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1NCIC CTG JBR.10
NCIC CTG BR.10NCIC CTG BR.10((SWOG JBR10, ECOG JBR10, CALGB 9795)SWOG JBR10, ECOG JBR10, CALGB 9795)
Phase III Randomized Trial of Adjuvant Vinorelbine and
Cisplatin in Completely Resected Stage IB and II
Non Small Cell Lung Cancer
Timothy Winton, Robert Livingston, David Johnson, James Rigas, Yvon Cormier, Charles Butts, Keyue Ding, Lesley
Seymour, Nadine Magoski, Frances Shepherd.
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JBR.10 JBR.10 -- ObjectivesObjectives
• Prospective, randomized controlled trial designed to determine whether adjuvant vinorelbine and cisplatin is superior to observation alone, in terms of overall survival, in patients who have undergone complete resection of early stage (IB and II) Non Small Cell Lung Cancer
• Secondary Endpoints– Recurrence free survival– Evaluate Toxicity of the Regimen– Health related Quality of Life Analysis– Explore the prognostic significance of ras mutations
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JBR.10 JBR.10 -- Study DesignStudy Design
RANDOM I SE
Stratified byNodal* N0* N1
ras* Neg* Pos* UNK
T
I SSUE
REGI STER
ObservationOnly
CisplatinVinorelbine
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JBR.10 JBR.10 -- Statistical DesignStatistical Design
• Expected 3 year survival - 60%• To detect an improvement of 10%
(HR 1.43)– 198 events– Require 450 patients randomised over 7
years• Two planned interim analyses
– 66 events– 132 events
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JBR.10 JBR.10 -- Inclusion CriteriaInclusion Criteria
• T2N0, T1N1 or T2N1 NSCLC• Complete resection
– Segmentectomy/wedge resection not eligible
• Tissue submission (fresh/paraffin)• ECOG PS ≤ 1• QoL (mandatory Canada)• Acceptable hematology / biochemistry• Randomised within 40 days of surgery
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JBR.10 JBR.10 -- Exclusion CriteriaExclusion Criteria
• Prior malignancy– Any breast, melanoma or renal cell– Any Other Malignancy within 5 years
• BAC (unless discrete nodule)• Mixed NSCLC/SCLC• Multiple site, T3, Level 10 nodes (N2)• Severe co-morbid disorders
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JBR.10 JBR.10 -- ChemotherapyChemotherapy
Agent Dose Schedule
Cisplatin 50 mg/m2 D 1 & 8 Q 4 weeks X 4 cycles
30 mg/m2 * Weekly 16 weeks
25 mg/m2 Weekly 16 weeksVinorelbine
Doses adjusted for hematologic, renal and neurologic toxicity* Protocol Modification August 1995 because of hematologic
toxicity/patient compliance
NCIC CTG JBR.10
JBR.10 JBR.10 -- ResultsResults• Opened July 1994, closed April 2001• Randomized: 482
– 41 patients - ineligible post randomization• Incomplete staging/screening: 7• N2/M1/T4 disease: 15• Incomplete resection: 1• Inadequate / abnormal labs 18
• Analyses: – Interim # 1: March 2000– Interim # 2: March 2002 – Final, ITT, March 2004
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Completely Resected Early Stage NSCLCCompletely Resected Early Stage NSCLCStage IB Stage IB --IIII
482
Randomized to
ChemotherapyCisplatin –Vinorelbine
243
Standard of CareObservation Only
239VS
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JBR.10 JBR.10 -- Patient CharacteristicsPatient CharacteristicsObservation
(239)Vin/Cis(243)
Median Age (yrs) 61 61Male 64% 66%Female0 49% 49%
Undifferentiated 7% 8%Mixed 2% 2%
1 51% 51%Adenocarcinoma 54% 53%Squamous 38% 37%
Histology
35% 34%ECOG PS
Gender
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JBR.10 JBR.10 -- Patient CharacteristicsPatient CharacteristicsObservation
(239)Vin/Cis(243)
1 13 % 16 %2 87 % 84 %
I 45 % 46 %IIA 13 % 16 %
Stage
IIB 41 % 39 %
T
0 45 % 46 %N1 55 % 54 %
Lobectomy 71 % 66 %Bilobectomy 7 % 8 %
Extent of Resection
Pneumonectomy 22 % 26 %
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JBR.10 JBR.10 -- Patient CharacteristicsPatient Characteristics
Observation(239)
Vin/Cis(243)
Present 23% 24%Absent 63% 60%Unknown/pending 14% 15%
Ras Mutation*
* Subset analysis of prognostic significance of Ras and other molecular markers continues
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JBR.10 JBR.10 –– Chemotherapy Chemotherapy -- Dose DeliveryDose Delivery
• 65 % of patients received 3 or 4 cycles of chemotherapy
• Median number of cycles of chemotherapy therapy received was 3
• All patients on chemotherapy required at least one dose reduction or treatment delay
