dugo iasgo 09

The road to R0Several paths for one goal ?

Domenico D’UGOFull Professor of Surgery

Catholic University - Rome

Survival after R0-Resection

36.1%

5 yrs

German Gastric Cancer Study (1654 pts); Ann Surg, 1998 (1654 pts); Ann Surg, 1998

Memorial Sloan-Kettering Cancer Center, New York (1172 pts); Ann Surg, 2004Memorial Sloan-Kettering Cancer Center, New York (1172 pts); Ann Surg, 2004

7%

92%

Recurrence after R0-Resection

Personal Series (294 pts) – D. D’Ugo 2009

Risk factorsRisk factors

pT3-4pT3-4

pN+pN+

diffuse type

G3

larger size

proximal site

Time to recurrenceTime to recurrence

Locoregional 19.1

Lymph nodal 24.2

Peritoneal 19.9

Haematogenous 25.9

months19.0%

16.7%

39.3%

25.0%

Peritoneal

Lymph nodal

HaematogenousLocoregional

60.7%60.7%

Recurrence after R0-Resection

or

Recurrence (of disease)

Failure(of treatment)

“It’s what the surgeon doesn’t

see that kills the patients”

Sugarbaker PH

?

J Nippon Med Sch. 2000 Feb;67(1):5-8

No residual disease ,

“high probability” of cure

The curative potential of gastric resection

T1 or T2

N0 treated by D1, 2, 3 resection

N1 treated by D2, 3 resection

M0, P0, H0, CY0

Proximal and Distal margins >10 mm

CRITERIA

Japanese Gastric Cancer Association, 1998

D>N

Nishi M, et al. Gastric Cancer, 1993Nishi M, et al. Gastric Cancer, 1993

1962

General Rules for Gastric Cancer StudyGeneral Rules for Gastric Cancer Studyin Surgery and Pathologyin Surgery and Pathology

Survival after R0-Resection

according to the “Japanese Rules”

N0 patientsN+ Patients

Randomized Controlled Trials

No survival benefit

Dutch

MRC

Maruyama Index:paradigm of tailored extension of LND

Median MI = 26

“Calculating the probability of detecting metastases ...

this probability increased steeply in the lower range

and more gradually in the higher range yield”

Chance of detecting lymph node metastases

Overall survival: p=0.041

Disease-free survival: nsCancer specific survival: ns

Per-protocol analysis: OS, CSS, DFS: p=ns

Overall survival: p=ns

Disease-free survival: p= ns

36.1%Siewert 1998

64.8%Kim 1998≈

≈

German Gastric Cancer Study (1654 pts); Ann Surg, 1998

Korea Gastric Cancer Center (10783 pts); Gastric Cancer, 1998

The E/W Survival Gap

Magic Trial

INT-0116

ACTS-GC

CH-RT

ECF

courtesy by : T. SANO (2009)

The E/W Survival Gap

20

04

20

05

20

06

20

08

“ “ In

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““Induction” of R0 byInduction” of R0 byNeoadjuvant ChemotherapyNeoadjuvant Chemotherapy

Staging LaparoscopyStaging Laparoscopy

D2 LymphadenectomyD2 Lymphadenectomy

““Induction” of R0 byInduction” of R0 byNeoadjuvant ChemotherapyNeoadjuvant Chemotherapy

Neoadjuvant Chemotherapy Neoadjuvant Chemotherapy with Epirubicin, Etoposide and Cisplatin: with Epirubicin, Etoposide and Cisplatin:

7-year follow-up 7-year follow-up

84%84% 58%58% 46%46%

R0-Resection Rate: 83% R0-Resection Rate: 83%

60%60%

36%36%

T-downstaging: 42% T-downstaging: 42% = Induction of R0 Resection ?

Neoadjuvant Chemotherapy Neoadjuvant Chemotherapy with Epirubicin, Etoposide and Cisplatin: with Epirubicin, Etoposide and Cisplatin:

7-year follow-up 7-year follow-up

Circumferential Margin at EGJ

The high proportion of “open & close”

laparotomies” (12%) and of

positive circumferential resection margin positive circumferential resection margin

(32-47%) (32-47%) highlights limitations in the

current staging techniques for identifying

patients at risk for potential CRM

involvement.

