ASTRO News Briefing: Innovations in RT DeliveryTuesday, September 27, 1:30-2:30pm ETModerator: Geraldine M. Jacobson, MD, MPH, MBA, FASTRO, West Virginia University

• A Phase III Randomized Trial Comparing Patient Reported Toxicity and Quality of Life (QOL) During Pelvic IMRT as Compared to Conventional RT

Ann H. Klopp, MD, PhD, MD Anderson Cancer Center

• Radiation Boost for Ductal Carcinoma In Situ After Whole Breast Radiation Therapy (WBRT) Improves Local Control: Analysis from Ten Pooled Academic Institutions

Meena S. Moran, MD, Yale University

• Results of COG ACNS0331: A Phase III Trial of Involved-Field Radiotherapy (IFRT) and Low Dose Craniospinal Irradiation (LD-CSI) with Chemotherapy in Average-Risk Medulloblastoma: A Report from the Children’s Oncology Group

Jeff M. Michalski, MD, MBA, FASTRO, Washington University in St. Louis

https://www.astro.org/uploadedFiles/_MAIN_SITE/Meetings_and_Education/ASTRO_Meetings/2016/Annual_Meeting/Content_Pieces/AllDisclosures.pdf

A Phase III Randomized Trial Comparing Patient Reported Toxicity and Quality of Life (QOL) During Pelvic IMRT as

Compared to Conventional RT

A. H. Klopp1, A. R. Yeung2, S. Deshmukh3, K. M. Gil4, L. Wenzel5, S. N. Westin1, K. Gifford1, D. K. Gaffney6, W. Small Jr7, S. Thompson8, D. E. Doncals9, G. H. C. Cantuaria10, B. Yaremko11, A. Chang12, V. Kundapur13, D. S.

Mohan14, M. L. Haas15, Y. B. Kim16, C. L. Ferguson17, and D. W. Bruner18

1MD Anderson Cancer Center, Houston, TX, 2Department of Radiation Oncology, University of Florida, Gainesville, FL, 3American College of Radiology, Philadelphia, PA, 4Summa Health System, Akron, OH, 5University of California, Irvine, Irvine, CA, 6Huntsman

Cancer Institute, University of Utah, Salt Lake City, UT, 7Stritch School of Medicine, Loyola University Chicago, Maywood, IL, 8Stephenson Cancer Center, Oklahoma City, OK, 9SUMMA Akron City Hospital, Akron, OH, 10Northside Hospital, St. Petersburg, FL,

11London Regional Cancer Program, London, ON, Canada, 12Pamela Youde Nethersole Eastern Hospital, Hong Kong, Hong Kong, 13Saskatoon Cancer Centre, Saskatoon, SK, Canada, 14Kaiser Permanente Cancer Treatment Center, San Francisco, CA, 15Reading

Hospital, Reading, PA, 16Yonsei University Health System-Severance Hospital, Sinchon-dong, Korea, The Republic of, 17Georgia Regents University, Augusta, GA, 18Nell Hodgson Woodruff School of Nursing, Winship Cancer Institute at Emory University, Atlanta, GA

IMRT for post-operative pelvic RT

• IMRT reduces the dose delivered to small bowel in center of pelvis.

• Retrospective studies show lower rates of acute and chronic GI toxicity with IMRT as compared to standard 4-field RT.

• RTOG 0418 found IMRT to be feasible with a favorable rate of acute 2+ GI toxicity (25%).

Study Schema

Eligibility

Women with endometrial or cervical cancer requiring post-op pelvic RT or chemoRT

Stratification Factors

Disease Site: Endometrial, Cervix

XRT Dose: 45 Gy, 50.4 Gy

Chemo: No chemo, 5 cycles of weekly cisplatin at 40mg/m2

RA

ND

OM

IZE

IMRT pelvic

radiation treatment

4-field pelvic radiation treatment

Treatment Planning

Nodal CTV

-RTOG atlas

Vaginal

-ITV w bladder full and empty

7mm PTV expansion

OARs: Bone marrow, bowel,

bladder, rectum

Rapid review of contours and plans required on the first case on each arm for a site.

