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13th Turkish Thoracic Society Congress

13th Turkish Thoracic Society Congress Early stage lung cancer: Is there a role for chemotherapy or radiotherapy ? J. Vansteenkiste. Respiratory Oncology Unit Dept. Pulmonology Univ . Hospital Leuven Leuven Lung Cancer Group. E arly stage NSCLC > stages I – II – IIIA.

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13th Turkish Thoracic Society Congress

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  1. 13th Turkish Thoracic Society Congress Early stage lung cancer: Is there a role for chemotherapy or radiotherapy ? J. Vansteenkiste Respiratory Oncology Unit Dept. Pulmonology Univ. Hospital Leuven Leuven Lung Cancer Group

  2. Early stage NSCLC> stages I – II – IIIA Surgery = cornerstone Advances lung sparing surgery better anesthesia, ICU and postoperative care advances in radical radiotherapy Recent years: increasing data on benefit of combined treatment N0-1 T1a-3

  3. Early stage NSCLC> outcome Goldstraw et al, J Thorac Oncol 2:706-714, 2007

  4. Early stage NSCLC> need for adjuvant therapy ± 1,300,000 lung cancers worldwide about 80% non-small cell lung cancer about 20 to 30% of these resectable ± 300,000 patients with a 5-year survival of 73% to 24% post resection effective adjuvant strategies would save many lifes

  5. Early stage NSCLC> adjuvanttherapy Adjuvant radiotherapy Adjuvant chemotherapy Ongoing research improve efficacy / tolerability ratio use of prognostic and predictive factors Conclusions

  6. Early stage NSCLC> adjuvanttherapy Adjuvant radiotherapy Adjuvant chemotherapy Ongoing research improve efficacy / tolerability ratio use of prognostic and predictive factors Conclusions

  7. Early stage NSCLC> recurrence after “curative resection”

  8. PORT meta-analists, Lancet 352:257, 1998Burdet et al, Lung Cancer 47:81-83,2005 Early stage NSCLC> adjuvant radiotherapy HR: 1.21

  9. No role in N0 or N1 disease Role of PORT in N2 is controversial recent subset analyses and retrospective analyses suggest possible benefit ongoing “Lung ART” trial 700 patients with completely resected N2 randomize to PORT (conformal 54 Gy / 27-30 fractions) or not pre- or postoperative chemo allowed (but not concurrent) Early stage NSCLC> PORT

  10. Early stage NSCLC> adjuvanttherapy Adjuvant radiotherapy Adjuvant chemotherapy Ongoing research improve efficacy / tolerability ratio use of prognostic and predictive factors Conclusions

  11. Early stage NSCLC> adjuvant chemotherapy: IALT Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J International Adjuvant Lung cancer Trial 14% reduction risk of death 4.1% better 5-year survival IALT investigators, N Engl J Med 350:351-360, 2004

  12. Early stage NSCLC> adjuvant chemotherapy: IALT Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J International Adjuvant Lung cancer Trial 14% reduction risk of death 4.1% better 5-year survival Later chemotherapy trials 30% reduction risk of death 10% better 5-year survival IALT investigators, N Engl J Med 350:351-360, 2004

  13. Early stage NSCLC >adjuvant chemo: LACE meta-analysis • LACE meta-analysis [Lung Adjuvant Cisplatin Evaluation] • Pooling of IP data from ALPI, IALT, NCI-C, BLT and ANITA • pooled HR 0.89 [0.82-0.96] • P<0.005 • 5YS 43 ->49% Pignon et al, J Clin Oncol 26:3552-3559, 2008

  14. Indicated with level 1 evidence several positive RCTs, literature and IP based meta-analyses Which patients? age: not crucial (65-75 age group as well) stage II / IIIA , some IB (>4-5cm?) Which platinum? Cisplatin! Which other drug with cisplatin? existing adjuvant data Cis-Etoposide + 600 patients; Cis-Vinorelbine + 950 patients any modern 3rd generation no direct comparative adjuvant studies, but based on abundant comparative studies in advanced NSCLC Early NSCLC> adjuvant chemotherapy

  15. Early stage NSCLC> adjuvanttherapy Adjuvant radiotherapy Adjuvant chemotherapy Ongoing research improve efficacy / tolerability ratio use of prognostic and predictive factors Conclusions

  16. Early stage NSCLC > adjuvant chemotherapy LACE meta-analysis 5-year survival 43% -> 49% Room for further improvement

  17. Trial N cycles Compliance IALT 3-4 cycles 74% ALPI 3 cycles 69% NCI-C 4 cycles 50% BLT 3 cycles 64% 4 cycles 50% BR 10 Early stage NSCLC > adjuvant chemotherapy LACE meta-analysis 5-year survival 43% -> 49% Cisplatin-based chemotherapy Room for further improvement Room for better tolerated therapy

  18. Trial N cycles Compliance IALT 3-4 cycles 74% ALPI 3 cycles 69% NCI-C 4 cycles 50% BLT 3 cycles 64% 4 cycles 50% BR 10 Early stage NSCLC > adjuvant chemotherapy LACE meta-analysis 5-year survival 43% -> 49% Cisplatin-based chemotherapy Room for further improvement Room for better tolerated therapy Vaccine therapy Angiogenesis / EGFR inhibition

