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Phase III Trial of Accelerated versus Standard Phase III Trial of Accelerated versus Standard Fractionation Plus Concurrent Cisplatin for HNSCC Fractionation Plus Concurrent Cisplatin for HNSCC

(RTOG 0129): Report of Secondary Analyses(RTOG 0129): Report of Secondary Analyses

Ang KK*, Zhang QE, Wheeler R, Rosenthal DI*, Nguyen-Tan F,

Lu C, Kim H, Axelrod R, Silverman C , Weber RS

Supported by Grants U10 CA21661 and U10 CA37422 from the National Cancer Institute

Acknowledgment: Patients, Participating Teams, RTOG staff, etc.

*Served on Advisory Board of BMS*Served on Advisory Board of BMS

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Background & RationaleBackground & Rationale

Altered Fractionation vs Standard FractionationAltered Fractionation vs Standard Fractionation

Bourhis (Pignon), Lancet 368:843, 2006

Regimens Absolute benefitat 5 years

Riskreduction p

Local-regional ControlHyperfractionationAFX ( Total Dose)

( Total Dose)

9.4 %7.3 %2.3 %

24 %21 %10 %

<0.0001<0.0001

NS

SurvivalAll group

SurvivalAll group 3.4 %3.4 % 8 %8 % 0.0030.003

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Background & RationaleBackground & Rationale

Radiation + Chemotherapy vs Radiotherapy AloneRadiation + Chemotherapy vs Radiotherapy Alone

Pignon (Designé), Lancet 335:949, 2000 Pignon & Bourhis, Multidisciplinary H&N Meeting, 2007

Regimens Absolute benefitat 5 years

Riskreduction p

AdjuvantNeoadjuvantConcurrent Cisplatin

NSNS

< 0.0001< 0.00001

2.3 %2.2 %6.3 %9.4 %

2 %5 %

19 %24 %

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RTOG 0129: Objective & Study DesignRTOG 0129: Objective & Study Design

Test relative efficacy of combining accelerated fractionation (AFX-C) or standard fractionation (SFX)

with cisplatin for the treatment of LA-HNSCC

Stage III & IV* SCC of:• Oral cavity• Oropharynx• Larynx• Hypopharynx

Stratify :• Lx vs Non-Lx• No vs N+• KPS

60-80 VS 90-100

RANDOMIZE

1. AFX-CB: 72 Gy/42 F/6 W + CDDP: 100 mg/m2, q3W x 2

2.2. SFX: 70 Gy/35 F/7 W +SFX: 70 Gy/35 F/7 W +CDDP: 100 mg/mCDDP: 100 mg/m22, q3W , q3W x 3x 3

Excluded T1N+, T2N1

1° endpoint: overall survivalSample size: 720 patients to detect 25% reduction in the death rate (80% power)

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RTOG 0129: Study PopulationRTOG 0129: Study Population

Enrolled: 743 patientsin 3 years (7/’02 - 6/’05)

Withdrew Consent: 5

Found Ineligibleon Review: 17

Analyzed: 721 (97%)

AFX-C + CDDP: 360 SFX + CDDP: 361

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RTOG 0129: Study PopulationRTOG 0129: Study Population

CDDP plusCDDP plus AFX-CAFX-C SFXSFX

AgeAge 55 (26-82)55 (26-82) 56 (34-56 (34-82)82)

Gender - MaleGender - Male 288 (80%)288 (80%) 309 309 (86%)(86%)

Zubrod: 0 - 1Zubrod: 0 - 1 59% - 41 %59% - 41 % 57% - 57% - 43%43%

Primary sitePrimary site OropharynxOropharynx 217 (60%)217 (60%)

216 (60%)216 (60%) LarynxLarynx 98 (27%)98 (27%)

90 (25%)90 (25%) T3-4T3-4 261 (73%)261 (73%) 292 292

(81%)(81%) N+N+ 291 (81%)291 (81%) 294 294

(81%)(81%) AJCC stage IVAJCC stage IV 279 (78%)279 (78%) 284 284

(79%)(79%)

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RTOG 0129: Outcome Endpoints by ITTRTOG 0129: Outcome Endpoints by ITTPrimary Endpoint

ASTRO 2009

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RTOG 0129: Secondary AnalysesRTOG 0129: Secondary AnalysesRelative Impact of Tumor, Patient, and Therapy VariablesRelative Impact of Tumor, Patient, and Therapy Variables

