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Multimodality Treatment Of Stage Iii Nsclc
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Multimodality Treatment Of Stage Iii Nsclc

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  • Eligible patients with stage IIIA-N2 were first treated with 3 cycles of platinum based induction chemotherapy. Patient showing stable disease or progression went off study. After stratification for the type of response, histological subtype and institution, patients showing objective or minor response were randomized between either or surgical resection or radical thoracic radiotherapy consisting of 60 Gy administered at 2 Grays per fraction once daily.
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    • 1. Multimodality treatment of stage III NSCLC Jan P van Meerbeeck EIS-Geneva
    • 2. Are you « out » when not offering your patient concurrent chemoradiotherapy?
    • 3. 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
    • 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
    • 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
    • 6. Chemotherapy strategies
      • Platinum-based
      • Induction: 10/22 trials in 1995 MA:
      • Consolidation
      • Simultaneous
        • Single agent
        • Combination
        • Systemic or sensitizing dose
      • Combinations
      Jassem, 2001
    • 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
    • 8. 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
    • 9. 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
    • 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
    • 11. Which platinum? Ardizzoni, 2006
    • 12. 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)
    • 13. 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
    • 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
    • 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
    • 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
    • 17.
      • 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
    • 18. 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
    • 19. 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
    • 20.
      • 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
    • 21. 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
    • 22.  
    • 23.  
    • 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)
    • 25. Expected meta-analyses 1199 C -> R vs. cCR 2910 R vs. cCR ? 3839 R vs. C -> R HR N Interventions NSCLC coll, 2007 (IPD)
    • 26. Novel drugs and radiotherapy
      • EGFR-TKI
        • Gefitinib - Erlotinib
        • ZD 6474
      • EGFR – MoAb
        • Cetuximab: head & neck cancer ( Bonner, 2005 )
        • Zalutumumab
      • Bevacizumab
    • 27. SWOG 0023
    • 28.  
    • 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
    • 30. 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
    • 31. 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
    • 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%
    • 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
    • 34. 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

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