V. Budach – Statements on H&N Cancer - 1 Discussion Panel on Primary Radiochemotherapy Volker Budach, MD, PhD Head Department for Radiation Oncology Charité Campus-Mitte Berlin Interdisciplinary Workshop on Modern Treatment Options Statements on Head and Neck Caner Frankfurt, of January 2006

V. Budach – Statements on H&N Cancer - 2 Meta-analysis: Radiotherapy vs. Radiochemotherapy (adjuvant, neoadjuvant und simultaneous) Pignon et al. Lancet 2000

V. Budach – Statements on H&N Cancer - 3 Meta-analysis: Radiotherapy vs. Radiochemotherapy Subgroup: Simultaneous Chemotherapy 0,81 (HR) Pignon et al. Lancet 2000

V. Budach – Statements on H&N Cancer - 4 Meta-analysis: Radiotherapy vs. Radiochemotherapy Subgroup: Neoadjuvant Chemotherapy 0,95 (HR) Pignon et al. Lancet 2000

V. Budach – Statements on H&N Cancer - 5 Meta-analyse: Radiotherapy vs. Radiochemotherapy Subgroup: Adjuvant Chemotherapy 0,98 (HR) Pignon et al. Lancet 2000

V. Budach – Statements on H&N Cancer - 6 Meta-analysis: Radiotherapy vs. Radiochemotherapy Results from different chemotherapeutic drug regimens Pignon et al. Lancet 2000

V. Budach – Statements on H&N Cancer - 7 Update of the MACH-NC database focusing on concomitant chemo-radiotherapy. J Bourhis, C Amand, JP Pignon on behalf of the Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) Collaborative Group

V. Budach – Statements on H&N Cancer - 8 Purposes Confirm the magnitude of the benefit of CT on survival Validate the effect in concomitant RT-CT because of uncertainties in the MACH-NC-1* due to heterogeneity between trials Increase the statistical power to allow subgroup and subset analyses Bourhis et al., JCO 2005, Abstract

V. Budach – Statements on H&N Cancer - 9 Material & Methods Eligibility criteria Trials properly randomized performed between 1965 and 2000 R Loco-regional treatment Loco-regional + chemotherapy Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 10 Material and Methods Data collection and checking Updated individual data collected for all randomized patients from published and unpublished trials Extensive checking & validation to ensure integrity of rando-mization and follow-up in collaboration with investigators

V. Budach – Statements on H&N Cancer - 11 Intent to treat analysis Logrank test stratified by trial Survival times used to calculate relative risk (RR) Absolute benefit calculated from baseline survival and RR Material and Methods Statistical methods

V. Budach – Statements on H&N Cancer trials & patients  10% in adjuvant  5% in neoadjuvant  85% in concomitant New randomized trials Included Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 13  87 randomized trials and patients 3-arm trials 2 x 2 trials  105 comparisons and pts Data analyzed Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 14 Chemotherapy timing (n= ) Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 15 Site of the primary (n= ) Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 16 Stage (UICC 1997) (n= ) Treatment:ChemotherapyNo Chemotherapy PERCENT Stage I-IIStage IIIStage IV Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer Median follow-up = 5.7 years Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 18 * 5-year survival rate in control group : 30% Adjuvant Neoadjuvant Concomitant NS < % 2 % 8 % Total< % Chemotherapy timing p-value Absolute benefit at 5 years * Risk reduction -6 % 4 % 19 % 12 % Results : Overall survival Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer

V. Budach – Statements on H&N Cancer Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 21 Concomitant trials In MACH-NC-1 : uncertainties about the 8% absolute gain observed because of heterogeneity MACH-NC-2 : opportunity to explore the effect of concomitant RT-CT with a larger & more homogeneous sample Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 22 Overall survival : Concomitant trials 19% + 3% Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 24 Overall survival : Concomitant trials (n = 9 615) Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer Without incomplete data trials. Without old trials (< 1980). Without small trials (< 80 pts). Without confounded trials. Without short follow-up trials < All trials< Sensitivity analysis 18 % 19 % 17 % 19 % p-value Risk reduction n Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 27 Overall survival : Concomitant trials (n = 9 615) Bourhis et al., JCO 2005, Abstr. V. Budach, Statements on H&N Cancer 27

V. Budach – Statements on H&N Cancer - 28 Survival, concomitant trials by Stage 2% % % + 3 Test for trends: p=0.62 Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 29 Survival, concomitant trials by age Test for trends: p=0.003 < 50 > 70 24% % % + 4 3% + 9 V. Budach, Statements on H&N Cancer 29 Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 30 Concomitant trials survival by type of local treatment 21% % % + 5 1% + 13 Bourhis et al., JCO 2005, Abstr. V. Budach, Statements on H&N Cancer 29

