Locally Advanced Nsclc

Emerging Novel Combined Modality Treatment Approaches to Improve

Outcomes for Locally Advanced NSCLC

Combined Modality Therapy of Stage III NSCLCState of the Art

Hak Choy, MD

UT Southwestern Medical Center

Case PresentationStage IIIB NSCLC

• A 59 year old man presents with persistent cough• Smoking history: 20 pack-year• Chest X-ray reveals a left upper lobe mass• CT confirms a LUL mass with multiple mediastinal lymph

nodes

LUL Mass2L Nodes

Precarinal Nodes


LUL Mass

2L Lymphadenopathy

Precarinal Lymph Nodes

• Left suprahilar mSUV 13.9• Precarinal LN mSUV 5.0• 2R LN mSUV 4.7


• 2L LN mSUV 8.7• LN anterior to aortic arch mSUV 3.3

Initial Staging PET Scan


• Which treatment option would you recommend?1. Radiotherapy alone2. Chemotherapy alone3. Sequential chemoradiotherapy4. Concurrent chemoradiotherapy5. Other

Emerging Novel Combined Modality Treatment Approaches to Improve

Outcomes for Locally Advanced NSCLC

Combined Modality Therapy of Stage III NSCLCState of the Art

Hak Choy, MD

UT Southwestern Medical Center

Background: Stage III NSCLC

• Traditionally considered surgically unresectable & incurable

• Stage III NSCLC is heterogeneous (many distinct subsets)

• Radiotherapy (RT) alone remained standard of care for unresectable stage III NSCLC until early 1990s– Traditional RT dose and technique yielded poor survival rates:

• 2-year: 15%

• 5-year: 5%

• Combined modality therapy (chemotherapy + radiotherapy and/or surgery) has now emerged as the standard of care

2-year Overall SurvivalTrial Pts. RT CT RTFinnish 238 17% 19%NCCTG 107 16% 21% CALGB 155 13% 26% IGR-French 331 14% 21%

Locally Advanced NSCLC – 1980’s

Sequential Chemoradiation Therapy Improves Survival Compared to Radiation Alone

Locally Advanced NSCLC – 1990’s

• What is the optimal sequence of chemoradiation and radiation fractionation?

Optimal Sequence of Chemoradiation

West Japan LC Group Sequential: MVP x 2 Stn RT Day 50 Concurrent: MVP x 2/Stn RT Day 1

RTOG 9410Sequential: Vinb/CisP x 2 Stn RT Day 50Conc D: Vinb/CisP x 2/Stn RT Day 1Conc BID: CisP/Eto x 2/BID RT Day 1

French TrialSequential: CisP/NavStn RT Day 50Concurrent : CisP/Etop x2/RT CisP/Etop

Czech TrialSequential: Cisp/Nav X4 RTConcurrent: Cisp/Nav/RTCisp/Nav

LAMP Sequential: Paclitaxel/Carbo RT Induction Conc: Paclitaxel/Carbo p/c/RTConc Consolidation:p/c/RT Paclitaxel/Carbo

BROCATSequential: Paclitaxel/Carbo x 2 RT aloneConcurrent: Paclitaxel/Carbo x 2 Wkly Paclitaxel/RT

Survival Comparison Between Sequential and Concurrent Chemoradiation Therapy

10

12

14

16

18

20

22

24

Sequential Concurrent

Med

ian

Su

rviv

al

WJLCG

GLOT

CZECH

LAMP

RTOG 9410

BROCAT

14 (n=716)

17 (n=709)

P < 0.05 (Kruskal-Wallis Test)

5

7

9

11

13

15

17

19

21


WJLCG

% 5

yr

OS

9%

19%

5

7

9

11

13

15

17

19

21


RTOG 9410

% 4

yr

OS

12%

21%

Is Concurrent Chemoradiation now Standard of Care?Yes: for good performance status & pulmonary function; low comorbidities

Long Term Survival Comparison Between Sequential and Concurrent Chemoradiation Therapy

