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Adjuvant and neoadjuvant treatment of gastric cancer

Official reprint from UpToDate


www.uptodate.com 2014 UpToDate
Adjuvant and neoadjuvant treatment of gastric cancer
Authors
Craig Earle, MD, MSc, FRCPC
Harvey Mamon, MD, PhD

Section Editors
Richard M Goldberg, MD
Christopher G Willett, MD

Deputy Editor
Diane MF Savarese, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2014. | This topic last updated: Feb 14, 2014.
INTRODUCTION The incidence of gastric cancer has been declining steadily since the 1930s, yet it remains a
major cause of cancer death in the United States (US) [1]. The high mortality rate reflects the prevalence of
advanced disease at presentation [2]. In population-based series of Western populations, the five-year survival rate
for patients with completely resected stage I gastric cancer is approximately 70 to 75 percent, while it drops to 35
percent or less for stage II disease and beyond (table 1) [2]. These sobering results have spawned efforts to improve
the treatment results for this group of patients using adjuvant (postoperative) or neoadjuvant (preoperative) therapies.
(See "Surgical management of invasive gastric cancer", section on 'Prognosis'.)
The positive impact of such therapies on survival in patients with resected gastric cancer has become clearer over
time, although there is no consensus as to the best approach. In many parts of the world, chemotherapy alone
(either following surgery or combined preoperative and postoperative administration as in the multinational MAGIC
trial [3]) is the preferred treatment strategy. On the other hand, a large American Intergroup trial (INT0116)
demonstrating a significant survival benefit for chemoradiotherapy after complete resection resulted in the adoption
of this strategy in the United States (US) despite concerns that inadequate surgical staging (particularly the extent
of lymphadenectomy) may have led to an overestimation of benefit [4]. The issues surrounding extent of lymph node
dissection in gastric cancer are discussed in detail elsewhere. (See "Surgical management of invasive gastric
cancer", section on 'Extent of lymph node dissection'.)
Another controversial issue is the management of cancers arising at the esophagogastric junction (EGJ).
Classification and management of these tumors has evolved over time. In the latest edition of the TNM staging
manual, tumors arising at the EGJ or in the cardia of the stomach (figure 1) within 5 cm of the EGJ that extend into
the EGJ or esophagus (the so-called Siewert III EGJ tumors [5]) are staged and treated as esophageal (table 2)
rather than stomach cancers [6]. However, tumors that arise beyond 5 cm of the EGJ or are within 5 cm of the EGJ
but without extension to the esophagus or EGJ are still classified and treated as gastric cancers. (See "Diagnosis
and staging of esophageal cancer", section on 'TNM staging criteria' and "Clinical features, diagnosis, and staging
of gastric cancer", section on 'TNM staging criteria'.)
This topic review will focus on adjuvant and neoadjuvant therapies for non-cardia gastric cancer. The epidemiology,
staging, and surgical treatment of gastric cancers, and multimodality approaches for treatment of esophageal and
EGJ tumors are covered elsewhere. (See "Epidemiology of gastric cancer" and "Clinical features, diagnosis, and
staging of gastric cancer" and "Surgical management of invasive gastric cancer" and "Radiation therapy,
chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the
esophagus" and "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia
adenocarcinomas".)
ADJUVANT CHEMORADIOTHERAPY Interest in adjuvant radiation therapy (RT) stems from the observation that
over 80 percent of patients who die from gastric cancer experience a local recurrence at some point [7]. Although
the available data on whether there is a survival benefit from either postoperative or intraoperative RT in patients with
resected gastric cancer are mixed [8-11], three randomized trials of postoperative combined chemoradiotherapy
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have shown a significant survival benefit compared to surgery alone after complete resection of gastric cancer
[4,12,13].
Intergroup 0116 The largest and most recent trial, US Intergroup INT0116, provides the most compelling data in
support of adjuvant chemoradiotherapy following complete surgical resection, particularly since it used
contemporary RT techniques and concurrently administered fluoropyrimidine radiosensitization [4]. Following
potentially curative resection of gastric or EGJ cancer (T1-4, N0-1), 556 patients were randomly assigned to
observation alone or adjuvant combined chemoradiotherapy. Treatment consisted of one cycle of FU (425 mg/m2
per day) and leucovorin calcium (20 mg/m2 per day) daily for five days, followed one month later by RT (45 Gy in
daily 1.8 Gy fractions) given with concurrent FU and leucovorin calcium (400 mg/m2 and 20 mg/m2, respectively) on
days 1 through 4, and on the last three days of RT. Radiation treatment volumes were subject to centralized
pretreatment review. Two more five-day cycles of chemotherapy (FU 425 mg/m2 per day and leucovorin calcium 20
mg/m2 per day) were given at monthly intervals beginning one month after completion of chemoradiotherapy.
The majority of tumors were T3/T4 (68 and 69 percent of the treated and control groups, respectively), and 85
percent had nodal metastases. Three-year disease-free (48 versus 31 percent) and overall survival rates (50 versus
41 percent) were significantly better with combined modality therapy, and median survival was significantly longer
(36 versus 27 months). Benefits were maintained with longer followup (five-year overall survival 43 versus 28 percent,
hazard ratio [HR] for survival 1.32 (95% CI 1.10-1.60) [14]).
In the chemoradiotherapy group, grade 3 and grade 4 acute toxic effects occurred in 41 and 32 percent of patients,
respectively, while three (1 percent) died from treatment-related toxicity [4]. The most frequent grade 3 or worse
adverse effects were hematologic (54 percent), gastrointestinal (33 percent), infectious (6 percent), and neurologic
(4 percent).
A later patterns of failure analysis disclosed a similar frequency of distant metastasis (16 versus 18 percent in the
chemoradiotherapy and control groups, respectively), but fewer local (2 versus 8 percent) and regional (22 versus 39
percent) recurrences with chemoradiotherapy [14].
The initial report of this study changed the standard of care in the US following potentially curative resection of
gastric cancer from observation alone to surgery followed by adjuvant combined chemoradiotherapy. The impact of
these results on the management of patients with EGJ tumors is addressed in detail elsewhere. (See
"Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas",
section on 'Adjuvant chemoradiotherapy'.)
A criticism of this trial was the limited extent of the surgical procedure in most cases. Although D2 lymph node
dissection (removal of nodes along the hepatic, left gastric, celiac and splenic arteries, and in the splenic hilum)
was recommended, it was only performed in 10 percent of cases, and 54 percent did not even have clearance of the
D1 (perigastric) nodal regions. This noncompliance likely contributed to inferior survival and a 64 percent relapse
rate in the surgery alone arm. (See "Surgical management of invasive gastric cancer", section on 'Extent of lymph
node dissection'.)
Approximately 7 to 22 percent of gastric cancers overexpress the type II epidermal growth factor receptor (HER2).
Retrospective analysis of data from the INT-0116 trial suggest that benefit from postoperative chemoradiotherapy
may have been limited to the 90 percent of patients without HER2 amplification, possibly because HER2
overexpression is associated with radiation resistance [15]. These data are hypothesis generating and need to be
confirmed in other cohorts before routine assay of HER2 expression can be recommended as a means of selecting
patients with postoperative chemoradiotherapy. The role of HER2 expression in selecting therapy for patients with
advanced gastric cancer is discussed in detail elsewhere. (See "Systemic therapy for locally advanced
unresectable and metastatic esophageal and gastric cancer".)
CALGB 80101 As will be discussed below, the MAGIC trial demonstrated a significant survival benefit for the use
of perioperative chemotherapy with epirubicin, cisplatin, and infusional FU (ECF, (table 3)) versus surgery alone in
patients with resectable gastric and EGJ cancer. (See 'MAGIC trial' below and "Treatment protocols for
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esophagogastric cancer".)
CALGB 80101, a US Intergroup study, compared the INT0116 protocol regimen (bolus FU and leucovorin with FU
plus concurrent RT) versus postoperative ECF before and after FU plus concurrent RT in 546 patients with
completely resected gastric or EGJ tumors that extended beyond the muscularis propria or were node positive [16].
The fraction of enrolled patients with EGJ versus gastric primary tumors was not reported.
In a preliminary report presented at the 2011 meeting of the American Society of Clinical Oncology (ASCO),
patients receiving ECF had lower rates of diarrhea, mucositis, and grade 4 or worse neutropenia. Overall survival,
the primary endpoint, was not significantly better with ECF (at three years, 52 versus 50 percent for ECF and
FU/LV, respectively). The trial was not adequately powered to assess non-inferiority. The location of the primary
tumor (EGJ versus proximal versus distal stomach) did not have any effect on treatment outcome.
ARTIST trial Additional evidence in favor of chemoradiotherapy is provided by the ARTIST trial, which directly
compared adjuvant chemoradiotherapy to adjuvant chemotherapy in 458 patients with completely resected gastric
cancer and a D2 lymph node dissection [17]. Disease-free survival was similar in both arms, although there was a
suggestion of better outcomes with chemoradiotherapy in those with node-positive disease. This trial is described in
more detail below. (See 'Chemotherapy versus chemoradiotherapy' below.)
Choice of regimen The INT0116 study established postoperative chemoradiotherapy as a standard approach
for completely resected gastric cancer; however, the optimal regimen has not yet been established. In INT0116, the
chemoradiotherapy component was given with bolus IV FU and leucovorin calcium on days 1 through 4 and on the
last three days of RT, an approach that has fallen out of favor given the better tolerability and comparable efficacy of
daily low-dose infusional FU in other gastrointestinal sites such as rectal cancer. Most clinicians utilize continuous
infusion FU (200 mg/m2 daily) during RT instead of bolus FU plus leucovorin. Another acceptable option, as was
tested in the ARTIST trial, is daily oral capecitabine (825 mg/m2 twice daily five days per week on radiation days)
[17]. (See 'Chemotherapy versus chemoradiotherapy' below and "Adjuvant therapy for resected rectal cancer",
section on 'Infusional versus bolus FU' and "Adjuvant therapy for resected rectal cancer", section on 'Orally active
fluoropyrimidines'.).
The chemotherapy alone component of the adjuvant combined modality therapy regimen can be either a single
agent fluoropyrimidine such as leucovorin with short-term infusional FU (table 4) or ECF (table 3). (See "Treatment
protocols for esophagogastric cancer".)
Patient selection The optimal selection of patients for adjuvant chemoradiotherapy after complete resection of
gastric cancer is not settled. In particular, there is controversy surrounding patients with IB, especially T2N0,
disease. While patients with T2N0 gastric cancer were included in the INT 0116 trial of observation versus
chemoradiotherapy, the TNM staging system in use at that time (the 3rd edition) defined T2 disease as invading
muscularis propria or subserosa. It was not clearly specified in the paper whether the enrolled T2N0 patients were
limited to patients with subserosal invasion or also included those with invasion limited to the muscularis propria. A
subsequent nonrandomized trial that reportedly used the same eligibility criteria as the INT 0116 trial excluded
patients with T2aN0 disease (which, according to the 5th edition of the American Joint Committee on Cancer
[AJCC] staging system, which was in use at that time, reflected invasion into the muscularis propria but not
beyond; invasion into the subserosa was T2b disease) [18]. Thus, it could be that while patients with stage IB
disease were included in INT 0116, they may have really been patients with subserosal involvement, and those with
T2aN0 disease (in AJCC 5th edition terminology) were observed. (See 'Intergroup 0116' above.)
The newest TNM staging system (as of January 2010) classifies subserosal invasion as T3 disease; while T2N0 is
still stage IB, T3N0 is IIA. A subset of patients with nodal positivity (T1N1) is also classified as stage IB disease
(table 1).
Some have attempted to stratify outcomes among patients with resected stage IB to IIA gastric cancer according to
the presence of absence of adverse clinicopathologic features, using data from the Surveillance, Epidemiology and
End Results (SEER) registry of the National Cancer Institute [19]. The authors concluded that patients with stage
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IB-IIA gastric adenocarcinoma and 2 adverse features (age >60 years, tumor size >5 cm, proximal location, and
high grade) had a five-year disease-specific survival 76 percent and recommended that this subset was appropriate
