Protokolle und Indikationen für die adjuvante Radio / Radiochemotherapie Prof. Dr. med. R. Fietkau Strahlenklinik Erlangen Hamburg, 03.02.2012

Head and Neck Tumors: Effect of Postoperative RT regional control S S + RT Bartelink 1983* ~ 50 % ~ 80 % p = 0,036 Huang et al. 1992** 31 % 59 % p = 0,001 Nisi et al. 1998 68 % 87 % p = 0,04 * ECS ** ECS and or R+

Adjuvant radiotherapy and survival for patients with node-positive head and neck cancer: an analysis by primary site and nodal stage Kao J, Lavaf A, Teng MS, Huang D, Genden EM. (Int J Radiat Oncol Biol Phys. 2008)

Adjuvant radiotherapy and survival for patients with node-positive head and neck cancer: an analysis by primary site and nodal stage Kao J, Lavaf A, Teng MS, Huang D, Genden EM. (Int J Radiat Oncol Biol Phys. 2008)

Behandlung der Lymphabflussgebiete: Sofortige postoperative RT oder im Rezidiv (Regine et al. 1999, Head and Neck) Ergebnisse Rezidive Primäre Therapie (OP + RT) (OP + RT) (N = 31 ; 5 Jahre) (N = 143 ; 5 Jahre) Lokoregionäre Kontrolle 46 % 69 % p = 0,03 NED – Überleben 32 % 54 % p = 0,04

Kopf – Hals – Tumoren: Indikation zur postoperativen Bestrahlung Primärtumor : • pT3 / pT4 • R1 – Resektion • Resektionsrand < 5 mm

Kopf – Hals – Tumoren: Indikation zur postoperativen Bestrahlung Lymphabflussgebiete : • N + a b e r : - umstritten bei einem befallenen Lymphknoten - unstrittig bei extrakapsulärem Wachstum oder  2 LK +

Einfluss der Dosis auf die regionäre Rezidivrate (Peters et al. 1993) Randomisierte Studie zur postoperativen RT (R0 / R) Stratifizierung nach Risikofaktoren : - Zahl der LK – Metastasen - Zahl der befallenen LK – Regionen - LK – Größe - Extrakapsuläres Wachstum - Invasion von Muskulatur, Gefäßen, Haut, Nerven, Schädelbasis Low Risk High Risk 57,6 Gy 63 Gy 68,4 Gy

2 year control actuarial control rates at the primary site RT-Dosis postoperativ: Randomisierte Studie von Peters et al 1993; n = 240 2 year control actuarial control rates at the primary site Primärtumor: Niedriges 54 Gy 63% Risiko: 57,6 Gy 92% 63,0 Gy 89% Hohes 63,0 Gy 89% Risiko: 68,4 Gy 81% p = 0,02

„2 year control actuarial locoregional control rates“ ECS + RT-Dosis postoperativ: Randomisierte Studie von Peters et al 1993; n = 240 „2 year control actuarial locoregional control rates“ ECS + 57,6 Gy 52% 63,0 Gy 74% 68,4 Gy 72% p = 0,003

Positive surgical margins in neck dissection specimens in patients with head and neck squamous cell carcinoma and the effect of radiotherapy Smeele LE, Leemans CR, Langendijk JA, Tiwari R, Slotman BJ, van Der Waal I, Snow GB. (Head Neck. 2000)

Postoperative therapy in head and neck cancer: state of the art, risk subset, prognosis and unsolved questions. Denaro N, Russi EG, Adamo V, Colantonio I, Merlano MC. (Oncology 2011)

Postoperative therapy in head and neck cancer: state of the art, risk subset, prognosis and unsolved questions. Denaro N, Russi EG, Adamo V, Colantonio I, Merlano MC. (Oncology 2011)

Postoperative RT/RCT bei Kopf-Hals-Tumoren: Einfluss Intervall OP RT Intervall Lokoregionäre Kontrolle Ang 2001 - 31 Tage: 80% x 72% p=0,34 x et al >31 Tage: 65% x 43% p=0,03 xx Bastit 2001 0-30 Tage: 78% et al >30 Tage: 73% n.s. Muriel 2001 0-50 Tage: 83% et al >50 Tage: 68% p=0,02 Langendijk 2005 6-8 Wochen: 73% n.s. et al >8 Wochen: 73% Parsons 1997 0-50 Tage: 79% p=0,02 et al >50 Tage: 54% X: akzelerierte RT XX: konventionelle RT