Davies et al., Dis Esoph (2008)Dexter et al., GUT (2001)

Preoperative radiotherapy :Preoperative radiotherapy :RCT – chinese report, 1998RCT – chinese report, 1998

“Preoperative radiation therapy is able to improve the results of

surgery for adenocarcinoma of the gastric cardia”

Treatment: 40 Gy / 4 weeks by 2 Gy qd x 20

OS: 30% vs 19%

Zhang, et al. Int. J. Radiation Oncology Biol. Phys., 1998

Arm A : 2.5 PLF(cisplatin+fluorouracil+leucovorin)

Arm B: 2 PLF+ cisplatin+etoposide+30 Gy

““Although the study was Although the study was closed early closed early and statistical significance was not achieved,and statistical significance was not achieved,

results point to a survival results point to a survival advantage for preoperative chemo-radiotherapyadvantage for preoperative chemo-radiotherapy

compared with preoperative chemotherapy in adenoca. of the EGJ ”compared with preoperative chemotherapy in adenoca. of the EGJ ”

Preoperative ChemoradiationPreoperative Chemoradiation

Preoperative Chemoradiation : Preoperative Chemoradiation : RTOG 9904 TrialRTOG 9904 Trial

Ajani J, et al. J Clin Oncol 2006, 24, p3953

Pathologic Complete Response : 26% Pathologic Complete Response : 26%

Ajani J, et al. J Clin Oncol 2006, 24, p3953

““With some guideline refinements, the preoperative chemoradiotherapy With some guideline refinements, the preoperative chemoradiotherapy

strategy is poised for a comparison with postoperative chemoradiotherapy in strategy is poised for a comparison with postoperative chemoradiotherapy in

patients with localized gastric cancer”patients with localized gastric cancer”

71%71%

Preoperative Chemoradiation : Preoperative Chemoradiation : RTOG 9904 TrialRTOG 9904 Trial

Preoperative ChemoradiationPreoperative Chemoradiation

Fujitani K, Ajani J, et al. Ann Surg Oncol 2007, 14, p1305

Morbidity rate:Morbidity rate: 38.0% (27 patients)

Mortality rate: Mortality rate: 2.8% (2 patients)

Prospectively collected database on 71 consecutive patientsProspectively collected database on 71 consecutive patients

Induction chemotherapy chemo-radiotherapy (45 Gy)Induction chemotherapy chemo-radiotherapy (45 Gy)

Postoperative resultsPostoperative results

(…careful consideration of added risk…)

Tran CL, et al. Am J Surg 2006, 192, p873

For Colorectal CancerFor Colorectal Cancer

Francois Y, et al. J Clin Oncol 1999, 8, p2396

Multimodal Preoperative Treatment:Multimodal Preoperative Treatment:Surgical ImplicationsSurgical Implications

Delayed surgery…Delayed surgery… …increases probability of downstaging of the tumor when there is a correctly long interval between the completion of therapy and surgery

…doesn’t modify toxicity and early clinical results

diverting stoma avoids major morbidity diverting stoma avoids major morbidity due to anastomotic leak (fatal in 0-3% of cases)

but…but…

Matthiessen P, et al. Ann Surg 2007, 246, p207

For Gastric CancerFor Gastric Cancer

Bozzetti F, et al. Ann Surg 1997, 226, p613

Delayed surgery…Delayed surgery… …increases probability of downstaging of the tumor when there is a long interval between the completion of therapy and surgery

…doesn’t modify toxicity and early clinical results

No tools to avoid major morbidityNo tools to avoid major morbiditydue to anastomotic leak (fatal up to 1/3 of cases!)but…but…

Sauvanet A, et al. J Am Coll Surg. 2005, 201 (2):p253

Multimodal Preoperative Treatment:Multimodal Preoperative Treatment:Surgical ImplicationsSurgical Implications

Multimodal Preoperative Treatment:Multimodal Preoperative Treatment:Extreme Salvage SurgeryExtreme Salvage Surgery

FOX-RT for Previously Unresectable DiseaseFOX-RT for Previously Unresectable Disease

ConclusionsConclusions

Multimodal preop. approachMultimodal preop. approachwith delayed surgery…with delayed surgery…

……is only seldom associatedis only seldom associatedwith tumor progressionwith tumor progression- accurate pretreatment staging?

- radiation therapy optimization?

……no increase of surgical morbi/no increase of surgical morbi//mortality in experienced hands/mortality in experienced hands - high volume – post-RT surgery

……doesn’t modify toxicitydoesn’t modify toxicityand early clinical resultsand early clinical results