william f. regine, k.a. winter, r. abrams, h. safran, j.p. hoffman, a. konski, a.b. benson,

www.rtog.org 1

RTOG 9704: A Phase III Study of Adjuvant RTOG 9704: A Phase III Study of Adjuvant

Pre and Post Chemoradiation 5-FU vs. Pre and Post Chemoradiation 5-FU vs.

Gemcitabine for Resected Pancreatic Gemcitabine for Resected Pancreatic

AdenocarcinomaAdenocarcinoma

William F. Regine, K.A. Winter, R. Abrams, William F. Regine, K.A. Winter, R. Abrams, H. Safran, J.P. Hoffman, A. Konski, A.B. Benson, H. Safran, J.P. Hoffman, A. Konski, A.B. Benson,

J.S. Macdonald, C.G. Willett, Tyvin A. RichJ.S. Macdonald, C.G. Willett, Tyvin A. Rich

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

www.rtog.org 2

Gemcitabine Single-Agent First-Line: Results of a Randomized Trial*

Gemcitabine Single-Agent First-Line: Results of a Randomized Trial*

*In Patients with locally advanced/metastatic Pancreatic Ca*In Patients with locally advanced/metastatic Pancreatic Ca

www.rtog.org 3

Main ObjectiveMain Objective

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

• To evaluate the impact of the addition of To evaluate the impact of the addition of

Gemcitabine to 5–FU Chemoradiation (CRT) Gemcitabine to 5–FU Chemoradiation (CRT)

in the postop in the postop adjuvantadjuvant treatment of patients treatment of patients

with pancreatic adenocarcinoma (adenoCa)with pancreatic adenocarcinoma (adenoCa)

www.rtog.org 4

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

www.rtog.org 5

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


www.rtog.org 6

• Localized AdenoCa of the pancreas

• S/P gross total/potentially curative 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


www.rtog.org 7


• CA19-9 drawn for central submission

• M1 or NX Disease ineligible

• Prior RT/ChemoRx ineligible

• Tumor Types excluded:

Non-AdenoCa, AdenoSquamCa,

CystAdenoCa, Duodenal, Distal Bile Duct,

Ampullary Cas


www.rtog.org 8


Prospective Quality Assurance of

Radiation Therapy Fields Required*


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

www.rtog.org 9

Study EndpointsStudy Endpoints Primary

• Overall Survival Pts with ‘Pancreatic Head’ tumorsPts with ‘Pancreatic Head’ tumors All PatientsAll Patients

Secondary

• Disease Free Survival

• Toxicity

• Prospectively correlate CA19-9 to outcome

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

www.rtog.org 10

Statistical ConsiderationsStatistical Considerations

• Original expected accrual: 330 pts/5.5yrs ( 5/month )

• Study activated July 1998

• By 2001 avg. accrual > 13 pts/mos

• > 330 pts by May 2001

• 15-20% Body/Tail lesions ( Different Biology? )


www.rtog.org 11

Study Extension Proposed to NCI and Approved

• Increase accrual to 518; increasing statistical power

• Power of 85% to detect HR of .71 (18 mos vs. 25 mos)

• Two-sided Significance level of 0.05, 2 interim tests

• Allowed 80% power to evaluate difference among

‘Pancreatic Head’ pts as a Prospective Primary Endpoint


Statistical ConsiderationsStatistical Considerations

www.rtog.org 12


AccrualAccrual

• Study closed July 2002 @ 538pts:

RTOG* –370, ECOG –86, SWOG -82

*Includes Canadian Affiliates*Includes Canadian Affiliates

www.rtog.org 13


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

TotalTotal

Total patients enteredTotal patients entered 270270 268268 538538

IneligibleIneligible 4444 4646 90 (17%)90 (17%)

Withdrew consentWithdrew consent 11 00 11

No follow-up infoNo follow-up info 33 00 33

No on-study infoNo on-study info 11 11 22

AnalyzableAnalyzable 221221 221221 442442

Status of CasesStatus of Cases

www.rtog.org 14


442/538 pts Eligible and Analyzable442/538 pts Eligible and Analyzable

Reasons for IneligibiltyReasons for Ineligibilty

Ineligibility reasonsIneligibility reasons FrequencyFrequency

CA 19-9 not submittedCA 19-9 not submitted 2020

Protocol Rx started > 8 weeks after surgeryProtocol Rx started > 8 weeks after surgery 1919

Incomplete/Ineligible stagingIncomplete/Ineligible staging 1818

Caloric intake is ineligibleCaloric intake is ineligible 1414

Ineligible primaryIneligible primary 1010

Unable to confirm any eligibility/No FUUnable to confirm any eligibility/No FU 55

Previous RT/CancerPrevious RT/Cancer 33

Unable to confirm KPSUnable to confirm KPS 11

TOTALTOTAL 90 (17%)90 (17%)

www.rtog.org 15

CRT + 5-FUCRT + 5-FU

(n = 221)(n = 221)

CRT + CRT + GemcitabineGemcitabine

(n = 221)(n = 221)

p-valuep-value

Age (Median)Age (Median) 6262 6161

GENDERGENDER

MaleMale 60%60% 53%53%0.120.12

FemaleFemale 40%40% 47%47%

LOCATIONLOCATION

HeadHead 88%88% 85%85%0.330.33

Non-Head Non-Head 12%12% 15%15%

TUMOR DIAM.TUMOR DIAM.

