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Protokolle und Indikationen für die kombinierte Radiochemotherapie

Protokolle und Indikationen für die kombinierte Radiochemotherapie. Wilfried Budach Düsseldorf. Meta- analysis of 93 randomized trials ( Pignon et al. 2009) Individual data of 17,346 patients. Meta- analysis : Induction TPF vs. Induction PF before RT or RT-CHX.

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Protokolle und Indikationen für die kombinierte Radiochemotherapie

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  1. Protokolle und Indikationen für die kombinierte Radiochemotherapie Wilfried Budach Düsseldorf

  2. Meta-analysisof 93 randomizedtrials (Pignon et al. 2009) Individual dataof 17,346 patients

  3. Meta-analysis: Induction TPF vs. Induction PF before RT or RT-CHX Hitt et al. ESMO 2008

  4. MARCH- Meta-analysis on earlydeath (<=day 90) Pignon et al. RadiotherOncol Web figures 2009

  5. Meta-analysisbytumorsite(Blanchard et al. RadiotherOncol2011)

  6. Meta-analysis of 93 randomized trials (Pignon et al. 2009) (no head to head comparisons of different chemotherapy schedules) death

  7. ARO/-AHMO 04-01 TRIAL Overall Survival + 5FU + 5FU V. Budach, ARO 04-01 Trial, ESTRO 2010

  8. ConcomitantChemoradiation: Whichscheduleshouldbeused? • Manyconsider100 mg/m² cisplatin (d1, 22, 43) standard • Fractionatedcisplatine.g. 30-40 mg/m² weeklyor 20mg/m² d1-5 + d29-33seemtobeequallyeffectiveandlesstoxic • MitomycinC (10 mg/m² weeks 1+5) + 5-FU (600 mg/m² CI d1-5 + d29-33) hasalso beenshowntobeeffective • Carboplatin 70-75 mg/m² + 5-FU 1000 mg/m² CI d 1-4 + d29-33 ofRT is also an option • The exactvalueofaditional 5-FU isunknown W. Budach, Düsseldorf MedikamentöseTumortherapie der Kopf-, Hals-Tumoren

  9. Meta-analysis of 93 randomized trials (Pignon et al. 2009) Age dependence death

  10. Meta-Analysis : Which fractionation is the best? End Point: Locoregional Recurrence Hyperfractionation (with moderate dose escalation) vs. conventional fractionation Accelerated fractionation without decreased total dose vs. conventional fractionation Very accelerated fractionation with decreased total dose vs. conventional fractionation Bourhis, Lancet 2006

  11. Meta-Analysis : Which fractionation is the best? Bourhis, Lancet 2006 End Point: Overall Survival Hyperfractionation (with moderate dose escalation) vs. conventional fractionation Accelerated fractionation without decreased total dose vs. conventional fractionation Very accelerated fractionation with decreased total dose vs. conventional fractionation

  12. RTOG 0129: Objective & Study Design Do we need accelerated RT, if RT is combined with concurrent CHX? 72 Gy + 200 mg/m² Cisplatin 70 Gy + 300 mg/m² Cisplatin Does 100 mg/m² cisplatin compansate for 1 week longer overall treatment time?

  13. RTOG 0129: Intent to treat analysis Kian Ang et al. 2010

  14. Toxicity in random. H&N trials: RT vs. RT-CHX (grade >=III) “Older random trials” on concurrent Chemoradiation

  15. Toxicity in random. H&N trials: RT vs. RT-CHX (grade >=III) “newer random trials” on concurrent Chemoradiation

  16. Multivariate analysis with grade 2–4 RTOG swallowing dysfunction at 6 months as primary endpoint n=529 Langendijk et al. Radiother Oncol 2009

  17. Locally advanced head and neck cancer: RT vs. RT + cetuximab RT (n = 213) Stadium III und IV nicht metastasierendes SCCHN (n = 424) R Cetuximab + RT (n = 211) Initialdosis 400 mg/m² (1 Woche vor RT) dann 250 mg/m² + RT(Wochen 2 – 8) • Primärer Endpunkt • Dauer der lokoregionären Kontrolle • Sekundäre Endpunkte • Gesamtüberleben (OS) • Progressionsfreies Überleben (PFS) • Ansprechrate (RR) • Sicherheit Bonner et al., N Engl J. Med 2006; 354: 567 – 578. Stratifiziert durch: • KPS • Lymphknotenbeteiligung • Tumor Stadium • RT Regime

  18. Locally advanced head and neck cancer: RT vs. RT + cetuximab locoregional control overall survival Bonner et al. NEJM 2006

  19. Locally advanced head and neck cancer: RT vs. RT + cetuximab Overall Survival: Update with 5 years follow up Bonner et al Lancet Oncol 2010

  20. Locally advanced head and neck cancer: RT vs. RT + cetuximab Overall survival and cetuximab induced skin rash Bonner et al Lancet Oncol 2010 Bonner et al, ASTRO 2008

  21. Locally advanced head and neck cancer: RT vs. RT + cetuximab Foster plot: Update with 5 years follow up Bonner et al Lancet Oncol 2010

