adjuvant and neoadjuvant treatment of gastric cancer

21/5/2014 Adjuvant and neoadjuvant treatment of gastric cancer

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Official reprint from UpToDate www.uptodate.com ©2014 UpToDate

AuthorsCraig Earle, MD, MSc, FRCPCHarvey Mamon, MD, PhD

Section EditorsRichard M Goldberg, MDChristopher G Willett, MD

Deputy EditorDiane MF Savarese, MD

Adjuvant and neoadjuvant treatment of gastric cancer

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/m

per day) and leucovorin calcium (20 mg/m 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/m and 20 mg/m , 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/m per day and leucovorin calcium 20

mg/m 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/m 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/m 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 3 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 5 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 5 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 7 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/m daily for five days plus cisplatin 100 mg/m 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 node-

positive 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/m twice daily in days 1 to 14) plus

oxaliplatin (130 mg/m 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]:

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].

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/m 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.)

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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/m per day and leucovorin calcium 25 mg/m 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).

●

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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:

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:

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.

●

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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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:

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 5 to 6 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

10 to 12 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.)

SUMMARY AND RECOMMENDATIONS

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].

●

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.●

th th

th th

Basics topic (see "Patient information: Stomach cancer (The Basics)")●

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/m per day) and leucovorin calcium (20 mg/m per day) daily for five days.• 2 2

This is followed one month later by 45 Gy (1.8 Gy/day) of RT given with FU (400 mg/m per day) and

leucovorin calcium (20 mg/m 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/m /day

during RT, or capecitabine (825 mg/m twice daily during RT).

• 2

2

2

2

Two more five-day cycles of chemotherapy (FU 425 mg/m per day and leucovorin calcium 20 mg/m

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/m daily) or, as used in the ARTIST trial, daily oral capecitabine (850 mg/m 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".)

• 2 2

2 2

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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●

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●

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44. Stahl M, Walz MK, Stuschke M, et al. Phase III comparison of preoperative chemotherapy compared withchemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J ClinOncol 2009; 27:851.

45. Ajani JA, Winter K, Okawara GS, et al. Phase II trial of preoperative chemoradiation in patients with localizedgastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. J ClinOncol 2006; 24:3953.

46. Ajani JA, Mansfield PF, Janjan N, et al. Multi-institutional trial of preoperative chemoradiotherapy in patientswith potentially resectable gastric carcinoma. J Clin Oncol 2004; 22:2774.

47. Ajani JA, Mansfield PF, Crane CH, et al. Paclitaxel-based chemoradiotherapy in localized gastric carcinoma:degree of pathologic response and not clinical parameters dictated patient outcome. J Clin Oncol 2005;23:1237.

48. Cascinu S, Scartozzi M, Labianca R, et al. High curative resection rate with weekly cisplatin, 5-fluorouracil,epidoxorubicin, 6S-leucovorin, glutathione, and filgastrim in patients with locally advanced, unresectablegastric cancer: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD). Br J Cancer2004; 90:1521.

49. Gallardo-Rincón D, Oñate-Ocaña LF, Calderillo-Ruiz G. Neoadjuvant chemotherapy with P-ELF (cisplatin,etoposide, leucovorin, 5-fluorouracil) followed by radical resection in patients with initially unresectable gastricadenocarcinoma: a phase II study. Ann Surg Oncol 2000; 7:45.

50. Nakajima T, Ota K, Ishihara S, et al. Combined intensive chemotherapy and radical surgery for incurablegastric cancer. Ann Surg Oncol 1997; 4:203.

51. Yoshikawa T, Sasako M, Yamamoto S, et al. Phase II study of neoadjuvant chemotherapy and extendedsurgery for locally advanced gastric cancer. Br J Surg 2009; 96:1015.

52. Lowy AM, Feig BW, Janjan N, et al. A pilot study of preoperative chemoradiotherapy for resectable gastriccancer. Ann Surg Oncol 2001; 8:519.

53. Ajani JA, Komaki R, Putnam JB, et al. A three-step strategy of induction chemotherapy then chemoradiationfollowed by surgery in patients with potentially resectable carcinoma of the esophagus or gastroesophagealjunction. Cancer 2001; 92:279.

54. Saikawa Y, Kubota T, Kumagai K, et al. Phase II study of chemoradiotherapy with S-1 and low-dose cisplatinfor 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 94012-FFCD 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 chemoradiotherapyversus preoperative chemotherapy for resectable gastric cancer (AGITG/TROG/EORTC/NCIC CTG). J clinOncol 30, 2012 (suppl; abstr TPS4141). Abstract available online athttp://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.

Topic 2523 Version 34.0
















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


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

IA

T1 N0 M0

Stage

IB

T2 N0 M0

T1 N1 M0

Stage

IIA

T3 N0 M0

T2 N1 M0

T1 N2 M0

•Δ

•Δ

◊



Stage

IIB

T4a N0 M0

T3 N1 M0

T2 N2 M0

T1 N3 M0

Stage

IIIA

T4a N1 M0

T3 N2 M0

T2 N3 M0

Stage

IIIB

T4b N0 M0

T4b N1 M0

T4a N2 M0

T3 N3 M0

Stage

IIIC

T4b N2 M0

T4b N3 M0

T4a N3 M0

Stage

IV

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.

