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Emerging Novel Combined Modality Treatment Approaches to Improve Outcomes for Locally Advanced NSCLC Combined Modality Therapy of Stage III NSCLC State of the Art. Hak Choy, MD UT Southwestern Medical Center. Case Presentation Stage IIIB NSCLC. A 59 year old man presents with persistent cough

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Hak choy md ut southwestern medical center

Emerging Novel Combined Modality Treatment Approaches to Improve Outcomes for Locally Advanced NSCLCCombined Modality Therapy of Stage III NSCLCState of the Art

Hak Choy, MD

UT Southwestern Medical Center


Case presentation stage iiib nsclc
Case Presentation Improve Outcomes for Locally Advanced NSCLCStage 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

2L Nodes

LUL Mass

Precarinal Nodes


Case presentation stage iiib nsclc1

LUL Mass Improve Outcomes for Locally Advanced NSCLC

2L Lymphadenopathy

Precarinal Lymph Nodes

Case PresentationStage IIIB NSCLC


Case presentation stage iiib nsclc2
Case Presentation Improve Outcomes for Locally Advanced NSCLCStage IIIB NSCLC

Initial Staging PET Scan

  • 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


Case presentation stage iiib nsclc3
Case Presentation Improve Outcomes for Locally Advanced NSCLCStage IIIB NSCLC

  • Which treatment option would you recommend?

    • Radiotherapy alone

    • Chemotherapy alone

    • Sequential chemoradiotherapy

    • Concurrent chemoradiotherapy

    • Other


Hak choy md ut southwestern medical center1

Emerging Novel Combined Modality Treatment Approaches to Improve Outcomes for Locally Advanced NSCLCCombined Modality Therapy of Stage III NSCLCState of the Art

Hak Choy, MD

UT Southwestern Medical Center


Background stage iii nsclc
Background: Stage III NSCLC Improve Outcomes for Locally Advanced 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


Locally advanced nsclc 1980 s

Sequential Chemoradiation Therapy Improves Survival Compared to Radiation Alone

Locally Advanced NSCLC – 1980’s

  • 2-year Overall Survival

    • Trial Pts. RT CT RT

    • Finnish 238 17% 19%

    • NCCTG 107 16% 21%

    • CALGB 155 13% 26%

    • IGR-French 331 14% 21%


Locally advanced nsclc 1990 s
Locally Advanced NSCLC – 1990’s Compared to Radiation Alone

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


Optimal sequence of chemoradiation

West Japan LC Group Compared to Radiation Alone

Sequential: MVP x 2  Stn RT Day 50

Concurrent: MVP x 2/Stn RT Day 1

RTOG 9410

Sequential: Vinb/CisP x 2 Stn RT Day 50

Conc D: Vinb/CisP x 2/Stn RT Day 1

Conc BID: CisP/Eto x 2/BID RT Day 1

French Trial

Sequential: CisP/NavStn RT Day 50

Concurrent : CisP/Etop x2/RT CisP/Etop

Czech Trial

Sequential: Cisp/Nav X4 RT

Concurrent: Cisp/Nav/RTCisp/Nav

LAMP

Sequential: Paclitaxel/Carbo  RT

Induction  Conc: Paclitaxel/Carbo  p/c/RT

Conc Consolidation:p/c/RT Paclitaxel/Carbo

BROCAT

Sequential: Paclitaxel/Carbo x 2 RT alone

Concurrent: Paclitaxel/Carbo x 2 Wkly Paclitaxel/RT

Optimal Sequence of Chemoradiation


Survival comparison between sequential and concurrent chemoradiation therapy

17 (n=709) Compared to Radiation Alone

14 (n=716)

Survival Comparison Between Sequential and Concurrent Chemoradiation Therapy

P < 0.05 (Kruskal-Wallis Test)


Long term survival comparison between sequential and concurrent chemoradiation therapy

RTOG 9410 Compared to Radiation Alone

WJLCG

21%

19%

% 4 yr OS

% 5 yr OS

12%

9%

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


Survival improvement with chemoradiotherapy in stage iii nsclc since 1980 s

9.8 Compared to Radiation Alone

13.8

17.7

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


Clinical research issues in chemoradiotherapy of stage iii nsclc
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: NSCLC

1. STDF: Can not deliver High Dose RT

Increased Pneumonitis, Esophagitis

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

Immobilization

Risk of not treating LN may be too high !

