The Role of Neoadjuvant Chemotherapy in Nonsmall Cell Lung Cancer
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The Role of Neoadjuvant Chemotherapy in
Nonsmall Cell Lung Cancer
Nil Molinas MandelIstanbul University
Cerrahpaşa Medical Faculty
Medical Oncology Department
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The use of systemic therapy before definitive local regional therapy is generally referred to as induction or neoadjuvant therapy
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Rationale
• 55% of patients with lung cancer have distant metastasis at diagnosis.
• 25% have regional node involvement.
• 15% have localized disease.
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Rationale
• At the time of the diagnosis, fewer than 25% of all pts are candidate for surgery
• Cure after resection is higly dependent of stage and nodal status of disease
• After resection 5yr survivalWithout nodal metastasis 70%Hilar metastasis 50%Mediastinal metastasis 5%
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5 Year Survival Rate
Stage Grouping 5 Year SurvivalIA T1N0 75%IB T2N0 55%IIA T1N1 50%IIB T2N1 40%
T3N0IIIA T1-3N2 15%
T3N1 35%IIIB T1-3N3 5-10%
T4anyN 5-10%
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Surgery alone is not enough to cure the majority of patients even with resectable disease
Need of multimodality approach to the treatment...
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ADVANTAGES NEOADJUVANT THERAPY
• Early eradication of micrometastasis
• Cytoreduction of local disease
• Improvement in resection rates
• In vivo test of chemosensitivity
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DISADVANTAGES NEOADJUVANT THERAPY
• Increased morbidity and mortality
• Ineffective induction regimen
• Progression of resectable disease
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Evidence
5 meta-analyses, 20 phase III trials, 100 phase II trials
• Stage I and II
• Stage IIIA
• Stage IIIB
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Stage I and Stage II
• Bimodality Lung Oncology Team (BLOT) Trial (updated in ASCO 2003 meeting) MSK and MD Anderson Phase II, 134 pts IB-IIIA (N0/N1) were included, 2-3 preop paclitaxel+carbo (-/+ postop)were given. Perop mortality was %1 with acceptable toxicity.Preop RR: %533yr survival was 61%, 5yr survival is 42%
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Stage I and Stage II
• SWOG 9900 phase III trial, 3cycles of CT (T2N0, T1-2N1, %30 T3N0-1)
• Preop RR: %40,
mSV preop CT arm 47 mo, surgery alone 40 mo (HR: 0.84, p=0.32)
• The trial closed earlier because investigators considered that having surgery alone arm could no longer be considered ethical.
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Stage I and Stage II
• NATCH Trial, since 2000, NCSLC Stage I, II (T3N0-1) 3-arm randomized trial is comparing:Surgery alone
3 cycles of neoadjuvant CT with paclitaxel/carbo
3 cycles of adjuvant CT with paclitaxel/carbo
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5-Year Results of French randomized study comparing preop CT followed by surgery and primary surgery in
resectable Stage I, II, IIIA NSCLC
• Deppierre A et al, World conference on Lung Cancer 2003• Only phase III trial in IB, II, IIIA pts • 355 pts were randomized to surgery and primary CT+S
Arm 1yr % 3yr % 5yr %Preop CT 76,5 52 41,3Surgery 73,3 41,5 31,6Difference 3,2 10,5 9,7P 0,48 0,04 0,06
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Stage IIIA
• Stage IIIA (N2) around 25 phase II trial• 1000 pts were included• Average response rate 62% (38-86)• 55% pts underwent thoracotomy• 49,1% were successfuly resected• Pathological complete response rates were 10-20%• Median survival time was 16,5 mo• 5yr survival was 30% in responsive pts, 50% in CR
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Phase III Trials in Resectable NSCLC
Study Stage CT RT pts 2-3yr p
NCI IIIA(N2)Bx EP(+/+) post op control 28 46/21% 0,12Japan IIIA, IIIB c VdP(+/-) concurrent 83 40/37% NSMDA IIIA(N2) c CEP(+/+)post op 60 56/15% 0,05Spain IIIA (N2) c PIM(+/-) post op 60 0/30% 0,05FTCG IB, II, IIIA c MIP(+/+) post op T3/N2 355 41/52% 0,09
(French Thoracic Cooperative Group)
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Criticism
