Andrés CervantesAndrés Cervantes

Stefano Cascinu Clinica di Oncologia Medica Università Politecnica delle Marche Ancona

Adjuvant or neoadjuvant therapy?

Changing incidence of gastric cancers in Western populations

Distal esophagus

Proximal stomach

Distal stomach

GE junction

Blot

0

YearYear1950 1960 1970 1980 1990 1997

Stomach

•More aggressive disease

•Locally advanced

•Early hematogenous spread

Stomach Cancer - Presentation

• Location at Presentation

US Italy

(1980) (2000)

Upper third: 37% 12% 30%

Middle third: 20% 70% 50%

Lower third: 30% 15% 10%

Diffuse: 12% 3% 10%

Il tipo istologico

• Intestinale in calo

• Diffuso in aumento

• Giovani donne; T. di Krukenberg:– Follow up mirato– Chirurgia come migliore approccio nelle

pazienti senza carcinosi peritoneale

Krukenberg tumours: the treatment

• Surgical management and outcome of metachronous Krukenberg tumors from gastric cancer. Cheong JH et al, J Surg Oncol 2004

Metastasectomy may improve the overall and progression free survival

La prognosi nel carcinoma gastrico radicalmente resecato

50%50%

70%70%

80%80%

Anni 80 Anni 2000

80%80%

50%50%

20%20%

5%5% 5%5%

Come migliorare la prognosi dei pazienti radicalmente operati

• Chemioterapia postoperatoria

• Chemio-radioterapia postoperatoria

• Chemioterapia perioperatoria

La terapia adiuvante nel carcinoma gastrico: le linee guida

– Stati Uniti: CT/RT

– Europa controllo

– Italia chemioterapia

– Giappone S-1

ADJUVANT CHEMOTHERAPY

Meta-analyses Studies (n) Patients (n) Odds ratio (CI)

Hermans 93 11 2096 0.88 (0.78-1.08)

Earle 99 13 1990 0.80 (0.66-0.97)

Mari 00 21 3658 0.82 (0.75-0.89)

Janunger 02 21 3962 0.84 (0.74-0.96)

Panzini 02 18 3118 0.72 (0.62-0.84)

% 5 years OS5052

HR=0.95, 95% CI=0.70-1.29

Cascinu S, JNCI 2007Cascinu S, JNCI 2007

De Vita F, Ann Oncol 2007De Vita F, Ann Oncol 2007

Adjuvant chemotherapy: new trialsAdjuvant chemotherapy: new trials

Di Costanzo F, JNCI 2008

Di Costanzo F, JNCI 2008

FOLLOW-UP

0.0

1.0

0.8

0.6

0.4

0.2Overa

ll s

urv

ival

1 2 3 4 60 5

Patients at risk

HR: 0.90 [95% CI 0.64-1.26]

Totals128130

Events7067 2 (log-rank): 0.4462 (p=0.504)

3932

Follow-upChemotherapy

128130

109114

86100

7275

5755

4943

Years from randomisation

Follow-upChemotherapy

TrialTrialControl Control

arm 5 year arm 5 year OSOS

Experimental Experimental arm 5 year arm 5 year

OSOS

GOIM 9602GOIM 9602 2020 3535

ITMOITMO 3030 4545

FFCD 8801FFCD 8801 4040 5555

GISCADGISCAD 2020 3535

GOIRCGOIRC 3030 5050

15-20%15-20%

Increase in 5 year

OS

Increase in 5 year

OS

4%4%

Survivalbenefit from

meta-analysis

Survivalbenefit from

meta-analysis

Post-op CT: statistical endpointsPost-op CT: statistical endpoints

86% 87%

42%

42%

61%

25%

62%61%

0

50

100

ITMO FFCD8801

GISCAD GOIM MAGIC MAGIC FFCD9703

FFCD9703

86% 87%

42%

42%

61%

25%

62%61%

0

50

100

ITMO FFCD8801

GISCAD GOIM MAGIC MAGIC FFCD9703

FFCD9703

POST-OP

PRE-OP

POST-OP

PRE-OP

Adjuvant chemotherapy: Rate of pts completing post-CT according to the planned dose and timingAdjuvant chemotherapy: Rate of pts completing post-CT according to the planned dose and timing

0.600.40 0.80 0.90 1.00 1.10 1.20 1.30 1.400.700.50Surgery

alone betterAny

chemotherapy betterHazard ratio

Overall effortHR: 0.83 (95% CI 0.76-0.91)P<0.0001

16 RCT3710 pts

16 RCT3710 pts

Absolute benefit at 5 years: 6.3%

Absolute benefit at 5 years: 6.3%

Buyse ME, 2009

Adjuvant CT: meta-analysis on individual data. Global Advanced/Adjuvant Stomach Tumor Research International Collaboration (Gastric Project)

Adjuvant CT: meta-analysis on individual data. Global Advanced/Adjuvant Stomach Tumor Research International Collaboration (Gastric Project)

s1 Attenzione a polimorfismi enzimatici:

Chemioterapia adiuvanteun ruolo nella pratica clinica?

• 5-fluorouracile: nei pazienti ad alto rischio (pT3 N0; istotipo diffuso o scarsamente differenziato; linfonodi positivi N1)

• 5-fluorouracile/cisplatino (+/- antraciclina): nei pazienti ad altissimo rischio (N2-3), sostanzialmente metastatici.

