d2 Maruyama

Surg Oncol Clin N Am
16 (2007) 133–155
Gastric Cancer: D2 Dissection

or Low Maruyama Index-Based
Surgeryda Debate
Harold O. Douglass, Jr, MD, FACSa,b,c,
Scott A. Hundahl, MD, FACS, FSSO, FAHNSd,e,
John S. Macdonald, MDf,g,
Vijay P. Khatri, MBChB, FACSh,*
a
State University of New York at Buffalo, Capen Hall, Buffalo, NY 14260, USA
b
GI Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets,
Buffalo, NY 14263, USA
c
Department of Surgical Oncology, Roswell Park Cancer Institute,
Elm and Carlton Streets, Buffalo, NY 14263, USA
d
University of California at Davis, One Shields Avenue, Davis, CA 95616, USA
e
VA Northern California Health Care System, Surgical Service, SMAT-112,
10535 Hospital Way, Mather, CA 95655-1200, USA
f
St. Vincent’s Comprehensive Cancer Center, 325 West 15th Street,
New York, NY 10011, USA
g
Aptium Oncology, 325 West 15th Street, NewYork, NY 10011, USA
h
Division of Surgical Oncology, University of California Davis Cancer Center,
4501 X Street, Suite 3010, Sacramento, CA 95817, USA
Case for D2 dissection for gastric cancer

by Harold O. Douglass, Jr, MD, FACS
Synopsis
Long-term survival rates after surgical treatment for gastric cancer in the
United States and in Europe have, stage for stage, changed little in the past
half-century. Fiberoptic endoscopy has led to an increase in the frequency of
diagnosis at earlier stages, but most cancers are still diagnosed late. Superior
results reported from Japan and Korea are in part the result of a greater
proportion of patients diagnosed at earlier stages, but also reflect the result
of a methodical approach to gastrectomy and lymphadenectomy, the D2
* Corresponding author.
E-mail address: vijay.khatri@ucdmc.ucdavis.edu (V.P. Khatri).
1055-3207/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.soc.2006.10.005 surgonc.theclinics.com
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134 DOUGLASS et al
dissection, which requires the removal of 12 to 16 regional lymph node

groups. Recently, the prognostic importance of surgical removal and path-
ologic examination of 15 or more regional lymph nodes as an integral part
of resections for gastric cancer has been emphasized by the American Joint
Commission for the Staging of Cancer.
Introduction
Stage for stage, there has been little improvement in the 5-year survival
rates after resection of gastric cancer over the last half-century. Surgical spec-
imens usually consist of a portion of the stomach sufficient grossly to encom-
pass the cancer, with adjacent omentum. According to surveillance
epidemiology and end results (SEER) and other data, pathology reports
show sometimes close but generally tumor-free margins and a few lymph no-
des [1–4]. Many surgeons have little experience with gastric resections, and the
5-year survival after resection for gastric cancer remains between 19% and
27% [2,5–8]. As a result of inadequate margins of normal stomach and failure
to perform a lymph node dissection, local and lymph node recurrences ac-
count for more than half of all surgical failures [9–11].
A half-century ago, in the age before vagotomy, H2 blockade, and proton
pump inhibitors, most surgeons had extensive and continuing experience
with surgical resection of the stomach, not only for peptic ulcer disease,
but also for gastric cancer, which only two decades earlier had been the larg-
est cause of cancer death in the United States. Today’s surgeons have little
such experience: gastric cancer is less common and surgical resection for
peptic ulcer disease is very rarely indicated.
During this same time interval, survival rates after gastric cancer surgery
had risen to more than 50% in Japan [12,13], raising the question as to
whether these surgeons were dealing with the same cancer as seen in the
United States and elsewhere in the West. Surgical results approximating
those of the Japanese and Koreans have been reported from several western
centers staffed by surgeons with particular interests in gastric cancer [14–21],
but have not been replicated in randomized trials [22,23]. Technical factors
leading to unacceptable surgical mortality and morbidity rates have been
noted in these randomized trials [7].
In the United States, the first multi-institutional attempt at surgical qual-
ity control was developed as part of the Gastrointestinal Tumor Study
Group’s initial controlled gastric cancer adjuvant trial, which began in
1974 [5]. The minimalistic requirements required an en bloc resection
with surgical margins free of cancer, and that there be pathologically exam-
ined lymph nodes in the specimen, not all of which could contain meta-
static cancer. Early prompt review of operative and pathology reports
identified a number of patients in whom these criteria had not been satis-
fied, resulting in their ineligibility with refusal of entry or removal from
the study.

GASTRIC CANCER 135
The D2 resection
In Japan, and later in Korea [24], where gastric cancer was endemic, rec-
ognition of the importance of adequate lymphadenectomy as part of a po-
tentially curative resection led to the development and publication of ‘‘The
General Rules for the Gastric Cancer Study in Surgery and Pathology,’’
which were published in English in 1981 [25]. A series of multi-institutional
trials confirmed the safety and enhanced survival of patients in whom a gas-
tric resection accompanied by a methodical resection of the second echelon
of lymph nodes had been performed by experienced surgeons working in
high-volume centers.
Subsequently, several reports from the United States and a number of
other Western countries confirmed that a more thorough lymphadenectomy,
similar to that recommended in the General Rules, could be performed with
low morbidity and mortality [15,16]. The challenge was to show that these
experiences could be generalized across a broader patient base in a random-
ized multi-institutional setting. This challenge was taken up by the Dutch
surgeons, who elected to compare the classic D2 resection, including resec-
tion of the second echelon of lymph nodes, omentectomy, omentobursec-
tomy (ie, resection of the superior leaf of peritoneum of the transverse
mesocolon and the capsule of the pancreas, simplified by injecting saline un-
der these layers [26]), and selective distal pancreatectomy and splenectomy
(for tumors in certain gastric locations), with a D1 dissection in which
only the perigastric lymph nodes were removed [27].
Because the Dutch surgeons had scant experience with the D2 resection,
a well-known Japanese surgeon was invited to The Netherlands to train a small
group of surgeons and, for the next 4 months, to oversee the operations they
performed. Patients throughout The Netherlands with gastric cancer became
eligible for randomization to a D1 or to a D2 dissection. If randomization as-
signed a D1 procedure, the operation was performed by the local attending
surgeon. If randomization resulted in assignment to D2, an itinerant surgeon,
one of those originally trained in the procedure, visited the hospital where the
patient was located to perform the operation, then returned to his or her own
hospital leaving the postoperative care to the local staff in the patient’s hospi-
tal. Complications were handled locally. With 711 patients randomized and
treated in 80 participating centers over 4 years, the average center seemed to
have managed only one or two patients each year, volume that cannot be con-
sidered high enough for the development of expertise in the postoperative
management of these patients and their complications.
Two major groups of technical complications were the major cause of
morbidity and mortality: pancreatic fistula and abscess, and failure of the
esophageal anastomosis with fistula and sepsis [22,28]. In addition, a number
of the patients assigned to the D1 dissection had more extensive resections
(probably because of the intraoperative findings), whereas several assigned
to the D2 dissection were found at time of surgical review to have had lesser