  19. IA IB IIA IIB IIIA IIIB IV 35% 16% 47% Lung cancervaccination> MAGE-A3 antigen • No expression in normal cellstumour • Reallytumourspecific, expressed (RT-PCR) in: • NSCLC* • Head & neck 49%, bladder 35%, melanoma 56% * Sienel et al, Eur J CardiothoracSurg 25: 131-134, 2004

  20. Lung cancervaccination> MAGE-A3 phase III: MAGRIT study • MAGE-A3 as Adjuvant Non-Small Cell LunGCanceRImmunoTherapy • worldwide multicenter, randomized, double-blind, placebo-controlled ph III trial • expected N=10,000 screened -> N=2270 patients randomized • primaryendpoint: disease-free survival Resected MAGE-A3 (+) NSCLC Decision for chemo No chemo Chemo Up to 4 cycles of chemo Randomization Randomization MAGE-A3 immunotherapy Placebo MAGE-A3 immunotherapy Placebo

  21. Early stage NSCLC> adjuvanttherapy Adjuvantradiotherapy Adjuvantchemotherapy Ongoing research improveefficacy / tolerability ratio use of prognostic and predictive factors Conclusions

  22. Early stage NSCLC> current issues alive and well after surgery alive and wellaftersurg + chemo death of relapse death of relapse deathco-morbididty death co-morbididty

  23. Early stage NSCLC> current issues alive and well after surgery alive and wellaftersurg + chemo • Target thosewho are likely to benefit: • improve NNT ratio • prognosticfactors • WHO TO TREAT? death of relapse death of relapse deathco-morbididty death co-morbididty

  24. Early stage NSCLC> prognostic models TNM stage newversion 7 –> T factor changes (T >5cm) FDG-PET prognosticvalue – implemented in a Dutch study Molecular staging rapidlyevolving field

  25. Early stage NSCLC> FDG-PET Vansteenkiste et al, J ClinOncol 17:3201-3206, 1999

  26. Early stage NSCLC> molecularstaging Potti et al, N Engl J Med 355:570-580, 2006

  27. Early stage NSCLC>molecularstaging in trial (CALGB) Potti et al, N Engl J Med 355:570-580, 2006

  28. Have gene expressionsignatures been definedwhichcorrelatewith high risk of relapse? yes, butmany of its kind is a basis forongoingclinical studies in high-risk stage IA operatedpatients (e.g. CALGB) need universalapplicability and prospectivevalidationbefore entering clinical routine Early stage NSCLC> molecular staging

  29. Early stage NSCLC> current issues alive and well after surgery alive and wellaftersurg + chemo • 3. Enlarge the possible benefit: • improve HR of .89 • predictive factors • HOW TO TREAT? death of relapse death of relapse deathco-morbididty death co-morbididty

  30. Part of “IALT-BIO” Excision Repair Cross Complementing 1 protein nuclease excision repair system essential for repair of DNA-abberations (e.g. adducts caused by cisplatin) ERCC1 prognostic factor untreated group: ERCC1+ do better (HR 0.66, P<0.009) ERCC1 predictive factor Early stage NSCLC> ERCC1 predictive model Olaussen et al, N Engl J Med 355:983-991, 2006

  31. Early stage NSCLC> ERCC1 predictive model ERCC1- pts: HR 0.65 [0.50-0.86], P<0.002 ERCC1+ pts: HR 1.14 [0.84-1.45], P=0.40 Olaussen et al, N Engl J Med 355:983-991, 2006

  32. Retrospective analysis : long-term stored samples variation in sample collection no control for tumor heterogeneity variation in storage semiquantitative method IHC not fine-tuned is IHC (protein) representative for DNA level? Subset analysis ERCC1 probably good marker for platinum resistance needs prospective confirmation before clinical implementation Early stage NSCLC> ERCC1 predictive value, but …

  33. Early stage NSCLC> predictive molecular markers Custodio et al, J Thorac Oncol 4:891-910, 2009 (review)

  34. Early stage NSCLC> pharmacogenomic driven trial (ITACA) Taxane Profile 4 High Control* TS Pemetrexed High Profile 3 Low Control* Cis/Gem ERCC1 Profile 2 High Low Control* TS Cis/Pem Low Profile 1 Control* Slidekindlyprovidedby G. Scagliotti

  35. Early stage NSCLC> adjuvanttherapy Adjuvantradiotherapy Adjuvantchemotherapy Ongoing research improveefficacy / tolerability ratio use of prognostic and predictive factors Conclusions

  36. Role of adjuvant radiotherapy: limited – perhaps N2? Level I evidence for adjuvant chemotherapy stages (IB) II IIIA in well recovered patients, preferably <6 weeks post-surgery cisplatin-based, cumulative dose up to 300 mg/m2 doublet combination with a 3rd generation cytotoxic agent carboplatin alternative if specific toxiciy is a concern Ongoing research use of biological agents and vaccines improve “who to treat” (prognostic factors) improve “how to treat” (predictive factors) Early stage NSCLC > conclusion

  37. Thank you for your kind attention Leuven, Gothic Town Hall (1448)

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