The relationship between waiting time for radiotherapy and clinical outcomes: a systematic review of the literature Chen Z, King W, Pearcey R, Kerba M, Mackillop WJ. (Radiother Oncol. 2008)

Postoperative radiotherapy in squamous cell carcinoma of the oral cavity: the importance of the overall treatment time Langendijk JA, de Jong MA, Leemans CR, de Bree R, Smeele LE, Doornaert P, Slotman BJ. (Int J Radiat Oncol Biol Phys. 2003)

Risk-group definition by recursive partitioning analysis of patients with squamous cell head and neck carcinoma treated with surgery and postoperative radiotherapy. Langendijk JA, Slotman BJ, van der Waal I, Doornaert P, Berkof J, Leemans CR. (Cancer 2005)

Risk-group definition by recursive partitioning analysis of patients with squamous cell head and neck carcinoma treated with surgery and postoperative radiotherapy. Langendijk JA, Slotman BJ, van der Waal I, Doornaert P, Berkof J, Leemans CR. (Cancer. 2005)

Risk-group definition by recursive partitioning analysis of patients with squamous cell head and neck carcinoma treated with surgery and postoperative radiotherapy. Langendijk JA, Slotman BJ, van der Waal I, Doornaert P, Berkof J, Leemans CR. (Cancer 2005)

Risk-group definition by recursive partitioning analysis of patients with squamous cell head and neck carcinoma treated with surgery and postoperative radiotherapy. Langendijk JA, Slotman BJ, van der Waal I, Doornaert P, Berkof J, Leemans CR. (Cancer. 2005)

Postoperative therapy in head and neck cancer: state of the art, risk subset, prognosis and unsolved questions. Denaro N, Russi EG, Adamo V, Colantonio I, Merlano MC. (Oncology. 2011)

Postoperative therapy in head and neck cancer: state of the art, risk subset, prognosis and unsolved questions. Denaro N, Russi EG, Adamo V, Colantonio I, Merlano MC. (Oncology. 2011)

Kopf-Hals-Tumore: Adjuvane RT versus RCT Laramore et al. 1992 3 x Cisplatin/5-FU  RT OP RT

Kopf-Hals-Tumore: Adjuvane RT versus RCT Laramore et al. 1992 OP/RT OP/CT/RT 4-Jahres-Überlebensrate 44 % 48 % n. s. 4-Jahres NED-Rate 38 % 46 % n. s. Lokoregionäre Rezidive 29 % 26 % n. s. Fernmetastasen (erstes Ereignis) 10 % 5 % p=0,03 (insgesamt) 23 % 15 % p=0,03

Postoperative concomitant irradiation and chemotherapy with mitomycin C and bleomycin for advanced head-and-neck carcinoma Smid L, Budihna M, Zakotnik B, Soba E, Strojan P, Fajdiga I, Zargi M, Oblak I, Dremelj M, LeSnicar H. (Int J Radiat Oncol Biol Phys. 2003)

Postoperative RT vs. RCT: Postoperative RT vs. RCT: Haffty et al 2003; Postoperative RCT mit Mitomycin C ± Dicumarol (n=182) RT RCT Lokale Kontrolle 67% 87% p=0,015 (5 Jahre) DFS 44% 67% p=0,03 Überleben 41% 56% n.s.

