Download - Multimodality Treatment Of Stage Iii Nsclc
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Multimodality treatment of stage III NSCLC
Jan P van Meerbeeck
EIS-Geneva
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Are you « out » when not offering your patient
concurrent chemoradiotherapy?
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EIS-Geneva 3
Evidence-based medicine
• In a disease with a high prevalence, treatment guidelines are based on:– very good evidence: meta-analysis and/or
several prospective randomised studies, adequately powered, comparable outcome, and published as full papers
– a large or moderate benefit: advantage of intervention >>/> its potential harm
ACCP guidelines
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EIS-Geneva 4
Why multimodality?
• Stage III NSCLC is – A heterogenous disease– A systemic disease
• After local treatment only, relapses occur– In >80%– Locally in ~one third– Distantly in ~one third– Combined in ~one third
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EIS-Geneva 5
Chemotherapy in MMT• Sterilise
– Micrometastatic disease– Mediastinal lymph nodes
• Reduce primary tumour volume– Lesser resection– Smaller RT field– Higher RT dose (?)
• Outcome benefit: – Cisplatin based – + 4% at 2 y– + 2% at 5 y
BMJ 1995
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EIS-Geneva 6Jassem, 2001
Chemotherapy strategies
• Platinum-based• Induction: 10/22 trials
in 1995 MA:• Consolidation• Simultaneous
– Single agent– Combination– Systemic or sensitizing
dose
• Combinations
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EIS-Geneva 7
Questions regarding chemotherapy
• Is there an optimal induction regimen?– Number and kind of drugs– Number of cycles
• Which is the better sequence with RT?– Sequential (~induction)– Concurrent at systemic dose– [Concurrent at sensitizing dose]– Combinations
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EIS-Geneva 8
EORTC 08941
3 cycles platinum-based induction chemotherapy
Overall response: 61%
Surgical resectionThoracic radiotherapy
60 Gy, 2 Gy/f oid
No responseOff study
Is there an optimal induction regimen?
Van Meerbeeck 2007
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EIS-Geneva 9
response rate (%) in regimens with >= 20 pts
regimen N ORR* (%) 95% CIgemcitabine-cisplatin 221 67 60-73
vinb-ifosf-cisplatin 23 65 43-84
vindesin-cisplatin 55 59 45-72
paclitaxel-carboplatin 76 58 46-69
etoposide-carboplatin 20 45 23-69
docetaxel-cisplatin 30 43 26-63
etoposide-cisplatin 54 41 28-55
*: CR + PR + mRVan Meerbeeck, 2003
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EIS-Geneva 10
response rate (% of pts)
regimens with ORR(%) 95% CI
– cisplatin 59 54-64– carboplatin 56 47-65
– 2 drugs 58 54-62– >2 drugs 62 52-72
– etoposide 50 40-59– no etoposide 61 56-65
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EIS-Geneva 11Ardizzoni, 2006
Which platinum?
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EIS-Geneva 12
3rd generation drugs
CALGB 9431IIIB
n= 175
Cis gemcitabine Full dose x2
Cis paclitaxel Full dose x2
Cis vinorelbineFull dose x2
Cis gemcitabineX 2 reduced dose
+ 66 Gy TRT
Cis paclitaxelX2 reduced dose
+ 66 Gy TRT
Cis vinorelbine X2 reduced dose
+ 66 Gy TRT
ORR: 40% (27-55) ORR: 33% (20-48) ORR: 44% (29-60)
Vokes, 2002
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EIS-Geneva 13
Conclusions (1)
• Is there an optimal induction regimen? – 2-3 cycles– Platinum + one 3rd generation drug– Activity in IIIA (~50%) > IIIB (~40%)– “standard” hematological toxicity– All non-progressing patients proceed to RT
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EIS-Geneva 14
Which is the better sequence with RT?
