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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
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
duct
ion
” o
f R
0 In
duct
ion
” o
f R
0
““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