(ovviamente dipende da eta’ e condizioni generali)

Come migliorare la prognosi dei pazienti radicalmente operati

• Chemioterapia postoperatoria

• Chemio-radioterapia postoperatoria

• Chemioterapia perioperatoria

Disease-free survivalDisease-free survival

CRT of resected GC: a 10 year follow-up of the INT0116

trial

CRT of resected GC: a 10 year follow-up of the INT0116

trialOverall survivalOverall survival

SWOG 9008/INT 0016SWOG 9008/INT 0016

OSOS Hazard Hazard ratioratio 95% CI95% CI P-valueP-value Median Median

obsobsMedian Median

RXRX

NEJM NEJM ‘‘0101 1.321.32 (1.06-1.64)(1.06-1.64) .005.005 27 mos27 mos 36 mos36 mos

UpdateUpdate 1.311.31 (1.09-1.59)(1.09-1.59) .005.005 27 mos27 mos 35 mos35 mos

DFSDFS

NEJM NEJM ‘‘0101 1.521.52 (1.23-1.86)(1.23-1.86) <.001<.001 19 mos19 mos 30 mos30 mos

UpdateUpdate 1.521.52 (1.25-1.83)(1.25-1.83) <.001<.001 19 mos19 mos 27 mos27 mos

Macdonald JS, 2009Macdonald JS, 2009

CRT of resected GC: a 10 year follow-up of the INT0116 trial

CRT of resected GC: a 10 year follow-up of the INT0116 trial

Macdonald JS, 2009Macdonald JS, 2009

Chemioradioterapia adiuvantequale ruolo nella pratica clinica?

• Nei pazienti con R1

• Nei pazienti che hanno ricevuto una linfoadenectomia insufficiente

<15 linfonodi se N negativi e T3

(soprattutto se invasione vascolare)

<25 linfonodi se N positivi (ovviamente dipende da eta’ e condizioni generali)

Come migliorare la prognosi dei pazienti radicalmente operati

• Chemioterapia postoperatoria

• Chemio-radioterapia postoperatoria

• Chemioterapia perioperatoria

MAGIC-Trial MAGIC-Trial

St. II + IIIGastric +Junction +Esophagus

N = 503

1994-2002

St. II + IIIGastric +Junction +Esophagus

N = 503

1994-2002

RANDOM

Chemotherapy:ECF x 3 Resection ECF x 3Chemotherapy:ECF x 3 Resection ECF x 3

Surgery aloneSurgery alone

Primary endpoint: 5-y-survival

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

FFCD 9703 FFCD 9703

St. II + IIIGastric +JunctionN = 224

1995-2003

St. II + IIIGastric +JunctionN = 224

1995-2003

RANDOM

Chemotherapy:CF x 2 Resection CF x 4Chemotherapy:CF x 2 Resection CF x 4

Surgery aloneSurgery alone

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

Ychou et al.

Pre-operative CT: the EORTC 40954 trial

144 patients

resectable adenoca. of the stomach R

Surgery

PLF x 1 cycle

Surgery

PLF x 1 cycle

144 patients randomized /360 in 4 years

Study prematurely closed because of poor accrual

Surgery

RestagingIf NO PD/tox/WHO 2

N= 72

N= 72

NeoadjuvantArm

Surgery arm

p

R0 resection 59 (81.9%) 48 (66.7%) 0.036

N0 node 27 (38.6%) 13 (19.1%) 0.018

Preoperative CT: the EORTC 40954 trial

EORTC 40954: DFS and OS

(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 : Treatment44 72 44 34 28 16 11 4

40 72 56 41 31 24 13 5

S

CS

Overall Logrank test: p=0.200

(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 : Treatment35 72 58 48 34 20 11 4

32 72 61 49 41 29 15 6

S

CS

Overall Logrank test: p=0.466

DFS OS

I punti critici

• I tumori della giunzione esofago-gastrica

• La sopravvivenza nei due studi

Treatment Effect by Primary Site

2007

Chemotherapy is more active against proximal than distal gastric carcinoma

• 270 pazienti con carcinoma gastrico avanzato:

Risposte Sopravv. su primitivo (giorni)

Terzo superiore 91 (33.7%) 51/87 (58.6%) 318

Distale 179 (66.3%) 59/168 (35%) 251

Higuchi, Ajani Oncology 2004

I punti critici

• I tumori della giunzione esofago-gastrica

• La sopravvivenza nei due studi

IL PROBLEMA DELLA SOPRAVVIVENZA NEI DUE STUDI

5y DFS 5y OS

• Magic 20% 23%

• Studio francese 21% 24%

Ricordate gli studi italiani: 5y OS 50% !!!

• Attenzione:

Due popolazioni completamente differenti:– Postoperatoria pazienti resecati R0– Preoperatoria pazienti con malattia non

resecabile

IL PROBLEMA DELLA SOPRAVVIVENZA NEI DUE STUDI

D2 in oltre 60% dei casi

19 LN asportati in media

D2 nel 40% dei casi

N° LN non riportati

MAGIC

Chemoradiotherapy

Can radiotherapy add something to chemotherapy?

We have no randomised trials to support its use in combination with chemotherapy, but……

Terapia integrata nel cancro gastrico

• La terapia intraperitoneale

• La chemioipertermia intraperitoneale

Le nuove frontiere

• I fattori predittivi di risposta– La PET– La genomica/proteomica– La farmacogenomica

Nel carcinoma gastrico: modificazioni metaboliche dopo 4 settimane