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RTOG 9704: A Phase III Study of Adjuvant Pre and Post Chemoradiation 5-FU vs. Gemcitabine for Resected Pancreatic Adenocarcinoma. William F. Regine, K.A. Winter, R. Abrams, H. Safran, J.P. Hoffman, A. Konski, A.B. Benson, J.S. Macdonald, C.G. Willett, Tyvin A. Rich. - PowerPoint PPT Presentation
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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
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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
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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)
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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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• 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
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 Adjuvant StudyRTOG 9704 / US Intergroup Phase III Adjuvant Study
• 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
Entry CriteriaEntry Criteria
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Entry CriteriaEntry Criteria
Prospective Quality Assurance of
Radiation Therapy Fields Required*
RTOG 9704 / US Intergroup Phase III Adjuvant StudyRTOG 9704 / US Intergroup Phase III Adjuvant Study
*First Phase III Adjuvant Pancreas Trial to Do So*First Phase III Adjuvant Pancreas Trial to Do So
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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
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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? )
RTOG 9704 US / Intergroup Phase III Adjuvant StudyRTOG 9704 US / Intergroup Phase III Adjuvant Study
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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
RTOG 9704 US / Intergroup Phase III Adjuvant StudyRTOG 9704 US / Intergroup Phase III Adjuvant Study
Statistical ConsiderationsStatistical Considerations
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RTOG 9704 US / Intergroup Phase III Adjuvant StudyRTOG 9704 US / Intergroup Phase III Adjuvant Study
AccrualAccrual
• Study closed July 2002 @ 538pts:
RTOG* –370, ECOG –86, SWOG -82
*Includes Canadian Affiliates*Includes Canadian Affiliates
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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
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
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RTOG 9704 / US Intergroup Phase III Adjuvant StudyRTOG 9704 / US Intergroup Phase III Adjuvant Study
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%)
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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%
RTOG 9704 / US Intergroup Phase III Adjuvant StudyRTOG 9704 / US Intergroup Phase III Adjuvant Study
Pretreatment Patient CharacteristicsPretreatment Patient Characteristics
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RTOG 9704 / US Intergroup Phase III Adjuvant StudyRTOG 9704 / US Intergroup Phase III Adjuvant Study
Pretreatment Patient CharacteristicsPretreatment Patient CharacteristicsCRT + 5-FUCRT + 5-FU
(n = 221)(n = 221)
CRT + CRT + GemcitabineGemcitabine
(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
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Overall Survival – ‘Pancreatic Head’ Pts OnlyOverall Survival – ‘Pancreatic Head’ Pts Only
RTOG 9704 / US Intergroup Phase III Adjuvant StudyRTOG 9704 / US Intergroup Phase III Adjuvant Study
%
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%
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Disease-Free Survival – ‘Pancreatic Head’ Pts OnlyDisease-Free Survival – ‘Pancreatic Head’ Pts Only
RTOG 9704 / US Intergroup Phase III Adjuvant StudyRTOG 9704 / US Intergroup Phase III Adjuvant Study
%
A L
I V
E
0
25
50
75
100
YEARS FROM RANDOMIZATION0 1 2 3 4
//
//
//
/
/
///
/ // / // / ////// / ////// / //
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
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RTOG 9704 / US Intergroup Phase III Adjuvant StudyRTOG 9704 / US Intergroup Phase III Adjuvant Study
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
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RTOG 9704 / US Intergroup Phase III Adjuvant StudyRTOG 9704 / US Intergroup Phase III Adjuvant Study
Overall Survival – All Eligible Patients Overall Survival – All Eligible Patients %
A
L I
V E
0
25
50
75
100
YEARS FROM RANDOMIZATION0 1 2 3 4
/ // ///
///
///
/ // / // ///// // // / // / / /////// / //// ////// / // ////
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
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Salvage TherapySalvage Therapy
RTOG 9704 US / Intergroup Phase III Adjuvant StudyRTOG 9704 US / Intergroup Phase III Adjuvant Study
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
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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)
CRT + CRT + GemcitabineGemcitabine
(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
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RTOG 9704 / US Intergroup Phase III Adjuvant StudyRTOG 9704 / US Intergroup Phase III Adjuvant Study
Ability to Complete Therapy as per StudyAbility to Complete Therapy as per Study
CRT + 5-FUCRT + 5-FU
(n = 221)(n = 221)
CRT + CRT + GemcitabineGemcitabine
(n = 221)(n = 221)
ChemoRxChemoRx 88%88% 90%90%
RTRT 86%86% 88%88%
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RTOG 9704 / US Intergroup Phase III Adjuvant StudyRTOG 9704 / US Intergroup Phase III Adjuvant Study
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