for adjuvant therapy. However, information on use of adjuvant chemotherapy and radiation therapy was not available
for patients reported to this database, and outcome estimates could have been influenced by the use of adjuvant
therapy. Furthermore, the analysis was limited to those patients with pathologic evaluation of 15 or more regional
lymph nodes.
Using the definitions from the 7th edition of the AJCC staging system, we consider that observation is appropriate
for T2N0 stage IB patients, but adjuvant treatment would be recommended for any T stage with N1 disease (which
would include T1N1 stage IB) and for patients with T3N0 (stage IIA) disease and above.
NEOADJUVANT/PERIOPERATIVE CHEMOTHERAPY In contrast to the situation in the US, the standard of
care for treatment of gastric cancer in many parts of Europe is neoadjuvant or perioperative (preoperative plus
postoperative) chemotherapy. In Japan and Southern Europe, patients routinely receive postoperative chemotherapy
alone [20], although this practice seems to be changing, given the better tolerability of preoperative chemotherapy
[21]. (See 'Adjuvant chemotherapy' below.)
Neoadjuvant chemotherapy may be administered as a means of "downstaging" a locally advanced tumor prior to an
attempt at curative resection. This approach has been applied to patients thought to have resectable disease as
well as those with apparently unresectable but nonmetastatic disease. (See 'Initially locally unresectable
nonmetastatic disease' below.)
Another benefit of neoadjuvant chemotherapy is that patients who are at high risk of developing distant metastases
(eg, those with bulky T3/T4 tumors, visible perigastric nodes by preoperative imaging studies including endoscopic
ultrasound [EUS], a linitis plastica appearance, or positive peritoneal cytology in the absence of visible peritoneal
disease) may be spared the morbidity of unnecessary gastrectomy if evidence of distant metastases emerges after
chemotherapy.
Three large, adequately powered trials have directly compared surgery with or without IV neoadjuvant or
perioperative chemotherapy, two of which demonstrate a survival benefit for this approach [3,22,23]. Two other trials
which compared preoperative treatment using an oral fluoropyrimidine versus surgery alone failed to show a
significant benefit for chemotherapy and are not discussed further here [24,25].
MAGIC trial The largest and most influential trial is the United Kingdom Medical Research Council MAGIC trial,
in which 503 patients with potentially resectable gastric (74 percent), distal esophageal (11 percent), or EGJ
adenocarcinomas (15 percent) were randomly assigned to surgery alone or surgery plus perioperative
chemotherapy (three preoperative and three postoperative cycles of epirubicin, cisplatin and infusional 5-fluorouracil
[ECF]) (table 3) [3]. (See "Treatment protocols for esophagogastric cancer".)
Eligibility criteria included patients of any age with a performance status of 0 or 1 (table 5), a histologically proven
adenocarcinoma of the stomach or lower third of the esophagus that was considered to invade through the
submucosa (stage T2 or higher, (table 1)), with no evidence of distant metastases or locally advanced inoperable
disease, as evaluated by CT, ultrasonography or laparoscopy.
A higher proportion of chemotherapy-treated patients with gastric cancer who underwent radical surgery had a
potentially curative procedure (79 versus 70 percent), and significantly more had T1/2 tumors (52 versus 37 percent)
and N0/N1 disease (84 versus 71 percent). Chemotherapy was well tolerated overall; excluding patients with
neutropenia (23 percent), fewer than 12 percent of all patients had serious (grade 3 or 4) toxic effects. However,
only 104 (42 percent) were able to complete protocol treatment, including surgery and all three cycles of the
postoperative chemotherapy. These data underscore one of the major problems with the perioperative approach,
which is the difficulty in administering the full number of postoperative chemotherapy cycles.
Despite this, overall survival was significantly better in the chemotherapy group (hazard ratio [HR] for death 0.75,
95% CI 0.60-0.93) as was progression-free survival (PFS, HR for progression 0.66). The 25 percent reduction in the
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risk of death favoring chemotherapy translated into an improvement in five-year survival from 23 to 36 percent. Local
failure occurred in 14 percent of the chemotherapy-treated patients compared to 21 percent of those undergoing
surgery alone. Distant metastases developed in 24 and 37 percent of patients, respectively.
French FNLCC/FFCD trial A similar benefit for perioperative chemotherapy was noted in a French multicenter
trial in which 224 patients with potentially resectable stage II or greater adenocarcinoma of the stomach (n = 55),
EGJ (n = 144) or distal esophagus (n = 25) were randomly assigned to two to three cycles of preoperative
chemotherapy (infusional FU 800 mg/m2 daily for five days plus cisplatin 100 mg/m2 on day 1 or 2, every four
weeks) or surgery alone [26]. Patients in the chemotherapy arm were to receive three to four cycles of
postoperative chemotherapy as well.
Patients undergoing neoadjuvant chemotherapy were significantly more likely to undergo R0 (microscopically
complete) resection (84 versus 73 percent), and there was a statistically insignificant trend toward fewer nodepositive tumors (67 versus 80 percent, p=0.054) that favored this group as well. Among the patients who received at
least one cycle of preoperative chemotherapy, only one-half received any postoperative chemotherapy. With a
median 5.7-year follow-up, perioperative chemotherapy was associated with a significant 35 percent reduction in the
risk of disease recurrence (five-year disease-free survival 34 versus 19 percent) and a significant, 31 percent lower
risk of death (five-year survival 38 versus 24 percent).
EORTC trial 40954 In contrast to these two trials, a survival benefit for neoadjuvant chemotherapy could not be
shown in EORTC trial 40954, in which patients with locally advanced (AJCC stage III or IV [cM0], (table 1 and table
2)) cancer of the stomach or EGJ (one-half in the upper third or cardia) were randomly assigned to surgery with or
without preoperative chemotherapy [23]. The chemotherapy consisted of two 48-day cycles of cisplatin on days 1,
15, and 29 plus leucovorin and a 24-hour infusion of FU on days 1, 8, 15, 22, 29, and 36. The trial was closed
because of poor accrual after only 144 of the planned 360 patients were enrolled. The group receiving neoadjuvant
chemotherapy had a significantly higher rate of complete (R0) resections (82 versus 67 percent), but they also had
more postoperative complications (27 versus 16 percent), and at a median follow-up of 4.4 years, no significant
survival advantage (HR for death 0.84, 95% CI 0.52 to 1.35). However, given the limited accrual, the study was
underpowered to demonstrate a survival endpoint.
Summary and patient selection The impressive results of the well conducted MAGIC and French trials have
led to the adoption of the perioperative chemotherapy approach to treatment of gastric cancer in much of Europe
and other parts of the world. The impact of these trials on treatment of patients with EGJ and proximal (cardia)
gastric cancer is addressed elsewhere. (See "Multimodality approaches to potentially resectable esophagogastric
junction and gastric cardia adenocarcinomas", section on 'Lower GI tract trials'.)
However, whether these results have changed (or should change) practice in the US is more difficult to address.
The results of the MAGIC and French trials are not directly comparable to those of INT0116 as patients were
randomized prior to surgery; randomization occurred after complete resection in INT0116. However, the magnitude
of the survival difference between the surgery alone and the treatment arms of all three studies are similar. (See
'Intergroup 0116' above.)
A major problem in the US is that patients with gastric cancer are commonly taken to the operating room prior to
consultation by medical or radiation oncologists. Multidisciplinary preoperative evaluation is preferable.
In terms of patient selection for this approach, it is reasonable to utilize the eligibility criteria for the MAGIC trial
(patients of any age with a performance status of 0 or 1 (table 5), a histologically proven adenocarcinoma of the
stomach that was considered to invade through the submucosa [stage T2 or higher, (table 1)], with no evidence of
distant metastases or locally advanced inoperable disease, as evaluated by CT, ultrasonography, or laparoscopy)
[3]. (See 'MAGIC trial' above.)
ADJUVANT CHEMOTHERAPY More than 30 randomized trials have compared adjuvant systemic chemotherapy
to surgery alone in resectable gastric cancer, with variable, mostly negative results when overall survival is
considered as the primary endpoint (table 6). While some of the trials were clearly underpowered to detect a
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significant survival difference, others utilized inferior surgical techniques, or much of the planned chemotherapy was
not given because of prolonged recovery from surgery.
Benefits
Meta-analyses Given the variability in outcomes in these phase III trials, several meta-analyses have been
undertaken, all of which support a significant survival benefit for perioperative or adjuvant chemotherapy [27-29],
including one that was limited to trials from Western (ie, non-Asian) countries [30]. Several studies indicate a
somewhat better prognosis in Asian as compared to Western populations with gastric cancer. This subject is
discussed in detail elsewhere. (See "Surgical management of invasive gastric cancer", section on 'Prognosis'.)
One of the most recent of these analyses evaluated data from 34 randomized trials comparing adjuvant systemic
chemotherapy versus surgery alone, conducted in both Asian and Western populations [28]. The risk of death in
patients receiving adjuvant chemotherapy was reduced by 15 percent (HR for death 0.85, 95% CI 0.80 to 0.90).
Choice of regimen The optimal regimen is not established. Acceptable alternatives include ECF (as was used
in the perioperative MAGIC trial, described above), capecitabine plus oxaliplatin (as was used in the CLASSIC trial),
and for Asian patients, S-1, where available. (See 'MAGIC trial' above.)
Japanese S-1 trial S-1 is an oral fluoropyrimidine that includes three different agents: ftorafur (tegafur),
gimeracil (5-chloro-2,4 dihydropyridine, a potent inhibitor of DPD [dihydropyrimidine dehydrogenase]), and oteracil
(potassium oxonate, which inhibits phosphorylation of intestinal 5-FU, thought responsible for treatment-related
diarrhea).
The benefit of adjuvant treatment with S-1 was demonstrated in a Japanese ACTS-GC trial in which 1059 patients
with stage II or III gastric cancer who had undergone potentially curative surgery with D2 lymphadenectomy were
randomly assigned to six months of S1 (80 to 120 mg daily for four weeks, repeated every six weeks for one year)
versus surgery alone [31]. Five-year overall survival was significantly better with S-1 (72 versus 61 percent), with
better than expected survival in both groups. By comparison, the five-year survival rates for the INT0116 and the
MAGIC trials were 43 versus 28 percent, and 36 versus 23 percent for the treatment and control groups,
respectively [3,14].
These results led to the adoption of one year of postoperative S-1 as a standard adjuvant therapy approach for
gastric cancer in East Asian patients. It is difficult to know whether the benefit of adjuvant therapy with S-1, as
demonstrated in the ACTS-GC trial, can be extrapolated to other populations, given the markedly better outcomes
seen in both the treated and the surgery alone control groups, stage for stage, when compared to outcomes in
other non-Japanese populations.
S-1 is approved in Japan for adjuvant therapy of gastric cancer and in Europe for treatment of advanced gastric
cancer; it is not available in the US.
CLASSIC trial The benefit of adjuvant therapy using capecitabine in combination with oxaliplatin was
addressed in the multicenter CLASSIC trial, in which 1035 patients with stage II, IIIA, or IIIB (table 1) gastric cancer
were randomly assigned to eight 21-day cycles of capecitabine (1000 mg/m2 twice daily in days 1 to 14) plus
oxaliplatin (130 mg/m2 on day 1) or surgery alone after D2 gastrectomy [32]. The study was conducted in South
Korea, China, and Taiwan. Only 67 percent of the patients assigned to chemotherapy received all eight cycles of
chemotherapy as planned, and adverse events (most commonly neutropenia, nausea, vomiting, thrombocytopenia,
and anorexia) led to chemotherapy dose modifications in 90 percent of patients. Despite this, at a median follow-up
of 34 months, chemotherapy was associated with a significant improvement in three-year disease-free survival (74
versus 59 percent, HR for death 0.56, 95% CI 0.44-0.72), with only a borderline statistically significant improvement
in overall survival (83 versus 78 percent, HR 0.72, 95% CI 0.52-1.00). However, with longer follow-up, in a preliminary
report presented at the 2013 ESMO World Congress on Gastrointestinal Cancer, the improved overall survival with
chemotherapy was statistically significant (five-year overall survival 78 versus 69 percent, HR for death 0.66 percent,
95% CI 0.51-0.85) [33].
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Chemotherapy versus chemoradiotherapy Adjuvant chemoradiotherapy has been directly compared to


