Multimodality treatment of stage III NSCLC

Jan P van Meerbeeck

EIS-Geneva

Are you « out » when not offering your patient

concurrent chemoradiotherapy?

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

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

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

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

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

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

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

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

EIS-Geneva 11Ardizzoni, 2006

Which platinum?

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

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

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

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

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

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

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)

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)

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)

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

EIS-Geneva 22

EIS-Geneva 23

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)

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

EIS-Geneva 26

Novel drugs and radiotherapy

• EGFR-TKI– Gefitinib - Erlotinib– ZD 6474

• EGFR – MoAb– Cetuximab: head & neck cancer (Bonner, 2005)– Zalutumumab

• Bevacizumab

EIS-Geneva 27

SWOG 0023

EIS-Geneva 28

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

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

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%

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%

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

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