V. Budach – Statements on H&N Cancer - 31 Concomitant trials : effect by type of CT 23% % % % + 4 Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 32 Concomitant trials : effect by type of CT 23% % % % + 4

V. Budach – Statements on H&N Cancer - 33 Concomitant trials: with or without platin 23% % % % + 4 Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 34 Conclusion Absolute benefit in concomitant = 8% at 5 years (11% with Cisplatin alone) Evidence of a higher survival benefit with concurrent = confirmed Small benefit of chemotherapy on survival = confirmed (5%) Benefit of chemotherapy observed in post-op, and with definitive RT (conventional or hyperfractionated) Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 35 Acknowledgments Trialists and patients Association pour la Recherche sur le Cancer Aventis, Sanofi Synthelabo Institut Gustave-Roussy Programme Hospitalier de Recherche Clinique Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 36 Standard Fractionated Radiotherapy ± Concurrent Chemotherapy W. Budach et al., BMC Cancer 2006, in press

V. Budach – Statements on H&N Cancer - 37 W. Budach et al., BMC Cancer 2006, in press Standard Fractionated Radiotherapy ± Concurrent Chemotherapy

V. Budach – Statements on H&N Cancer - 38 Altered Fractionated Radiotherapy ± Concurrent Chemotherapy (same OTT) W. Budach et al., BMC Cancer 2006, in press

V. Budach – Statements on H&N Cancer - 39 Altered Fractionated Radiotherapy ± Concurrent Chemotherapy (same OTT) W. Budach et al., BMC Cancer 2006, in press

V. Budach – Statements on H&N Cancer - 40 Altered Fractionated Radiotherapy ± Concurrent Chemotherapy (prolonged OTT) W. Budach et al., BMC Cancer 2006, in press

V. Budach – Statements on H&N Cancer - 41 Altered Fractionated Radiotherapy ± Concurrent Chemotherapy (prolonged OTT) W. Budach et al., BMC Cancer 2006, in press

V. Budach – Statements on H&N Cancer - 42 Median Survival Impact of Cytostatic Drugs with Concurrent Chemoradiation W. Budach et al., BMC Cancer 2006, in press

V. Budach – Statements on H&N Cancer - 43 Altered Fractionated Radiotherapy vs. Standard Fractionated Radiotherapy W. Budach et al., BMC Cancer 2006, in press

V. Budach – Statements on H&N Cancer - 44 Hyperfractionated Radiotherapy vs. Standard Fractionated Radiotherapy W. Budach et al., BMC Cancer 2006, in press

V. Budach – Statements on H&N Cancer - 45 Chemoradiation vs. Radiotherapy Only studies published after 1992 Reduction of odds ratios Local control Survival hyperfract. XRT vs. convent. XRT accelerat. XRT vs. convent. XRT * concurr. CXRT vs. convent. XRT HFX-AF-XRT vs. HFX-AF-XRT concurr. CHX *= not significant W. Budach et al., BMC Cancer 2006, in press

V. Budach – Statements on H&N Cancer - 46 Locally Advanced Squamous Cell Carcinomas of the Oro- und Hypopharynx Concurrent chemoradiation is the standard of care for inoperable H&N-Cancer ! For patients not amenable for concurrent CXRT, hyperfractionated XRT is the standard of care! Conclusions

V. Budach – Statements on H&N Cancer - 47 Perspectives in Head and Neck Cancer Potential improvement of the Therapeutic Index by means of: Optimized Radiotherapy Techniques “IMRT” = Intensity-Modulated RadioTherapy for dose escalation and organs at risk/tissue protection  “IMRT” = Intensity-Modulated RadioTherapy for dose escalation and organs at risk/tissue protection Small molecules  EGFR-MoAb (Cetuximab, Erbitux, Gefinitib)  Cox-II Inhibitors  Bevacuzimab Cytostatic drugs:  Taxanes (Paclitaxel, Doxetaxel), Gemcitabine, Irinotecan

V. Budach – Statements on H&N Cancer - 48  Optimal combination of chemoradiation with standard or altered fractionation?  Do late effects of chemoradiation compromize the therapeutic benefit (therapeutic ratio )?  Can the addition of „small molecules“ additionally improve chemoradiation results?  Is there a definitive role of surgery (for salvage) after chemoradiation? Open Questions in the Definitive Treatment of Locally Advanced Head and Neck Cancer