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

STDF

IF

Tumor =

Tumor

50 Gy

50 Gy

63 Gy

63 +Gy

Optimizing Radiotherapy Involved Volume Approaches


Optimizing radiotherapy involved volume approaches1

Stage III NSCLC: Chemo NSCLCChemo/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

Tumor

Tumor

50Gy

50Gy

60-64Gy

68-74Gy

Optimizing Radiotherapy Involved Volume Approaches

STDF

IF

Yuan , ASCO 2006, Abstract # 7044


Optimizing radiotherapy high dose approaches

Group NSCLCRT DoseMedian 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

Optimizing Radiotherapy High Dose Approaches

* Low dose weekly chemo/RT


Optimizing radiotherapy high dose approaches1

STD Dose NSCLC

High Dose

Tumor

Tumor

64 cGy

74 cGy

Optimizing Radiotherapy High Dose Approaches

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?


Optimizing radiotherapy high dose approaches2

Accrual target is 512 patients vs High-Dose Conformal Radiotherapy (74 Gy) with Concurrent Consolidation Carboplatin/Paclitaxel in Patients with Stage IIIA/B NSCLC

Target accrual of 9 pts/month = 56 mos

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

STD Dose

High Dose

Tumor

Tumor

64 cGy

74 cGy

Optimizing Radiotherapy High Dose Approaches

VS


Chemotherapeutic agents for concurrent chemoradiation therapy 1990 s 2000 s
Chemotherapeutic Agents for Concurrent Chemoradiation Therapy: 1990’s–2000’s

  • Paclitaxel

  • Irinotecan

  • Docetaxel

  • Vinorelbine

  • Gemcitabine

  • Pemetrexed


Stage III NSCLC Treatment Outcome Based on Agent Therapy: 1990’s–2000’s

Study-RT (Gy) Chemo MS (mos) 1 yr (%) 2 yr (%)

Paclitaxel/RT 20.0 66 36

P/C/RT 20.5 54 46

P/C/HFX RT 14.3 18.1 61 61 35 41

P/C/3-D RT 26 70 51

P/C/RT(CALGB) 14 56 43

P(tw)/C/RT 17 - 40

Docetaxel/RT 12 48 -

Docetaxel/RT 13.6 59

Doc/CisP/RT 23 18.2 74 63 41 44

Doc/CisP/RT 15 55 43

PE/RT-Doc 27 78 54

CPT-11/RT - 61 38

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

CPT-11/CisP/RT - 72

Gem/RT(CALGB) 18 65 40

Nav/RT (CALGB) 17 68 38


Optimizing chemotherapy phase ii trial of cisplatin etoposide rt consolidation docetaxel swog 9504

100% Therapy: 1990’s–2000’s

80%

N

Events

Median Survival

83

62

26 mos

60%

40%

20%

0%

0

24

48

72

96

Months After Registration

Optimizing ChemotherapyPhase II Trial of Cisplatin/Etoposide + RT → Consolidation Docetaxel (SWOG 9504)

Requires Confirmation

3 year survival 37%

4 year survival 29%

5 year survival 29%

Gandara: ASCO 05


Optimizing chemotherapy confirmation study for consolidation hoosier oncology group lun 01 24

ChemoRT Induction Therapy: 1990’s–2000’sCisplatin 50 mg/m2 d 1,8,29,36Etoposide 50 mg/m2 IV d 1-5 & 29-33Concurrent RT 59.4 Gy (1.8 Gy/fr)

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

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

Randomize

Taxotere 75 mg/m2 q 3 wk  3

Observation


Molecular targeted combined modality therapy
Molecular-Targeted Therapy: 1990’s–2000’sCombined-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


Head and neck phase iii randomized trial of cetuximab

IMC-C225 Therapy: 1990’s–2000’s

Loading Dose

IMC-C225 Maintenance Doses

Week 1 2 3 4 5 6 7 8

RTX (qd or bid)

Registration, Stratify:

1, T1-3 vs. T4

2, N0 vs. N1

3. Fractionation

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

RTX Alone (qd or bid)

Head and NeckPhase III Randomized Trial of Cetuximab

Bonner JA, et al. NEJM 2006


Phase iii randomized trial of cetuximab locoregional control
Phase III Randomized Trial of Cetuximab Therapy: 1990’s–2000’sLocoregional Control

