Phase III Study of Concurrent Chemotherapy and Radiotherapy (CT/RT) versus CT/RT followed by Surgical Resection for Stage IIIA(pN2) NSCLC

Outcomes Update of North American Intergroup Trial 0139 (R9309)

Conducted by:

RTOG (chair), SWOG, NCIC CTG, ECOG, CALGB and NCCTG

Radiation Therapy Oncology Group

Lung Intergroup Trial 0139Rationale

• Patients with stage III NSCLC and clinically-evident N2 disease have poor outcomes with surgery or radiotherapy (RT) alone

• Chemotherapy (CT) plus RT is standard for pathologically-confirmed N2 nodes (pN2)

• Surgical resection after CT/RT, although promising in phase II trials, is controversial due to increased morbidity and mortality

Lung Intergroup Trial 0139

Objectives

1. Determine if resection after CT/RT results in improved outcome compared to CT plus full-course RT (arms based on SWOG 8805 and SWOG 9019)

2. Analyze progression-free, overall, and long-term survival; toxicity; and patterns of failure

Lung Intergroup Trial 0139

Eligibility Criteria

• T1-3, pN2, M0 non-small cell lung cancer

• Resection technically feasible

• FEV1 >2.0 liters, or, predicted post-resection FEV1 800 cc

• Medically fit

Lung Intergroup Trial 0139 Study Design

STRATIFY

KPS 70-80 vs 90-100T1 vs T2 vs T3

RANDOMIZE

RE-EVALUATE RE-EVALUATE 2-4 weeks after 7 days before completion of RT completion of RT

Induction CT/RT

Cisplatin, 50 mg/m2 IV d1, 8, 29, 36Etoposide, 50 mg/m2 IV d1-5, 29-33

Thoracic RT, 45 Gy (1.8 Gy/d), begin d1

Lung Intergroup Trial 0139 Study Design

No progression at re-evaluation

Surgical Resection

Continue RT to 61 Gy without interruption

CONSOLIDATIONcisplatin plus etoposide

X 2 cycles

Lung Intergroup Trial 0139

Statistical Considerations

• Sample size assumed 25% 2-year survival for CT/RT and 10% absolute improvement by the addition of surgery

• 80% statistical power and 0.05 significance level

• Final accrual 484 eligible patients

Lung Intergroup Trial 0139 Results

• Opened 3/94 and closed 11/01

• Accrual longer than planned with more events, thus closure allowed at n = 429

• First analysis in 2003 reported better PFS, but not OS, for surgical arm

• Second planned analysis this report:

Median follow-up: 81 months

All patients followed >2.5 years

Lung Intergroup Trial 0139Patient and Tumor Characteristics*

Randomized/Eligible CT/RT/S CT/RTFemaleAge median yrs/70KPS 70-80Weight loss 5 kgT3 tumorsSquamous histologyLDH abnormal

429/396 (93%)202194144 (36%)60/63 (16%) 48 (12%) 84 (21%) 48 (12%) 129 (33%) 72 (18%)

*balanced in both arms

Lung Intergroup Trial 0139

Eligible for thoracotomy 177 (88%)

Thoracotomy performed 164 (81%) Complete resection 144 (71%) Incomplete resection 11 (5.5%) No resection 9 (4.5%)

Eligible for consolidation CT/RT 179 (92%)

Commenced consolidation 155 (80%)

Treatment Delivered

ARM 1 (n=202)

ARM 2 (n=194)

Lung Intergroup Trial 0139

Treatment CT/RT/S CT/RT p-value (n=202) (n=194)

Induction 191 (95%) 177 (92%) NSchemotherapy

Consolidation 112 (56%) 144 (75%) p<0.0001chemotherapy

Radiotherapy 193 (96%) 154 (79%) p<0.0001

Treatment Delivered*

*Per protocol or with an acceptable variation (study chair review)

INT 0139 Grade 3/4 Toxicity from CT/RTINT 0139 Grade 3/4 Toxicity from CT/RT

*p=0.0006*p=0.0006

00

1010

2020

3030

4040

5050

NeutropeniaNeutropenia Pneumonia/Pneumonia/respiratoryrespiratory

CT/RT/S(n=202)

CT/RT(n=194)

Nausea/Nausea/emesisemesis

Esophagitis*Esophagitis*

Per

cen

t (%

)P

erce

nt

(%) 7777

8080

2020

4444

2929 26261818 2424

Lung Intergroup Trial 0139

• During induction none, either arm

• CT/RT/S total 16 (7.9%)

30 days postop. 10 (5.0%) misc. other 6 (2.9%)

• CT/RT (during or 4 (2.1%) after consolidation)

Treatment-Related Mortality

INT 0139 Treatment-Related Deaths on CT/RT/S Arm (n=16)

Type of Total DeathsSurgery (of n=202) n (% total) Cause of Death

None 38 1 (3%) Pneumonitis

Exploration only 9 0 -

Wedge 3 0 -

Lobectomy 98 1 (1%) ARDS

Pneumonectomy 54 14 (26%) ARDS/respiratory

11; miscellaneous, 3

(R) simple 17 5 (29%)

(R) complex 12 6 (50%) (L) simple 6 0 (L) complex 19 3 (16%)

Lung INT 0139: Patterns of Failure

Site of First Arm 1 Arm 2 p-valueProgression (CT/RT/S) (CT/RT)

Local relapse only 10% 22% 0.002 primary 2% 14% nodes 7% 3% both 1% 5%

Brain only 11% 15% 0.29

All distant metastases 37% 42% 0.35

INT 0139 Pathologic T and N Status at Time of Surgery

pT/N N % Thoracotomies % Total (n=164) (n=202)

