ASTRO News Briefing: Refining Treatment Decisions · Puneeth Iyengar, MD, PhD, University of Texas Southwestern •Extreme Hypofractionation vs. Conventionally Fractionated Radiotherapy

$Page 1: ASTRO News Briefing: Refining Treatment Decisions · Puneeth Iyengar, MD, PhD, University of Texas Southwestern •Extreme Hypofractionation vs. Conventionally Fractionated Radiotherapy$
ASTRO News Briefing: Refining Treatment DecisionsMonday, September 26, 8-9am ETModerator: 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 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

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

Radiotherapy (WBRT) for Resected Metastatic Brain Disease

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*

Stratify

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

Randomize

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 SurvivalII: Overall Survival

*194 patients, 59% Lung Primary Tumor, 77% single metastasis

Results

No Difference in Survival

SRS

WBRT

Worse Cognitive Function with WBRT

However, with WBRT…- Worse quality of life (QOL)

- More toxicity

- Longer treatment course and delayed systemic therapy

SRS

WBRT

Results

Surgical bed control similar, although long-term better with WBRT

Conclusions

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






• A Phase III Randomized Study of Image Guided Conventional vs Accelerated, HypofractionatedRadiation for Poor Performance Status Stage II and III NSCLC Patients – An Interim Analysis




Post-operative Stereotactic Radiosurgery vs. Observation for Completely Resected Brain Metastases: Results of a

Prospective Randomized Study

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 aloneSurgery + 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-operative 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

MethodStratification1. 1 vs 2-3 BM2. Melanoma vs other3. Pre-operative tumor size <3cm vs >

3cm

Randomization• 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 & RandomizeRegister & Stratify

1. Histology2. 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 6 mo LC 12 mo LC 95% CI Hazard Ratio

OBS 57% 45% 33-61% 0.46 (0.25-0.85)

P=0.01SRS 83% 72% 60-87%

ARM Med Time to Loc Rec 95% CI

OBS 7.6 mo 5.3 - nr

SRS Not reached 15.6 - nr

Local Control

Results: DBM & OS

ARM Med OS Hazard Ratio

OBS 17 mo 1.22 (0.79-1.87)P=0.37SRS 17 mo

ARM 12 mo DBM Free Hazard Ratio

OBS 33% 0.79 (0.50-1.24)P=0.29SRS 43%

Distant Brain Metastasis

v

Overall Survival

v

Variables influencing LC

Initial Tumor Diameter

N LC

< 2.5 cm 40 91%

2.6-3.5 cm 55 43%

>3.5 cm 33 46%

p=0.0004

Months

Fre

ed

om

fro

m L

oc

al

Re

cu

rre

nc

e

0 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










A Phase III Randomized Study of Image Guided Conventional (60Gy/30fx) vs Accelerated, Hypofractionated(60Gy/15fx) Radiation for Poor Performance Status Stage II

and III NSCLC Patients – An 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

Fundamentally, we aim to determine if accelerated, hypofractionated radiation therapy can improve

survival while halving treatment time in poor performing stage II/III NSCLC patients who cannot

receive surgery or radiation + chemotherapy.

• 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 of 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.






• A Phase III Randomized Study of Image Guided Conventional vs Accelerated, HypofractionatedRadiation for Poor Performance Status Stage II and III NSCLC Patients – An Interim Analysis




Extreme Hypofractionation vs. Conventionally Fractionated Radiotherapy for Intermediate Risk Prostate Cancer: Early

Toxicity Results from the Scandinavian Randomized Phase III Trial "HYPO-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) schedules have recently been reported (CHHiP, HYPRO, RTOG 0415)

• Data from randomized trials with extreme hypofractionation (E-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 factorswere required

- No androgen deprivation therapy as allowed

Equieffective for late normal tissue complication probability(α/β=3 Gy)

RANDOMIZE

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

Extremehypofractionation (E-HF):7∗6.10 Gy = 42.7 Gyover 2.5 weeks

Radiation Therapy

• IGRT based 3D-CRT or VMAT/IMRT

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

Urinary toxicity ≥ grade 2

0

10

20

30

40

50

60

70

80

90

100

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

Prev

alen

ce o

f gra

de

≥ 2

uri

nar

y to

xici

ty (%

)

CF E-HF

Bowel toxicity ≥ grade 2

0

10

20

30

40

50

60

70

80

90

100

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

Prev

alen

ce o

f gra

de

≥ 2

bo

wel

toxi

city

(%)

CF E-HF

n (CF ) 432 429 319 369 405 385 373n (E-HF) 428 427 344 369 399 387 369

n (CF ) 432 433 320 370 405 386 374n (E-HF) 428 427 344 370 400 387 371

p=0.59

≈5%

Results: Physician’s evaluation

p=0.20

≈3%

p=0.015

CF 1 m E-HF 2.5 m

p=0.023

0

1

2

3

4

5

6

7

8

9

10

pre RT RT end 3m 6m 12m 24m

Sym

pto

m s

ever

ity

CF E-HF

0

1

2

3

4

5

6

7

8

9

10


Sym

pto

m s

ever

ity

CF E-HF

p=0.17p=0.12

n (CF ) 325 290 270 285 287 302n (E-HF) 323 285 285 298 304 300

n (CF ) 325 291 268 285 286 304n (E-HF) 329 285 292 300 303 299

2016-09-13/PN

Results: Patient-reported outcome measurements (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

0

1

2

3

4

5

6

7

8

9

10


Sym

pto

m s

ever

ity

CF E-HF

p=0.71

n (CF ) 316 283 265 281 281 294n (E-HF) 319 270 280 286 293 284

2016-09-13/PN

Results: Patient-reported outcome measurements (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










Q & A

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Additional questions and interview requests:

ASTRO’s On-site Press Office in Boston

Room 151A, Boston Convention and Exhibition Center

September 25-27, 8am-4pm ET; September 28, 8am-12pm ET

703-286-1600

[email protected]

Slides, photos, and audio will be available following the briefing at www.astro.org/AMpress

http://www.astro.org/AMpress

Documents

ASTRO News Briefing: Refining Treatment Decisions · Puneeth Iyengar, MD, PhD, University of Texas Southwestern •Extreme Hypofractionation vs. Conventionally Fractionated Radiotherapy