• IMRT planning • Standard RT

EPIC Bowel Questions

Bowel Function:

- rectal urgency?

- uncontrolled leakage of stool?

- stools that were loose?

- bloody stools?

- your bowel movements been painful?

How often have you had…

How many bowel movements have you had on a typical day?

How often have you had crampy pain in your abdomen or pelvis?

Bowel Bother:

- has each of these issues been for you?

- have your bowel habits been for you?How big of a problem…

EPIC Bowel Score

50

70

90

Baseline Week 3 of RT Week 5 of RT 4-6 weeks post-RT

IMRT 128 113 111 1024 Field 148 132 130 125

p-value = 0.048

IMRT

4-field

Pro-CTCAE Results

0

10

20

30

40

50

60 standard

IMRT

Pe

rce

nt

of

pat

ien

ts w

ith

PR

O-

CTC

AE

Sco

re ≥

3 a

t 5

we

eks

Abdominal pain Diarrhea Fecal incontinence

Frequency Interference Frequency Interference

*

* *

*, p <0.05

Use of Anti-Diarrheal Medications

0%

10%

20%

30%

40%

50%

60%

70%

0 or 1 2 or 3 4 or more

standard

IMRT

Pe

rce

nta

ge o

f p

atie

nts

Number of anti-diarrheal medications daily

p <0.05

Quality of Life: FACT-Cx

Physical well-being

Energy, pain, feeling ill, time in bed, nausea, meeting needs of family

Social well-being

Emotional well-being

Functional well-being

Work, enjoy life, accept illness, sleep well

Additional treatment related concerns

Vaginal symptoms, interest in sex, body appearance, urinary fxn, appetite

Trial Outcome Index

Quality of Life: FACT-Cx

Change in FACT-Cx IMRT 4 Field p-value

Physical Well-Being (n=86) (n=106)

Mean -4.2 -6.1 0.03

Std. Dev. 6.0 6.1

Add’l treatment concerns (n=87) (n=104)

Mean -2.7 -4.9 0.01

Std. Dev. 6.1 6.5

Trial Outcome Index (n=86) (n=106)

Mean -8.8 -12.8 0.06

Std. Dev. 14.4 14.3

Conclusions

• Pelvic IMRT reduces acute patient reported GI and GU toxicity compared to standard pelvic RT.

• Pelvic IMRT reduces need for anti-diarrheal medications as compared to standard pelvic RT.

• Pelvic IMRT improves quality of life with regard to physical functioning and other treatment effects during treatment .

• Longer term follow up will be needed to determine if these differences in acute toxicity result in lower rates of late toxicity.

ASTRO News Briefing: Innovations in RT DeliveryTuesday, September 27, 1:30-2:30pm ETModerator: Geraldine M. Jacobson, MD, MPH, MBA, FASTRO, West Virginia University

• A Phase III Randomized Trial Comparing Patient Reported Toxicity and Quality of Life (QOL) During Pelvic IMRT as Compared to Conventional RT

Ann H. Klopp, MD, PhD, MD Anderson Cancer Center

• Radiation Boost for Ductal Carcinoma In Situ After Whole Breast Radiation Therapy (WBRT) Improves Local Control: Analysis from Ten Pooled Academic Institutions

Meena S. Moran, MD, Yale University

• Results of COG ACNS0331: A Phase III Trial of Involved-Field Radiotherapy (IFRT) and Low Dose Craniospinal Irradiation (LD-CSI) with Chemotherapy in Average-Risk Medulloblastoma: A Report from the Children’s Oncology Group

Jeff M. Michalski, MD, MBA, FASTRO, Washington University in St. Louis

Radiation Boost for Ductal Carcinoma In Situ After Whole Breast Radiation Therapy (WBRT) Improves Local Control:

Analysis from Ten Pooled Academic Institutions

M. S. Moran1, Y. Zhao1, S. Ma1, Y. M. Kirova2, A. Fourquet3, P. Y. Chen4, K. E. Hoffman5, K. K. Hunt6, J. S. Wong7, L. M. Halasz8, G. M. Freedman9, R. G. Prosnitz10, M. Yassa11, D. H. A. Nguyen11, T. Hijal12, B. G.