T0N0(pCR) 29 18% 15%

T1N0 31 18% 15%

T2-4N0 16 10% 8%

Tany N0 76 46% 38%

N1-3 or 88* 54% 43%unknown

*3 were unknown

Intergroup 0139/RTOG 9309Progression-Free Survival by Treatment Arms

CT/RT/S 159/202 CT/RT 172/194

Logrank p = 0.017Hazard ratio = 0.77 (0.62, 0.96)%

Aliv

e w

ith

ou

t P

rog

ress

ion

0

25

50

75

100

0 12 24 36 48 60

/

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

Months from Randomization

Failed/Total

INT 0139/RTOG 9309 Survival Endpoints

Endpoint CT+RT+S CT+RT

Progression-Free Survival*

Median 12.8 months 10.5 months 5-year ( 95% CI) 22.4% (6) 11.1% (5)

Overall Survival*

Median 23.6 months 22.2 months 5-year ( 95% CI) 27.2% (6) 20.3% (6) *crossing survival curves due to treatment-related deaths, 96 (24.2%) alive/censored

INT 0139 Survival Data

• CT/RT/S: more alive without progression (21% vs 11%, p = .008), but more died without progression (18% vs 10%, p = .02)

• Survival curves indistinguishable through year 2, then separate

• By year 5, absolute survival benefit of 7% favors surgical arm: odds ratio 0.63 (0.36, 1.10), p = 0.10; no other factor predicted 5-yr survival by logistic regression

Intergroup 0139/RTOG 9309Overall Survival by Treatment Arms

CT/RT/S 145/202CT/RT 155/194

Logrank p = 0.24

Hazard ratio = 0.87 (0.70, 1.10)

% A

live

0

25

50

75

100

Months from Randomization

0 12 24 36 48 60

Dead/Total

INT 0139 Cox Stepwise Selection Model for Overall Survival

Variable* Hazard Ratio p-value (95% CI)

Weight loss 1.54 (1.16, 2.05) 0.003<5 kg vs 5 kg

Female vs male 1.42 (1.09, 1.84) 0.009

1 N2 station 1.38 (1.04, 1.83) 0.024positive vs 2

CT/RT/S vs CT/RT 1.07 (0.84, 1.36) 0.61

*Not significant: age, KPS, T stage, LDH, histology

INT 0139 Trimodality Arm (n=202) Survival by Pathologic Status at Surgery

T/N Median SurvivalSubset (months) 5-year

Tany N0* 34 41%

Tany N1-3 26 24%or unknown

No surgery 8 8%

*29 of these = T0N0 (pCR): MS, 40 months; 5-year, 42%

Intergroup 0139 Trimodality ArmOverall Survival by Pathologic Nodal Status

No surgery (n=38)

Pathologic N0 (n=76)

Pathologic N1-3, unknown (n=88)

p < 0.0001

% A

live

0

25

50

75

100

Months from Randomization

0 20 40 60 80 100 120

INT 0139 Exploratory Survival Analysis

• All but 1 postoperative death followed a pneumonectomy

• Hypothesized survival advantage for CT/RT/S if lobectomy performed and for CT/RT if pneumonectomy

• Patients on CT/RT/S were matched with those on CT/RT arm on 4 prestudy factors (KPS, age, sex, T stage); match feasible for 90/98 lobectomies and 51/54 pneumonectomies

INT0139 Overall Survival of the Lobectomy Subset versus Matched CT/RT Subset

% A

live

0

25

50

75

100

Months from Randomization0 12 24 36 48 60

///

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

/ / // /

Logrank p = 0.002

CT/RT/S 57/90CT/RT 74/90

Dead/Total

MS 34 mos. 22 mos.5 yr OS 36% 18%

CT/RT/S CT/RT

Lung Intergroup Trial 0139/RTOG 9309

• Both approaches have median and 5-year survivals better than predicted from phase II data in stage IIIA(pN2) NSCLC

• Longer follow-up confirms significantly improved PFS, but not OS, when surgery follows CT/RT

• There is a trend for increased 5-year survival with trimodality therapy

Conclusions

Lung Intergroup Trial 0139/RTOG 9309

• N0 status at surgery significantly predicts greater 5-year survival

• The trimodality approach is not optimal when a pneumonectomy is required due to high mortality risk

• Surgical resection after CT/RT can be considered for fit patients if lobectomy is feasible

Conclusions

Radiation Therapy Oncology Group INT 0139 Acknowledgements

Study Chairs: Kathy S. Albain, M.D. – Medical Oncology

Valerie R. Rusch, M.D. – Thoracic Surgery

Andrew T. Turrisi, III, M.D. – Radiation Oncology

Biostatisticians:R. Suzanne Swann, Ph.D.

Rebecca Paulus, B.S.

Radiation Therapy Oncology Group

INT 0139 Acknowledgements

Other Coauthors: Frances A. Shepherd, M.D. Colum Smith, M.D.David R. Gandara, M.D.David H. Johnson, M.D.Mark R. Green, M.D.Robert C. Miller, M.D.Yuhchyau Chen, M.D., Ph.D.Robert B. Livingston, M.D.Gail Darling, M.D.William T. Sause, M.D.James D. Cox, M.D.

Radiation Therapy Oncology Group

INT 0139 Other Acknowledgements

Additional Protocol Discipline Chairs:Yvon Cormier, M.D. Mark Krasna, M.D.Claude Deschamps, M.D. Randolph Marks, M.D.Bahman Emami, M.D. Tom Rice, M.D.David Ettinger, M.D. Stephen Seagren, M.D.Richard Feins, M.D. Henry Wagner, M.D.Daniel Ihde, M.D.

Major Thoracic Surgical Support:Willard Fry, M.D.

RTOG Headquarters:Joanne Ley, R.N., C.C.R.P.