12m 18m 24m

Prevale lence of f gr grad ade ≥ 2 bow bowel to toxic icit ity (%)

CF CF E-HF

n (CF ) 432 429 319 369 405 385 373 n (E-HF) 428 427 344 369 399 387 369 n (CF ) 432 433 320 370 405 386 374 n (E-HF) 428 427 344 370 400 387 371

p=0 p=0.59

≈5%

Results: Physician’s evaluation

p=0 p=0.20

≈3%

p=0.015 CF 1 m E-HF 2.5 m p=0.023

1 2 3 4 5 6 7 8 9 10 10 pre RT RT end 3m 3m 6m 6m 12m 12m 24m 24m

Symptom se severity

CF CF E-HF 1 2 3 4 5 6 7 8 9 10 10 pre RT RT end 3m 3m 6m 6m 12m 12m 24m 24m

Symptom se severity

CF CF E-HF p=0 p=0.17 p=0 p=0.12

n (CF ) 325 290 270 285 287 302 n (E-HF) 323 285 285 298 304 300 n (CF ) 325 291 268 285 286 304 n (E-HF) 329 285 292 300 303 299 2016-09-13/PN

Results: Pati

tient-reported outcome measurements (P (PROM)

”Do you have problems with your urinary tract?” “Do you have problems with your bowel?”

p=<0.001 p=0.001

CF 1 m E-HF 2.5 m

1 2 3 4 5 6 7 8 9 10 10 pre RT RT end 3m 3m 6m 6m 12m 12m 24m 24m

Symptom se severity

CF CF E-HF p=0 p=0.71

n (CF ) 316 283 265 281 281 294 n (E-HF) 319 270 280 286 293 284 2016-09-13/PN

Results: Pati

tient-reported outcome measurements (P (PROM)

“Do you have a problem with your sex life?”

Conclusions

• Extreme hypofractionation resulted in a low incidence of side-effects

with no significant differences compared to conventional fractionation at two years

• Evaluation of primary endpoint due in approximately one year

ASTRO News Brie iefin ing: Refin inin ing Treatment Decis isions

Monday, September 26, 8-9am ET Moderator: George Rodrigues, MD, PhD, London Health Sciences Centre

• N107C/CEC.3: A Phase

e II III Tria rial of

• f Pos
• st-Operativ

ive Stereotactic ic Radio iosurgery Com Compared with ith Whol

• le Br

Brain in Radio iotherapy for Res esec ected ed Metastatic Br Brain Dis Disease

Paul D. Brown, MD, Mayo Clinic

• Pos
• st-operativ

ive Stereotactic Radio iosurgery vs. . Observation for Co Comple letely Res esec ected Br Brain in Metastases es: Res esult lts of

• f a Prospective Randomized

ed Stu tudy

Anita Mahajan, MD, MD Anderson Cancer Center

• A Phase III

III Randomized Stu tudy of

• f Im

Image Guid ided Co Conventional l vs Acce ccelerated, Hy Hypofractionated Radia iati tion for

• r Poo
• or Perf

erformance e Statu tus Stage II II and II III NSCLC Patien tients – An In Interim Analy lysis is

Puneeth Iyengar, MD, PhD, University of Texas Southwestern

• Extreme Hy

Hypofractionati tion vs. . Co Conventionall lly Fractionated Radio iotherapy for In Intermedia iate Ris isk Prostate Ca Cancer: Earl rly Toxicity Res esult lts fr from th the e Scandin inavia ian Randomized Phase e II III Tria rial "H "HYP YPO-RT RT-PC PC"

Anders Widmark, MD, PhD, Umeå University, Sweden

Q & A

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• ston

Room 151A, Boston Convention and Exhibition Center September 25-27, 8am-4pm ET; September 28, 8am-12pm ET 703-286-1600 press@astro.org

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