adjuvant chemotherapy in at least four trials [17,34-36], only one of which has shown a significant overall survival
benefit for the addition of RT to chemotherapy [34]:
In the largest trial, the ARTIST trial, 458 patients with complete resected gastric cancer and a D2 lymph node
dissection were randomly assigned to six courses of postoperative capecitabine plus cisplatin (XP) or two
courses of postoperative XP followed by chemoradiotherapy (45 Gy RT with concurrent daily capecitabine [825
mg/m2 twice daily]) and two additional courses of XP [17]. Compared to chemotherapy alone, the addition of
RT to XP chemotherapy did not significantly reduce recurrence rates, although in unplanned subgroup
analysis, patients with nodal metastases had superior disease-free survival with combined therapy as
compared to XP alone. Overall survival, a secondary endpoint, was not analyzed.
At a median follow-up of 53 months, estimated three-year DFS (the primary endpoint) was not significantly
better in patients who received combined modality therapy (78 versus 74 percent, p = 0.0862), although
unplanned subset analysis did indicate a significantly better outcome with chemoradiotherapy in those with
node-positive disease. Overall survival, a secondary endpoint, was not analyzed.
In our view, this trial should not be interpreted as disproving the benefit of chemoradiotherapy relative to
chemotherapy alone. The hypothesis that adjuvant chemoradiotherapy may represent a better approach than
adjuvant chemotherapy for patients with node-positive disease will be tested in a successor trial, the ARTIST-II
trial. (See 'Adjuvant chemoradiotherapy' above and 'Ongoing research' below.)
A Chinese trial randomly assigned 380 patients undergoing gastrectomy and a D2 lymph node dissection to
intensity modulated RT (IMRT) plus chemotherapy (one cycle of bolus FU plus leucovorin followed by IMRT
plus bolus FU and leucovorin on the first four and last three days of RT, and followed by two five-day cycles of
bolus FU/leucovorin) versus chemotherapy alone (the same chemotherapy regimens as the IMRT group but no
RT) [36]. The addition of IMRT was associated with a significant improvement in median recurrence free
survival (50 versus 36 months, HR for recurrence 1.35, 95% CI 1.03-1.78), but the difference in overall survival
favoring chemoradiotherapy (58 versus 48 months) was not statistically significant.
The only trial to show a significant survival benefit for the addition of RT randomly assigned 68 patients
undergoing complete resection with a D1 or D2 lymph node dissection for previously untreated gastric cancer
to chemoradiotherapy administered according to the INT 0116 trial (but using intensity modulated RT) or
chemotherapy alone (five cycles of FU 425 mg/m2 per day and leucovorin calcium 25 mg/m2 per day given five
days in a row, once monthly) [34]. (See 'Intergroup 0116' above.) All patients were followed for at least three
years. Three-year disease-free survival rate was significantly higher in the chemoradiotherapy group (56 versus
29 percent) as was overall survival (68 versus 44 percent).
A Cochrane review of 14 trials comparing perioperative chemo(radio)therapy versus primary surgery concluded that
there was only a trend toward better outcomes with chemoradiotherapy as compared to chemotherapy, but this
analysis did not include any of the four trials directly comparing both approaches in patients with gastric cancer
[27].
Taken together, the available data leave some question as to the benefit contributed by adjuvant RT; however, they
have not yet led to the abandonment of RT for postoperative treatment in North America.
Intraperitoneal chemotherapy The observation that resected gastric cancer tends to recur within the
peritoneum has provided the rationale for the evaluation of adjuvant intraperitoneal (IP) chemotherapy. Although
preliminary reports demonstrated feasibility and safety, the results of randomized studies have been mixed. Several
meta-analyses have been conducted, all of which have found a survival benefit for hyperthermic (but not
normothermic) intraperitoneal chemotherapy (HIPEC) in this setting. However, the methodologic quality of the
analyzed studies has been generally low [37-39].