Kopf-Hals-Tumoren: postoperativ RT vs. RCT; Einschlußkriterien Bachaud et al 1996 III , IV + extrakapsuläres Wachstum EORTC 22931 pT3, pT4 pT1 pT2 pN2 – 3 extrakapsuläres Wachstum R1-Resektion perineurale Infiltration vaskulärer Befall RTOG 9501 > 2 LKs positiv ARO-Studie > 3 LKs positiv pT3 R1, pT4

HNO-Tumoren: Postoperative RCT versus RT Studien : Chemotherapie Bachaud et al 1996 : cis-Platin 50 mg / m² / Woche EORTC 22931 : cis-Platin 100 mg / m² d 1, 22, 43 RTOG : cis-Platin 100 mg / m² d 1, 22, 43 ARO 95 – 6 : cis-Platin 20 mg / m² d 1 – 5 u. 29 – 33 500 mg / m² 5-FU

Radiochemotherapie Kopf-Hals-Tumoren Adjuvante RCT Strahlentherapie Cooper et al. 2004 RTOG 9501 Intergroup PT + LAG 60Gy Boost 6Gy Bernier et al. 2004 EORTC Trial 22931 PT + LAG 54Gy Boost 12Gy Fietkau et al. 2006 ARO 96-3 PT: 64Gy pN0: 50Gy pN+: 56Gy Extrakapsuläres Wachstum: 64Gy

Radiochemotherapie Kopf-Hals-Tumoren Adjuvante RCT Lokale Kontrolle [%] Überlebensrate [%] Fernmetastasen RT RCT Cooper et al.° 70 81 p=0.01 47 56 p=0.19 23 20 n.s. Bernier et al.* 69 82 p=0.007 40 53 p=0.02 25 21 Fietkau et al.* 62 83 p=0.006 49 58 p=0.11 32 31 °2-Jahresdaten, *5-Jahresdaten Cooper et al., NEJM 350;19, 05/2004 Bernier et al., NEJM 350;19, 05/2004 Fietkau et al., ASCO 2006

Radiochemotherapie Kopf-Hals-Tumoren Adjuvante RCT Akuttoxizität Mukositis G3/G4 [%] Alle G3/G4 [%] RT RCT Cooper et al. 2004 RTOG 9501 Intergroup 37 62 p=0.001 34 77 p<0.0001 Bernier et al. 2004 EORTC Trial 22931 21 44 p=0.004 41 Fietkau et al. 2006 ARO 96-3 13 p=0.04 ---

Radiochemotherapie Kopf-Hals-Tumoren Adjuvante RCT Spättoxizität RT RCT Bernier et al. 2004 41% 38% p=0.25 Cooper et al. 2004 17% 21% p=0.29 Bernier et al., NEJM 350;19, 05/2004

Adjuvante RCT bei Kopf-Hals-Tumoren Durchführbarkeit der RT / CT RT CT EORTC 22931 90% 64% RTOG 9501 80% 83% ARO 96 – 3 96 % 73 %

Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, Ozsahin EM, Jacobs JR, Jassem J, Ang KK, Lefèbvre JL. (Head Neck 2005)

Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, Ozsahin EM, Jacobs JR, Jassem J, Ang KK, Lefèbvre JL. (Head Neck 2005)

Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Pignon JP, le Maître A, Maillard E, Bourhis J; MACH-NC Collaborative Group. Radiother Oncol. 2009

Adjuvant chemotherapy prior to postoperative concurrent chemoradiotherapy for locoregionally advanced head and neck cancer. Choe KS, Salama JK, Stenson KM, Blair EA, Witt ME, Cohen EE, Haraf DJ, Vokes EE. (Radiother Oncol. 2010)

Adjuvant chemotherapy prior to postoperative concurrent chemoradiotherapy for locoregionally advanced head and neck cancer. Choe KS, Salama JK, Stenson KM, Blair EA, Witt ME, Cohen EE, Haraf DJ, Vokes EE. (Radiother Oncol. 2010)

Radiochemotherapie Kopf-Hals-Tumoren Adjuvante RCT Zusammenfassung: Postoperative RT Indiziert: pT3/4; R1; >/= 2 LK +; Bei 1 LK + (?; Dösak-Studie) Postoperative RCT zeigt Vorteile im Überleben und lokoregionärer Kontrolle bei Hochrisikopatienten v.a. bei R1-/R2-Resektion und extrakapsulärem LK-Wachstum Postoperative RT-Dosis: 56-66Gy (Risikoadaptiert) Akuttoxizität erhöht bei RCT versus RT Spättoxizität nicht erhöht Keine Reduktion der Fernmetastasierung Offene Fragen: Adjuvante Chemotherapie nach postoperativer Radiochemotherapie? Andere Chemotherapeutika: Taxane? Small Molecules/Antikörper?