Evolving treatment paradigms for Stage III NSCLC

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Evolving treatment paradigms for Stage III NSCLC

• Saiama N Waqar, MD

2
Disclosure

• No financial disclosures

3
Overview

• Introduction
• TNM Staging
• Proposed changes
• Prognostic factors
• Criteria for resectable disease
• Treatment paradigms
• Resectable
• Unresectable
• Conclusions

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Introduction

• The American Cancer Society estimates 161,840
  lung cancer-related deaths for the year 2008
• NSCLC accounts for 87 of lung cancer
• 1/3 present with locally advanced disease, which
  accounts for over 40,000 cases annually Gandara
  2004
• Stage III NSCLC comprises a heterogeneous group
  of patients with clinically distinct subgroups
• T3N1 disease which is treated surgically
• T4 tumors with bulky mediastinal involvement (N2
  or N3) treated with chemotherapy and radiation

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TNM staging Stage 3 NSCLC
Mountain CF. The international system for staging
lung cancer. Semin Surg Oncol. 2000
Mar18(2)106-15.
6
Davies A, Gandara DR, Lara P et al Current and
Future Therapeutic Approaches in Locally Advanced
(Stage III) Non-small cell lung cancer. Seminars
in Oncology 29(3)10-16, 2002
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Definition of LANSCLC
Mountain CF. The international system for staging
lung cancer. Semin Surg Oncol. 2000
Mar18(2)106-15.
8
Proposed Changes in the TNM Classification for
Stage III Disease
Goldstraw P et al. J Thorac Oncol 2706-714, 2007
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Prognostic Factors

• No. of nodes nodal stations, gender, absence of
  significant wt loss, tumor size, FEV1 gt2L
• SWOG retrospective analysis (1974 to 1988)
• best survival in patients with a good PS, who
  had a hemoglobin level gt11 g/dL and older than 47
  years
• Takigawa et al. prospectively studied prognostic
  factors for 185 stage III patients
• worst survival observed for patients with poor PS
  and weight loss, irrespective of stage (median
  survival of 17.1 weeks)

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Subgroups of patients with Stage IIIA N2 disease
Prognosis better for IIIA1 and IIIA2, select
IIIA3 IIIA4 Worst prognosis
Prognosis better for mN2 L1, selected mN2 L2,
cN2 L1 cN2 L2 Worst prognosis
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Survival and relapse for NSCLC
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Criteria for resectable Stage III

• Tumor factors
• T3N1
• T1-3N2 role of surgery controversial
• Selected T4
• Patient factors
• Pulmonary function
• Comorbid conditions

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Adjuvant chemotherapy

• Lung Adjuvant Cisplatin Evaluation (LACE)
• 5 largest trials (4,584 patients) of
  cisplatin-based chemotherapy
• completely resected patients
• 5-year absolute benefit of 5.4 from Chemotherapy

Pignon, J.-P. et al. J Clin Oncol 263552-3559
2008
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Role of Surgery in N2 disease

• PS 0-1 and T1-3 pN2 M0 NSCLC randomized if
  resection technically feasible
• Cisplatin ,etoposide ,RT
• /- surgical resection (if nonprogressed) vs RT
• Unplanned subset analysis surgery may be
  beneficial if pneumonectomy not needed

K. S. Albain, et al. Phase III study of
concurrent chemotherapy and radiotherapy (CT/RT)
vs CT/RT followed by surgical resection for stage
IIIA(pN2) non-small cell lung cancer (NSCLC)
Outcomes update of North American Intergroup 0139
(RTOG 9309). ASCO 2005 Abstract No 7014
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Adjuvant XRT

• Randomized trial- LCSG
• 230 pts with resected squamous cell NSCLC
• 1/3 stage III 2/3 stage II
• Randomized to postoperative RT or no further
  therapy
• No OS difference
• Locoregional recurrences 41 vs 3
• PORT metanalysis
• 2128 patients in nine randomized trials 1966-
  1994
• 7 percent absolute reduction in 2-yr survival
  overall
• No survival difference in stage III

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Unresectable Stage III

• Comprises
• N3
• Bulky N2
• Not fit for surgery
• Historically, treated with RT until Dillman
  Trial which showed that sequential induction
  chemo followed by RT is better than RT alone

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Radiation Therapy (RT) vs Induction
Chemotherapy/RT in Unresectable Stage III NSCLC
The Dillman Trial
Dillman RO et al. N Engl J Med. 1990323940-945.
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Concurrent vs Sequential Chemoradiotherapy
Govindan R, Bogart J, Vokes EE Locally advanced
non-small cell lung cancer the past, present,
and future. J Thorac Oncol 3917-28, 2008
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SWOG 9504Gandara et al JCO 2003212004-10
Overall survival
Concurrent Chemoradiation PE Cisplatin 50 mg/m2
IV d 1, 8, 29, 36 Etoposide 50 mg/m2 IV d 1-5,
29-33 RT 45 Gy (1.8 Gy/fraction) 16 Gy boost (2
Gy/fraction)
Consolidation Docetaxel X 3 cycles
Median Survival Time 26 months
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HOG LUN 01-24/USO 02-033

• ChemoRT
• Cisplatin 50 mg/m2 IV d 1,8,29,36Etoposide 50
  mg/m2 IV d 1-5 29-33Concurrent RT 59.4 Gy (1.8
  Gy/fr)

Stratification Variables PS 0-1 vs 2 IIIA vs
IIIB CR vs. non-CR
Randomize
Docetaxel 75 mg/m2 q 3 wk ? 3
Observation
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Comparison of Patient and Disease Characteristics
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Targeted therapy