136 DOUGLASS et al
procedures. In the face of these confounding factors, it does not come as

a surprise that the median long-term survival in the D2 group was not sig-
nificantly longer than that of patients randomized to D1. The Dutch sur-
geons should be congratulated for their meticulous analysis of this study.
Modification of the D2 operation

The authors [26,29], and others [30–34], recognized that modification of
the classic D2 resection reduces the morbidity and mortality of the proce-
dure. Not all patients require a total gastrectomy. Only when the cancer en-
croaches on an imaginary line between the angula incisura of the lesser
curvature and the ‘‘bare’’ area on the greater curvature between the gastro-
epiploic vessels and the short gastrics (or when a diffuse cancer was present)
is total gastrectomy essential [26,29].
Although pancreatosplenectomy expedited the procedure, it was also
a major source of postoperative problems. Meticulous dissection of the
lymph nodes along the splenic vessels and removal of obvious enlarged
lymph nodes in the splenic hilum added about an hour to the operative
time, but reduced the risk of pancreatic leak and subphrenic abscess. Met-
astatic disease in the lymph nodes in the splenic hilum was uncommon ex-
cept for cancers involving the upper half of the greater curvature of the
posterior wall of the stomach. Only in these patients did the authors rou-
tinely add splenectomy [26,29].
The infradiaphragmatic esophagus receives most of its blood supply from
below, whereas above the diaphragm it is supplied by arteries arising from
the aorta. Resection of the gastroesophageal junction always includes resec-
tion of the infradiaphragmatic esophagus except on rare occasions when the
ascending esophageal branch of the left gastric artery can be identified and
saved [26,29].
After seeing patients who have undergone potentially curative surgical
resection for gastric cancer return with obstructive jaundice because of
involvement of lymph nodes along the proper hepatic artery, the authors
have added routine removal of these lymph nodes for those patients with
cancers of the antrum and prepyloric region [26,29,35].
In the British cooperative trial, only slightly more than half of the pa-
tients assigned to a D2 resection underwent pancreatosplenectomy [7]. Post-
operative morbidity was noted to be remarkably less frequent among
patients in whom pancreatosplenectomy was not performed. Although
this trial did not show a significant survival benefit for D2 resection, the au-
thors raised the question that D2 resection without pancreatosplenectomy
might indeed show a survival advantage.
Attempts to generalize the data

Surveys of large numbers of surgically treated patients have also attemp-
ted to answer the question as to whether a more extensive lymphadenectomy
GASTRIC CANCER 137
improves survival [1]. Unfortunately, these tended to include any operation

that removed any lymph nodes beyond the first echelon in the D2 classifica-
tion [2]. The authors considered these as D1.5, and patient survival after this
operation was no better than that following D1 resection [16].
In the Intergroup adjuvant chemotherapy trial, station-by station nodal
dissection data were prospectively collected and Japanese D-level designa-
tions were rigorously applied. Only 10% of patients had a D2 resection;
36% had D1 dissection; and 54% of patients did not have all first echelon
nodes removed (ie, so-called ‘‘D0 resection’’). In this trial, patients under-
going a D2 resection enjoyed a median survival of 48 months, versus
29 months for D1 dissection, versus 27 months for D0 dissection. Three-way
univariate comparison of survival curves did not reach statistical signifi-
cance, possibly because of the low proportion of D2 cases [3,8]. The signifi-
cant survival advantage of adjuvant chemotherapy in this trial yielded
survivals no better than those reported from higher-volume institutions
whose patients had D2 resections and no chemotherapy [15,17,19]. Itshould
be noted, however, that the stage distribution of cases in the chemoradiation
trial was unusually adverse [3,8].
The D2 dissection (and pathologist cooperation) guarantees a sufficient
number of lymph nodes for proper staging according to the current Amer-
ican Joint Commission criteria [36]. In the authors’ experience, among pa-
tients with cancer-containing lymph nodes in the second echelon (which is
not removed in a D1 resection), one of every three has become a 5-year sur-
vivor [16]. The total number of lymph nodes containing metastatic cancer
may be more important than their location [19]. It is likely that the ratio
of uninvolved lymph nodes to those nodes containing metastatic cancer is
the determining prognostic factor, because patients in whom only 10% to
29% of resected lymph nodes contain metastases have a much better prog-
nosis than patients in whom more than half of the removed lymph nodes are
involved [37,38].
The future
The D2 dissection is modified for the location of the cancer within the
stomach. It should also be modified for the T stage. Cancers confined to
the mucosa can be treated endoscopically. For cancers extending into the
submucosa, a D1 resection is probably sufficient. The best candidates for
the D2 dissection are the T2 cancers invading the muscularis, or those
with microscopic peritoneal invasion, particularly on the posterior gastric
wall. When the peritoneum is grossly invaded, it is unlikely that survival
will be determined by the extent of surgical therapy until better techniques
for control of peritoneal metastatic disease are proved in controlled trials.
The omentobursectomy portion of the D2 resection may help to control
cancer spread when unexpected minimal or microscopic invasion of the pos-
terior wall is identified at laparotomy.
138 DOUGLASS et al
Critics of the D2 procedure often claim that stage migration is the reason
D2 advocates have demonstrated improved survival rates. There can be no
question that pathologic staging is improved following a D2 dissection. Yet,
with the long-term survival of nearly one third of patients in whom the pa-
thologist identified a few positive nodes in the second echelon, lymph nodes
that would not have been resected with a lesser resection, the D2 resection
must be given some credit for enhanced survival beyond the statistical ma-
nipulation of ‘‘stage migration.’’
The management of gastric cancer continues to evolve, with the values of
neoadjuvant and intraperitoneal hyperthermic chemotherapy yet to be
proved. The value of radiation therapy is probably confined to those same
patients who could potentially benefit from D2 lymphadenectomy. Because
of methodologic problems in patient selection and the need for surgical ex-
pertise that results from the management of a volume of patients, combined
with confounding benefits of more effective chemotherapy than had been
available in the past, the true benefit (or lack thereof) can only be deter-
mined if gastric cancer patients are funneled to institutions where the surgi-
cal expertise is available.
In this era, in which preoperative or postoperative chemotherapy, with or
without radiation therapy, is becoming standard treatment for gastric can-
cer, it will be interesting to follow reports from these high-volume institu-
tions to learn whether they continue with the D2 dissection. If they do, it
must be noted as to whether the addition of adjuvant therapy further im-
proves long-term survival.
The chemotherapy of gastric cancer has made great strides in the past two
decades. Unfortunately, it has not progressed to the level seen in breast can-
cer and a few other malignancies where, alone, it has brought apparent long-
term cure. When this potential level is reached in gastric cancer, it will be
time to explore lesser surgical procedures, perhaps local excision and lymph
node sampling, as has been the case for breast cancer.
Commentary on H. Douglass section

