adenokarzinom des Ösophagus und magens filechristian meyer zum büschenfelde klinikum rechts der...

Christian Meyer zum Büschenfelde

Klinikum rechts der Isar der Technischen Universität München

III. Medizinische Klinik und Poliklinik

Schwerpunkt: Hämatologie / Internistische Onkologie

Adenokarzinom des Ösophagus und

Magens

Neoadjuvant

Adjuvant

Palliativ

Second line

Therapiekonzepte

MAGIC-Studie

St. II + III

Gastric +

Junction +

Esophagus

N = 503

1994-2002

RANDOM

Chemotherapy:

ECF x 3 Resection ECF x 3

Surgery alone

Primary endpoint: 5-y-survival

*ECF: Epirubicin 50mg/m2 d1, Cisplatin 60mg/m2 d1, 5-FU 200mg/m2/d cont iv, qd 22

Cunningham D et al. N Engl J Med 2006;355:11-20

MAGIC Trial - Gesamtüberleben

Cunningham D et al. N Engl J Med 2006;355:11-20

23%

5-y-OS

36%

St. II + III

Gastric +

Junction +

N = 224

1995-2003

RANDOM

Chemotherapy:

CF* x 2 Resection CF x 4

Surgery alone

*CF: Cisplatin 100mg/m2 d1, 5-FU 800mg/m2/d d1-5, qd 28

Primary endpoint: Survival20% 35% after 5 years, =5%, =20%

Boige, V. et al. ASCO 2007 #4510

FNCC 94012 – FFCD 9703

FNCC 94012 – FFCD 9703

Boige, V. et al. ASCO 2007 #4510

713162738537911114172741536593113

0,00

0,20

0,40

0,60

0,80

1,00

0 1 2 3 4 5 6 7

A risque

logrank : p = 0,021

___ S___ CT + S

yearsAt risk

5-year-survival: 24% (16-33%) vs 38% (28-47%)

Logrank p value = 0.021Hazard Ratio = 0.69(95% CI 0.50-0.95)

St. II + III

Gastric +

Junction +

N = 144

T3/T4 NxM0

RANDOM

Chemotherapy:

PLF x 2 Resection

Surgery alone

PLF: Cisplatin 50mg/qm d1, 15, 29 , 5-FU 2000mg/qm + FA 500 mg/qm weekly

Primary endpoint: Survival

Schuhmacher et al. ASCO 2009

Neoadjuvant chemotherapy + surgery versus surgery alone

for locally advanced adenocarcinoma

of the stomach and cardia: EORTC phase III trial

CS

(N=70)

S

(N=68)

D2 lymphadenectomy 67 (95.7%) 63 (92.6%)

+ transhiatal resection 31 (44.3%) 35 (51.5%)

+ hepatoduodenal lig. & rt. retroperitoneal excision 20 (28.6%) 22 (32.4%)

Subtotal distal resection w/ systemic LN resection 1 (1.4%) 2 (2.9%)

Multivisceral resection 6 (8.6%) 12 (17.6%)

Type of reconstruction

Roux-en-Y

Pouch

48 (68.6%)

17 (24.3%)

50 (73.5%)

12 (17.6%)

Schuhmacher, ASCO 2009; Abstract 4510



of the stomach and cardia: EORTC phase III trial # 4510


CS

(N=72)

S

(N=72)

R0 59 (81.9%) 48 (66.7%)

R1 9 (12.5%) 15 (20.8%)

R2 2 (2.8%) 5 (6.9%)

Not operated 2 (2.8%) 4 (5.6%)





(years)

0 1 2 3 4 5 6 7

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment

35 72 58 48 34 20 11 4

32 72 61 49 41 29 15 6

S

CS

Overall Logrank test: p=0.466




HR 0.84

(0.52,1.35)


(years)

0 1 2 3 4 5 6 7

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment

35 72 58 48 34 20 11 4

32 72 61 49 41 29 15 6

S

CS

Overall Logrank test: p=0.466

713162738537911114172741536593113

0,00

0,20

0,40

0,60

0,80

1,00

0 1 2 3 4 5 6 7

A risque

logrank : p = 0,021

D2 40% D2 90%

Intensivierte Therapie

Verbesserte Selektion

Therapiekonzepte

T3,T4 NXM0

Esophageal

+ Junction

N = 126

RANDOM

Chemotherapy:

