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RTOG 9704: RTOG 9704:

Correlation of Survival Results With Correlation of Survival Results With

Radiotherapy ComplianceRadiotherapy Compliance

RA Abrams, KA Winter, WF Regine, H Safran, JP RA Abrams, KA Winter, WF Regine, H Safran, JP Hoffman, AA Konski, AB Benson, JS MacDonald, Hoffman, AA Konski, AB Benson, JS MacDonald,

TA Rich, CG WillettTA Rich, CG Willett

A U.S. GI INTERGROUP TRIALA U.S. GI INTERGROUP TRIAL

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• Localized AdenoCa of the pancreas

• S/P gross total resection

• AJCC 5th Ed. Stages T1-4, N0-1

• Protocol Rx to begin w/i 3-8 wks of surgery

• KPS > 60; Age > 18

• Adequate nutrition ( > 1500 calories/day)

Entry CriteriaEntry Criteria

RTOG 9704 / US Intergroup Phase III Adjuvant StudyRTOG 9704 / US Intergroup Phase III Adjuvant Study

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RTOG 9704 / US INTERGROUP Phase III Study RTOG 9704 / US INTERGROUP Phase III Study (Schema)(Schema) Resected AdenoCa of the PancreasResected AdenoCa of the Pancreas

Nodal Status

Neg. vs. Pos.

Tumor Diameter

< 3cm vs. >3 cm

Surgical Margins

Neg. vs. Pos.

Vs. Unknown

ARM 1: Pre-CRT 5 – FU

+

CHEMORADIATION (CRT)

+

Post – CRT 5 – FU

ARM 2: Pre-CRT GEMCITABINE

+

CHEMORADIATION (CRT)

+

Post – CRT GEMCITABINE

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PRE - CRT CHEMOTHERAPYPRE - CRT CHEMOTHERAPY (Starting 3 - 8 wks Post-op): (Starting 3 - 8 wks Post-op):

Arm 1Arm 1: 5–FU, 250mg/m: 5–FU, 250mg/m22/d, Continuous Infusion (CI) x 3 weeks/d, Continuous Infusion (CI) x 3 weeks Arm 2:Arm 2: Gemcitabine, 1000mg/m Gemcitabine, 1000mg/m22, weekly x 3, weekly x 3

CRTCRT (Initiated 1 - 2 wks after pre – CRT Chemo): (Initiated 1 - 2 wks after pre – CRT Chemo):

Arm 1 & 2Arm 1 & 2:: 50.4 Gy/1.8Gy/Fx + 5–FU, 250mg/m 50.4 Gy/1.8Gy/Fx + 5–FU, 250mg/m22/d, CI x 5 1/2 wks/d, CI x 5 1/2 wks

POST – CRT CHEMOTHERAPYPOST – CRT CHEMOTHERAPY (Initiated 3 – 5 wks after CRT): (Initiated 3 – 5 wks after CRT):

Arm 1Arm 1:: 3 mos of CI 5–FU [(4 wks on + 2 wks off) x 2] 3 mos of CI 5–FU [(4 wks on + 2 wks off) x 2] Arm 2Arm 2:: 3 mos of Gemcitabine [(3 wks on + 1 wk off) x 3] 3 mos of Gemcitabine [(3 wks on + 1 wk off) x 3]

TreatmentTreatment

RTOG 9704 / US Intergroup Phase III Adjuvant StudyRTOG 9704 / US Intergroup Phase III Adjuvant Study

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RTOG 9704 / US INTERGROUP Phase III Study (Schema)RTOG 9704 / US INTERGROUP Phase III Study (Schema)1998 – 2002 1998 – 2002

AdenoCa of the Pancreas S/P “Potentially” Curative ResectionAdenoCa of the Pancreas S/P “Potentially” Curative Resection

Nodal Inv

Neg. vs. Pos.

Tumor Diam

< 3cm vs. >3 cm

Margins

Neg. vs. Pos.