• 77% of patients required at least one dose reduction
• 74% of dose reductions were required because of Neutropenia
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JBR.10 JBR.10 –– ChemotherapyChemotherapy--Related ToxicityRelated ToxicityVin/Cis N= 243
Total % Grade 3 or 4 %Fatigue 77% 14%Anorexia 53% 9%Local Toxicity 33% 3%Dyspnea 17% 4%
Nausea 76% 10%Vomiting 46% 7%Constipation 44% 3%
Diarrhea 22% <1%
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JBR.10 JBR.10 –– ChemotherapyChemotherapy--Related ToxicityRelated Toxicity
Vin/Cis N= 243Total % Grade 3 or 4 %
Hearing 20% 1.5%
Alopecia 31% 0%Hemoglobin 91% 7.3%Granulocytes 98% 73%Infection 21% 1%Febrile Neutropenia 7% * 7%
Sensory 45% 2%
* 6% after dose reduction
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JBR.10 JBR.10 -- Reasons Off StudyReasons Off StudyVin/Cis
Number off study ProgressionToxicity 30 (12%)
Treatment complete 120 (49%)
RefusalDeathIntercurrent IllnessOther 4 (2%)
123Reason 9 (4%)
72 (30%)3 (1%)5 (2%)
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QOL Results: During TreatmentQOL Results: During Treatment
• Clinically and statistically significant differences during treatment in :
– Global QOL– Physical, Role, Social, Cognitive function– Fatigue, Nausea, Dyspnea, Appetite,
Alopecia
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QOL Results: After Completion of QOL Results: After Completion of TreatmentTreatment
• No differences in global or any of the QoL performance scales
• Clinically and statistically significant differences after completion of treatment in :– Parasthesias, numbness, hearing
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0
20
40
60
80
100
0.0 2.0 4.0 6.0 8.0
JBR.10 RecurrenceJBR.10 Recurrence--Free SurvivalFree Survival
____ Vin/Cis, ____ Observation
*HR 0.61, p=0.0002
61%
48%
Years
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JBR.10 JBR.10 –– Recurrence Free SurvivalRecurrence Free Survival
Observation(95% CI)
Vin/Cis(95% CI)
HR p
MedianSurvival
46.7 months Not reached
0.61 0.0002
RF 5 yr Survival
48%(42-55%)
61%(54-68%)
0.012
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JBR.10 JBR.10 -- Overall SurvivalOverall Survival
0
20
40
60
80
100
0.0239
2.0182
4.094
6.047
8.013
____ Vin/Cis, ____ Observation
*HR 0.7, p=0.012
69%
54%
Years
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JBR.10 JBR.10 -- Causes of DeathCauses of Death
Observation Vin/CisAlive 127 155
Lost to Follow UP 1 2
Died 111 86Disease - NSCLC 92 70Toxicity 0 2*Disease and non-protocol toxicity 3 0Other primary malignancy 5 4Other 11 10
* Sepsis, Pulmonary Fibrosis.
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JBR.10 JBR.10 -- SurvivalSurvival
Observation(95% CI)
Vin/Cis(95% CI)
HR p
MedianSurvival
73 months(48 - ~ )
94 months(CI 75 - ~)
0.7 0.012
5 Year Survival
54%(48-61%)
69%(CI 62-75%)
0.0022
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JBR.10 JBR.10 -- ConclusionsConclusions• Vinorelbine and Cisplatin can be administered
safely post resection of NSCLC
• Impact on QoL was limited and generally reversiblewith the exception of neurotoxicity
• Adjuvant treatment with this 3rd generation chemotherapy combination significantly improves disease free and overall survival as compared to observation alone post complete resection of Stage IB and Stage II Non Small Cell Lung Cancer
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JBR.10 JBR.10 --Intergroup PartnersIntergroup Partners
• National Cancer Institute of Canada Clinical Trials Group
• Eastern Cooperative Oncology Group• Southwest Oncology Group• Cancer and Leukemia Group B
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AcknowledgmentsAcknowledgments
• Financial support– National Cancer Institute of Canada– Medical Research Council of Canada– Glaxo-Smith-Kline Canada– National Cancer Institute (USA)
• Ras Mutation / Tissue Bank– Dr Ming Sound Tsao, PMH/UHN, Toronto
Canada
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AknowledgementsAknowledgements• Thanks to the many patients and their families that
agreed to enter the trial and help pave the way for improved treatment for future Lung Cancer patients
• Thanks to our many collaborators around North America – Canada and USA - who participated and supported this trial
• Personal thanks to Dr Joe Pater and Leslie Seymour & Staff of the NCIC – CTG and Dr Frances Shepherd, Chair of the NCIC Lung Site Group, for their leadership and support