Multimodality Treatment Of Stage Iii Nsclc

Multimodality treatment of stage III NSCLC Jan P van Meerbeeck EIS-Geneva

Are you « out » when not offering your patient concurrent chemoradiotherapy?

Evidence-based medicine
In a disease with a high prevalence, treatment guidelines are based on:
very good evidence: meta-analys is and/or several prospecti ve randomised studies, adequately powered, comparable outcome, and published as full papers
a large or moderate benefit: advantage of intervention >>/> its potential harm
ACCP guidelines

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

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

Chemotherapy strategies
Platinum-based
Induction: 10/22 trials in 1995 MA:
Consolidation
Simultaneous
Single agent
Combination
Systemic or sensitizing dose
Combinations
Jassem, 2001

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

Is there an optimal induction regimen? Van Meerbeeck 2007 EORTC 08941 3 cycles platinum-based induction chemotherapy Overall response : 61% Surgical resection Thoracic radiotherapy 60 Gy, 2 Gy/f oid No response Off study

response rate (%) in regimens with >= 20 pts *: CR + PR + mR Van Meerbeeck, 2003 23-69 45 20 etoposide-carboplatin 54 30 76 55 23 221 N 26-63 43 docetaxel-cisplatin 43-84 65 vinb-ifosf-cisplatin 45-72 59 vindesin-cisplatin 28-55 41 etoposide-cisplatin 46-69 58 paclitaxel-carboplatin 60-73 67 gemcitabine-cisplatin 95% CI ORR* (%) regimen

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

Which platinum? Ardizzoni, 2006

3 rd generation drugs Vokes, 2002 CALGB 9431 IIIB n= 175 Cis gemcitabine Full dose x2 Cis paclitaxel Full dose x2 Cis vinorelbine Full dose x2 Cis gemcitabine X 2 reduced dose + 66 Gy TRT Cis paclitaxel X2 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)

Conclusions (1)
Is there an optimal induction regimen?
2-3 cycles
Platinum + one 3 rd generation drug
Activity in IIIA (~50%) > IIIB (~40%)
“ standard” hematological toxicity
All non-progressing patients proceed to RT

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

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

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

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 Induction chemotherapy Concurrent chemoradiotherapy

CALGB 39801 Median survival: 11.4 m 14m (p= 0.15 ) Stage III: N= 366 randomization CT/TRT Weekly paclitaxel 50 mg/m2 Weekly Cb AUC 2 Daily TRT - 66 Gy Induction CT 2 cycles q 3w Paclitaxel 200 mg/m2 Cb AUC 6 CT/TRT Weekly paclitaxel 50 mg/m2 Weekly Cb AUC 2 Daily TRT – 66 Gy Vokes, 2004

IFCT Median survival: 11m 14m (p= NS ) Stage III: N= 574 Induction Chemo Cis-vinorelbine x3 Daily TRT - 66 Gy TRT 66 Gy + daily carboplatine 15 mg/m² Gervais, 2005

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) Consolidation chemotherapy Concurrent chemoradiotherapy

US Oncology Median survival: 27m 16 m (p= 0.07 ) Carter, 2004 Stage III: N= 220 Induction Carboplatin-paclitaxel CT/TRT Weekly paclitaxel 45 mg/m2 Weekly Cb AUC 2 Daily TRT – 66 Gy Observation N= 58 Paclitaxel 3-weekly for 6m N= 61

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)

Expected meta-analyses 1199 C -> R vs. cCR 2910 R vs. cCR ? 3839 R vs. C -> R HR N Interventions NSCLC coll, 2007 (IPD)

Novel drugs and radiotherapy
EGFR-TKI
Gefitinib - Erlotinib
ZD 6474
EGFR – MoAb
Cetuximab: head & neck cancer ( Bonner, 2005 )
Zalutumumab
Bevacizumab

SWOG 0023

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

Treatment plan in stage III week staging PET/ CT Cycle 1 Cycle 2 Cycle 3 Radiotherapy Restaging and RT- planning -X 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 -X

Multimodality treatment anno 2007 *Brain met’s as first failure site in 15-30% 35+ 30+ 25+ Distant progression* 30+ 25+ 20 Local progression 10 20 30 60 Alive: median 17m 5y 3y 2y 1y % of pts, after diagnosis

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%

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

Take home messages
Induction chemoradiotherapy is still a good standard of care in good PS patients with stage III NSCLC
Platinum with 3 rd 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

Multimodality Treatment Of Stage Iii Nsclc

by fondas vak on Feb 04, 2010

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