PLF x 2 Resektion

Radiochemotherapie:

PLF x 2 CE+30 Gy

Resektion

Primary endpoint: Survival

Phase III Comparison of Preoperative Chemotherapy

Compared with Chemoradiotherapy in Patients with Locally

Advanced Adenocarcinoma of the Esophagogastric Junction

Stahl M. et al. J Clin Oncol 2009

Primärer Endpunkt: OS

*PLF: Cisplatin 50 mg/m2 d1 biweekly, LV 500mg/m2/d, 5-FU 2g/m2/d, weekly; 6wk cycle

*CE: Cisplatin 50 mg/m2 d1+8; Etoposide 80 mg/m2 d3+5

*Studie vorzeitig beendet; *Letalität RCTX>CTX; p NS

3-year-survival: 27.7% (14-42.3%) vs 47.4% (32.8-60.7%; p=0.07)

Stahl M. et al. J Clin Oncol 2009

Neoadjuvante RCTX: Overall Survival

Intensivierte Therapie

Verbesserte Selektion

Therapiekonzepte

Weber et al. J Clin Oncol, 2001; 19:3058-3065

Response-Prediction

AEG

type I-II

uT3/N+

n = 111

CTx

Resection

Resection

Non-

Responder

Responder

CTx: 3 months

PET d0

PET d14

Response definition: Decrease of the SUVmean PETd14 / PETbaseline > 35%Weber et al. J Clin Oncol 2001;19:3058-65 Ott et al. J Clin Oncol 2006;24:4692-8

Lordick et al. Lancet Oncol 2007 Sep; 8: 797-805

MUNICON I

Lordick et al. Lancet Oncol 2007 Sep; 8: 797-805

Median survival

[95% CI] in months:

Metabolic Responder:

Not reached

Metabolic Non-Responder:

25.8 [19.4; 32.3]

Hazard ratio 2.13 [1.14-3.99]

Log-rank p-value: p=0.015

Median follow-up: 28.0 months

PET-Non-Responder

PET-Responder

MUNICON I

Municon II

PET

d 14

Resect

Non-Responder

ResponderCTx: 3 Months

Resect

RCTx

CF + 32 Gy

MUNICON II

Neoadjuvant

Adjuvant

Palliativ

Second line

Therapiekonzepte

SWOG 9008 / INT0116

R0 res.

Adeno-Ca

des Magens

n= 556

RANDOM

Radiatio 45 Gy

Surgery alone

5-FU/LV 5-FU/LV x 2

5-FU/LV5-FU/LV

Mac Donald JS et al. N Engl J Med 2001;345:725-30

Mac Donald JS et al. ASCO 2009

Radiochemotherapie-Survival

0%

20%

40%

60%

80%

100%

0 24 48 72 96 120 144 168 192

5-FU+leucovorin+RT

Observation

N

282

277

Events211

231

Median OS

3527

P = .0051

months


Radiochemotherapie-Survival

0%

20%

40%

60%

80%

100%

0 24 48 72 96 120 144 168 192

5-FU+leucovorin+RT

Observation

N

282

277

Events211

231

Median OS

3527

P = .0051

months

Aber: D0- Resektion 54%

D1- Resektion 36%

D2- Resektion 10%

Subgruppenanalyse


S1-Studie

St. II + III

D2 Resektion

N = 1059

2001-2004

RANDOM

Chemotherapy:

S1 80 mg/qm d1-28 Wdh d 43

Surgery alone

Primary endpoint: survival

Sakuramoto et al. N Engl J Med 2007;357:1810-20

HR = 0.62

(95% CI; 0.50-0.77)

p<0.001


Orales Fluoropyrimidin S1- Rezidiv freies Überleben

70%

3-y-OS

80%


Orales Fluoropyrimidin S1-Survival

Metanalysen Studien (n)Patienten

(n)odds ratio (CI) Ergebnis

Hermans

199311 2096 0.88 (0.78-1.08) Kein Benefit

Earle 1999 13 1990 0.80 (0.66-0.97) Benefit gering

Mari 2000 21 3658 0.82 (0.75-0.89) Benefit gering

Janunger

200221 3962 0.84 (0.74-0.96) Benefit unklar

Adjuvante Therapie beim AEG/Magenkarzinom

Neoadjuvant

Adjuvant

Palliativ

Second line

Therapiekonzepte

Gibt es eine Standardchemotherapie für

metastasierte Stadien?