Haffty13, E. S. Wai14, and P. Truong15

1Yale University, New Haven, CT, 2Institut Curie, Paris, France, 3Institut Curie, Paris 75005, France, 4Beaumont Health System, Royal Oak, MI, 5The University of Texas MD Anderson Cancer Center, Division of Radiation Oncology, Houston, TX, 6MD Anderson Cancer Center, Houston, TX, 7Brigham and Women's Hospital, Boston, MA, 8University of Washington, Department of Radiation Oncology,

Seattle, WA, 9University of Pennsylvania, Department of Radiation Oncology, Philadelphia, PA, 10Allentown Radiation Oncology Associates, Allentown, PA, 11Maisonneuve-Rosemont Hospital, Montreal, QC, Canada, 12McGill University Health Centre, Montreal,

QC, Canada, 13Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 14BC Cancer Agency, Surrey, BC, Canada, 15British Columbia Cancer Agency, Victoria, BC, Canada

Background• Breast Conservation Therapy (BCT), defined as local excision to remove

the tumor followed by whole breast radiation therapy (WBRT), is a standard treatment option for early-stage breast cancers

• After WBRT, a common practice is delivery of a “radiation boost” directed to the tumor bed whereby an additional 4-8 fractions allow for dose-escalation to the region at highest risk for local recurrence

• The practice of ‘boosting’ has been demonstrated to provide a small but statistically significant reduction in IBTR risk in all age groups for invasive cancers (4% at 20 years) but robust data for DCIS specifically are lacking

Background

• Because DCIS has an excellent prognosis with very few recurrences after WBRT, demonstrating similar results specific to DCIS require large numbers of patients with very long follow up

• The purpose of this study was to create a DCIS database of patients treated with WBRT with and without a boost, to analyze the effects of the boost specifically for DCIS

Method• An a priori power calculation was conducted to determine the number of patients

needed to demonstrate a significant difference of 3% between boost and no-boost

• >2,982 patients (nboost=1,988; nno-boost =994) estimated to be required

• 10 academic institutions in the US, Canada, and France contributed de-identified patient-level data

• All patients had newly diagnosed pure DCIS (no micro-invasion), treated with breast conserving surgery and received WBRT+/-boost

• Data were uniformly re-coded at the host institution and underwent primary and secondary reviews prior to analysis

Results

• The final cohort consisted of 4,131 DCIS patients (nboost =2,661; nno-

boost =1,470), exceeding the sample size estimation by 39%

• Median follow-up =9 years

• Median boost dose =14 Gy

• Median age = 56.1 years

• + Margins=4%

ResultsIBTR-free survival for boost vs. no boost:

97.1% vs. 96.3% 5 yrs94.1% vs. 92.5% 10 yrs91.6% vs. 88.0% 15 yrs(p = 0.0389)

N=4, 131

Results

• Use of boost significant for IBTR on UVA (0.013)

Characteristics HRHR P-value

Boost no 1.0 -

yes 0.69(0.53-0.91) <0.010

Grade I 1.0 -

II/III 1.62 (1.06-2.47) 0.020

Comedo no 1.0 -

yes 1.13 (0.81-1.57) 0.470

Tamoxifen no 1.0 -

yes 0.60 (0.42-0.95) 0.030

Margin neg 1.0 -

positive 1.79(1.05-3.05) 0.030

Age <50 1.0 -

≥50 0.57 (0.45-0.74) 0.010

MVA: Model incorporates other prognostic features

DCIS Boost/No Boost by Margin Definition Stratified by Margin Status

”Ink on tumor” (NSABP) “<2mm” (SSO/ASTRO/ASCO)