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The latest of these included 10 randomized controlled trials totaling 1062 patients (518 who underwent HIPEC and
544 controls) with gastric cancer and macroscopic serosal invasion without distant metastases or peritoneal
carcinomatosis [39]. Three trials were described as low quality, although seven failed to provide specific details
about the process of randomization. The largest trial enrolled 212 patients, and the smallest 40 patients. Four trials
utilized systemic chemotherapy after surgery in both the HIPEC and control groups; the use of HIPEC was
associated with a significant improvement in survival (relative risk for death 0.73, 95% CI 0.64-0.83).
Summary and patient selection Meta-analyses provide support for a survival benefit from adjuvant
chemotherapy following complete resection of gastric cancer. Adjuvant chemotherapy for one year with S-1 is
accepted as routine following resection of gastric cancer in Japan and some parts of Europe [40], while in other
parts of Europe, a combination of preoperative plus postoperative chemotherapy using ECF (as was used in the
MAGIC trial [3]) is more commonly recommended.
When adjuvant therapy is used, the optimal regimen is not established. Results with adjuvant capecitabine plus
oxaliplatin (CAPOX, XELOX), as was used in the CLASSIC trial, or capecitabine plus cisplatin (XP), as was used in
the ARTIST trial, are not as mature as those of perioperative ECF (as was used in the MAGIC trial) or S-1 (where
available); therefore, these approaches cannot be recommended with the same degree of confidence. Furthermore,
it is unclear how the results of adjuvant CAPOX and XP translates to the Western setting.
In the US, adjuvant chemotherapy has not replaced chemoradiotherapy as the common standard of care, and
adjuvant chemotherapy alone is infrequently used, despite the finding of a lack of survival benefit for the addition of
RT compared to adjuvant chemotherapy alone in three of four randomized trials. (See 'Adjuvant chemoradiotherapy'
above and 'Chemotherapy versus chemoradiotherapy' above.)
The optimal selection of patients with resected gastric cancer for postoperative adjuvant chemotherapy is debated.
Many of the adjuvant chemotherapy trials limited enrollment to patients with resected stage II or III gastric cancer,
while some included patients with stage IB disease [32,41,42]. None of the trials that demonstrated a survival
benefit for adjuvant chemotherapy was appropriately powered to analyze subgroups according to disease stage.
(See 'Adjuvant chemotherapy' above.)
As is the case with adjuvant chemoradiotherapy being considered, we consider that observation is appropriate for
T2N0 stage IB patients, but adjuvant chemotherapy would be recommended for any T stage with N1 disease (which
would include T1N1 stage IB) and for patients with T3N0 (stage IIA) disease and above. (See 'Patient selection'
above.)
There is insufficient evidence from randomized trials to recommend intraperitoneal chemotherapy as an acceptable
adjuvant treatment after resection of gastric cancer. Higher quality randomized trials are needed. In our view and
that of others [43], this technique remains investigational and should only be considered in the context of a clinical
trial.
NEOADJUVANT CHEMORADIOTHERAPY Preoperative combined chemotherapy and RT is more commonly
used for esophageal, EGJ, and gastric cardia cancers than for potentially resectable non-cardia gastric
adenocarcinomas. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative
adjuvant therapy for localized cancers of the esophagus" and "Multimodality approaches to potentially resectable
esophagogastric junction and gastric cardia adenocarcinomas".)
Neoadjuvant chemoradiotherapy was compared to induction chemotherapy alone in the multicenter German POET
(PreOperative chemotherapy or radiochemotherapy in Esophagogastric adenocarcinoma Trial) trial that was limited
to patients with EGJ adenocarcinoma [44]. Although there were potentially clinically meaningful survival differences
that favored chemoradiotherapy, they were not statistically significant. Furthermore, whether the results can be
extrapolated to patients with true non-cardia gastric cancer is uncertain. These data are discussed in detail
elsewhere. (See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia
adenocarcinomas", section on 'German POET trial'.)

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There are no randomized trials addressing the benefit of preoperative chemoradiotherapy for non-cardia gastric
cancers. In three separate phase II studies using different chemoradiotherapy protocols, the pathologic complete
response rates ranged from 20 to 30 percent, and 70 to 78 percent were able to undergo a complete (R0) resection
after chemoradiotherapy [45-47]. Whether these results are better than could be achieved with surgery alone,
neoadjuvant chemotherapy, or surgery followed by adjuvant chemoradiotherapy is unclear.
The use of induction chemoradiotherapy for patients with initially unresectable gastric cancer is discussed below.
(See 'Initially locally unresectable nonmetastatic disease' below.)
INITIALLY LOCALLY UNRESECTABLE NONMETASTATIC DISEASE The optimal management of patients with
locally advanced unresectable but nonmetastatic gastric cancer is uncertain, and there is no standard approach.
Palliative methods for control of local symptoms are discussed elsewhere. (See "Local palliation for advanced
gastric cancer".)
Options for anticancer therapy include chemotherapy alone or chemoradiotherapy:
Unresectable locally advanced gastric cancer is often treated primarily with chemotherapy, using regimens for
metastatic disease. (See "Systemic therapy for locally advanced unresectable and metastatic esophageal
and gastric cancer".)
Initial chemotherapy treatment may render some patients resectable. However, the benefit of neoadjuvant
chemotherapy in patients who are deemed initially unresectable but without distant metastatic disease is
uncertain. No randomized trials have been completed.
Several uncontrolled studies have explored the use of preoperative chemotherapy for patients with locally
advanced gastric cancer without distant metastases [48-51]. All have shown that some patients initially
thought to be unresectable respond to chemotherapy sufficiently that they are able to undergo potentially
curative surgery. However, pathological complete response rates are low, between 5 and 15 percent, and
treatment-related toxicity may be prominent [51].
Preliminary uncontrolled data suggest that with preoperative combined modality therapy (chemoradiotherapy
with or without induction chemotherapy), approximately 70 percent of patients with localized but initially
unresectable gastric cancer can undergo potentially curative resection, with pathologically complete response
rates as high as 30 percent [45-47,52-54]. Although these early data seem encouraging, the studies have
been conducted in highly selected patients, and randomized trials will ultimately be necessary to confirm
benefit from any of these approaches over chemotherapy alone.
Summary The role of induction therapy in patients with locally advanced initially unresectable but nonmetastatic
disease is unclear. Data from single arm studies can address the question of increasing resectability, but not its
impact on survival. An initial attempt at downstaging with chemotherapy, chemoradiotherapy, or a combination
followed by careful restaging and surgical exploration in responders who have no evidence of metastatic disease is
a reasonable approach for a fit patient who initially had locally unresectable but nonmetastatic disease. Whenever
possible, such patients should be encouraged to enroll on clinical trials testing new approaches.
ONGOING RESEARCH The focus of future research is on optimizing the chemotherapy regimen, defining the
role of RT, and exploring the effect of treatment timing (preoperative, postoperative or both). The following are
examples of ongoing trials:
As described above, CALGB 80101 compared the INT-0116 protocol regimen (bolus FU and leucovorin with
FU plus concurrent RT) versus postoperative ECF (the MAGIC trial perioperative chemotherapy regimen)
before and after FU plus concurrent RT in patients with gastric or EGJ tumors. Unfortunately, this trial failed to
show a survival advantage for ECF. A similarly designed study is also being undertaken in Australia and New
Zealand (TROG 03.02). (See 'Choice of regimen' above.)