Vs. Unknown

ARM 1: Pre-CRT 5 – FU

+

5-FU + XRT (CRT)

+

Post – CRT 5 – FU*

ARM 2: Pre-CRT GEM

+

5-FU + XRT (CRT)

+

Post – CRT GEM

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Entry CriteriaEntry Criteria

Quality Assurance of Radiation Therapy

Performed

RTOG 9704 / US Intergroup Phase III Postop Adjuvant StudyRTOG 9704 / US Intergroup Phase III Postop Adjuvant Study

*First Phase III Adjuvant Pancreas Trial to Do So*First Phase III Adjuvant Pancreas Trial to Do So

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Background: Background: Why a Radiotherapy QA Why a Radiotherapy QA Component For This Pancreatic Trial?Component For This Pancreatic Trial?

1.1. Variation In Radiotherapy Execution As Compared To Protocol Requirements Variation In Radiotherapy Execution As Compared To Protocol Requirements Is Well Documented ( RTOG – Ortiz et al.. 1985; EORTC - Schaake-Koning et Is Well Documented ( RTOG – Ortiz et al.. 1985; EORTC - Schaake-Koning et al. 1991)al. 1991)

2.2. Experience In GI Intergroup Gastric Adjuvant Trial: 35% Major Deviations In Experience In GI Intergroup Gastric Adjuvant Trial: 35% Major Deviations In Radiotherapy Planning In Pretreatment Screening ( Macdonald et al. – 2001)Radiotherapy Planning In Pretreatment Screening ( Macdonald et al. – 2001)

3.3. A Major Concern In Interpreting Results Of ESPAC-1 Was The Absence Of A A Major Concern In Interpreting Results Of ESPAC-1 Was The Absence Of A Defined Radiotherapy QA ProcessDefined Radiotherapy QA Process

4.4. Therefore, This Analysis Undertaken To See If A Correlation Between Therefore, This Analysis Undertaken To See If A Correlation Between Radiotherapy Compliance And Survival Could Be Identified For Patients On Radiotherapy Compliance And Survival Could Be Identified For Patients On This Trial.This Trial.

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RTOG XRT Guidelines In 9704RTOG XRT Guidelines In 9704

Criteria: Section 6.1. And 6.3Criteria: Section 6.1. And 6.3– Correct Treatment Volumes– Dose W/i 5%, W/i 10%, Or > 10% Deviation From

Protocol– Duration: < 7 Days Of Break, 8-14 Days Of Break,

>14 Days Of Break– Physical Factors: >4 MV; > 80cm SAD– Critical Normal Organ Tolerance

Liver At Least 40% To Get < Than 30 Gy

Cord Max Dose < 45 Gy At Any Point

Kidney At Least 2/3rds Of 1 Kidney < 20 Gy

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RTOG XRT QA GuidelinesRTOG XRT QA Guidelines

Specified In Detail Specified In Detail

(Sections 6.1.8, 6.1.9, 6.2, and 6.3)(Sections 6.1.8, 6.1.9, 6.2, and 6.3)

Conceptually:Conceptually:

Per ProtocolPer Protocol

Variation AcceptableVariation Acceptable – – No Significant Impact On Toxicity Or No Significant Impact On Toxicity Or Potential Tumor Control AnticipatedPotential Tumor Control Anticipated

Variation UnacceptableVariation Unacceptable – – Significant Risk Of Increased Significant Risk Of Increased Toxicity Or Compromise Of Tumor Control PotentialToxicity Or Compromise Of Tumor Control Potential

Incomplete/Not EvaluableIncomplete/Not Evaluable – – Xrt Not Started Or Not Completed; Xrt Not Started Or Not Completed; These Pts Excluded from Further AnalysisThese Pts Excluded from Further Analysis

Requested Requested – GTV and PTV for Cone Down on Sim Film– GTV and PTV for Cone Down on Sim Film

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QA SchemaQA Schema

1.1. Simulation W/i 14 Days Of RegistrationSimulation W/i 14 Days Of Registration

2.2. Sim Films To Be Reviewed Prior To Start Of XRT Sim Films To Be Reviewed Prior To Start Of XRT (Pre-op GTV, Renal Volumes Drawn In)(Pre-op GTV, Renal Volumes Drawn In)