• Gefitinib
• Gefitinib maintenance
• Cetuximab
• With chemoradiation
• Bevacizumab
• Phase 2 trial of avastin, carbo, irinoteca and RT
• Closed prematurely 3 deaths TE fistula

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Gefitinib maintenance
Definitive TX Consolidation
Maintenance
R A N D O M I Z E
Cisplatin 50 mg/2 d 1,8,29,36 Etoposide 50
mg/m2 d1-5, 29-33 XRT 1.8- 2 Gy/d 61
Gy
PLACEBO
DOCETAXEL 75 mg/m2 x 3 cycles
Median Survival 35 mths
GEFITINIB 500 mg/day 250 mg/day (5-1-03)
Median Survival 23 mths
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Brain Metastasis/ PCI

• Brain metastases appear to be an important site
  of relapse in LA-NSCLC
• Patients with concurrent therapy at greater risk
  than sequential (19 vs 9) in West Japan Group
  trials
• Role of PCI?
• RTOG 0214 randomized Stage IIIA/B patients post
  definitive therapy to 30Gy PCI or observation
• Closed Summer 2007, did not meet accrual goals

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Conclusions

• Resectable Stage III
• Adjuvant chemotherapy (cisplatin-based) 5.4
  absolute benefit
• Treatment for N2 disease controversial surgery
  in select patients
• RT decreases local recurrence, does not affect
  survival
• Unresectable stage III
• C-RT is better than RT alone
• Concurrent C-RT is better than sequential
  induction C followed by RT
• Targeted therapies under investigation
• Not enough evidence to recommend PCI

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References

• Jemal A, Siegel R, Ward E, et al Cancer
  statistics, 2008. CA Cancer J Clin 5871-96, 2008
• Takigawa N, Segawa Y, Okahara M, et al
  Prognostic factors for patients with advanced
  non-small cell lung cancer univariate and
  multivariate analyses including recursive
  partitioning and amalgamation. Lung Cancer
  1567-77, 1996
• Gandara DR, Chansky K, Albain KS, et al
  Consolidation docetaxel after concurrent
  chemoradiotherapy in stage IIIB non-small-cell
  lung cancer phase II Southwest Oncology Group
  Study S9504. J Clin Oncol 212004-10, 2003
• Blackstock AW, Govindan R Definitive
  chemoradiation for the treatment of locally
  advanced non small-cell lung cancer. J Clin Oncol
  254146-52, 2007
• Govindan R, Bogart J, Vokes EE Locally advanced
  non-small cell lung cancer the past, present,
  and future. J Thorac Oncol 3917-28, 2008
• Goldstraw P, Crowley J, Chansky K, et al The
  IASLC Lung Cancer Staging Project proposals for
  the revision of the TNM stage groupings in the
  forthcoming (seventh) edition of the TNM
  Classification of malignant tumours. J Thorac
  Oncol 2706-714, 2007.
• K. S. Albain, et al. Phase III study of
  concurrent chemotherapy and radiotherapy (CT/RT)
  vs CT/RT followed by surgical resection for stage
  IIIA(pN2) non-small cell lung cancer (NSCLC)
  Outcomes update of North American Intergroup 0139
  (RTOG 9309). ASCO 2005 Abstract No 7014
• Effects of postoperative mediastinal radiation on
  completely resected stage II and stage III
  epidermoid cancer of the lung. The Lung Cancer
  Study Group. N Engl J Med 1986 Nov
  27315(22)1377-81.
• Postoperative radiotherapy in non-small-cell lung
  cancer systematic review and meta-analysis of
  individual patient data from nine randomised
  controlled trials. PORT Meta-analysis Trialists
  Group. Lancet 1998 Jul 25352(9124)257-63.

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• Davies A, Gandara DR, Lara P et al Current and
  Future Therapeutic Approaches in Locally Advanced
  (Stage III) Non-small cell lung cancer. Seminars
  in Oncology 29(3)10-16, 2002
• Dillman RO et al. N Engl J Med. 1990323940-945.
  16.       Pass HI, Pogrebniak HW, Steinberg SM,
  et al Randomized trial of neoadjuvant therapy
  for lung cancer interim analysis. Ann Thorac
  Surg 53992-998, 1992.
• Roth JA, Atkinson EN, Fossella F, et al
  Long-term follow-up of patients enrolled in a
  randomized trial comparing perioperative
  chemotherapy and surgery with surgery alone in
  resectable stage IIIA non-small-cell lung cancer.
  Lung Cancer 211-6, 1998.
• Rosell R, Gomez-Codina J, Camps C, et al
  Preresectional chemotherapy in stage IIIA
  non-small-cell lung cancer a 7-year assessment
  of a randomized controlled trial. Lung Cancer
  267-14, 1999.
• Depierre A, Milleron B, Moro-Sibilot D, et al
  Preoperative chemotherapy followed by surgery
  compared with primary surgery in resectable stage
  I (except T1N0), II, and IIIa non-small-cell lung
  cancer. J Clin Oncol 20247-253, 2002.
• Nagai K, Tsuchiya R, Mori T, et al A randomized
  trial comparing induction chemotherapy followed
  by surgery with surgery alone for patients with
  stage IIIA N2 non-small cell lung cancer (JCOG
  9209). J Thorac Cardiovasc Surg 125254-260,
  2003.
• Pignon JP, Tribodet H, Scagliotti GV, et
  al. LACE collaborarive group J Clin Oncol. 2008
  Jul 2026(21)3552-9. Epub 2008 May 27.