Locally Advanced Nsclc

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Information about Locally Advanced Nsclc
Health & Medicine

Published on March 21, 2009

Author: fovak

Source: slideshare.net

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 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 Mass 2L Nodes Precarinal Nodes

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

Case Presentation Stage IIIB NSCLC LUL Mass 2L Lymphadenopathy Precarinal Lymph Nodes

Case Presentation Stage IIIB NSCLC 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

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 NSCLC Which treatment option would you recommend? Radiotherapy alone Chemotherapy alone Sequential chemoradiotherapy Concurrent chemoradiotherapy Other

Which treatment option would you recommend?

Radiotherapy alone

Chemotherapy alone

Sequential chemoradiotherapy

Concurrent chemoradiotherapy

Other

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

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

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 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%

Sequential Chemoradiation Therapy Improves Survival Compared to Radiation Alone

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 What is the optimal sequence of chemoradiation and radiation fractionation?

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 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

West Japan LC Group

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

Survival Comparison Between Sequential and Concurrent Chemoradiation Therapy P < 0.05 (Kruskal-Wallis Test) 14 (n=716) 17 (n=709)

Long Term Survival Comparison Between Sequential and Concurrent Chemoradiation Therapy WJLCG % 5 yr OS 9% 19% RTOG 9410 % 4 yr OS 12% 21% Is Concurrent Chemoradiation now Standard of Care? Yes: for good performance status & pulmonary function; low comorbidities

Survival Improvement with Chemoradiotherapy in Stage III NSCLC since 1980’s 9.8 13.8 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

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, 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 Tumor = 50 Gy 63 Gy STDF Tumor 50 Gy 63 +Gy IF

Issues:

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

Optimizing Radiotherapy Involved Volume Approaches Stage III NSCLC: Chemo  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 STDF IF Yuan , ASCO 2006, Abstract # 7044 Tumor 50Gy 60-64Gy Tumor 50Gy 68-74Gy

Stage III NSCLC: Chemo  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

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

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

Optimizing Radiotherapy High Dose Approaches VS STD Dose Tumor 64 cGy High Dose Tumor 74 cGy

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?

Participating Groups

RTOG 0617

NCCTG

CALGB

ECOG?

Optimizing Radiotherapy High Dose Approaches 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 VS STD Dose Tumor 64 cGy High Dose Tumor 74 cGy

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

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 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 CPT-11/RT - 61 38 CPT-11/Carbo/RT - 55 62 51 45 CPT-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 43 PE/RT-Doc 27 78 54 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) 3 year survival 37% 4 year survival 29% 5 year survival 29% Gandara: ASCO 05 Requires Confirmation 0% 20% 40% 60% 80% 100% 0 24 48 72 96 Months After Registration N 83 Events 62 Median Survival 26 mos

Optimizing Chemotherapy Confirmation Study for Consolidation Hoosier Oncology Group (LUN 01-24) ChemoRT Induction Cisplatin 50 mg/m 2 d 1,8,29,36 Etoposide 50 mg/m 2 IV d 1-5 & 29-33 Concurrent RT 59.4 Gy (1.8 Gy/fr) CR, PR, or SD; ECOG PS 0-2 Taxotere 75 mg/m 2 q 3 wk  3 Observation Randomize

ChemoRT Induction Cisplatin 50 mg/m 2 d 1,8,29,36 Etoposide 50 mg/m 2 IV d 1-5 & 29-33 Concurrent RT 59.4 Gy (1.8 Gy/fr)

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

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 Bonner JA, et al. NEJM 2006 RTX Alone (qd or bid) RTX (qd or bid) Week 1 2 3 4 5 6 7 8 IMC-C225 Maintenance Doses IMC-C225 Loading 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 Probability Months Bonner JA, et al. NEJM 2006 36 mos 19 mos Median Survival 90 105 Events 211 213 Patients RT + E RT