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In the United Kingdom, the MAGIC B/ST03 study is exploring epirubicin plus cisplatin and capecitabine (ECX)
with or without bevacizumab followed by surgery, and adjuvant ECX with and without maintenance
bevacizumab.
Neoadjuvant therapy is under study in a European trial comparing preoperative FU and cisplatin versus
surgery alone [55] and a joint Swiss/Italian trial of preoperative docetaxel, cisplatin and FU compared to
surgery alone. Similarly, a Japanese study is evaluating preoperative cisplatin plus S-1 (an oral
fluoropyrimidine) followed by surgery and postoperative S-1 versus surgery and postoperative S-1 alone
(KYUH-UHA-GC04-03).
In the Dutch CRITICS (ChemoRadiotherapy after Induction chemoTherapy In Cancer of the Stomach) trial, all
patients receive induction chemotherapy followed by surgery and randomization to postoperative
chemotherapy versus chemoradiotherapy [56].
As noted above, the Korean ARTIST-II trial is comparing adjuvant chemotherapy (S-1 versus S-1/oxaliplatin)
with or without radiotherapy for completely resected gastric adenocarcinoma. (See 'Chemotherapy versus
chemoradiotherapy' above.)
A randomized trial, the TOPGEAR trial, is underway in Europe and Canada to directly compare preoperative
chemotherapy alone (ECF) versus chemoradiotherapy (two cycles of ECF followed by concurrent
fluoropyrimidine-based chemoradiotherapy) in patients with resectable adenocarcinoma of the stomach and
esophagogastric junction; both groups will receive three further cycles of ECF postoperatively [57].
POSTTREATMENT CANCER SURVEILLANCE There are no randomized trials to guide the postoperative
surveillance strategy. Consensus-based guidelines from the National Comprehensive Cancer Network suggest the
following:
History and physical examination every three to six months for one to three years, then every six months for
years 4 and 5, then as clinically indicated
CBC and chemistry profile, as clinically indicated
Radiologic imaging or endoscopy, as clinically indicated
Monitor for nutritional deficiency in surgically treated patients and treat as indicated.
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and
Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the
Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the
10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with
some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
patient info and the keyword(s) of interest.)
Basics topic (see "Patient information: Stomach cancer (The Basics)")
SUMMARY AND RECOMMENDATIONS
The poor long-term survival rates after surgery alone for patients with gastric and esophagogastric junction
(EGJ) cancer have led to the exploration of a variety of adjuvant (postoperative) and neoadjuvant (preoperative)
treatment strategies incorporating chemotherapy with or without radiation therapy (RT). The survival benefit
from combined modality therapy has become clearer over time. (See 'Introduction' above.)
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Most clinicians now treat EGJ and proximal gastric (ie, cardia, (figure 1)) cancers as esophageal cancers,
using preoperative chemoradiotherapy. However, these tumors have been included in many of the trials
examining the benefit of adjuvant and neoadjuvant chemotherapy for gastric cancer, and institutional practice
varies. The therapeutic approach to tumors of the EGJ and gastric cardia is addressed in detail elsewhere.
(See "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia
adenocarcinomas".)
For patients with non-cardia gastric cancer, randomized trials and meta-analyses provide support for a number
of approaches including adjuvant chemoradiotherapy, perioperative (preoperative plus postoperative)
chemotherapy, as was used in the MAGIC trial [3], and adjuvant chemotherapy. Few studies have compared
these approaches, and the optimal way to integrate combined modality therapy has not been definitively
established. The decision often is based upon institutional and/or patient preference. A major problem, at
least in the US, is that patients with gastric cancer are commonly taken to the operating room prior to
consultation by medical or radiation oncologists. Multidisciplinary preoperative evaluation is preferable, as is
participation in clinical trials when possible.
For patients in whom protocol participation is not feasible and who have already undergone potentially curative
gastric resection, we suggest adjuvant chemoradiotherapy rather than surgery alone for patients with N1
disease (which would include T1N1 stage IB), and for patients with T3N0 (stage IIA) disease and above (table
1), based upon the results of US Intergroup trial INT0116 [4] (Grade 2B). For the subgroup of patients with
T2N0 disease, either observation or adjuvant treatment is acceptable, and the decision can be based upon
individualized patient (such as age, performance status, and motivation for treatment) and disease risk factor
(eg, histologic grade or the presence of lymphovascular or perineural invasion) considerations. (See 'Patient
selection' above.)
Although the optimal regimen has not been established, the treatment arm of INT-0116 could be considered a
standard protocol. (See 'Adjuvant chemoradiotherapy' above.):
One cycle of 5-FU (425 mg/m2 per day) and leucovorin calcium (20 mg/m2 per day) daily for five days.
This is followed one month later by 45 Gy (1.8 Gy/day) of RT given with FU (400 mg/m2 per day) and
leucovorin calcium (20 mg/m2 per day) on days 1 through 4 and the last three days of RT. As an
alternative, current randomized trials are using continuous infusion FU at a dose of 200 mg/m2/day
during RT, or capecitabine (825 mg/m2 twice daily during RT).
Two more five-day cycles of chemotherapy (FU 425 mg/m2 per day and leucovorin calcium 20 mg/m2
per day) are given at monthly intervals beginning one month after completion of radiation.
An acceptable fluoropyrimidine alternative for concurrent chemoradiotherapy is continuous infusion FU
(200 mg/m2 daily) or, as used in the ARTIST trial, daily oral capecitabine (850 mg/m2 twice daily). (See
'Chemotherapy versus chemoradiotherapy' above.)
For the chemotherapy alone component, other acceptable options include two months of weekly 5-FU
plus leucovorin (the Roswell Park regimen), short-term infusional 5-FU plus leucovorin (the de Gramont
regimen (table 4)), or ECF, as was used in CALGB 80101 (table 3). (See "Adjuvant therapy for resected
stage III (node-positive) colon cancer", section on 'Bolus 5-FU plus LV' and "Adjuvant therapy for
resected stage III (node-positive) colon cancer", section on 'Short-term infusional 5-FU/LV' and "Adjuvant
therapy for resected stage III (node-positive) colon cancer", section on 'Capecitabine' and "Treatment
protocols for esophagogastric cancer".)
An acceptable alternative approach for patients who are seen prior to resection is perioperative (combined
preoperative and postoperative) chemotherapy alone (ECF, (table 3)). (See "Treatment protocols for
esophagogastric cancer".)
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In terms of patient selection for this approach, it is reasonable to utilize the eligibility criteria for the MAGIC
trial (patients of any age with a performance status of 0 or 1 (table 5), a histologically proven adenocarcinoma
of the stomach that was considered to invade through the submucosa [stage T2 or higher, (table 1)], with no
evidence of distant metastases or locally advanced inoperable disease, as evaluated by CT, ultrasonography
or laparoscopy) [3]. (See 'MAGIC trial' above.)
Since this regimen has not been compared head-to-head with postoperative chemoradiotherapy, it is not
known whether this approach is superior to postoperative chemoradiotherapy. However, this approach may be
preferred over initial surgery for patients with a high likelihood of developing distant metastases (ie, those with
bulky T3/T4 tumors, visible perigastric nodes by preoperative imaging studies, a linitis plastica appearance, or
positive peritoneal cytology in the absence of visible peritoneal disease). (See 'Neoadjuvant/perioperative
chemotherapy' above.)
East Asian patients with resected node-positive disease or T3N0 (stage IIA) disease and above (table 1), may
take one year of postoperative S-1 chemotherapy as an alternative to combined preoperative plus
postoperative chemotherapy with ECF. (See 'Patient selection' above.)
It is difficult to know whether the benefit of adjuvant therapy with S-1, as demonstrated in the Japanese ACTSGC trial [31], can be extrapolated to other populations, given the markedly better outcomes seen in both the
treated and the surgery alone control groups, stage for stage, when compared to outcomes in other nonJapanese populations [58]. Until further information becomes available, we suggest that this approach be
limited to East Asian patients (Grade 2C). (See 'Japanese S-1 trial' above.)
Other alternative chemotherapy regimens for adjuvant therapy include capecitabine plus oxaliplatin, as was
used in the CLASSIC trial [32], or capecitabine plus cisplatin, as was used in the ARTIST trial [17]. However,
results from these trials are not as mature as they are for the MAGIC (perioperative chemotherapy) and
INT0116 (postoperative chemoradiotherapy) trials, and, as with S-1, it is unclear if the results can be
extrapolated to Western populations. (See 'CLASSIC trial' above and 'Chemotherapy versus
chemoradiotherapy' above.)
There is insufficient evidence from randomized trials to support the use of intraperitoneal chemotherapy, and
we recommend against its use unless in the context of a clinical trial (Grade 1B). (See 'Intraperitoneal
chemotherapy' above.)
The optimal approach to patients with locally advanced, unresectable but nonmetastatic disease is uncertain.
An initial attempt at downstaging with chemotherapy, chemoradiotherapy, or a combination followed by careful
restaging and surgical exploration in responders who have no evidence of metastatic disease is a reasonable
approach for a fit patient with a good performance status. Whenever possible, such patients should be
encouraged to enroll on clinical trials testing new approaches. (See 'Initially locally unresectable
nonmetastatic disease' above.)
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for inoperable advanced gastric cancer. Int J Radiat Oncol Biol Phys 2008; 71:173.
55. Ychou M, Pignon JP, Lasser P, et al. Phase III preliminary results of preoperative fluorouracil (F) and cisplatin
(P) versus surgery alone in adenocarcinoma of the stomach and lower esophagus (ASLE): FNLCC 94012FFCD 9703 trial (abstract). J Clin Oncol 2006; 24:185s.
56. Information on the Dutch CRITICS trial is available online at http://clinicaltrials.gov/ct2/show/NCT00407186
(Accessed on December 14, 2010).
57. Leong T, et al. TOPGEAR: an international randomized phase III trial of preoperative chemoradiotherapy
versus preoperative chemotherapy for resectable gastric cancer (AGITG/TROG/EORTC/NCIC CTG). J clin
Oncol 30, 2012 (suppl; abstr TPS4141). Abstract available online at
http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=114&abstractID=99024
(Accessed on June 14, 2012).
58. Macdonald JS. Gastric cancer: Nagoya is not New York. J Clin Oncol 2011; 29:4348.
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GRAPHICS
TNM staging for gastric cancer
Primary tumor (T)
TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria

T1

Tumor invades lamina propria, muscularis mucosae, or submucosa


T1a

Tumor invades lamina propria or muscularis mucosae

T1b

Tumor invades submucosa

T2

Tumor invades muscularis propria*

T3

Tumor penetrates subserosal connective tissue without invasion of visceral


peritoneum or adjacent structures

T4

Tumor invades serosa (visceral peritoneum) or adjacent structures


T4a

Tumor invades serosa (visceral peritoneum)

T4b

Tumor invades adjacent structures

Regional lymph nodes (N)


NX

Regional lymph node(s) cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in 1-2 regional lymph nodes

N2

Metastasis in 3-6 regional lymph nodes

N3

Metastasis in seven or more regional lymph nodes


N3a

Metastasis in 7-15 regional lymph nodes

N3b

Metastasis in 16 or more regional lymph nodes

Distant metastasis (M)


M0

No distant metastasis

M1

Distant metastasis

Anatomic stage/prognostic groups


Stage
0

Tis

N0

M0

Stage

T1

N0

M0

Stage
IB

T2

N0

M0

T1

N1

M0

Stage
IIA

T3

N0

M0

T2

N1

M0

T1

N2

M0

IA

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Stage
IIB

Stage
IIIA

Stage
IIIB

Stage
IIIC

Stage
IV

T4a

N0

M0

T3

N1

M0

T2

N2

M0

T1

N3

M0

T4a

N1

M0

T3

N2

M0

T2

N3

M0

T4b

N0

M0

T4b

N1

M0

T4a

N2

M0

T3

N3

M0

T4b

N2

M0

T4b

N3

M0

T4a

N3

M0

Any T

Any N

M1

Note: cTNM is the clinical classification, pTNM is the pathologic classification.


* A tumor may penetrate the muscularis propria with extension into the gastrocolic or
gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral
peritoneum covering these structures. In this case, the tumor is classified T3. If there is perforation
of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be
classified T4.
The adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm,
pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum.

Intramural extension to the duodenum or esophagus is classified by the depth of the greatest
invasion in any of these sites, including the stomach.
A designation of pN0 should be used if all examined lymph nodes are negative, regardless of the
total number removed and examined.
Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The
original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by
Springer New York, Inc.
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Anatomy of the stomach

The relationship of the stomach to surrounding structures is depicted in the figure.


The arterial supply to the stomach is derived primarily from the celiac axis. The
celiac axis arises from the proximal abdominal aorta and typically branches into the
common hepatic, splenic, and left gastric arteries. The common hepatic artery
usually gives rise to the gastroduodenal artery (in approximately 75 percent of
people), which, in turn, branches off into the right gastroepiploic artery and the
anterior and posterior superior pancreaticoduodenal arteries, which supply the
pancreas. The right gastroepiploic artery joins with the left gastroepiploic artery,
which emanates from the splenic artery in 90 percent of patients. The right gastric
artery branches from the hepatic artery and anastomoses with the left gastric
artery along the lesser curvature of the stomach. Because of its highly redundant
blood supply, stomach ischemia is rare.
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TNM staging of esophageal and esophagogastric junction (EGJ)


adenocarcinoma
Primary tumor (T)*
TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

High-grade dysplasia

T1

Tumor invades lamina propria, muscularis mucosae, or submucosa


T1a

Tumor invades lamina propria or muscularis mucosae

T1b

Tumor invades submucosa

T2

Tumor invades muscularis propria

T3

Tumor invades adventitia

T4

Tumor invades adjacent structures


T4a

Resectable tumor invading pleura, pericardium, or diaphragm

T4b

Unresectable tumor invading other adjacent structures, such as aorta, vertebral body,
trachea, etc.

Regional lymph nodes (N)


NX

Regional lymph node(s) cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in 1-2 regional lymph nodes

N2

Metastasis in 3-6 regional lymph nodes

N3

Metastasis in seven or more regional lymph nodes

Distant metastasis (M)


M0

No distant metastasis

M1

Distant metastasis

Histologic grade (G)


GX

Grade cannot be assessed - stage grouping as G1

G1

Well differentiated

G2

Moderately differentiated

G3

Poorly differentiated

G4

Undifferentiated - stage grouping as G3 squamous

Anatomic stage/prognostic groups


Adenocarcinoma carcinoma
Stage

Grade

Tis (HGD)

N0

M0

1, X

IA

T1

N0

M0

1-2, X

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IB

T1

N0

M0

T2

N0

M0

1-2, X

IIA

T2

N0

M0

IIB

T3

N0

M0

Any

T1-2

N1

M0

Any

T1-2

N2

M0

Any

T3

N1

M0

Any

T4a

N0

M0

Any

IIIB

T3

N2

M0

Any

IIIC

T4a

N1-2

M0

Any

T4b

Any

M0

Any

Any

N3

M0

Any

Any

Any

M1

Any

IIIA

IV

Note: cTNM is the clinical classification, pTNM is the pathologic classification.


* At least maximal dimension of the tumor must be recorded and multiple tumors require the T(m)
suffix.
High-grade dysplasia (HGD) includes all noninvasive neoplastic epithelia that was formerly called
carcinoma in situ, a diagnosis that is no longer used for columnar mucosae anywhere in the
gastrointestinal tract.
Number must be recorded for total number of regional nodes sampled and total number of
reported nodes with metastasis.
Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The
original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by
Springer New York, Inc.
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Epirubicin, cisplatin, and fluorouracil (ECF) for advanced


esophagogastric cancer [1,2]
Cycle length: 21 days.