3.3. Preliminary Review; Feedback To Investigator For Preliminary Review; Feedback To Investigator For ConcernsConcerns

Problem: Not All Data Available- Forms, Op Note, Path Report, Diagnostic CT (Requested, Not Always Sent)

4.4. Final Review Later (After Treatment) When All Data Final Review Later (After Treatment) When All Data AvailableAvailable

5.5. Scores < Per Protocol agreed by Both WR & RAScores < Per Protocol agreed by Both WR & RA

6.6. Data Presented Here Based On Final ReviewData Presented Here Based On Final Review

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RTOG 9704 US / Intergroup Phase III Adjuvant StudyRTOG 9704 US / Intergroup Phase III Adjuvant Study

CRT + 5-FUCRT + 5-FU CRT + CRT + GemcitabineGemcitabine

TotalTotal

Potentially Potentially AnalyzableAnalyzable

RT Incomplete /

Not evaluable

230230

19

221221

16

451451

3535

Cases Eligible For QA Review- All PtsCases Eligible For QA Review- All Pts

Actually analyzed 211 205 416“Head of Pancreas” 186 173 359

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%

ALI

VE

0

25

50

75

100

YEARS FROM RANDOMIZATION0 1 2 3 4 5

RTOG 9704 / US Intergroup Phase III Adjuvant StudyRTOG 9704 / US Intergroup Phase III Adjuvant StudyOverall Survival – All Eligible Patients by RTQA Overall Survival – All Eligible Patients by RTQA

Per Protocol vs. < Per ProtocolPer Protocol vs. < Per Protocol

< Per Protocol

Per Protocol

153144

9271

5743

3730

p = 0.019

Patients at Risk

Per ProtocolUnaccept, Accept

216200

Total Dead MST

216 152 1.74

200 167 1.47

1916

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HEAD PTS ByRx Arm

ALL PTS ByRx Arm

ALL PTS ByRT QA

ALL PTS ByQA Score

HEAD PTS ByQA Score

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Multivariate Analysis: Impact of Nodal Involvement, Multivariate Analysis: Impact of Nodal Involvement, Treatment, And QA Score On Survival Treatment, And QA Score On Survival

All Eligible PatientsAll Eligible Patients (n=416) (n=416)EndpointEndpoint AdjustmentAdjustment

VariableVariable

ComparisonComparison Adjusted HRAdjusted HR

(95% CI)(95% CI)

PP

ValueValue

Nodal Nodal InvolvementInvolvement

No vs. YesNo vs. Yes 1.621.62

(1.27, 2.06 )(1.27, 2.06 )

0.00010.0001

Overall Overall SurvivalSurvival TreatmentTreatment

Gemcitabine Gemcitabine vs. vs.

5-FU5-FU

1.151.15

(0.92, 1.43)(0.92, 1.43)

0.220.22

RT QA ScoreRT QA Score <Per Protocol<Per Protocol

Vs. Vs.

Per ProtocolPer Protocol

0.770.77

(0.62, 0.96)(0.62, 0.96)

0.020.02

HR > 1 Indicates Increased Risk of Death For The Second Variable HR < 1 Indicates Decreased Risk of Death For The Second Variable

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Median Survival By Rx Arm AndMedian Survival By Rx Arm And RT Compliance—All Patients RT Compliance—All Patients

Treatment ArmTreatment Arm Per protocolPer protocol Variation Variation AcceptableAcceptable

VariationVariation

UnacceptableUnacceptable

p-value p-value for trend for trend

(1 sided)(1 sided)

5FU Arm5FU Arm

(95% CI)(95% CI)

nn

1.50 yrs1.50 yrs

(1.28, 1.90)(1.28, 1.90)

117117

1.52 yrs1.52 yrs

(1.21,1.91)(1.21,1.91)

8282

1.18 yrs1.18 yrs

(1.06,1.84)(1.06,1.84)

1212

0.080.08

0.030.03Gem ArmGem Arm

( 95% CI)( 95% CI)

nn

1.89 yrs1.89 yrs

(1.54, 2.48)(1.54, 2.48)