• Pts were staged clinically, not pathologically
• T3N0 pts were included
• Small number of patients
• Prognostic factors like k-ras were not balanced
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Radiotherapy as a part of induction therapy
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CONCURRENT INDUCTION CHEMORADIOTHERAPY TRIALS
Study IIIA(N2)T4/N3 CT RT post op
SWOG 8805 60% 40% EP 45Gy no resp 2XCT+RT
LCSG 852 87% 13% PF 30Gy none
R-Presbyterian 73% 6% PF/PEF 40Gy none
CALGB 80% 20% PVF 30Gy 1xCT+RT
Tufts 47% 53% EP 59Gy PE or Carbo + T
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Study Pts RR% Res R% Op mortality Surv
SWOG 8805 126 59 71 8 15 mo
LCSG 852 85 56 52 7 13
R-Prebs. 85 92 71 4 22
CALGB 41 64 61 15 16
Tufts 55 69 76 5 20
CONCURRENT INDUCTION CHEMORADIOTHERAPY TRIALS
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NEW AGENTS
• Docetaxel + platinum In stage III, 3 phase II trials, In stage III one phase III trials (single agent) RR 68-82 %Complete resection is possible in 69-79% of pts
• Gemcitabine + platinumIn stage III, 4 phase II trialsRR 52-62%, CR 4,7-15%Downstaging 41-77%
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What is the role of surgery after induction therapy ?
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Intergroup trial 0139 ( RTOG 93-09), ASCO 2003
• Phase III comparison of concurrent CT+RT and CT+RT followed by surgical resection for stage IIIA (pN2)
• Tested the role of surgery after induction with chemoradiotherapy for PFS and OS
• T1-3N2M0 pts were included ( resection is technically feasible)
• PE X2 + RT 45Gy Surgery vs PE X4 + RT 61Gy
• Compliance was good for induction therapy
• CT+RT+ surgery arm had better PFS (14 vs10,7m p0,02)• 3 yr overall survival was 38% vs 33%
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Nodal stage after induction therapy in Stage IIIA
• Retrospective analysis of 103 pts with cisplatin based neoadjuvant CT and surgery
• Pts with N2+ disease whose nodal disease was eradicated after neoadjuvant therapy and surgery had significantly improved cancer free survival
• Pts, whose nodal disease was not downstaged after neoadjuvant therapy did not benefit from surgical resection
Bueno R et al , Ann Thorac Surg, 2000
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Stage IIIB
• Limited number of phase II trials, no phase III • Pts with T4N0-1 (satellite nodule within the primary
tumor lobe) have 20% 5yr survival with surgery alone
• Pts with T4N0-1( main carinal involvement) have 15% 5yr survival with surgery
• In 51 pts with stage IIIB (excluding pts with SVCS) SWOG study showed 80% resectability rate, and 24% 3 year survival with concurrent chemo-radiotherapy
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Treatment Related Morbidity and Mortality in
Combined Modality Induction Trials
• All combined modality induction programs were tested in “fittest” pts, who were fully ambulatory and had good general medical condition
• It may be harmful to offer this type of therapy to pts who have a poor performance status and major co-morbidities
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Toxicity
• During Induction:
myelosuppression, emesis, mucositis, esophagitis ( RT)
• During the 30-Day Postoperative Time:
Pneumonitis, ARDS, Bronchopleural fistules
• After Postoperative Time: Toxicities of additional therapies
Post-treatment constitutional syndrome
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Future Challenges
• Is there a role of prophylactic brain metastasisi in stage III patients?
• Trials analyzing customized neoadjuvant chemotherapy is warranted. Pts with lowest BRCA1, RRM1 mRNA levels after chemotherapy have better outcome.
• Neoadj CT with new drugs (Premetrexed/CDDDP)?• The role of biological agents? Erlotinib, gefitinib,
bevacizumab (CT+ biological agents )
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Conclussion
• In spite of these promising results with neaoadjuvant therapy, surgery remains the mainstay of treatment of lung cancer
• In stage IIIA trials suggest that induction chemotherapy (with or without RT) improves survival, particulary in pts with significant downstaging of the disease
• In stage I, II, and IIIB use of the neoadjuvant therapy is still not a standard approach