Δ 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.

Graphic 57916 Version 9.0



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.




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)Δ

NX Regional lymph node(s) cannot be assessed

N0 No regional lymph node metastasis



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 T N M Grade

0 Tis (HGD) N0 M0 1, X

IA T1 N0 M0 1-2, X



IB T1 N0 M0 3

T2 N0 M0 1-2, X

IIA T2 N0 M0 3

IIB T3 N0 M0 Any

T1-2 N1 M0 Any

IIIA 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

IV Any Any M1 Any

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.

Δ 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.




Epirubicin, cisplatin, and fluorouracil (ECF) for advanced

esophagogastric cancer

Cycle length: 21 days.

Drug Dose and route Administration Given on days

Epirubicin 50 mg/m IV Administer into a free

flowing IV solution

with normal saline

(NS)*, generally over

3 to 20 minutes.

Day 1

Cisplatin 60 mg/m IV Dilute with 250 mL

NS and administer

over two hours. Do

not administer with

aluminum needles or

intravenous sets.

Day 1

Fluorouracil (FU) 200 mg/m 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 ;

in a second trial, 14 percent developed either febrile neutropenia or infection ). 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

[1,2]

2

2

2

[3]

[1]

[2]



60 mL/min, the dose of cisplatin (in mg) equaled the GFR value in mL/min . Lower

starting doses of epirubicin may be needed in patients with preexisting renal or hepatic

impairment . Lower starting doses of FU may be needed with severe liver impairment .

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 .

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 mm and the

absolute neutrophil count is ≥1500 cells/mm . 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/mm or the total WBC was <2000 cells/mm on day 1 .

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/mm or rapidly declining) or platelet

count <100,000/mm .

• Renal dysfunction: Hold cisplatin until serum creatinine <1.5 mg/dL and/or blood urea

nitrogen <25 mg/dL . 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 . 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) .

• 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/m per day for grade 2 toxicity, and at 100 mg/m per

day for grade 3 or 4 toxicity . 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/m , although there is marked interindividual variation. Patients with mild neuropathy

can continue to receive full cisplatin doses. If neuropathy interferes with function, the risk

[2]

[4] [5]

[2]

3

3[4]

3 3 [2]

3

3[5]

[6]

[2]

[2]

2 2

[2]

2



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/m per day . Refer to UpToDate topic on "Cutaneous complications of conventional

chemotherapy agents".

• Other toxicity: Hold epirubicin until all non-hematologic toxicity resolved to ≤ grade 1 .

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).


2 [2]

[4]



Short-term infusional fluorouracil and leucovorin for gastrointestinal

cancer (modified de Gramont schedule) *

Cycle length: 14 days.

Drug

Dose

and

route

Administration

Given

on

days

Leucovorin 400

mg/m

IV

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

and administer over two hours.

Day 1

Fluorouracil

(FU)

400

mg/m

IV

bolus

Slow IV push over five minutes (administer immediately

after leucovorin).

Day 1

Fluorouracil

(FU)

2400

mg/m

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 ). 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/mm , absolute neutrophil count is <1500 cells/mm , or platelets are less than

100,000/mm . 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.

[1,2]

Δ

2

◊

2

2

[1,2]

3 3

3



• Diarrhea: Withhold treatment for grade 2 or worse diarrhea and restart at a lower dose

after complete resolution . NOTE: Severe diarrhea, mucositis, and myelosuppression afterFU 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 , which eliminates the day 2 bolus doses of FU and leucovorin.

Δ Leucovorin dose is given for d,l-racemic mixture . Use half the dose for LEVOleucovorin (l-

leucovorin).

◊ 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).


[3]

[4]

[5]



Eastern Cooperative Oncology Group (ECOG, Zubrod, WHO)

performance scale

Performance

statusDefinition

0 Fully active; no performance restrictions

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

light work

2 Capable of all selfcare but unable to carry out any work activities. Up and

about >50 percent of waking hours.

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

waking hours

4 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.




Randomized trials of surgery with and without adjuvant combination

chemotherapy in resected gastric cancer

Author, year Country n 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,

oxaliplatin

0.72 (0.52-1.00)*

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)

•



Tsavaris N;

1996

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;

2008

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 (0.676-

1.169)

S-1 monotherapy

Sasako M; 2011 Japan 1059 S-1 0.67 (0.54-0.83)*

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.

Δ Both trials reported together, neither of which reached its accrual goal (760 for the EORTC and

480 for the ICCG trials).


Δ

Δ



Disclosures: Craig Earle, MD, MSc, FRCPC Nothing to disclose. Harvey Mamon, 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: FreseniusKabi; Sanofi Aventis (colorectal, gastric cancer). Christopher G Willett, MD Nothing to disclose. Diane MF Savarese, MD Employee ofUpToDate, Inc.

Contributor disclosures are review ed for conflicts of interest by the editorial group. When found, these are addressed by vetting througha multi-level review process, and through requirements for references to be provided to support the content. Appropriately referencedcontent is required of all authors and must conform to UpToDate standards of evidence.

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Disclosures

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