Drug
Epirubicin

Dose and route


50 mg/m2 IV

Administration
Administer into a free
flowing IV solution
with normal saline

Given on days
Day 1

(NS)*, generally over


3 to 20 minutes.
Cisplatin

60 mg/m2 IV

Dilute with 250 mL


NS and administer

Day 1

over two hours. Do


not administer with
aluminum needles or
intravenous sets.
Fluorouracil (FU)

200 mg/m2 per day


IV

Infuse through a
central line as a
continuous infusion
via a portable
infusion device.

Daily for up to six


months

Pretreatment considerations:
Hydration: Give IV fluid to establish a urine flow of at least 100 mL/hour for at least two
hours prior to and two hours after cisplatin administration. Refer to UpToDate topic on
"Cisplatin nephrotoxicity", section on Prevention.
Emesis risk: Epirubicin plus cisplatin: HIGH; daily low-dose continuous infusion FU: LOW.
Refer to UpToDate topic on "Prevention and treatment of chemotherapy-induced nausea
and vomiting".
Prophylaxis for infusion reactions: There are no recommended premedications to
prevent infusion reactions with the ECF regimen. Refer to UpToDate topic on "Infusion
reactions to systemic chemotherapy".
Vesicant/irritant properties: Epirubicin is a vesicant; cisplatin is an irritant but can cause
significant tissue damage. Avoid extravasation of either agent. Refer to UpToDate topic on
"Extravasation injury from chemotherapy and other non-neoplastic vesicants".
Infection prophylaxis: Primary prophylaxis with granulocyte colony stimulating factors is
not warranted (incidence of grade 3 or 4 febrile neutropenia was 9 percent in one trial [3];
in a second trial, 14 percent developed either febrile neutropenia or infection [1]). Refer to
UpToDate topic on "Use of granulocyte colony stimulating factors in adult patients with
chemotherapy-induced neutropenia and conditions other than acute leukemia,
myelodysplastic syndrome, and hematopoietic cell transplantation".

Dose adjustment for baseline liver or renal dysfunction: The optimal approach to
cisplatin therapy in patients with preexisting renal impairment is unknown. In the original
ECF protocol, cisplatin was not given to patients with a GFR <40 mL/min, full-dose cisplatin
was administered to patients with a GFR 60 mL/min, and if the GFR was between 40 and
[2]

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60 mL/min, the dose of cisplatin (in mg) equaled the GFR value in mL/min [2]. Lower
starting doses of epirubicin may be needed in patients with preexisting renal or hepatic
impairment [4]. Lower starting doses of FU may be needed with severe liver impairment [5].
Refer to UpToDate topics on "Chemotherapy hepatotoxicity and dose modification in
patients with liver disease" and "Chemotherapy-related nephrotoxicity and dose
modification in patients with renal insufficiency".
Cardiac issues: Epirubicin is associated with dose-dependent cardiomyopathy, the
incidence of which is related to cumulative dose. Assess baseline LVEF prior to initiating
therapy. Epirubicin is contraindicated for patients with recent myocardial infarction, severe
myocardial dysfunction, severe arrhythmias, or prior treatment with maximum cumulative
doses of anthracyclines. In the original protocol, patients were excluded from receiving
epirubicin if their baseline LVEF was less than 50 percent [2].

Monitoring parameters:
CBC with differential and platelet count on day 1 prior to each treatment cycle.
Assess basic metabolic panel including creatinine and liver function tests once per cycle
on day 1 prior to each treatment cycle.
Monitor for neurotoxicity prior to each treatment cycle.
Monitor for hearing loss prior to each dose of cisplatin; audiometry as clinically indicated.
Monitor cumulative epirubicin dose. Reassess LVEF periodically during ECF therapy as
clinically indicated. Refer to UpToDate topic on "Cardiotoxicity of anthracycline-like
chemotherapy agents".

Suggested dose alterations for toxicity:


Myelotoxicity: Hold epirubicin until the platelets are 100,000 per mm3 and the
absolute neutrophil count is 1500 cells/mm3[4]. In the original ECF protocol, cisplatin and
epirubicin doses were delayed by one week or until myelosuppression was resolved if the
platelet count was <100,000/mm3 or the total WBC was <2000 cells/mm3 on day 1 [2].
The dose of epirubicin was reduced by 25 percent for a second episode of treatment delay
due to myelosuppression or for febrile neutropenia. There were no dose reductions for
infusional FU based on blood counts, but the FDA labeling recommends treatment
discontinuation for neutropenia (WBC <3500 cells/mm3 or rapidly declining) or platelet
count <100,000/mm3[5].
Renal dysfunction: Hold cisplatin until serum creatinine <1.5 mg/dL and/or blood urea
nitrogen <25 mg/dL [6]. In the original trial of ECF, full dose cisplatin was given each cycle if
the estimated GFR was >60 mL/min, and the drug was held if the estimated GFR was <40
mL/min [2]. For an estimated GFR of 40 to 60 mL/min, the dose of cisplatin (in mg) was
equivalent to the estimated GFR (in mL/min) [2].
Mucositis or diarrhea: In the original protocol, a treatment break from FU was
recommended for grade 2 or worse diarrhea. Treatment was withheld until symptoms
resolved, then restarted at 150 mg/m2 per day for grade 2 toxicity, and at 100 mg/m2 per
day for grade 3 or 4 toxicity [2]. NOTE: Severe diarrhea and mucositis after FU should
prompt evaluation for dihydropyrimidine dehydrogenase deficiency. Refer to UpToDate
topic on "Enterotoxicity of chemotherapeutic agents".
Neurotoxicity: Neuropathy usually is seen with cumulative doses of cisplatin >400
mg/m2, although there is marked interindividual variation. Patients with mild neuropathy
can continue to receive full cisplatin doses. If neuropathy interferes with function, the risk
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of potentially disabling neurotoxicity must be weighed against the benefit of continued


treatment. Refer to UpToDate topic on "Neurologic complications of platinum-based
chemotherapy".
Palmar-plantar erythrodysesthesias: In the original trial, FU was withheld for one week
for any grade of palmar-plantar erythrodysesthesia and then restarted at a dose of 150
mg/m2 per day [2]. Refer to UpToDate topic on "Cutaneous complications of conventional
chemotherapy agents".
Other toxicity: Hold epirubicin until all non-hematologic toxicity resolved to grade 1 [4].
Reduce epirubicin dose by 25 percent for any grade 3/4 non-hematologic toxicity in
previous cycles.
If there is a change in body weight of at least 10 percent, dose should be recalculated.

This table is provided as an example of how to administer this regimen; there may be
other acceptable methods. This regimen must be administered by a clinician trained in
the use of chemotherapy. The clinician is expected to use his or her independent
medical judgment in the context of individual circumstances to make adjustments, as
necessary.
IV: intraveneous; GFR: glomerular filtration rate; LVEF: left ventricular ejection fraction; CBC:
complete blood count; WBC: white blood cell count.

* Diluent solutions should not be modified without consulting a detailed reference due to potential
incompatibility(ies).
References:
1. Webb A, et al. J Clin Oncol 1997; 15:261.
2. Findlay M, et al. Ann Oncol 1994; 5:609.
3. Cunningham D, et al. N Engl J Med 2008; 358:36.
4. Ellence (epirubicin hydrochloride) injection. US FDA-approved manufacturer's package insert. US
National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on December 6,
2011).
5. Fluorouracil injection. FDA-approved manufacturer's package insert. US National Library of
Medicine. (Available online at dailymed.nlm.nih.gov, accessed on December 6, 2011).
6. Platinol (cisplatin) injection. FDA-approved manufacturer's package insert. US National Library of
Medicine. (Available online at dailymed.nlm.nih.gov, accessed on December 6, 2011).
Graphic 62502 Version 19.0

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Short-term infusional fluorouracil and leucovorin for gastrointestinal


cancer (modified de Gramont schedule) [1,2]*
Cycle length: 14 days.

Drug

Dose
and

Administration

route

Given
on
days

Leucovorin

400
mg/m2
IV

Diute with 250 mL 5 percent dextrose in water (D5W)


and administer over two hours.

Day 1

Fluorouracil
(FU)

400
mg/m2
IV
bolus

Slow IV push over five minutes (administer immediately


after leucovorin).

Day 1

Fluorouracil
(FU)

2400
mg/m2
IV

Dilute in 500 to 1000 mL D5W and administer over 46


hours (begin immediately after FU IV bolus). To
accommodate an ambulatory pump for outpatient
treatment, can be administered undiluted (50 mg/mL) or
the total dose can be diluted in 100 to 150 mL normal
saline.