Consolidation chemotherapy
Concurrent chemoradiotherapy Curran, 2001
Fournel, 2005
Induction chemotherapy
Concurrent chemoradiotherapy
Consolidation chemotherapy
Zatloukal, 2004
Concurrent chemoradiotherapy
Induction chemotherapy
Radiotherapy
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EIS-Geneva 15
Induction vs. systemic dose chemoradiotherapy
• Cochrane meta-analysis: 3 studies, 711 pts, – 1 cCR only but not yet published (RTOG 9410)– 1 with consolidation chemo (GFPC)– 1 with induction and consolidation chemo (Zatloukal)
• Short follow-up and incomplete late toxicity data• cCR
– HR: 0.86 (0.78-0.95) – ARR of death at 2 years: 14%– NNT: 8– Increase in acute severe esophagitis (17-26%)– More toxic deaths, but NS (3% overall)
Rowell, 2006
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EIS-Geneva 16
Conclusions (2)• Caution is advised in adopting concurrent
chemoradiotherapy as the standard of care because of uncertainties about the true magnitude of late benefit and late toxicity
• With short follow up and uncertainties about possible increased toxicity, the optimal chemotherapy regimen remains uncertain
Rowell, 2006
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EIS-Geneva 17
Induction chemotherapy
Concurrent chemoradiotherapy
• At least 5 RCT comparing with C→R or cCR• All with taxanes and/or platinum during RT• None show significant improvement in OS or PFS• Higher toxicity and mortality in some
Combined strategies
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EIS-Geneva 18
CALGB 39801Stage III: N= 366
randomization
CT/TRTWeekly paclitaxel 50 mg/m2
Weekly Cb AUC 2Daily TRT - 66 Gy
Induction CT2 cycles q 3w
Paclitaxel 200 mg/m2Cb AUC 6
CT/TRTWeekly paclitaxel 50 mg/m2
Weekly Cb AUC 2Daily TRT – 66 Gy
Vokes, 2004
Median survival: 11.4 m 14m (p= 0.15)
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EIS-Geneva 19
IFCT
Stage III: N= 574
Induction ChemoCis-vinorelbine x3
Daily TRT - 66 Gy TRT 66 Gy + daily TRT 66 Gy + daily carboplatine 15 mg/m²carboplatine 15 mg/m²
Gervais, 2005
Median survival: 11m 14m (p= NS)
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EIS-Geneva 20
Consolidation chemotherapy
Concurrent chemoradiotherapy
• Based on 1 promising phase 2 trial S9504 with docetaxel (Gandara, 2003)
• Promoted as new standard• 1 ongoing and at least 1 negative RCT • Added toxicity and mortality not negligeable
Combined strategies (2)
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EIS-Geneva 21
US OncologyStage III: N= 220
InductionCarboplatin-paclitaxel
CT/TRTWeekly paclitaxel 45 mg/m2
Weekly Cb AUC 2Daily TRT – 66 Gy
ObservationN= 58
Paclitaxel 3-weekly for 6m
N= 61
Median survival: 27m 16 m (p= 0.07)
Carter, 2004
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EIS-Geneva 22
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EIS-Geneva 23
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EIS-Geneva 24
• Criteria of « very good evidence » and of « large or moderate benefit » do not yet apply for combining sequential and concurrent strategies
• These combinations cannot yet be recommended
Conclusions (3)
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EIS-Geneva 25
Expected meta-analyses
NSCLC coll, 2007
(IPD)
Interventions N HR
R vs. C→R 3839
?R vs. cCR 2910
C→R vs. cCR 1199
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EIS-Geneva 26
Novel drugs and radiotherapy
• EGFR-TKI– Gefitinib - Erlotinib– ZD 6474
• EGFR – MoAb– Cetuximab: head & neck cancer (Bonner, 2005)– Zalutumumab
• Bevacizumab
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EIS-Geneva 27
SWOG 0023
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EIS-Geneva 28
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EIS-Geneva 29
Patient selection
• Little evidence for differential benefit in patient subgroups– Be cautious in the elderly (75+)– Avoid PS 2 or more and major comorbidity
• GTV constraints and PFT criteria– DLCO and FEV1 > 40% predicted
• Adequately staged– Contrast enhanced chest CT– PET/(CT) with at least 1 confirmatory exam of any FDG-avid
extrathoracic lesion – Proof of mediastinal involvement (EUS, EBUS, mediastinoscopy)– Compulsory contrast enhanced brain imaging
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EIS-Geneva 30
week
staging
-X 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17-X
PET/CT
Cycle 1 Cycle 2 Cycle 3 Radiotherapy
Restaging and RT- planning
Treatment plan in stage III
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EIS-Geneva 31
Multimodality treatment anno 2007
% of pts, after diagnosis
1y 2y 3y 5y
Alive:
median 17m
60 30 20 10
Local progression
20 25+ 30+
Distant progression*
25+ 30+ 35+
*Brain met’s as first failure site in 15-30%
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EIS-Geneva 32
Multimodality treatment anno 2007
• Grade 3-4 toxicity– Hematological: variable– Pulmonary: <10%– Acute esophageal:
• <5% if C->R• >20% if cCR
– Late esophageal: <5%
• Treatment related mortality: 3%
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EIS-Geneva 33
Conclusions (4)
• We have improved in the last decade– + 5m in median – + 10% in 1 and 2 y survival– Stage migration?
• We still need– Better systemic treatment– Improved local control
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EIS-Geneva 34
Take home messages
• Induction chemoradiotherapy is still a good standard of care in good PS patients with stage III NSCLC– Platinum with 3rd generation drug– At least 2 cycles– All non-progressing pts proceed to RT
• Particular attention should be paid to avoidance of delays in commencing radiotherapy
• Only selected patients should be offered concurrent chemoradiotherapy or combinations, preferably as part of a clinical trial