Patients meeting following criteria:Patients meeting following criteria:● Alive >3 months without disease progressionAlive >3 months without disease progression

● Received therapy per protocol or with minor Received therapy per protocol or with minor variationsvariations Cycles of cisplatin received: 1-3Cycles of cisplatin received: 1-3 RT dose: >63 Gy (≥90% of prescription)RT dose: >63 Gy (≥90% of prescription) Overall RT Duration: ≤9 weekOverall RT Duration: ≤9 week

ASCO 2010

Total number: 656 (91%) patients

Median FU (living patients): 4.8 (0.3 – 6.5) Years

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RTOG 0129: Secondary AnalysesRTOG 0129: Secondary AnalysesRelapse PatternRelapse Pattern

ASCO 2010

1Assumed as having LRR; 2Counted as LRR.

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RTOG 0129: Secondary AnalysesRTOG 0129: Secondary Analyses

ASCO 2010

Overall Survival Progression-Free Survival

Years after Randomization0 1 2 3 4 5

0

25

50

75

100

Years after Randomization0 1 2 3 4 5

1º Endpoint

SFX + DDPx3 (231)

SFX + DDPx2 (76)

AFX-C + DDPx2 (303)

SFX or AFX-C + DDPx1 (46)

P=0.50

P=0.55P=0.0003

SFX + DDPx3 (231)

SFX + DDPx2 (76)

AFX-C + DDPx2 (303)

SFX or AFX-C + DDPx1 (46)

P=0.66

P=0.22P=0.0031

Log-rank test

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RTOG 0129: Secondary AnalysesRTOG 0129: Secondary Analyses

ASCO 2010

Local-Regional Relapse1 Distant Metastasis

0

25

50

75

100

Years after Randomization0 1 2 3 4 5

Years after Randomization0 1 2 3 4 5

1Includes patients dying of cancer NOS or having LRR+DM

SFX + DDPx3 (231)

SFX + DDPx2 (76)

AFX-C + DDPx2 (303)

SFX or AFX-C + DDPx1 (46)

P=0.047

P=0.11P=0.049

SFX + DDPx3 (231)

SFX + DDPx2 (76)

AFX-C + DDPx2 (303)

SFX or AFX-C + DDPx1 (46)

P=0.33

P=0.91P=0.63

Gray’s test

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RTOG 0129: Secondary AnalysesRTOG 0129: Secondary AnalysesMultivariate Analysis Multivariate Analysis withoutwithout Therapy Variables Therapy Variables

ASCO 2010

1With 20 imputations of missing HPV and smoking data

ParametersHazard Ratio (95% Confidence Interval)

Overall Survival

P-F Survival

L-R Relapse

Distant Mets

HPV (ISH- vs ISH+)2.8

(1.92-3.99)2.3

(1.68-3.09)2.6

(1.69-3.83)2.1

(1.22-3.53)

Smoking (>10 vs ≤10 PY)1.9

(1.32-2.73)2.0

(1.45-2.78)2.1

(1.35-3.11)1.7

(0.97-2.93)

T-Stage (T4 vs T2-3)1.7

(1.31-2.20)1.3

(1.03-1.66)1.5

(1.08-1.97)1.0

(0.63-1.62)

N-Stage (N2b-3 vs N0-2a)1.6

(1.24-2.09)1.5

(1.22-1.95)1.4

(1.01-1.82)2.2

(1.39-3.50)

Zubrod PS (1 vs 0) 1.5 (1.16-1.93)

1.5 (1.19-1.88)

1.5 (1.13-2.04)

1.4 (0.88-2.08)

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RTOG 0129: Secondary AnalysesRTOG 0129: Secondary AnalysesMultivariate Analysis Multivariate Analysis withwith Therapy Variables Therapy Variables

ASCO 2010

ParametersHazard Ratio (95% Confidence Interval)

Overall Survival

P-F Survival

L-R Relapse

Distant Metastasis

HPV (ISH- vs ISH+) 2.7 (1.90-3.92) 2.3 (1.68-3.08) 2.6 (1.72-3.84) 2.0 (1.19-3.49)

Smoking (>10 vs ≤10 PY) 1.8 (1.28-2.65) 2.0 (1.43-2.74) 2.0 (1.34-3.08) 1.6 (0.94-2.85)