Metastasiertes Magenkarzinom

EOX or

EOF

ECX or

EOX

XP Gastro

Tax

FLO FUFIRI DCF ECF

Pts 489 513 160 37 109 170 221 126

%RR 44% 45% 41% 47% 34% 32% 37% 45%

TTP,

mos

6.7 6.5 5.6 8.1 5.5 5.0 5.6 7.4

OS,

mos

10.9 10.4 10.5 15.1 9.6 9.0 9.2 8.9

Metastasiertes Magen-Ca, welche Therapie?

TAX325-Studie DCF vs CF

N = 445 RANDOM

Docetaxel 75 mg/qm d1

Cisplatin 75 mg/qm d1

5-FU 750 mg/qm d1-5

Cisplatin 100 mg/qm d1

5-FU 1000 mg/qm d1-5

Van Cutsem et al JCO2006; 24:4991-7

Primärer Endpunkt: Zeit bis zur Progression

TAX325-Studie DCF vs CF

Van Cutsem et al JCO2006; 24:4991-7

Responserate

37 vs 25 % p=0,01

Zeit bis zur Progression

5,6 vs 3,7 Mo p<0,01

Medianes Überleben

9,2 vs 8,6 Mo p=0,02

2 Jahres Überleben

18 vs 9%

Gesamtüberleben

HER2-positive

advanced GC

(n=584)

5-FU or capecitabinea

+ cisplatin

(n=290)

R

aChosen at investigator’s discretion

GEJ, gastroesophageal junction

5-FU or capecitabinea

+ cisplatin

+ trastuzumab

(n=294) Stratification factors

− advanced vs metastatic

− GC vs GEJ

− measurable vs non-measurable

− ECOG PS 0-1 vs 2

− capecitabine vs 5-FU

Phase III, randomized, open-label, international, multicenter study

1Bang et al; Abstract 4556, ASCO 2009

3807 patients screened1

810 HER2-positive (22.1%)

Toga Studie: Studiendesign

0

10

20

30

40

50

60

2.4%5.4%

32.1%

41.8%

34.5%

47.3%

Intent to treat

ORR= CR + PR

CR, complete response; PR, partial response

p=0.0599

p=0.0145

F+C + trastuzumab

F+C

p=0.0017Patients

(%)

CR PR ORR

Tumoransprechen, Nebenwirkungen

Keine signifikante Zunahme der hämatologischen, nicht-

hämatologischen incl kardialen AEs Van Cutsem, ASCO 2009; Abstract 4509

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Event

294

290

258

238

201

182

141

99

95

62

60

33

41

17

28

7

21

5

13

3

9

3

8

2

6

2

6

1

6

1

4

0

2

0

0

0

5.5 6.7

No.

at risk

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time (months)

FC + T

FC

Events

226

235

HR

0.71

95% CI

0.59, 0.85

p value

0.0002

Median

PFS

6.7

5.5

Progressionsfreies Überleben

Van Cutsem, ASCO 2009; Abstract 4509

Time (months)

294

290

277

266

246

223

209

185

173

143

147

117

113

90

90

64

71

47

56

32

43

24

30

16

21

14

13

7

12

6

6

5

4

0

1

0

0

0

No.

at risk

11.1 13.8

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Event

FC + T

FC

Events

167

182

HR

0.74

95% CI

0.60, 0.91

p value

0.0046

Median

OS

13.8

11.1

T, trastuzumab

Overall Survival


Subgroup Median OS

(months)

All 11.1 13.8vs

Pre-planned analysis

IHC0/FISH+

IHC1+/FISH+

IHC2+/FISH+

IHC3+/FISH+

IHC3+/FISH-

7.2

10.2

10.8

12.3

17.7

10.6

8.7

12.3

17.9

17.5

Exploratory analysis

IHC0 or 1+/FISH+

IHC2+/FISH+ or IHC3+

8.7

11.8

10.0

16.0

vs

vs

0.2 0.4 0.6 1 2 3 4 5

vs

vs

vs

vs

vs

0.92

1.24

0.75

0.58

0.83

0.48, 1.76

0.70, 2.20

0.51, 1.11

0.41, 0.81

0.20, 3.38

Hazard

ratio

95% CI

0.74 0.60, 0.91

1.07

0.65

0.70, 1.62

0.51, 0.83

Risk ratioFavors T Favors no T

584

61

70

159

256

15

131

446

N

OS in Abhängigkeit des HER2 Status


11

3

1.0

0.8

0.6

0.4

0.2

0.0

363432302826242220181614121086420

Time (months)