by Scott Hundahl, MD, FACS, FSSO, FAHNS
In the first half of the last century, gastric cancer represented the domi-
nant neoplastic public health problem in the United States. Since that
time, as Dr. Douglass points out, the incidence of gastric cancer has plum-
meted, along with the frequency of gastrectomy for ulcer. Particularly given
this background, he correctly identifies both the importance and difficulty of
meaningful surgical quality control in prospective randomized trials involv-
ing gastric surgery. As a practical solution, limited institution studies, triage,
and centralized referral to experienced centers might help.
Dr. Douglass highlights the historical development of lymphadenectomy
in gastric cancer. He largely sees the somewhat rigid Japan Research Society
for Gastric Cancer tabular approach to planning lymphadenectomy (the
GASTRIC CANCER 139
routine D2 approach) as a key starting point. He also goes on, however, to

apply his considerable experience with the disease to modify substantially
the historic ‘‘one size fits all’’ approach. Along with Dr. Douglass, our Jap-
anese colleagues have certainly done the same over the years, ranging from
successful application of pancreas-preserving lymphadenectomy of station
11 (splenic artery) [39,40], to endoscopic mucosal resection for selected early
gastric cancers [41–45], and simple resections for others [46–48], according
to depth of invasion and other characteristics.
The next section describes data supporting an alternative to ‘‘one size fits
all,’’ one that emphasizes potential survival value for a customized ap-
proach, based on actual experience with actual patients treated in the previ-
ous era of ‘‘one-size fits all.’’ The approach aims surgically to treat nodal
disease where it is likely to reside, and not where it likely is absent. The
theme seems consistent with some of the depth-based recommendations
Dr. Douglass mentions in his concluding section.
Finally, is adjuvant chemoradiation’s value simply ‘‘clean-up’’ for incom-
plete surgery? The power to resolve this question depends on the proportion
of patients having optimal surgical resection in past, ongoing, and future ad-
juvant chemoradiation trials. Having reviewed existing data, I do not know
for sure. Perhaps Dr. Macdonald will comment in his ‘‘uber commentary’’ to
follow.
The case for low Maruyama Index surgery

by Scott A. Hundahl, MD, FACS, FSSO, FAHNS
Synopsis
Local-regional failure following surgical treatment for gastric cancer rep-
resents the dominant mode of recurrence, and salvage once such failure oc-
curs is rare. Using Maruyama Index (MI) as a quantitative measure for
regional disease left behind after primary surgical treatment, data from
two trials show that enhanced elimination of regional nodal disease signifi-
cantly decreases recurrence and improves survival. For a given individual
case, preoperative or intraoperative computerized searching to identify pat-
terns of nodal spread among actual cases with similar characteristics (ie, use
of the Maruyama Computer Program) can guide appropriate lymphadenec-
tomy and ensure a low MI operation. This customized, data-driven approach
to lymphadenectomy for gastric cancer eclipses previous lymphadenectomy
strategies.
Body
Despite various definitions and attestations of complete resection, local-
regional failure following surgical treatment of gastric cancer occurs
frequently. Owen Wangenstein’s University of Minnesota ‘‘second-look
140 DOUGLASS et al
laparotomy’’ series, wisely rescued from obscurity by Gunderson and Sosin

