5-year Results ( med f/u 6.9 yrs) CRTI + RTRT Lx Preserv84%70%66% LR Control69%55%51% Dist. Mets13%14%22% LF Survival47%45%34% DF Survival39% 27% Survival55%59%54%

Why larynx preservation at all ? quality of life patient social community organ preservation function preservation (swallow,speak,breathe) adverse events (therapeutical, compliance) cancer control treatment costs rehabilitation unemployment

Surgery CCS TLS SCPL neck dissection comprehensive / selective Radiation (3-D CRT/IMRT) standard hyperfractionated/accelerated(protocol?) Other therapy Larynx preservation / function tumor control adverse events (CTCAE v3.0) survival neoadjuvant (protocol?) concurrent (protocol?) Chemotherapy Vocal cord T 2 / T 3 N 0 / N 1 / N 2a/b/c / N 3

Vocal cord T 4a N 1 / N 2a/b/c / N 3 Surgery CCS TLS SCPL neck dissection comprehensive / selective Radiation (3-D CRT/IMRT) standard hyperfractionated/accelerated(protocol?) Other therapy Larynx preservation / function tumor control adverse events (CTCAE v3.0) survival neoadjuvant (protocol?) concurrent (protocol?) Chemotherapy

Vocal cord/subglottis T 3 / T 4a N 1 / N 2a/b/c / N 3 Surgery CCS TLS SCPL neck dissection comprehensive / selective Radiation (3-D CRT/IMRT) standard hyperfractionated/accelerated(protocol?) Other therapy Larynx preservation / function tumor control adverse events (CTCAE v3.0) survival neoadjuvant (protocol?) concurrent (protocol?) Chemotherapy

Supraglottis (central epiglottis) T 2 / T 3 / T 4a N 1 / N 2a/b/c / N 3 Surgery CCS TLS SCPL neck dissection comprehensive / (selective) Radiation (3-D CRT/IMRT) standard hyperfractionated/accelerated(protocol?) Other therapy Larynx preservation / function tumor control adverse events (CTCAE v3.0) survival neoadjuvant (protocol?) concurrent (protocol?) Chemotherapy

Supraglottis (carcinoma of the angle) T 2 / T 3 / T 4a N 1 / N 2a/b/c / N 3 Surgery CCS TLS SCPL neck dissection comprehensive / selective Radiation (3-D CRT/IMRT) standard hyperfractionated/accelerated(protocol?) Other therapy Larynx preservation / function tumor control adverse events (CTCAE v3.0) survival neoadjuvant (protocol?) concurrent (protocol?) Chemotherapy

Supraglottis / hypopharynx (carcinoma of the margin) T 1 / T 2 / T 3 / T 4a N 1 / N 2a/b/c / N 3 Surgery CCS TLS SCPL neck dissection comprehensive / selective Radiation (3-D CRT/IMRT) standard hyperfractionated/accelerated(protocol?) Other therapy Larynx preservation / function tumor control adverse events (CTCAE v3.0) survival neoadjuvant (protocol?) concurrent (protocol?) Chemotherapy

Which questions have to be answered in the future ? - standard evaluation of adverse events (CTCAE v.3.0?) and quality of life (EORTC QLQ C30 / HN 35 ?) under and after therapy - standard evaluation of costs observation period - realistic standard endpoints for studies cancer controladverse eventscosts 2 years 5 years larynx preservation rate local control regional control distant control Second primary LFS DFS OS CTEAE v. 3.0 organ function compliance treatment rehabilitation unemployment

- Studies 2 radiation / chemotherapy - conformal radiotherapy 3-DCRT, IMRT as standards - concurrent radiochemotherapy with standard or altered fractionation (hyperfractionation, acceleration). - altered fractionation without chemotherapy - chemotherapy with new protocols / application (TPF, TIC, Gemcitabine, Vinorelbine, Irinotecan,..../ intraarterial chemotherapy). postcricoid sinus piriformis posterior wall larynxhypopharynx glottis supraglottis Vocal cord commisura anterior central epiglottis 1 separation (larynx a functional but not a cancerlogic entity) medial posterolateral carcinoma of the angle

3 targeted therapy (combined modality) 4 interventional therapy LIT - epidermal growth factor/tyrosine kinase inhibitors C 225 OSI 774 ZD angiogenesis - RAS: Farnesyl Transferase inhibitors - tumor hypoxia Thalidomide SU 5416 Bevacizumab BMS R SCH 6636 Onyx 015 misonidazole nimorazole tirapazamine

Building up models for future studies 1. standard radiation ( standard 2Gy/d, 5 days /week, 70Gy/7weeks) larynx hypopharynx glottis (med./lat.) supraglottis (med./lat.) angle sinus piriformis (med./lat.) postcricoid posterior wall 2. hyperfract. radiation RTOG 9003 ( 2x1,2Gy/d, 5 days/week, 81,6 Gy/7weeks) 3. accelerated fract. radiation with boost RTOG 9003 ( 1,8Gy/d - 1,8 Gy+1,5Gy/d, 5 days/week, 72 Gy/6weeks) 4. concurrent radiochemo RTOG ( standard radiation+Cisplatin 100mg/m 2 /d ) 5. concurrent radiochemo with hyperfract: radiation ( Budach, Brizel, Wendt) 6. newer Inductionschemo + (TPF/TIC/....) 7. TLS / CCS+ 8. chemotherapy exclusive (protocol?)

larynx cancer III/IV (2/3 supraglottis 60% T3) 66 RTOG (n=547 foll. Up median 3,8 years) Veterans Affair (n=332 foll. Up median 2,75 years) induction chemo radiation (ICR) concurrent radiochemo (RC) radiation (R) radical surgery + radiation (S) Steiner TLS ± rad. (n=141,foll.up med. 3years, all supraglottis, III/IV=50%) Laccourreye chemo (platin) chemo+CCS/SCPL (n=231,foll.up >3years, glottis, T 1- 3 N 0 M 0 2y 5y 2y 5y 2y 5y 2y 5y 88* 85* larynx preservarion % local control % disease free survival % locoregional control % distant metastasis % laryngectomy free survival % overall survival % * 38* * * * 45* * 36* * p<0,05 5y 84 (all) (all) (all) (all) 74 (all) 45 (all) 0 66 (all) 74 (all) 45 (all)

EORTC Lefebvre (n=202 foll. up median 4.25 years) * P <0,05 hypopharynx cancer (II) III/IV (80% piriformis sinus 75% T 3 ) induction chemo radiation (ICR) radical surgery radiation 3y 5y 3y 5y m larynx preservarion % local control % overal survival % * 35* 59 k distant metastasis % disease free survival % locoregional control % 59 k 59 k 59 k Steiner TLS ± rad. II/ III/ IV piriformis sinus 60% T 2 25% T 3/4 (n=129,foll.up med. 3,75 years Laccourreye III / IV chemo n=31 5y (I/II) 47 (III/IV) (I / II) 69 (III / IV) 90 5y (pharyngolarynx foll. up > 3 years) CCS 5y