T-Stage (T4 vs T2-3) 1.6 (1.23-2.08) 1.3 (1.00-1.62) 1.4 (1.07-1.95) 1.0 (0.60-1.56)

N-Stage (N2b-3 vs N0-2a) 1.6 (1.20-2.02) 1.5 (1.20-1.92) 1.3 (0.98-1.77) 2.2 (1.37-3.46)

Zubrod PS (1 vs 0) 1.6 (1.21-2.03) 1.6 (1.25-1.99) 1.6 (1.20-2.17) 1.4 (0.92-2.19)

Cisplatin Cycles (1 vs 3) 2.1 (1.35-3.32) 1.8 (1.19-2.82) 1.9 (1.07-3.34) 1.5 (0.67-3.41)

Cisplatin Cycles (2 vs 3) 1.2 (0.84-1.59) 1.3 (0.98-1.76) 1.7 (1.20-2.54) 1.0 (0.57-1.66)

RT Dose (64-76 Gy, Cont) 1.08 (0.99-1.19) 1.03 (0.94-1.12) 1.02 (0.92-1.14) 1.04 (0.88-1.23)

RT Weeks (7 vs 6) 1.4 (0.88-2.15) 0.9 (0.64-1.32) 0.9 (0.55-1.35) 1.3 (0.59-2.62)

RT Weeks (8-9 vs 6-7) 2.2 (1.33-3.46) 1.4 (0.94-2.06) 1.5 (0.89-2.34) 1.7 (0.76-3.76)

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RTOG 0129: Secondary AnalysesRTOG 0129: Secondary AnalysesGrade 3-4 Late MorbidityGrade 3-4 Late Morbidity

ASCO 2010

Rx Parameters Odd Ratio (95% Confidence Interval)

RT Dose (64-76 Gy, Continuous) 1.15 (0.99-1.34)

RT Weeks (7 vs 6) 0.88 (0.51-1.51)

RT Weeks (8-9 vs 6) 0.86 (0.46-1.61)

Cisplatin Cycles (1 vs 3) 0.58 (0.25-1.35)

Cisplatin Cycles (2 vs 3) 0.83 (0.51-1.35)

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RTOG 0129 – Summary of Planned EndpointsRTOG 0129 – Summary of Planned Endpoints

● Strong investigator support – enrollment of 743 Strong investigator support – enrollment of 743 patients in 3 yearspatients in 3 years

● Compliance to therapy regimens was excellent Compliance to therapy regimens was excellent (91% received therapy per protocol or with (91% received therapy per protocol or with minor variations)minor variations)

● No differences in tumor outcome or toxicity No differences in tumor outcome or toxicity were detected between the two regimenswere detected between the two regimens

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RTOG 0129 – Summary of Secondary AnalysesRTOG 0129 – Summary of Secondary Analyses

● LRR was the main cause of cancer mortalityLRR was the main cause of cancer mortality

● HPV status was the strongest prognostic factor HPV status was the strongest prognostic factor - Confirming our previous finding that HPV+ OPSCC is - Confirming our previous finding that HPV+ OPSCC is a distinct HNSCC entitya distinct HNSCC entity

● Receiving only 1 cisplatin cycle was associated Receiving only 1 cisplatin cycle was associated with significantly worse OS, PFS, and LRR rateswith significantly worse OS, PFS, and LRR rates

● The third cisplatin cycle had no significant The third cisplatin cycle had no significant impact on OS or PFS rate but was associated impact on OS or PFS rate but was associated with a higher LRC ratewith a higher LRC rate11

11as defined in this studyas defined in this study

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RTOG 0129 – Summary of Secondary AnalysesRTOG 0129 – Summary of Secondary Analyses

● Within the range of 64 to 76 Gy, a trend for Within the range of 64 to 76 Gy, a trend for dose-response relationship was detected for dose-response relationship was detected for grade 3-4 late morbidity (grade 3-4 late morbidity (PP=0.063) but not for =0.063) but not for OS or other endpointsOS or other endpoints

● 2-3 weeks of RT prolongation correlated with 2-3 weeks of RT prolongation correlated with poorer OS but not with other endpointspoorer OS but not with other endpoints

● Only N-category and HPV-status were found to Only N-category and HPV-status were found to have significant impact on the DM ratehave significant impact on the DM rate