[49], documents that 87% of patients with early detected recurrence had
local-regional failure, 53% had peritoneal failure, and 26% had detectable
distant organ failure. Among clinical series (ie, no routine second look),
a Japanese series from the 1990s documented that, for advanced gastric can-
cer cases, local-regional and peritoneal recurrence accounted for 67% of all
recurrences [50]. In the Dutch D1-D2 trial, the absolute 11-year local-
regional recurrence rate was 58% for the D1 group (versus 70% total
relapse rate for the D1 group) and 45% for the D2 group (versus 65% total
relapse rate for the D2 group) [22,51]. The challenge of local-regional
control in this disease is perhaps emphasized by the fact that 44% of all
cases in the Dutch trial were node-negative [27].
Adjuvant postoperative chemoradiation, which may be viewed a local-
regional modality, has been shown to enhance survival, at least in patients
whose extent of lymphadenectomy was relatively limited [3,8,52]. This sur-
vival enhancement may relate more to delay of recurrence, however, rather
than long-term prevention of such recurrence [53]. In any case, because op-
timal surgical treatment of regional nodal disease constitutes the assigned
focus for this discussion, the topic of adjuvant chemoradiation is left aside.
For unselected patients, particularly those typical of North American and
European cohorts, lymphadenectomy based on predefined ‘‘one-size-fits-all’’
tables and concepts has failed to enhance survival reliably. Three prospective
randomized trials of Japanese-defined D1 versus D2 lymphadenectomy
[7,22,54], and three additional trials of routine total extended node dissec-
tion versus subtotal gastrectomy [55–57] have failed to generate evidence in
favor of Japanese-defined lymphadenectomy paradigms. Additionally,
recently reported survival curves for a large Japanese D2 versus D3 trial
are virtually identical [58]. Finally, a recent, single-institution Taiwanese
D1 versus D3 trial shows borderline ‘‘per protocol’’ overall survival ad-
vantage but no disease-free survival advantage (P ¼ 0.15) [59], one of several
problematic features pointed out in an accompanying editorial [60]. Of these
trials, the large Dutch D1-D2 trial merits particular scrutiny.
The Dutch trial of D1 versus D2 lymphadenectomy was conducted be-
tween August, 1989, and July, 1993, by surgeons participating in the Dutch
Gastric Cancer Group [22,27,61]. Eligibility criteria included age !85 years,
adequate physical condition with no serious comorbid diseases, no previous
cancer, no previous gastric surgery, and histologically confirmed gastric ad-
enocarcinoma without evidence of distant metastases. Patients in both
groups underwent distal or total gastrectomy according to the location of
the tumor, with subtotal gastrectomy allowed if a proximal tumor-free mar-
gin of 5 cm could be achieved. At the onset of the trial, surgeons from 80
centers and eight expert consulting surgeons were extensively instructed con-
cerning Japanese-type surgical treatment according to JRSGC definitions
and guidelines [62–64]. Patients were randomized preoperatively, to arrange
for the intraoperative presence of an expert consultant surgeon for all D2
GASTRIC CANCER 141
cases. A Japanese expert surgeon attended every case during the first
4 months of the trial. The D1 procedure involved removal of all JRSGC-
defined N1 nodes, generally the perigastric nodes at stations 1 through 6
along the greater and lesser curvatures of the stomach, along with removal
of the lesser and greater omentum. The D2 procedure involved omentobur-
sectomy (ie, removal of greater and lesser omentum, the superior leaf of the
transverse mesocolon, and the capsule of the pancreas); frequent distal pan-
createctomy and splenectomy (depending on tumor location); and removal
of JRSGC-defined N2 nodes from stations 7 through 12 (ie, left gastric,
celiac, common hepatic, proper hepatic, splenic artery, and splenic hilar
nodes, as designated N2 according to location of primary tumor and tabular
assignment based on that primary tumor location). Reconstruction follow-
ing completion of the D2 node dissection was left to the local institutional
surgeon, as was the postoperative care of the patient [27,61]. A total of
1078 patients were randomized preoperatively. Of the 1078 cases random-
ized preoperatively, 82 (8%) were excluded for various reasons, most com-
monly unavailability of a consultant reference surgeon (35 cases); poor
physical condition; or lack of histologic confirmation of the diagnosis. Of
the remaining 996 patients randomized and entered into the study, 285
had evidence of incurable or extraregional disease and were excluded. A to-
tal of 711 deemed potentially curable underwent the randomly assigned
treatment (ie, D1 or D2 resection) with curative intent. The 380 cases in
the D1 group and the 331 cases in the D2 group were well balanced with re-
spect to age, gender, tumor location, and tumor depth. Eighty-nine percent
of the cases in each group underwent apparent, pathologically confirmed,
negative-margin resection. A slightly higher proportion of cases in the D2
group underwent total gastrectomy (38% versus 30% in the D1 group).
Based on pathology analysis of recovered nodal tissue, undertreatment non-
compliance occurred in 51% of cases, and contaminating overtreatment
noncompliance occurred in 6% of D1 cases [27,65]. Although such quanti-
fication of compliance represented a unique and laudable attribute of this
trial, it also identified a potentially confounding problem [66].
Among randomized cases, morbidity (25% versus 43%, P !.001) and in-
hospital mortality (4% versus 10%, P ¼ .004) were higher for the D2 group
[27,61]. Complications and in-hospital mortality were significantly associ-
ated with age O65, male gender, assigned D-level, splenic resection, and
pancreatic resection. At the time of this trial, pancreatic-splenic resection
was a mandatory component of D2 resection for tumor locations in the mid-
dle and proximal third of the stomach, but not for D1 resection, and this
represented a further, potentially confounding factor) [22,67]. Overall, for
those who indeed had a negative-margin resection, which was deemed po-
tentially curative, risk of relapse at 5 years was 43% for the D1 group versus
37% for the D2 group (difference between relapse rates not significant) [27].
A recent follow-up report for this trial, with median 11-year follow-up, in-
dicates 30% survival for the D1 group and 35% survival for the D2 group
142 DOUGLASS et al
(not significant, P ¼ .53). Among the relatively few cases with pathologic
N2 disease (N ¼ 89 for this subgroup), however, there were nine 10-year
survivors, and eight of the nine were in the D2 group (P ¼ .01 for this
post hoc analysis of the N2 subgroup) [22]. Post hoc subgroup analysis not-
withstanding, this trial, and the others cited in the second paragraph, fail to
show any survival advantage associated with routine performance of a Jap-
anese-defined D2 lymphadenectomy [22,27,61].
In the late 1980s, Keiichi Maruyama and colleagues at the National Can-
cer Center Hospital in Tokyo created a computer program (known as the
‘‘Maruyama Program’’), which searched a meticulously maintained 3843-
patient database of gastric cancer cases treated by extensive lymphadenec-
tomy. The program is designed to match cases with characteristics similar
to a given case, and report observed nodal dissemination risk, survival,
and other information. With seven demographic and clinical inputs, all iden-
tifiable preoperatively or intraoperatively, the program predicts the statisti-
cal likelihood of nodal disease for each of 16 (JRSGC-defined) nodal
stations around the stomach (the most current version of the JRSGC Gen-
eral Rules now identifies 33 defined nodal stations or substations). Mar-
uyama Program predictions have been assessed in Japanese, German, and
Italian populations and found to be highly accurate [68–70]. The Maruyama
Program is designed to be used by surgeons preoperatively or intraopera-
tively, as a convenient means of rationally planning a more data-driven ex-
tent of lymphadenectomy for a given patient. Since the late 1980s, the
program has been used in exactly this way by many gastric cancer surgeons
around the world. To expand use of this computerized tool, a CD-ROM
with expanded case volume was prepared in 2000 [71].
In a prospectively planned surgical analysis of the large Macdonald
Adjuvant Chemoradiation Trail in the United States (SWOG 9008/Inter-
group 0116), the extent of surgical treatment was specifically assessed and
prospectively coded. The prospectively planned surgical analysis of survival
made use of a novel means of quantifying the adequacy of lymphadenec-
tomy relative to likely extent of nodal disease, the ‘‘Maruyama Index of
Unresected Disease.’’ MI was defined (by the author, SH) as the sum of
Maruyama Program predictions for those Japanese-defined regional node
stations (stations 1 through 12) left in situ by the surgeon [3]. Based on
the trial’s entry criteria, and the definition of MI, every case registered
could have had an MI of zero; this variable was under the surgeon’s con-
trol. As depicted in Fig. 1, median overall survival for the MI !5 subgroup
was 91 months versus 27 months for others (P ¼ .005). By multivariate
analysis, adjusting for treatment, Tstage, and number of nodes positive,
MI proved an independent predictor of survival (P ¼ .0049). Data for dis-
ease-free survival were similar [3,53]. Some impact of ‘‘dose of surgery,’’ as
measured by MI, was also evident. Median survival was 20 months for the
highest MI quartile and 46 months for the lowest MI quartile (treatment-
adjusted P ¼ .002) [3].
GASTRIC CANCER 143
100%
80%
60% MI < 5
40%
P < 0.001
20%
MI >
– 5
0%
0 2 4 6 8 10 12
Years After Registration
No. at Risk
MI < 5 62 43 35 28 18 4 0
– 5 491
MI > 263 166 103 55 13 0
Fig. 1. Updated overall survival curves for Maruyama Index (MI) !5 versus R5 in the Mac-
donald chemo-radiation trial (Intergroup 0116). (From Hundahl SA, Macdonald JS, Benedetti
J, et al. Surgical treatment variation in a prospective, randomized trial of chemoradiotherapy in
gastric cancer: the effect of undertreatment. Ann Surg Oncol 2002;9(3):282; with permission.)
To assess further the useMI as a prognostic tool, the Dutch D1 versus D2

