Protokolle und Indikationen für die adjuvante Radio / Radiochemotherapie

Prof. Dr. med. R. FietkauStrahlenklinik Erlangen Hamburg, 03.02.2012

2

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+

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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)

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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)

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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

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Kopf – Hals – Tumoren: Indikation zur postoperativen Bestrahlung

Primärtumor : • pT3 / pT4

• R1 – Resektion

• Resektionsrand < 5 mm

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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 +

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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

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RT-Dosis postoperativ:Randomisierte Studie von Peters et al 1993; n = 240

Primärtumor:

Niedriges 54 Gy 63%

Risiko: 57,6 Gy 92%

63,0 Gy 89%

Hohes 63,0 Gy 89%

Risiko: 68,4 Gy 81%

2 year control actuarial control rates at the primary site

p = 0,02

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57,6 Gy 52%

63,0 Gy 74%

68,4 Gy 72%

RT-Dosis postoperativ:Randomisierte Studie von Peters et al 1993; n = 240

„2 year control actuarial locoregional control rates“ ECS +

p = 0,003

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Positive surgical margins in neck dissection specimens in patients with head and neck squamous cell carcinoma and the

effect of radiotherapySmeele LE, Leemans CR, Langendijk JA, Tiwari R, Slotman BJ, van Der Waal I, Snow GB. (Head Neck. 2000)

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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)

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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)

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Postoperative RT/RCT bei Kopf-Hals-Tumoren:Einfluss Intervall OP RT

Intervall Lokoregionäre KontrolleAng 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=0,02et al >50 Tage: 54%

X: akzelerierte RT

XX: konventionelle RT

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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)

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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)

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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)

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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)

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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)

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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)

21

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)

22

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)

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Kopf-Hals-Tumore: Adjuvane RT versus RCTLaramore et al. 1992

3 x Cisplatin/5-FU RT

OP

RT

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Kopf-Hals-Tumore: Adjuvane RT versus RCTLaramore et al. 1992

OP/RT OP/CT/RT4-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

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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)

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Postoperative RT vs. RCT: Haffty et al 2003;Postoperative RCT mit Mitomycin C ± Dicumarol (n=182)

RT RCTLokale Kontrolle 67% 87% p=0,015(5 Jahre)

DFS 44% 67% p=0,03(5 Jahre)

Überleben 41% 56% n.s.(5 Jahre)

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Kopf-Hals-Tumoren: postoperativ RT vs. RCT; Einschlußkriterien

Bachaud et al 1996 III , IV + extrakapsuläres Wachstum

EORTC 22931 pT3, pT4

pT1 pT2 pN2 – 3extrakapsuläres WachstumR1-Resektionperineurale Infiltrationvaskulärer Befall

RTOG 9501 > 2 LKs positivextrakapsuläres WachstumR1-Resektion

ARO-Studie > 3 LKs positivextrakapsuläres WachstumpT3 R1, pT4

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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 – 33500 mg / m² 5-FU

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Radiochemotherapie Kopf-Hals-TumorenAdjuvante 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

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Radiochemotherapie Kopf-Hals-TumorenAdjuvante RCT

Lokale Kontrolle [%]

Überlebensrate[%]

Fernmetastasen[%]

RT RCT RT RCT 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 n.s.

Fietkau et al.*

62 83 p=0.006 49 58 p=0.11 32 31 n.s.

°2-Jahresdaten, *5-Jahresdaten

Cooper et al., NEJM 350;19, 05/2004Bernier et al., NEJM 350;19, 05/2004Fietkau et al., ASCO 2006

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Radiochemotherapie Kopf-Hals-TumorenAdjuvante RCT

Akuttoxizität

Mukositis G3/G4 [%] Alle G3/G4 [%]

RT RCT 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 21 41 p=0.001

Fietkau et al. 2006

ARO 96-3

13 21 p=0.04 --- --- ---

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Radiochemotherapie Kopf-Hals-TumorenAdjuvante 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

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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 %

34

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)

35

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)

36

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

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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)

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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)

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Radiochemotherapie Kopf-Hals-TumorenAdjuvante 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?