Day 1

Pretreatment considerations:
Emesis risk: LOW. Refer to UpToDate topic on "Prevention and treatment of
chemotherapy-induced nausea and vomiting".
Infection prophylaxis: Primary prophylaxis with granulocyte colony stimulating factors is
not justified (estimated risk of febrile neutropenia <5 percent [1,2]). Refer to UpToDate
topic on "Use of granulocyte colony stimulating factors in adult patients with
chemotherapy-induced neutropenia and conditions other than acute leukemia,
myelodysplastic syndrome, and hematopoietic cell transplantation".
Dose adjustment for baseline liver or renal dysfunction: A lower starting dose of FU
may be needed in patients with impaired liver function. Refer to UpToDate topic on
"Chemotherapy hepatotoxicity and dose modification in patients with liver disease".

Monitoring parameters:
CBC with differential and platelet count prior to each treatment.
Assess electrolytes and liver and renal function prior to each treatment.

Suggested dose alterations for toxicity:


Myelotoxicity: Delay treatment by one week if the total white blood cell count is <3000
cells/mm3, absolute neutrophil count is <1500 cells/mm3, or platelets are less than
100,000/mm3. If treatment is delayed for two weeks or delayed for one week on two
separate occasions, eliminate the day 1 FU bolus. With the second occurrence, reduce
infusional FU by 20 percent.

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Diarrhea: Withhold treatment for grade 2 or worse diarrhea and restart at a lower dose
after complete resolution [3]. NOTE: Severe diarrhea, mucositis, and myelosuppression after
FU should prompt evaluation for dihydropyrimidine dehydrogenase deficiency. Refer to
UpToDate topic on "Enterotoxicity of chemotherapeutic agents".
If there is a change in body weight of at least 10 percent, doses should be recalculated.

This table is provided as an example of how to administer this regimen; there may be
other acceptable methods. This regimen must be administered by a clinician trained in
the use of chemotherapy. The clinician is expected to use his or her independent
medical judgment in the context of individual circumstances to make adjustments, as
necessary.
IV: intravenous; CBC: complete blood count.
* This is a modification of the original de Gramont regimen of short-term infusional FU plus
leucovorin [4] , which eliminates the day 2 bolus doses of FU and leucovorin.
Leucovorin dose is given for d,l-racemic mixture [5] . Use half the dose for LEVOleucovorin (lleucovorin).
Diluent solutions should not be modified without consulting a detailed reference due to potential
incompatibility(ies).
References:
1. Cheeseman SL, et al. Br J Cancer 2002; 87:393.
2. Hochster HS, et al. J Clin Oncol 2008; 26:3523.
3. Fluorouracil injection. FDA-approved manufacturer's package insert. US National Library of
Medicine. (Available online at dailymed.nlm.nih.gov, accessed on November 30, 2011).
4. de Gramont A, et al. J Clin Oncol 1997; 15:808.
5. Leucovorin calcium injection. FDA-approved manufacturer's package insert. US National Library of
Medicine. (Available online at dailymed.nlm.nih.gov, accessed on November 30, 2011).
Graphic 65525 Version 15.0

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Eastern Cooperative Oncology Group (ECOG, Zubrod, WHO)


performance scale
Performance
status

Definition

Fully active; no performance restrictions

Strenuous physical activity restricted; fully ambulatory and able to carry out
light work

Capable of all selfcare but unable to carry out any work activities. Up and
about >50 percent of waking hours.

Capable of only limited selfcare; confined to bed or chair >50 percent of


waking hours

Completely disabled; cannot carry out any selfcare; totally confined to bed
or chair

Excerpted from: Oken MM, et al. Am J Clin Oncol 1982; 5:649.


Graphic 72901 Version 4.0

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Randomized trials of surgery with and without adjuvant combination


chemotherapy in resected gastric cancer

Author, year

Country

Chemotherapy

Hazard ratio
for survival
(95% CI)

Non-anthracycline-containing polychemotherapy
Huguier M;
1980

France

53

5-FU, VBL, CTX

No significant
survival difference

Schlag P; 1982

Germany

98

5-FU, BCNU

0.66 (0.31-1.41)

Douglass H;
1982

USA

142

5-FU, MeCCNU

0.58 (0.35-0.95)*

Ochiai T; 1983

Japan

59

MMC, 5-FU, Ara-C

1.08 (0.5-2.31)

Higgins G; 1983

USA

134

5-FU, MeCCNU

0.94 (0.58-1.53)

Engstrom P;
1985

USA

180

5-FU, MeCCNU

0.94 (0.58-1.53)

Jakesz R; 1988

Austria

87

Ara-C, MMC, 5-FU

0.65 (0.38-1.13)

Bonfanti G;
1988

Italy

144

5-FU, MeCCNU

0.97 (0.61-1.55)

Allum W; 1989

UK

271

MMC, 5-FU

0.99 (0.73-1.36)

Allum W; 1989

UK

270

CTX, 5-FU, VCR,


MTX then MMC,
5-FU

1.01 (0.74-1.38)

Nakajima T;
1999

Japan

573

MMC, 5-FU, UFT

0.74 (0.5-1.09)

Cirera L; 1999

Spain

148

MMC, Ftorafur

0.60 (0.39-0.93)*

Nashimoto A;
2003

Japan

252

MMC, 5-FU, Ara-C

No significant
survival difference

Bang Y; 2012

Korea

1035

Capecitabine,

0.72 (0.52-1.00)*

oxaliplatin
Anthracycline-containing polychemotherapy
Coombes R;
1990

UK

281

5-FU, DOX, MMC

0.89 (0.66-1.21)

Krook J; 1991

USA

125

5-FU, DOX

0.97 (0.62-1.51)

Hallissey M;
1994

UK

283

5-FU, DOX, MMC

0.95 (0.74-1.22)

Macdonald J;
1995

USA

193

5-FU, DOX, MMC

0.91 (0.65-1.28)

Lise M; 1995

Italy

294

5-FU, DOX, MMC

0.86 (0.64-1.14)

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Tsavaris N;

Greece

84

5-FU, EPI, MMC

0.76 (0.31-1.87)

Neri B; 1996

Italy

103

5-FU, LV, EPI

0.46 (0.27-0.77)*

Di Costanzo F;

Italy

258

PELF

0.91 (0.64-1.26)

Bouche O; 2005

France

260

Infusional 5-FU,
CIS

0.74 (0.54-1.02)

Nitti D; 2006

EORTC

206

5-FU, DOX, MTX

0.89 (0.51-1.31)

Nitti D; 2006

ICCG

191

5-FU, EPI, MTX

1.05 (0.69-1.41)

De Vita F; 2007

GOIM

228

5-FU, LV, EPI,


ETOP

0.91 (0.69-1.21)

Kulig J; 2010

Poland

309

EAP

0.889 (0.6761.169)

Japan

1059

S-1

0.67 (0.54-0.83)*

1996

2008

S-1 monotherapy
Sasako M; 2011

MMC: mitomycin C; 5-FU: 5-fluorouracil; VBL: vinblastine; CTX: cyclophosphamide; Ara C:


cytarabine; VCR: vincristine; MTX: methotrexate; UFT: ftorafur and uracil; DOX: doxorubicin; EPI:
epirubicin; LV: leucovorin; CIS: cisplatin; PELF: cisplatin, epirubicin, leucovorin, 5-FU; ETOP:
etoposide; EORTC: European Organization for Research and Treatment of Cancer; ICCG:
International Collaborative Cancer Group; GOIM: Grupopa Oncologico dell'Italia Meridionale; EAP:
etoposide, doxorubicin, cisplatin.

* Statistically significant values for survival.


Induction chemotherapy with five days of CTX, 5-FU, VCR, and MTX, followed by MMC and 5-FU.

Both trials reported together, neither of which reached its accrual goal (760 for the EORTC and
480 for the ICCG trials).
Graphic 71898 Version 8.0

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Adjuvant and neoadjuvant treatment of gastric cancer

Disclosures
Disclosures: Craig Earle, MD, MSc, FRCPC Nothing to disclose. Harvey Mam on, MD, PhD Nothing to disclose. Richard M Goldberg,
MD Grant/Research/Clinical Trial Support: Bayer; Sanofi Aventis (metastatic colon cancer clinical trials). Speaker's Bureau: Fresenius
Kabi; Sanofi Aventis (colorectal, gastric cancer). Christopher G Willett, MD Nothing to disclose. Diane MF Savarese, MD Employee of
UpToDate, Inc.
Contributor disclosures are review ed for conflicts of interest by the editorial group. When found, these are addressed by vetting through
a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced
content is required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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