trial has recently been reanalyzed [72]. Blinded to survival, and eliminating
cases with incomplete information, 648 of the 711 patients treated with cu-
rative intent had MI assigned. Median MI was 26 (versus median of 70 for
the Macdonald trial). Overall trial findings with respect to D level were not
affected by the absence of the 63 cases with incomplete data. In contrast to
D level, MI !5 proved a strong predictor of survival by both univariate and
multivariate analysis (Fig. 2). MI was an independent predictor of both
overall survival (P ¼ .016, HR ¼ 1.45, 95% confidence interval 1.07–1.95)
and relapse risk (P ¼ .010, HR ¼ 1.72, 95% confidence interval 1.14–2.60).
Strong dose-response with respect to MI and survival was also observed
(Fig. 3). The Dutch trial findings with respect to MI largely confirmed what
was observed in the Macdonald trial.
Based on results from these two trials, it seems that North American and
European surgeons might better impact patient survival by pursuing a low
MI operation instead of achieving a particular D level. By using the Mar-
uyama Program prospectively to plan a given patient’s lymphadenectomy,
achieving a low MI operation is relatively straightforward. In the current
era, what surgeon or operating room does not have the ability both to
run the program and print the conveniently displayed output?
The compelling dose-response effect for MI also suggests it can be viewed
as a quantitative yardstick for the adequacy of lymphadenectomy in a given
case of gastric cancer. As such a quantitative yardstick, it might someday be
used to identify patients at greater or lesser risk of local-regional recurrence,
144 DOUGLASS et al
Fig. 2. Overall survival for 648 cases in the blinded reanalysis of the Dutch D1-D2 Trial. (From
Peeters KCMJ, Hundahl SA, Kranenbarg EK, et al. ‘‘Low-Maruyama-Index’’ surgery for gas-
tric cancerda blinded re-analysis of the Dutch D1-D2 trial. World J Surg 2005;29:1581; with
permission.)
and perhaps influence decisions on postoperative adjuvant therapy. At

a minimum, MI should be explicitly calculated and reported for every pa-
tient entered into a postoperative adjuvant trial.
Commentary on S. Hundahl section by Harold Douglass, Jr, MD, FACS