P = 0.02

Probability

Months

Bonner JA, et al. NEJM 2006


Phase iii randomized trial of cetuximab overall survival

1.0 Therapy: 1990’s–2000’s

0.8

P = 0.02

0.6

Probability

0.4

0.2

0.0

0 6 12 18 24 30 36 42 48 54 60

Months

Phase III Randomized Trial of Cetuximab Overall Survival

Bonner JA, et al. NEJM 2006


Phase iii randomized trial of cetuximab most common adverse events
Phase III Randomized Trial of Cetuximab Therapy: 1990’s–2000’sMost Common Adverse Events

*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

ZD1839 250 Therapy: 1990’s–2000’s

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

Definitive TXConsolidationMaintenance

RANDOMIZE

CDDP/VP-16

XRT

Docetaxel

Placebo

CDDP/VP-16

XRT

Docetaxel


Swog 0023 a phase iii trial in unresectable stage iii nsclc1

ZD1839 250 Therapy: 1990’s–2000’s

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

Definitive TXConsolidationMaintenance

RANDOMIZE

CDDP/VP-16

XRT

Docetaxel

Placebo

CLOSED – Gefitinib Not Better

CDDP/VP-16

XRT

Docetaxel


Preliminary results of swog 0023 causes of deaths by treatment arm
Preliminary Results of SWOG 0023 Therapy: 1990’s–2000’s Causes of Deaths by Treatment Arm


Day 8: Therapy: 1990’s–2000’s

C225:

250 mg/m² wkly/7

Taxol/Carbo

RT: 63Gy

Day 1:

C225

400 mg/m2 IV loading dose

Taxol/Carbo

C225:

250mg/m² weekly x 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


Carboplatin Therapy: 1990’s–2000’sAUC 6 q3 week x 4 cycles

Pemetrexed 500 mg/m² q3 week x 8 cycles

XRT - 6600 cGy over 7 weeks

R

A

N

D

O

M

I

Z

E

Arm A

Carboplatin AUC 6 q3 week x 4 cycles

Pemetrexed 500 mg/m² q3 week x 8 cycles

XRT - 6600 cGy over 7 weeks

+

Cetuximab 400 mg/m² loading

and 250 mg/m² weekly

Arm B

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

A Randomized Phase II Trial


S0533 integration of bevacizumab into chemoradiation

Cohort 1 Therapy: 1990’s–2000’s(A introduced after Chemoradiotherapy)

Concurrent Chemoradiotherapy  Consolidation Chemotherapy

Concurrent Chemotherapy X X X X

RT

Consolidation Chemotherapy DA DA DA

Cohort 2(A introduced on day 8 during Chemoradiotherapy)

Concurrent Chemoradiotherapy  Consolidation Chemotherapy

Concurrent Chemotherapy X XA XAX

RT

Consolidation Chemotherapy DA DA DA

Cohort 3(A introduced on day 1 of Chemoradiotherapy)

Concurrent Chemoradiotherapy  Consolidation Chemotherapy

Concurrent Chemotherapy XA X XA X

RT

Consolidation Chemotherapy DA DA DA

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

S0533: Integration of Bevacizumab into Chemoradiation


Pattern of metastatic disease

Lun 56 Lun 63 SWOG9504 Therapy: 1990’s–2000’s

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

Pattern of Metastatic Disease

CNS Relapse 70% 69% 79%

Rate


Observation Therapy: 1990’s–2000’s

Stage III NSCLC Patients

Evaluate Neurotoxicity

N = 1058

PCI: 30 Gy/15 fx

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).



Case presentation stage iiib nsclc4
Case Presentation NSCLC Since 1980–2010Stage 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

2L Nodes

LUL Mass

Precarinal Nodes


Case presentation stage iiib nsclc5
Case Presentation NSCLC Since 1980–2010Stage IIIB NSCLC

  • Which treatment option would you recommend?

    • Radiotherapy alone

    • Chemotherapy alone

    • Sequential chemoradiotherapy

    • Concurrent chemoradiotherapy

    • Other


Following completion of concurrent cisplatin etoposide radiation consolidation docetaxel

Resolution of 2L Lymphadenopathy NSCLC Since 1980–2010

Resolution of LUL Mass and Precarinal Lymph Nodes

Following Completion of Concurrent Cisplatin/Etoposide + Radiation  Consolidation Docetaxel


Case presentation stage iiib nsclc6
Case Presentation NSCLC Since 1980–2010Stage IIIB NSCLC

Follow up PET Scan Shows Complete Remission


Locally advanced nsclc conclusions
Locally Advanced NSCLC NSCLC Since 1980–2010Conclusions

  • 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


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