5

7

9

11

13

15

17

19

1980's 1990's 2000's

Med

ian

Sur

viva

l

CALBG

Finsih

IGR

NCCTG

WJLCG

GLOT

CZECH

LAMP

RTOG 9410

MUNICH

ECOG 2597

9.8

13.8

Survival Improvement with Chemoradiotherapy in Stage III NSCLC since 1980’s

17.7

Clinical Research Issues in Chemoradiotherapy of Stage III NSCLC

• Optimizing radiotherapy– Total dose: are higher doses better?– Target volume– Fractionation: daily vs twice daily?– Sterotactic body radiotherapy (SBRT)

• Optimizing chemotherapy– New drugs: are they better?– Dose Schedule: full dose vs low dose?– Induction or consolidation?

• Prevention of brain metastases• Integration of molecular targeted therapies• Improved staging techniques (functional imaging)

Optimizing Radiotherapy Involved Volume Approaches

Issues:1. STDF: Can not deliver High Dose RT

Increased Pneumonitis, Esophagitis2. IF: Need reliably defined target ( T1/2, T3/4 ?)

ImmobilizationRisk of not treating LN may be too high !

3. We need a prospective trial comparing STDF vs. IF

Tumor =

50 Gy

63 Gy

STDF

Tumor

50 Gy

63 +Gy

IF

Optimizing Radiotherapy Involved Volume Approaches

Tumor

50Gy

60-64Gy

Tumor50Gy

68-74Gy

STDF IF

Stage III NSCLC: ChemoChemo/RT (200 patients randomized)

2 yr LF 1yr OS 2 yr OS 3 yr OS

ENI 49 59.7 25.6 19.2

IFRT 41 67.2 38.7 27.3

P = 0.048

Yuan , ASCO 2006, Abstract # 7044

Optimizing Radiotherapy High Dose Approaches

Group RT Dose Median Sv

RTOG 9410 63 Gy 17.1 mos

RTOG 0117* 74 Gy 21.6 mos

NCCTG N0028* 74 Gy 37 mos

CALGB 30105* 74 Gy 24.6 mos

North Carolina* 74 Gy 24 mos

* Low dose weekly chemo/RT


STD Dose

Tumor

64 cGy

High Dose

Tumor

74 cGy

VS

A Randomized Phase III Comparison of Standard Dose (63 Gy) vs High-Dose Conformal Radiotherapy (74 Gy) with Concurrent

Consolidation Carboplatin/Paclitaxel in Patients with Stage IIIA/B NSCLC

• Participating Groups– RTOG 0617– NCCTG– CALGB– ECOG?


STD Dose

Tumor64 cGy

High Dose

Tumor74 cGy

VS

• Accrual target is 512 patients

• Target accrual of 9 pts/month = 56 mos

• Estimated MS for control arm = 17.1 mos vs 24 mos for experimental arm

Chemotherapeutic Agents for Concurrent Chemoradiation Therapy: 1990’s–2000’s

• Paclitaxel• Irinotecan • Docetaxel• Vinorelbine • Gemcitabine• Pemetrexed

Stage III NSCLC Treatment Outcome Based on Agent Study-RT (Gy) Chemo MS (mos) 1 yr (%) 2 yr (%)Paclitaxel/RT 20.0 66 36P/C/RT 20.5 54 46

P/C/HFX RT 14.3 18.1 61 61 35 41P/C/3-D RT 26 70 51 P/C/RT(CALGB) 14 56 43P(tw)/C/RT 17 - 40

CPT-11/RT - 61 38

CPT-11/Carbo/RT - 55 62 51 45CPT-11/CisP/RT - 72

Docetaxel/RT 12 48 -Docetaxel/RT 13.6 59

Doc/CisP/RT 23 18.2 74 63 41 44

Doc/CisP/RT 15 55 43PE/RT-Doc 27 78 54

Gem/RT(CALGB) 18 65 40Nav/RT (CALGB) 17 68 38

0%

20%

40%

60%

80%

100%

0 24 48 72 96

Months After Registration

N

83

Events

62

Median Survival

26 mos

3 year survival 37%4 year survival 29%5 year survival 29%

Gandara: ASCO 05

Requires Confirmation

Optimizing Chemotherapy Phase II Trial of Cisplatin/Etoposide + RT →

Consolidation Docetaxel (SWOG 9504)