< 3 cm< 3 cm 44%44% 39%39%0.290.29

>> 3 cm 3 cm 56%56% 61%61%


Pretreatment Patient CharacteristicsPretreatment Patient Characteristics

www.rtog.org 16


Pretreatment Patient CharacteristicsPretreatment Patient CharacteristicsCRT + 5-FUCRT + 5-FU

(n = 221)(n = 221)


(n = 221)(n = 221)

p-valuep-value

N - STAGEN - STAGE

N0N0 35%35% 32%32%0.480.48

N1N1 65%65% 68%68%

T - STAGE T - STAGE

0.00620.0062 T1/2 T1/2 30%30% 19%19%

T3/4 T3/4 70%70% 81%81%

SURGICAL MARGINSSURGICAL MARGINS

0.480.48 NegativeNegative 44%44% 39%39%

PositivePositive 33%33% 35%35%

Unknown*Unknown* 23%23% 26%26%

* Not mentioned/commented on pathology report* Not mentioned/commented on pathology report

www.rtog.org 17

Overall Survival – ‘Pancreatic Head’ Pts OnlyOverall Survival – ‘Pancreatic Head’ Pts Only


%

A L

I V

E

0

25

50

75

100

YEARS FROM RANDOMIZATION0 1 2 3 4

/ // //

/ ///

/ // / // / // ///// // // / / / ///// ///// / / ////// / / //

134132

7763

4631

2419

RT + GEMRT + 5FU

187194

Patients at Risk

CRT+ 5-FU

CRT + Gemcitabine

p = 0.033

Total Dead MST

187 134 1.72

194 156 1.41

Median:Median: 20.620.6 vs 16.9mosvs 16.9mos3-Year:3-Year: 32%32% vs 21%vs 21%

www.rtog.org 18

Disease-Free Survival – ‘Pancreatic Head’ Pts OnlyDisease-Free Survival – ‘Pancreatic Head’ Pts Only


%

A L

I V

E

0

25

50

75

100


//

//

//

/

/

///

/ // / // / ////// / ////// / //

8781

5236

3019

1811

RT + GEMRT + 5FU

187194

Patients at Risk

CRT+ 5-FU

CRT + Gemcitabine

p = 0.10

Total Failed MDFST

187 155 0.95 194 166 0.84

www.rtog.org 19


Multivariate Analysis – OS -Multivariate Analysis – OS - ‘Pancreatic Head’ Pts Only‘Pancreatic Head’ Pts Only

VariableVariable ComparisonComparison Adjusted HRAdjusted HR

(95% CI)(95% CI)

p-valuep-value

TreatmentTreatment CRT+5-FU vs. CRT+5-FU vs. CRT+GemcitabineCRT+Gemcitabine

0.760.76

(0.61, 0.97)(0.61, 0.97)

0.0250.025

Nodal Nodal

InvolvementInvolvement

No vs. YesNo vs. Yes 1.421.42

(1.10, 1.85)(1.10, 1.85)

0.0030.003

Tumor Tumor

DiameterDiameter

<3cm vs. <3cm vs. ≥3cm≥3cm 1.271.27

(0.99, 1.62)(0.99, 1.62)

0.030.03

www.rtog.org 20


Overall Survival – All Eligible Patients Overall Survival – All Eligible Patients %

A

L I

V E

0

25

50

75

100


/ // ///

///

///

/ // / // ///// // // / // / / /////// / //// ////// / // ////

CRT+ 5-FU

CRT + Gemcitabine

152151

8774

5239

2724

p = 0.15

Patients at Risk

RT + GEMRT + 5FU

221221

Total Dead MST

221 163 1.57

221 175 1.41

www.rtog.org 21

Salvage TherapySalvage Therapy


CRT + 5-FU Arm (n=221)CRT + 5-FU Arm (n=221)

• 111/221 (50%) received salvage chemotherapy

• 92/221 (42%) Crossed Over to receive Gemcitabine

www.rtog.org 22

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

Toxicity- All Eligible PatientsToxicity- All Eligible Patients

>> Grade 3 Toxicity Grade 3 Toxicity

ToxicityToxicityCRT + 5-FUCRT + 5-FU

(n = 221)(n = 221)


(n = 221)(n = 221)p-valuep-value

Worst HematologicWorst Hematologic 10%10% 58%58% p<0.0001p<0.0001

Grade 4 *Grade 4 * 2%2% 14%14% p<0.0001p<0.0001

Worst non-hematologicWorst non-hematologic 58%58% 58%58% 0.940.94

Worst overallWorst overall 62%62% 79.5%79.5% 0.00060.0006

* No difference in febrile neutropenia or infection* No difference in febrile neutropenia or infection

www.rtog.org 23


Ability to Complete Therapy as per StudyAbility to Complete Therapy as per Study

CRT + 5-FUCRT + 5-FU

(n = 221)(n = 221)


(n = 221)(n = 221)

ChemoRxChemoRx 88%88% 90%90%

RTRT 86%86% 88%88%

www.rtog.org 24


ConclusionsConclusions

• The addition of Gemcitabine to postop adjuvant 5-FU CRTThe addition of Gemcitabine to postop adjuvant 5-FU CRT

improves survival in pts with pancreatic Head adenoCaimproves survival in pts with pancreatic Head adenoCa

• The increased hematologic toxicity seen with GemcitabineThe increased hematologic toxicity seen with Gemcitabine

is manageable with is manageable with >> 88% of pts able to complete 88% of pts able to complete

chemo/RT as per studychemo/RT as per study

• Postop adjuvant Gemcitabine + 5-FU CRT defines a newPostop adjuvant Gemcitabine + 5-FU CRT defines a new

standard which will serve as the platform forstandard which will serve as the platform for

developing/future Phase III studiesdeveloping/future Phase III studies

william f. regine, k.a. winter, r. abrams, h. safran, j.p. hoffman, a. konski, a.b. benson,

Documents