11.8 16.0

FC + T

FC

Events

120

136

HR

0.65

95% CI

0.51, 0.83

Median

OS

16.0

11.8

Event

0.1

0.3

0.5

0.7

0.9

218

198

4

0

5

3

12

4

20

11

228

218

196

170

170

141

142

112

122

96

100

75

84

53

65

39

51

28

1

0

0

0

No.

at risk39

20

28

13

OS bei ICH 2+/FISH+ oder IHC3+(exploratory analysis)


Neoadjuvant

Adjuvant

Palliativ

Second line

Therapiekonzepte

Autor Phase Pat. Therapie RR TTP OS

Rosati, Ann Oncol

2007

II 28 Doc 60mg,

Cap 2000

29% 4 Mo 6 Mo

Kodera,

Anticancer Res

2007

II 44 Paclitaxel

80 mg

47% 2,6 Mo 7,8 Mo

Barone, Gastric

Cancer 2007

II 38 Doc 75

mg, Ox 80

mg

47% 4 Mo 8,1 Mo

Ueda, Gastric

Cancer 2007

II 28 Iri 70 mg,

Cisplatin

80

28% 3,5 Mo 9,4 Mo

Kim, Br J Cancer

2005

II 57 Iri 150 mg,

5FU/LV

21% 2,5 Mo 7,6 Mo

Magenkarzinom: 2nd Line

Studiendesign

- zweistufiges Design (21: Disease Control in 8 -> Ergänzung mit 27 Patienten)

- vorbehandelt mit 5FU/Cis/Iri/Taxan

- Therapie: RAD 001 10 mg/day po

Primärer Endpunkt

Disease Control Rate

Sekundäre Endpunkte

• Progressionsfreies Überleben

• Gesamtüberlebensrate

• Sicherheit und Verträglichkeit von RAD 001

RAD 001

Chemo-

refraktäres,

metastasiertes

Magenkarzinom

bis zur Progression

oder Unverträglichkeit

Yamada Y, ASCO GI 2009

Multicenter Phase II Study of Everolimus in Patients with previously treated metastatic gastric cancer

Yamada Y, ASCO GI 2009

PPS (n=50) FAS (n=53)

CR 0 0

PR 0 0

SD 56% 55%

PD 44% 42%

DCR 56% 55%

*PPS: per protocol set

*FAS: full analysis set

Median PFS: 83 d; 9 Month OS: 71.6%

Multicenter Phase II Study of Everolimus in Patients with previously treated metastatic gastric cancer

FAZIT

Perioperative Therapie ist Standard beim lokal fortgeschrittenem

Magenkarzinom

Lk Metastasierung und Chirurg wesentliche prognostische Faktoren

Erfolg der adjuvanten Therapie abhängig vom Ausmaß der OP (?)

5FU=Cap, Cis=Ox, -> Standards in der palliativen Therapie

Targeted Therapy – HER2 Testung -> Kombination mit Herceptin

Second line Therapie: Innovative Konzepte in Entwicklung

Therapie des Magenkarzinoms

Danke für Ihre Aufmerksamkeit

F- -Ala

Neuro Toxicity

GI toxicity

Myelo

toxicity

5-FU

Anti-tumor

activity

an oral fluoropyrimidine widely used for AGC in Japan.

an oral formulation of Tegafur, CDHP (Gimeracil), and

Oxo (Oteracil) at a molar ratio 1:0.4:1.

observed high RR and MST of 44-49 % and 207-250 days

in two independent phase II trials1,2

1: Y Sakata et al. Eur J Cancer 1998; 34: 1715-1720 2: W Koizumi et al. Oncology 2000; 58: 191-7

DPD

Tegafur

CDHP

OPRT

Oxo

inhibit inhibit

S1

Metastasiertes Magenkarzinom

adenokarzinom des Ösophagus und magens filechristian meyer zum büschenfelde klinikum rechts der...

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