Optimizing ChemotherapyConfirmation Study for Consolidation Hoosier Oncology Group (LUN 01-24)

ChemoRT InductionCisplatin 50 mg/m2 d 1,8,29,36

Etoposide 50 mg/m2 IV d 1-5 & 29-33Concurrent RT 59.4 Gy (1.8 Gy/fr)

CR, PR, or SD;ECOG PS 0-2

Taxotere 75 mg/m2 q 3 wk 3 Observation

Randomize

Molecular-Targeted Combined-Modality Therapy

• Novel strategy resulting from increased understanding of underlying pathways and key molecules involved in tumor growth and progression

• Specificity of molecular-targeted therapy should improve therapeutic window by affecting tumor cells and sparing normal cells

Bonner JA, et al. NEJM 2006

Head and NeckPhase III Randomized Trial of Cetuximab

RTX Alone (qd or bid)

RTX (qd or bid)

Week 1 2 3 4 5 6 7 8

IMC-C225 Maintenance Doses

IMC-C225Loading Dose

Registration, Stratify: 1, T1-3 vs. T4

2, N0 vs. N1

3. Fractionation

4. KPS (60 - 80% vs. 90-100%)

Phase III Randomized Trial of Cetuximab Locoregional Control

P = 0.02

Pro

bab

ility

Months

RT RT + E

Patients 213 211

Events 105 90

Median Survival

19 mos 36 mos


Phase III Randomized Trial of Cetuximab Overall Survival

RT RT + E

Patients 213 211

Events 117 93

Median Survival

28 mos 54 mos

Pro

bab

ility

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 24 30 36 42 48 54 60

Months

P = 0.02


Phase III Randomized Trial of Cetuximab Most Common Adverse Events

% with toxicityRT (N=212) RT+E (N=208)

All Gr. G /4** All Gr. G /4**

Skin reaction 91 18 (<1) 97* 34*(2)

Mucositis/Stomatitis 93 52 (4) 91 54 (6)

Dysphagia 63 30 (1) 64 25 (<1)

Xerostomia 70 3 (–) 64 4 (–)

Fatigue/Malaise 50 5 (1) 52 4 (<1)

Infusion reaction*** 2 – 14* 3*(1)

*P < 0.05** Grade 4 in ( )*** Listed for its relationship to Erbitux Bonner JA, et al. NEJM 2006

SWOG 0023: A Phase III Trial in Unresectable Stage III NSCLC

CDDP/VP-16XRT Docetaxel Placebo

Definitive TX Consolidation Maintenance

CDDP/VP-16XRT ZD1839 250

RANDOMIZE

Docetaxel

SWOG 0023: A Phase III Trial in Unresectable Stage III NSCLC

CDDP/VP-16XRT Docetaxel Placebo

Definitive TX Consolidation Maintenance

CDDP/VP-16XRT ZD1839 250

RANDOMIZE

Docetaxel

CLOSED – Gefitinib Not Better

Preliminary Results of SWOG 0023 Causes of Deaths by Treatment Arm

ParameterGefitinib

(n=138)

Placebo

(n=146)

Alive 81 99

Dead 43 32

Disease 32 (74%) 19 (59%)

Toxicity 1 0

Disease + Toxicity 2 3

Other Causes 2 4

Toxicity from Chemo/RT 1 0

Under Review 5 6

RTOG 0234: A Phase II Study of Cetuximab in Combination with Chemoradiation in Subjects

with Stage IIIA/B NSCLC

Closed in 5/05 - 93 patients

Day 8:

C225: 250 mg/m² wkly/7

Taxol/CarboRT: 63Gy

Day 1:

C225400 mg/m2 IV loading dose

Taxol/Carbo

C225:

250mg/m² weekly x 6

CALGB Concurrent Carboplatin, Pemetrexed, and Radiation Therapy followed by Carboplatin, Pemetrexed with or without Cetuximab for Patients with Unresectable Stage III NSCLC

RANDOMIZE

Arm A

Arm B

Carboplatin AUC 6 q3 week x 4 cyclesPemetrexed 500 mg/m² q3 week x 8 cyclesXRT - 6600 cGy over 7 weeks

Carboplatin AUC 6 q3 week x 4 cyclesPemetrexed 500 mg/m² q3 week x 8 cyclesXRT - 6600 cGy over 7 weeks

+Cetuximab 400 mg/m² loading and 250 mg/m² weekly

A Randomized Phase II Trial

S0533: Integration of Bevacizumab into Chemoradiation

Cohort 1 (A introduced after Chemoradiotherapy)Concurrent Chemoradiotherapy Consolidation ChemotherapyConcurrent Chemotherapy X X X XRTConsolidation Chemotherapy DA DA DA

Cohort 2 (A introduced on day 8 during Chemoradiotherapy)Concurrent Chemoradiotherapy Consolidation ChemotherapyConcurrent Chemotherapy X XA XA XRTConsolidation Chemotherapy DA DA DA

Cohort 3 (A introduced on day 1 of Chemoradiotherapy)Concurrent Chemoradiotherapy Consolidation ChemotherapyConcurrent Chemotherapy XA X XA XRTConsolidation Chemotherapy DA DA DA

XX: Cisplatin/Etoposide; D: Docetaxel; A: Bevacizumab

Pattern of Metastatic Disease

Lun 56 Lun 63 SWOG9504 Sites #of Pts. #of Pts. #of Pts.

Brain Only 5 5 8

Brain & Other 2 4 15

Other Sites 3 4 3

TOTAL 10 13 29

Brain mets 7/10 9/13 23/29

CNS Relapse 70% 69% 79%Rate

CNS Relapse 70% 69% 79%Rate

A Phase III Comparison of Prophylactic Cranial Irradiation vs Observation in Patients with Locally

Advanced Non-small Cell Lung Cancer (RTOG 0214)

*Patients with partial response to locoregional therapy and Zubrod Performance Score 0 or 1 (KPS 70-100) or have complete response to therapy and Zubrod Performance Score 0-2 (KPS 50-100).

Stage III NSCLC Patients

Observation

PCI: 30 Gy/15 fx

Evaluate Neurotoxicity

N = 1058

5

7

9

11

13

15

17

19

21

23

25

27

29

31

1980's 1990's 2000's 2010's

me

dia

n s

urv

iva

l

CALBG

Finsih

IGR

NCCTG

WJLCG

GLOT

CZECHLAMP

RTOG 9410

MUNICH

ECOG 2597

HDChemo/RT

HD Biological/RT

HD/Chemo/Biol/RT

Survival Improvement with Chemoradiotherapy in Stage III NSCLC

Since 1980–2010

??

+PCI+PCI


• A 59 year old man presents with persistent cough.• Smoking history: 20 pack-year• Chest X-ray reveals a left upper lobe mass• CT confirms a LUL mass with multiple mediastinal lymph

nodes

LUL Mass2L Nodes

Precarinal Nodes


• Which treatment option would you recommend?1. Radiotherapy alone2. Chemotherapy alone3. Sequential chemoradiotherapy4. Concurrent chemoradiotherapy5. Other

Following Completion of Concurrent Cisplatin/Etoposide + Radiation Consolidation

Docetaxel

Resolution of 2L Lymphadenopathy

Resolution of LUL Mass and Precarinal Lymph Nodes


Follow up PET Scan Shows Complete Remission

Locally Advanced NSCLCConclusions

• Combined modality therapy has improved the survival of stage III NSCLC, providing long term survival in a subset of patients

• Current research efforts are attempting to optimize chemotherapy and radiotherapy

• Studies integrating new molecular targeted therapies are ongoing

Locally Advanced Nsclc

Health & Medicine

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