9999

1.41 yrs1.41 yrs

(1.24, 1.73)(1.24, 1.73)

9494

1.37 yrs 1.37 yrs

(1.18, 2.37)(1.18, 2.37)

1212

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Median Survival By Rx Arm AndMedian Survival By Rx Arm And RT Compliance—Head Patients RT Compliance—Head Patients

Treatment ArmTreatment Arm Per protocolPer protocol Variation Variation AcceptableAcceptable

VariationVariation

UnacceptableUnacceptable

p-value p-value for trend for trend

(1 sided)(1 sided)

5FU Arm5FU Arm

(95% CI)(95% CI)

nn

1.47 yrs1.47 yrs

(1.26, 1.89)(1.26, 1.89)

104104

1.34 yrs1.34 yrs

(1.17, 1.91)(1.17, 1.91)

7272

1.18 yrs1.18 yrs

(0.71, 1.92)(0.71, 1.92)

1010

0.140.14

0.120.12Gem ArmGem Arm

(95% CI)(95% CI)

nn

1.91 yrs1.91 yrs

(1.54, 2.48)(1.54, 2.48)

8181

1.47 yrs1.47 yrs

(1.26, 1.85)(1.26, 1.85)

8484

1.72 yrs1.72 yrs

(1.37, 3.14) (1.37, 3.14)

88

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Multivariate Analysis: Impact of Nodal Involvement, Multivariate Analysis: Impact of Nodal Involvement, Treatment Arm And QA Score On Survival Treatment Arm And QA Score On Survival

All Eligible All Eligible PancreaticPancreatic HeadHead Patients (n=359) Patients (n=359)EndpointEndpoint AdjustmentAdjustment

VariableVariable

ComparisonComparison Adjusted HRAdjusted HR

(95% CI)(95% CI)

PP

ValueValue

Nodal Nodal InvolvementInvolvement

No vs. YesNo vs. Yes 1.651.65

(1.27, 2.15 )(1.27, 2.15 )

0.00020.0002

Overall Overall SurvivalSurvival

TreatmentTreatment Gemcitabine Gemcitabine vs. vs.

5-FU5-FU

1.301.30

(1.03, 1.67)(1.03, 1.67)

0.030.03

RT QA ScoreRT QA Score <Per Protocol<Per Protocol

Vs. Vs.

Per ProtocolPer Protocol

0.780.78

(0.62, 0.99)(0.62, 0.99)

0.040.04

HR > 1 Indicates Increased Risk of Death For The Second Variable HR < 1 Indicates Decreased Risk of Death For The Second Variable

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ConclusionsConclusions

1.1. Prospective QA Requires Availability Of All Relevant Data To Prospective QA Requires Availability Of All Relevant Data To Be SuccessfulBe Successful

2.2. For Patients Whose RT was scored as “Per Protocol”:For Patients Whose RT was scored as “Per Protocol”:• Survival Was Significantly Better (p=0.019) Than the Survival of

Patients Whose RT Was Scored as < Per Protocol

• In MVA: RT QA Score significantly impacted on survival for both “all patients” and “pancreatic head” patients. Treatment arm

significantly impacted survival for only “pancreatic head” patients

3.3. When adjusted for nodal involvement and RTQASc, the When adjusted for nodal involvement and RTQASc, the demonstrated superiority of gemcitabine over 5-FU for demonstrated superiority of gemcitabine over 5-FU for pancreatic head patients was increased.pancreatic head patients was increased.

4.4. In This Context, RT QA ScoringIn This Context, RT QA Scoring• Needs To Be Considered In The Design of Future Co-Operative

Group Adjuvant Trials For Pancreatic Cancer

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ACKNOWLEDGEMENTSACKNOWLEDGEMENTS

Ms. Bernadine DunningMs. Bernadine Dunning –ACR –ACR Phila. - For Exemplary Assistance Phila. - For Exemplary Assistance With The RT QA Review ProcessWith The RT QA Review Process

Mr. Miguel GarciaMr. Miguel Garcia – RTOG – RTOG Statistics - For Assistance With Statistics - For Assistance With Data Analysis And PresentationData Analysis And Presentation