Gastric cancer spreads four ways: (1) to the lymph nodes (most com-
mon); (2) by the peritoneal cavity (next most common); (3) through the
blood stream; and (4) by direct invasion to the mesocolon and pancreas.
Surgical procedures can improve patient survival through lymphadenec-
tomy, lesser omental bursectomy, and resection of adjacent organs when
they are invaded. The Intergroup randomized trial confirmed that local re-
currence of cancer is reduced by 50% after a D2 resection [8,27].
The D2 operation, as modified, is designed to permit experienced sur-
geons safely to perform a gastrectomy and lymphadenectomy that provides
the pathologist with an ample number of lymph nodes properly to stage the
patient. Postoperative morbidity and mortality is not significantly greater
after a D2 resection than it is after a lesser procedure, when the operation
is performed in a higher-volume institution [18]. The authors have found
splenectomy not to be necessary except for those cancers arising from or
GASTRIC CANCER 145
Fig. 3. Overall survival for various MI quartiles in the Dutch D1-D2 Trial. (From Peeters KCMJ,
Hundahl SA, Kranenbarg EK, et al. ‘‘Low-Maruyama-Index’’ surgery for gastric cancerda
blinded re-analysis of the Dutch D1-D2 trial. World J Surg 2005;29:1583; with permission.)
involving the upper greater curvature of the stomach or its posterior wall.
Pancreatic resection is performed only for T4 cancers directly invading
the organ (these cancers are never ‘‘shaved off’’ the pancreas, because micro-
scopic residual cancer is almost always left behind). Similarly, the transverse
colon is resected if either it or the transverse mesocolon is found to have
been directly invaded by the cancer.
The D2 approach is relatively straight-forward. The lymph node groups
that are to be removed represent the logical first and second echelons of lym-
phatic tumor dissemination, easily remembered by the surgeon. As Table 1
shows, these lymph nodes are the ones most likely to contain metastases.
Several studies have demonstrated that increasing the number of resected
lymph node (and usually decreasing the proportion of lymph nodes contain-
ing metastatic cancer) is associated with improved patient survival
[14,37,73,74]. Patients with disease in the second echelon of lymph nodes
are unlikely to survive if these lymph nodes are not removed [22].
The Maruyama computer program similarly directs the surgeon to the
lymph nodes most likely to contain metastatic disease, acting as a therapeu-
tic and a prognostic tool [3]. Thanks to the availability of endoscopic ultra-
sound, which allows the assessment of the depth of invasion of the gastric
146 DOUGLASS et al
Table 1
Extent of recommended surgical resection and frequency of lymph node metastases in patients
with cancer of the stomach
Lymph node groups Site of cancer in stomach
Proximal Mid stomach or diffuse Distal
Location Group 1981 1988 %þ 1981 1988 %þ 1981 1988 %þ
R paracardial 1 1 1 38 1 1 15 1 d !10
L paracardial 2 1 1 22 1 d !10 2 d !10
Lesser curve 3 1 1 45 1 1 45 1 1 48
Gastroepiploic 4 1 1 15 1 1 37 1 1 34
Suprapyloric 5 2 d !10 1 1 !10 1 1 46
Infrapyloric 6 2 d !10 1 1 15 1 1 23
L gastric artery 7 2 2 27 2 2 23 2 2 24
Hepatic artery 8 2 2 10 2 2 11 2 2 13
Celiac axis 9 2 2 16 2 2 11 2 2 !10
Splenic hilum 10 2 2 17 2 * 12 2 2* !10
Splenic artery 11 2 2 16 2 2 !10 2 2 !10
Hepatoduodenal 12 d d d d 2 !10 d 2 !10
Retropyloric 13 d d d d d d d * !10
Supuperior 14 d d 10 d d !10 d 2 15
mesenteric
Para-aortic 16 d d 10 d d !10 d d 13
Abbreviations: 1, node groups removed in D1 resection; 1 and 2 are removed in a D2 resec-
tion; * for Group 10, author recommends removal when cancer is diffuse or involves the upper
half of the greater curvature or the posterior wall; * for Group 13, author recommends removal
for cancers in the prepyloric area; %þ, percent of lymph nodes in the group containing met-
astatic cancer.
Data from Refs. [25,30,32].
wall by the cancer, all aspects of the MI are assessable preoperatively. As

a result, it offers useful prognostic information as long as the pertinent areas
of potential lymphatic dissemination of the cancer are resected. For this rea-
son, it is likely to come to more frequent use, and may possibly help to de-
termine (after an appropriately controlled trial) which patients should be
referred to a higher-volume institution for a D2 resection, and which could
be safely kept at the referring hospital, because a lesser operation is proba-
bly almost as beneficial.
The D2 dissection should provide a low MI for most patients in whom it
is applied. After D2 resection, a number of patients may have an index of
five or less. Both approaches are designed for the management of stage II
and stage III gastric cancer. An extensive lymphadenectomy is not advised
for gastric cancers confined to the mucosa, whereas those tumors invading
the submucosa but no deeper uncommonly have metastases in the second
lymph node echelon. Similarly, the role of surgery for patients with stage
IV gastric cancer should be limited to the management of complications.
The weakest part in randomized controlled trials is the lack of surgical
quality control of a rigor equivalent to that of the quality control of
GASTRIC CANCER 147
radiation therapy and chemotherapy in those same trials [3]. Radiation and
chemotherapy as currently practiced for gastric cancer, however, are not
sufficiently effective to compensate for less than optimal surgery. Clinical tri-
als of multimodality adjuvant therapy have improved patient survival when
a less than optimal surgical procedure has been performed. One would hope
that similar treatment might also enhance survival of optimally resected pa-
tients, but this has yet to be proved.
Whether neoadjuvant therapy provides the same degree of benefit in
a combined multimodality approach should be tested in a randomized trial.
If it does, the question should again be raised as to whether a D2 lympha-
denectomy, along with lesser omental bursectomy, further adds to patient
benefit, or whether (as is the case for breast cancer) a lesser operation
may be equally effective and perhaps more desirable.
Whichever approach is used, there is good evidence that hospital and sur-
geon volume of gastric resections plays an important role in reducing patient
morbidity and mortality, whereas also improving the patient’s chance for
long-term survival.
Summative commentary by John S. Macdonald, MD