Results

Conclusions

• This series represents the largest cohort addressing the benefits of a boost in DCIS with data from academic institutions across USA, Canada and France

• Our findings suggest that the DCIS-boost results in a small, statistically significant, benefit in decreasing long-term IBTR across all age groups similar to that seen with invasive cancers

• For invasive cancer, the small decreases in IBTR resulted in reduced the number of mastectomies by ~40% for patients who had received a boost (compared with no-boost)

• These data support the use of a boost for DCIS patients who have a life expectancy of >10-15 years & in whom WBRT is part of the treatment plan, to provide an added incremental benefit in decreasing IBTR

ASTRO News Briefing: Innovations in RT DeliveryTuesday, September 27, 1:30-2:30pm ETModerator: Geraldine M. Jacobson, MD, MPH, MBA, FASTRO, West Virginia University

• A Phase III Randomized Trial Comparing Patient Reported Toxicity and Quality of Life (QOL) During Pelvic IMRT as Compared to Conventional RT

Ann H. Klopp, MD, PhD, MD Anderson Cancer Center

• Radiation Boost for Ductal Carcinoma In Situ After Whole Breast Radiation Therapy (WBRT) Improves Local Control: Analysis from Ten Pooled Academic Institutions

Meena S. Moran, MD, Yale University

• Results of COG ACNS0331: A Phase III Trial of Involved-Field Radiotherapy (IFRT) and Low Dose Craniospinal Irradiation (LD-CSI) with Chemotherapy in Average-Risk Medulloblastoma: A Report from the Children’s Oncology Group

Jeff M. Michalski, MD, MBA, FASTRO, Washington University in St. Louis

Results of COG ACNS0331: A Phase III Trial of Involved-Field Radiotherapy (IFRT) and Low Dose Craniospinal Irradiation

(LDCSI) with Chemotherapy in Average-Risk Medulloblastoma: A Report from the Children’s Oncology Group

J. M. Michalski1, A. Janss2, G. Vezina3, A. Gajjar4, I. Pollack5, T. E. Merchant4, T. J. FitzGerald6, T. Booth7, N. J. Tarbell8, Y. Li4, C. A. Billups9, S. M. Perkins1, R. D. Timmerman10, J. M. Cherlow11, and R. Packer3

1Washington University School of Medicine, St. Louis, MO, 2Children's Healthcare of Atlanta, Atlanta, GA, 3Children's National Medical Center, Washington, DC, 4St. Jude Children's Research Hospital, Memphis, TN, 5Children's Hospital of Pittsburgh of UPMC,

Pittsburgh, PA, 6UMass Memorial Medical Center, Worcester, MA, 7UT Southwestern/Simmons Cancer Center, Lincoln, RI, 8Massachusetts General Hospital, Boston, MA, 9St Jude Children's Research Hospital, Memphis, TN, 10University of Texas

Southwestern Medical Center, Dallas, TX, 11Long Beach Memorial Medical Center, Long Beach, CA

Background

• Largest trial conducted for average-risk (A-R) medulloblastoma

• Most common brain malignancy in children

• Aggressive tumor with a propensity to spread from the lower brain to the upper brain and spine

• Current standard of care following surgical resection: systemic chemotherapy + irradiation to both primary site (posterior fossa) and craniospinal axis

• Considerable negative effects on patients’ neurocognitive abilities, endocrinologic function and hearing

ACNS0331: Trial Objectives

• To determine if reducing the volume of the boost from the whole posterior fossa to the tumor bed will not compromise event-free and overall survival.