  22. Radiotherapy vs. radiotherapy + cetuximab: adverse events Bonner et al. NEJM 2006

  23. RT + Cetuximab: Radiodermatitis W. Budach et al. NEJM 2007

  24. RT + Cetuximab: Radiodermatitis EORTC questionnaire (Giro, Radiotherapy and Oncology 2009)

  25. Recommended schedulesforsimultaneouschemo(bio)radiation • Best evidence(2 ormorerandomizedtrials) • Cisplatin 100 mg/m² d 1,22, and 43 ofRT • Cisplatin 30-40 mg/m² weekly • Cisplatin 12-20mg/m² + 5-FU 600 mg/m² CI d 1-5 and 29-33 of RT • Mitomycin C 10mg/m² d 5 + 36 + 5-FU 600 mg/m² CI d 1-5 of RT • Goodevidence(at least 1 large randomized trial of high quality) • Carboplatin70-75 mg/m² + 5-FU 1000 mg/m² CI d 1-4 + d29-33 of RT • Cetuximab 400 mg/m² d-8 + weeklyCetuximab 250 mg/m² during RT • Someevidence(at least 1 randomized trial) • Cisplatin 20mg/m² d 1-5 and 29-33 of RT • Cisplatin 6 mg/m² on all RT days • Carboplatin weekly AUC 1.5 during RT • Carboplatin 25 mg/m² on all RT days • Mitomycin 10-15 mg/m² day 1 of RT • 5-FU 1000 mg/m² CI d1-4 and d 29-32 of RT

  26. Locallyadvaned HNC: Treatment Options

  27. Kian Ang et al. ASCO 2011

  28. Kian Ang et al. ASCO 2011

  29. Kian Ang et al. ASCO 2011

  30. Kian Ang et al. ASCO 2011

  31. Kian Ang et al. ASCO 2011

  32. Kian Ang et al. ASCO 2011

  33. Kian Ang et al. ASCO 2011

  34. Postoperative Chemoradiation vs. Radiation Locoregional tumor control pT3 R1 or pT4 or ECE or ≥ 3 LN+ 45% ECE Close margin ? pT3 or pT4 or LN+ 57% ECE Close margin: 29% R1 or ≥ 2 LN+or ECE 55% ECE Close margin 10% RTOG Cooper et. al. NEJM 2004 EORTC Bernier et. al. NEJM 2004 ARO 96-03 Fietkau et. al. ASCO 2006

  35. Meta-analyses: EORTC and RTOG studies adjuvant RT vs. RT-CHX J. Bernier et al. 2005

  36. Meta-analyses: EORTC and RTOG studies adjuvant RT vs. RT-CHX Subgroup: close margin (<5 mm) or extracapsular extention Overall survival J. Bernier et al. 2005

  37. Meta-analyses: EORTC and RTOG studies adjuvant RT vs. RT-CHX Subgroup: R0 (≥5 mm) and no extracapsular extention Overall survival J. Bernier et al. 2005

  38. Conclusion: adjuvant RT vs. RT-CHX Concurrent chemoradiation ist standard of care for high risk patients (ECE or close margin [<5 mm]) Overall survival in this high risk group is still below 50% at 5 years. DFS at 5 years is 36% EGFR antagonist have not been show to be effective in the adjuvant setting

  39. How much surgical safety margin is needed? Langendijk et al. Cancer 2005

  40. Chemotherapy schedules in combination postoperative radiotherapy EORTCCisplatin 100 mg/m² days 1,22, and 43 of radiotherapy RTOG Cisplatin 100 mg/m² days 1,22, and 43 of radiotherapy AROCisplatin 20mg/m² days 1-5 and 29-33 of radiotherapy + 5-FU 600 mg/m² CI days 1-5 and 29-33 of radiotherapy Radiotherapy: 5x2 Gy per week to 64 Gy (ARO) - 66 Gy (RTOG /EORTC)

  41. Acute toxicity: adjuvant RT vs. RT-CHX Grade III/IV mucositis RT+ Cisplatin RT p EORTC post –OP 41% 21% 0.001 RTOG post –OP 30% 18% 0,003 ARO* post –OP 21% 13% 0.038 Spätnebenwirkungen Grad III/IV jeweils tendenziell erhöht (nicht signifikant) *Cisplatin + 5FU

  42. Impact of HPV-status on outcome of different treatment strategies in head & neck cancer Locoregional control Overall survival n=131 DAHANCA: RT +/- nimorazole (?) CHAIR OP +: RT Overall survival Overall survival RTOG: RT + cisplatin TAX 324: PF/TPFRT + carboplatin

  43. HPV 16 • Promotestumorinductionby: • E6 and E7 genemaybeintegratedintothe human genom • E6 decreases p53 functionresulting in geneticinstability • E7 inhibitspRBresulting in lossofcellcyclecontrol • upregulationof p16 • Impact on radiationresponse: (Human cervicalcancercellline): • Transfectionwith E6 enhancesradiationsensitivity Shin et al. Int J Radiat Biol. 2010

  44. HPV pos. tumors do not have p53 mutations Stransky Science 2011

  45. HPV/p16: DAHANCA 6&7 trial CF vs. AF Locoregionaltumorcontrol Lassenet al. RadiotherOncol 2011

  46. Locallyadvancedheadand neck cancer: RT vs. RT + cetuximab Foster plot: Update with 5 yearsfollowup Bonner et al Lancet Oncol 2010

  47. Kian Ang et al. ASCO 2011

  48. Locallyadvancedunresectedheadand neck cancer • ConcurrentChemoradiationremainsthestandardofcare • ConcurrentCetuximabandradiotherapyis an also an option • Induction TPF remainsinvestigational • Accelerated RT isprobably not needed in caseofconcurrent CHX • HPV/p16 positive headand neck cancerare a distinctentity, however, itisunknownwhether different treatmentsshouldbeofferedfor HPV positive and HPV negative disease • Future trialsshouldtest different treatmentstrategiesfor HPV/p16 positive and negative tumors

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