Drs. Douglass and Hundahl provide excellent and insightful perspectives
on the surgical approaches required optimally to manage patients with re-
sectable gastric adenocarcinoma. This section addresses issues raised by
my surgical oncology colleagues from a different perspective. I do not pre-
tend to have any technical expertise in surgery, but provide a perspective
from a treating oncologist concerning the spectrum of options available
for managing cases with resectable gastric cancer. It is hoped that I also pro-
vide at least a partial answer to the question of how should we now be man-
aging these patients.
Dr. Douglass nicely reviews the status of techniques of surgical resection
in the management of gastric cancer. The premise of his approach is that ex-
tended gastrectomy with D2 lymph node dissection is good. The question I
ask, is good for what? Is D2 dissection curative in cases that could not be
cured with lesser surgery? Randomized trials [22,23,27,75] have failed to
demonstrate that D2 dissection is superior in survival compared with lesser
surgery. Dr. Douglass makes the point that there may be confounding issues
causing the poor outcome seen in D2 patients. He points out that the poor
results might be caused by increased morbidity and mortality from the re-
quirement for splenectomy and distal pancreatectomy in cases of proximal
gastric cancer in the Dutch study [23,27]. Both Drs. Douglass and Hundahl
note that surgical experience and training are important in performing high-
quality gastric cancer surgery. Dr. Douglass’ reservations may be correct
about confounding factors affecting mortality; however, the reality is that
if a more aggressive surgical approach thought to have the potential to be
curative cannot be performed safely and efficiently by a surgeon with
148 DOUGLASS et al
average skills, then it is never going to be widely applicable and loses its po-
tential advantage and can never become a standard of care.
Much is made by both Drs. Douglass and Hundahl that in the final re-
port of the Dutch Study [22,75] patients with metastases present in N2 nodes
benefit from D2 dissection. This outcome is, of course, intuitively obvious
because the definition of a D2 dissection is the en bloc removal of N1 and
N2 nodes; if a D1 or lesser resection is done in cases with metastases in
the N2 nodes, then there is no doubt that cancer would be left behind.
The observation of benefit from D2 dissection in cases with tumor in N2 no-
des begs the question of how does one recognize N2 metastases preopera-
tively. Although modern imaging techniques including endoscopic
ultrasound may be helpful, the identification of patients likely to have exten-
sive nodal metastases by the use of the Maruyama computer program may
be very useful and appropriate for directing, as Dr. Hundahl states, ‘‘the dose
density’’ of gastric surgery.
I hope that the proceeding makes it clear that I have doubts about the
overall appropriateness of D2 surgery for every gastric cancer patient. To
return to the question I originally posed, what is D2 dissection good for?
The answer to this question is that the D2 dissection is essential for accuracy
of staging. As part of their phase III study D1 versus D2 dissection, the
Dutch investigators [65] performed a very important analysis of the accu-
racy of TNM staging in D1 versus D2 dissection cases. Pathologic speci-
mens from cases undergoing D2 dissection were initially staged as if they
had only undergone a D1 dissection. This entailed examination of the nodes
within 3 cm of the primary tumor because this was the definition of N1 no-
des at the time this trial was performed. A pathologic stage (II, IIIA, IIIB,
or IV M0) was applied to the case. Subsequently, the rest of the D2 speci-
men was examined and a final stage was applied. It was found (see
Table 1) in node-positive cases that 60% to 75% of specimens was under-
staged when only N1 nodes were examined. This study very graphically il-
lustrates the values of increased nodal resection to the precision and
overall accuracy of pathologic staging of gastric cancer (Table 2).
Table 2
The value of increased nodal resection to the precision and overall accuracy of pathologic stag-
ing of gastric cancer is illustrated
Hazard 95% Confidence Median Median
Overall survival ratio interval P value obs (mo) Rx (mo)
NEJM (2001) 1.32 (1.06–1.64) .005 27 36
UDPATE (2004) 1.31 (1.08–1.61) .006 26 35
Disease-free survival
NEJM (2001) 1.52 (1.23–1.86) !.001 19 30
UPDATE (2004) 1.52 (1.25–1.85) !.001 19 30
Abbreviations: Obs, observation arm; Rx, postoperative adjuvant arm.
Data from SWOG 9008/Intergroup 0116.

GASTRIC CANCER 149
Dr. Hundahl has added to the discussion of surgical management of gas-

tric cancer and nicely compliments Dr. Douglass’ discussion. Dr. Hundahl
addresses prognostic and predictive factors in the surgical treatment of
stomach cancer. Dr. Hundahl is also a supporter of more aggressive surgery
but he advocates the attractive possibility of targeting aggressive surgery to
those patients who will benefit most from such therapy. He presents impres-
sive data that application of the Maruyama computer program for defining
risk of relapse and prognosis for gastric cancer cases can effectively predict
outcome and pathologic stage. I was impressed with this application, albeit
retrospectively, of the MI to the Dutch Study of D1 versus D2 lymph node
dissection and the Intergroup 0116 chemoradiation studies. Prognosis and
staging were accurately predicted by this technique. Just as those in medical
oncology are excited by targeted therapies, it should be anticipated that
Maruyama-like databases and programs will enable clinicians effectively
to target the ‘‘right dose’’ of gastric resection to the ‘‘right patient.’’
The major question confronting clinicians managing gastric cancer cases
remains, what is the best way to treat resectable gastric adenocarcinoma? In
North America for the last 6 years, postoperative chemoradiation [8,76] has
been accepted as a standard approach. The United States Intergroup 0116
[8,76] demonstrated that chemoradiation improved both disease-free and
overall survival in resected adenocarcinoma of the stomach. Because only
10% of the approximately 550 eligible cases in this study had D2 dissections
and 54% were treated with a less than D1 dissection, the population treated
in Intergroup 0116 did not have uniform surgery. The patient group included
in Intergroup 0116 was at particularly high risk for relapse because 85% of
cases had lymph node metastases and 65% of cases had T3 tumors. The ad-
vanced stages of these cases and the conservative surgical resection techniques
used make it highly likely that many cases would have microscopic residual
nodal metastases after D0 or D1 resections. It is possible that the benefit of
chemoradiation may be caused by the ability of this therapy to sterilize
small-volume residual cancers. In examining the outcome, the small number
(approximately 10%) of cases undergoing D2 resection, it seems that they
may have a better outcome than the cases undergoing lesser operations. It is
important to note, however, that the type of surgery performed was purely
at the discretion of the operating surgeons, so selection bias in choosing which
cases received which type of surgery was very possible. Irrespective of why
a patient was chosen to undergo a D2 dissection, one could ask if chemoradia-
tion benefited such cases. Although the only definitive way to answer this ques-
tion is by a properly designed and powered phase III clinical trial, it would be
of interest to examine the D2 subset to determine if there was evidence of ben-
efit for postoperative adjuvant therapy in patients treated by D2 surgery. Such
an analysis [76] has been performed. This exploratory subset analysis, using
statistical tests to test the probability of there being an interaction of therapy
(postoperative chemoradiation) with outcome, failed to show evidence that
chemoradiation was not beneficial.
150 DOUGLASS et al
Although not a prospectively randomized phase III trial, a study reported