Phase III Randomized Trial of Cetuximab Overall Survival Bonner JA, et al. NEJM 2006 54 mos 28 mos Median Survival 93 117 Events 211 213 Patients RT + E RT Probability 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 *P < 0.05 ** Grade 4 in ( ) *** Listed for its relationship to Erbitux Bonner JA, et al. NEJM 2006 3*(1) 14* – 2 Infusion reaction*** 4 (<1) 52 5 (1 ) 50 Fatigue/Malaise 4 ( –) 64 3 ( –) 70 Xerostomia 25 (<1) 64 30 (1) 63 Dysphagia 54 (6) 91 52 (4) 93 Mucositis/Stomatitis 34*(2) 97* 18 (<1) 91 Skin reaction G /4** All Gr. G /4** All Gr. % with toxicity RT+E (N=208) RT (N=212)

SWOG 0023: A Phase III Trial in Unresectable Stage III NSCLC CDDP/VP-16 XRT Docetaxel Placebo Definitive TX Consolidation Maintenance CDDP/VP-16 XRT RANDOMIZE Docetaxel ZD1839 250

SWOG 0023: A Phase III Trial in Unresectable Stage III NSCLC CDDP/VP-16 XRT Docetaxel Placebo Definitive TX Consolidation Maintenance CDDP/VP-16 XRT RANDOMIZE Docetaxel CLOSED – Gefitinib Not Better ZD1839 250

Preliminary Results of SWOG 0023 Causes of Deaths by Treatment Arm 32 43 Dead 6 5 Under Review 0 1 Toxicity from Chemo/RT 4 2 Other Causes 3 2 Disease + Toxicity 0 1 Toxicity 19 (59%) 32 (74%) Disease 99 81 Alive Placebo (n=146) Gefitinib (n=138) Parameter

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/Carbo RT : 63Gy Day 1 : C225 400 mg/m 2 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 A Randomized Phase II Trial R A N D O M I Z E Arm A Arm B Carboplatin AUC 6 q3 week x 4 cycles Pemetrexed 500 mg/m² q3 week x 8 cycles XRT - 6600 cGy over 7 weeks 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

S0533: Integration of Bevacizumab into Chemoradiation Cohort 1 ( A introduced after Chemoradiotherapy) Concurrent Chemoradiotherapy  Consolidation Chemotherapy Concurrent Chemotherapy X X X X RT Consolidation Chemotherapy D A D A D A Cohort 2 ( A introduced on day 8 during Chemoradiotherapy) Concurrent Chemoradiotherapy  Consolidation Chemotherapy Concurrent Chemotherapy X X A X A X RT Consolidation Chemotherapy D A D A D A Cohort 3 ( A introduced on day 1 of Chemoradiotherapy) Concurrent Chemoradiotherapy  Consolidation Chemotherapy Concurrent Chemotherapy X A X X A X RT Consolidation Chemotherapy D A D A D A 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

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

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

Survival Improvement with Chemoradiotherapy in Stage III NSCLC Since 1980–2010 ? +PCI

Case Presentation Stage 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 Mass 2L Nodes Precarinal Nodes

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

Case Presentation Stage IIIB NSCLC LUL Mass 2L Lymphadenopathy Precarinal Lymph Nodes

Case Presentation Stage IIIB NSCLC 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

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 NSCLC Which treatment option would you recommend? Radiotherapy alone Chemotherapy alone Sequential chemoradiotherapy Concurrent chemoradiotherapy Other

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 Resolution of LUL Mass and Precarinal Lymph Nodes

Resolution of 2L Lymphadenopathy

Case Presentation Stage IIIB NSCLC Follow up PET Scan Shows Complete Remission

Locally Advanced NSCLC Conclusions 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

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

Emerging Novel Combined Modality Treatment Approaches to Improve Outcomes for Locally Advanced NSCLC Combined Modality Therapy of Stage III NSCLC State of the Art DISCUSSION

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