• To determine whether reducing the craniospinal dose of radiation therapy from 23.4 Gy to 18 Gy in children 3-7 years of age does not compromise event-free survival and overall survival

• Endpoints included Event Free Survival (EFS) and Overall Survival (OS)

Study Schema Children ages 3-7 Children ages 8 and older

RANDOMIZE#

RANDOMIZE#

Low-Dose (18Gy)

Craniospinal Irradiation

Standard-Dose 23.4Gy

Craniospinal Irradiation

Involved Field RT Boost

(Radiation to Tumor Bed)*

Standard Volume Boost

(Radiation to Whole PF)

Maintenance Chemotherapy

9 Cycles

*Patients 3-7 randomized to reduced dose receive 5.4Gy to PF before IFRT

#Both randomizations occur at the time of study enrollment

Medulloblastoma Involved Field RT Boost of 54Gy

“Tumor bed”+ GTV

CTV = GTV + 1.5cm

Within Posterior fossa

PTV=CTV + 0.3to0.5cm If 18Gy CSI

dose to PF 23.4

Patient Characteristics

All Patientsn=513

All PatientsPatients 3-7 years of

ageIFRT

n=253PFRT

n=260LDCSIn=127

SDCSIn=118

Age on study (years)MedianRange

8.33.0 – 21.8

8.23.0 – 19.8

8.33.1 – 21.8

5.93.2 – 7.9

5.63.0 – 8.0

SexMaleFemale

329 (64%)184 (36%)

164 (65%)89 (35%)

165 (63%)95 (37%)

91 (72%)36 (28%)

74 (63%)44 (37%)

RaceWhiteBlack or African AmericanAsianNative Hawaiian or Other Pacific IslanderAmerican Indian or Alaska NativeUnknown

420 (82%)41 (8%)10 (2%)5 (1%)

2 (0.4%)35 (7%)

204 (81%)23 (9%)6 (2%)2 (1%)2 (1%)

16 (6%)

216 (83%)18 (7%)4 (2%)3 (1%)0 (0%)

19 (7%)

98 (77%)11 (9%)0 (0%)2 (2%)0 (0%)

16 (13%)

94 (80%)8 (7%)4 (3%)3 (3%)1 (1%)8 (7%)

Results: Primary Site Irradiation

Five year EFS estimates82.2% ± 2.9% IFRT (n=227)80.8% ± 3.0% PFRT (n=237)

Five year OS estimates84.1% ± 2.8% IFRT (n=227)85.2% ± 2.6% PFRT (n=237)

Results: Craniospinal Irradiation

Five year EFS estimates82.6% ± 4.2% SDCSI (n=110)72.1% ± 4.8% LDCSI (n=116)

Five year OS estimates85.9% ± 3.8% SDCSI (n=110)78.1% ± 4.4% LDCSI (n=116)

Results: Local and Distant Failure

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Years after Study Enrollment

Cumulative Incidence of Local Failure for Eligible and Evaluable ACNS0331 Patients by

RT Group

IFRT PFRT

Five year ILF estimates1.9% ± 1.0% IFRT (n=248)3.7% ± 1.3% PFRT (n=257)

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Years after Study Enrollment

Cumulative Incidence of Distant Failure for Eligible and Evaluable ACNS0331 Patients 3 to

7 Years of Age by CSI Group

LDCSI SDCSI

Five year IDF estimates12.8% ± 3.2% LDCSI (n=115)8.2% ± 2.8% SDCSI (n=109)

Conclusions

• Survival rates following reduced radiation boost volumes were comparable to standard treatment volumes for the primary tumor site

• First trial sufficiently powered to state definitively that there is no survival difference between the two approaches

• Reduced dose of craniospinal axis irradiation was associated with higher event rates and worse survival

• Physicians can adopt smaller boost volumes for posterior fossa RT but should maintain the standard RT dose for craniospinal irradiation

Q & A

Online attendees: Please use the Question function to submit questions.

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

press@astro.org

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