by Kim and colleagues [77] and published in 2005, provided interesting ev-
idence on the value of postoperative chemoradiation in D2 resected cases.
Kim and colleagues [77] did an observational study on 990 cases with re-
sected stomach cancer. All 990 cases underwent formal D2 resection with
98% of cases having O15 resected lymph nodes examined. Five hundred
forty-four cases received postoperative cheomradiation as delivered in Inter-
group 0116 and 446 cases were treated with D2 surgery alone. Keeping in
mind the important caveat that this study used a matched comparative con-
trol and was not a prospective phase III trial, the results are of great interest.
The postoperative chemoradiation group had consistent benefit: median
survivals were 95.3 months versus 62.6 months (P ¼ .0200) and median re-
lapse-free survival was 75.6 months versus 52.7 months (P ¼ .0160). The
benefit was seen in all stages (II, IIIA, IIIB, and IV M0). These data strongly
suggest that postoperative chemoradiation may improve the outcome of pa-
tients undergoing D2 gastric resection.
Given that the results of Intergroup 0116 where reported 5 years ago in
2001 [8], one may fairly ask if the benefits in overall and disease-free survival
in the chemoradiation cases result from a delay in recurrence and are not
caused by the postoperative adjuvant therapy curing microscopic residual
cancer. The 2001 report [6] of Intergroup 0116 was performed with approx-
imately 4 years median follow-up. The 2004 report [76] dealt with cases with
a median follow-up of approximately 7.5 years. Table 2 compares overall
and disease-free survival between the 2001 [8] and 2004 [76] analyses and
no differences (Table 3) in efficacy were detected. There also were no ex-
cesses of late cancer-related or toxicity-related deaths reported in cases
that had received chemoradiation. The benefit for chemoradiation as used
in Intergroup 0116 seems to be maintained.
Most clinicians agree that the treatment of resectable gastric cancer is not
optimal. At least in North America, clinicians also believe that chemoradia-
tion postoperatively is appropriate for most cases of resected gastric cancer.
Physicians caring for stomach cancer patients, however, also would like to
Table 3
Comparison of overall and disease free survival between the 2001 [8] and 2004 [76] analyses
D1 TNM D2 TNM
Stage
Stage No. Pts II IIIA IIIB IV % Change
II 48 30 18 d d 38
IIIA 49 d 19 29 1 61
IIIB 24 d d 6 18 75
Data from Bunt AM, Hermans J, Smit VT, et al. Surgical/pathologic-stage migration con-
founds comparisons of gastric cancer survival rates between Japan and Western countries.
J Clin Oncol 1995;13:19–25.

GASTRIC CANCER 151
see other approaches that, in conjunction with surgical resection, may im-
prove outcome. Recently, at the American Society of Clinical Oncology,
Cunningham and colleagues [78] reported the results of the MAGIC study
of neoadjuvant chemotherapy in cases with resectable adenocarcinoma of
the stomach or lower esophagus. This study randomized 503 cases between
preoperative and postoperative chemotherapy with epirubicin, cisplatin, and
5-fluorouracil chemotherapy and cases taken directly to gastric resection.
D2 resection was the recommended form of surgery. The results of this
study showed definite evidence of T and N downstaging and also improve-
ments in progression-free (log rank P ¼ .001) and overall survival. Median
2- and 5-year survivals with chemotherapy were 50% and 36% versus 41%
and 23% for surgery alone (log rank P ¼ .009). These results make neoadju-
vant chemotherapy an acceptable regimen to consider in cases of gastric can-
cer identified preoperatively.
Finally, to return to the question originally posed, is there a best way to
manage resectable gastric cancer? There are several ways that these patients
may be managed. In North America, postoperative chemoradiation is con-
sidered a standard of care with proved benefits in overall and disease-free
survival maintained with over 7 years follow-up. Whether some groups of
patients undergoing D2 dissection may not need postoperative chemoradia-
tion can only be determined by performing phase III trials. The use of D2
dissection always improves staging precision and may increase cure rates
in some cases. In patients identified preoperatively, neoadjuvant chemother-
apy as reported in MAGIC, is an approach that can improve overall and
disease-free survival.
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Surg Oncol Clin N Am

Gastric Cancer: D2 Dissection

Case for D2 dissection for gastric cancer

dissection, which requires the removal of 12 to 16 regional lymph node

Descargado para Daniel Simón Mestanza Guevara (daniel.mestanza@udla.edu.ec) en Conjunto Clinico

Descargado para Daniel Simón Mestanza Guevara (daniel.mestanza@udla.edu.ec) en Conjunto Clinico

procedures. In the face of these confounding factors, it does not come as

Modiﬁcation of the D2 operation

Attempts to generalize the data

improves survival [1]. Unfortunately, these tended to include any operation

Commentary on H. Douglass section

routine D2 approach) as a key starting point. He also goes on, however, to

The case for low Maruyama Index surgery

laparotomy’’ series, wisely rescued from obscurity by Gunderson and Sosin

To assess further the useMI as a prognostic tool, the Dutch D1 versus D2

and perhaps inﬂuence decisions on postoperative adjuvant therapy. At

Commentary on S. Hundahl section by Harold Douglass, Jr, MD, FACS

wall by the cancer, all aspects of the MI are assessable preoperatively. As

Summative commentary by John S. Macdonald, MD

Descargado para Daniel Simón Mestanza Guevara (daniel.mestanza@udla.edu.ec) en Conjunto Clinico

Dr. Hundahl has added to the discussion of surgical management of gas-

Although not a prospectively randomized phase III trial, a study reported

Descargado para Daniel Simón Mestanza Guevara (daniel.mestanza@udla.edu.ec) en Conjunto Clinico

Descargado para Daniel Simón Mestanza Guevara (daniel.mestanza@udla.edu.ec) en Conjunto Clinico

[9] Bozzetti F, Bonfanti G, Bufalino R, et al. Adequacy of margins of resection in gastrectomy

Descargado para Daniel Simón Mestanza Guevara (daniel.mestanza@udla.edu.ec) en Conjunto Clinico

Descargado para Daniel Simón Mestanza Guevara (daniel.mestanza@udla.edu.ec) en Conjunto Clinico

Descargado para Daniel Simón Mestanza Guevara (daniel.mestanza@udla.edu.ec) en Conjunto Clinico

Descargado para Daniel Simón Mestanza Guevara (daniel.mestanza@udla.edu.ec) en Conjunto Clinico

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