14 Adjuvant Therapy for Gastric Cancer

14
Adjuvant Therapy
for Gastric Cancer
DANIEL G. HALLER, MD
In 2001, Approximately 21,700 Americans will be
diagnosed with gastric cancer, and gastric cancer
will cause over 12,800 deaths.1 Worldwide, gastric
cancer is the third most common cancer, with
798,000 new cases in 1999.2 The prognosis for gastric cancer depends on the disease stage at diagnosis;
cure rates exceed 70 percent after surgery alone for
early-stage disease (T1 N0 or shallow-penetrating
T2 N0 M0 tumors). Postoperatively, patients with
locally advanced cancers (T3 N0 M0) have a 50 percent or greater chance of dying within 5 years, and
those with lymph node metastases fare much worse.
In the United States, 80 to 90 percent of patients fall
into these high-risk groups, and only 40 percent of
patients are eligible to undergo potentially curative
surgery. Even for those patients who undergo a complete resection, the rate of recurrence is very high.
Conversely, in other countries, such as Japan, the
presentation (and even the biology) of gastric cancer
may be different, so that it becomes difficult to compare the results of surgery or postoperative treatment
programs. As methods for potentially increasing the
rate of cure after surgery for gastric cancer, multidisciplinary approaches using postoperative adjuvant and preoperative neoadjuvant therapies are
receiving increasing attention, particularly in light
of evidence of benefit from such therapies in cases
of other common tumors of the gastrointestinal tract,
such as colon and rectal cancer. Many of these
approaches have been investigated for many years,
but no obvious survival benefit has been shown in
any large-scale well-controlled trial until recently.
278
ADJUVANT CHEMOTHERAPY
Postoperative chemotherapy alone for gastric cancer
has been extensively evaluated, with generally equivocal results. A number of prospective randomized trials have been performed by different groups, but few
studies have demonstrated any statistically significant benefit. It is difficult to perform a post hoc
analysis of why these trials failed, but it may be that
some of the same problems that were present in the
early trials of colon cancer could also be found in
these trials of postoperative treatment of gastric cancer. Many of these trials used relatively inactive
chemotherapy regimens or were underpowered to
detect small but clinically relevant survival benefits.
In the Gastrointestinal Tumor Study Group (GITSG)
study, 142 patients were randomized to receive adjuvant chemotherapy of semustine (methyl CCNU) and
5-fluorouracil (5-FU) or to be followed with no further treatment after curative-intent resection.3 At a
median follow-up of 4 years, a statistically significant survival advantage appeared in favor of the
chemotherapy arm. However, an identical study performed by the Eastern Cooperative Oncology Group
(ECOG) during the same time period and using the
same dose schedule of the identical drugs did not
show benefit.4 Mitomycin-C has been studied in a
series of trials in Europe and Japan. Although a small
Spanish trial (in which 33 patients received mitomycin after surgery and 37 had surgery alone)
showed a survival benefit for mitomycin treatment
(at 10 years of follow-up, 31 of the 37 patients in the
Adjuvant Therapy for Gastric Cancer
control arm and 16 of the 33 patients in the treatment
arm were dead because of relapse of disease,
[p < .01]),5 this has not been confirmed by larger
multicenter studies that have used mitomycin either
as a single agent or in combination.6,7
Several anthracycline-containing regimens used
as adjuvant treatment of gastric cancer have also
been reported. No significant difference in diseasefree survival or overall survival has been reported,
although there have been trends in favor of adjuvant
chemotherapy. The International Collaborative Cancer Group conducted a randomized study in 315 gastric cancer patients after curative resection.8 Patients
were randomized to receive either a combination of
5-FU, doxorubicin, and mitomycin (FAM) or no
treatment. The final analysis included 181 patients.
There was no difference noted in disease-free or
overall survival (p = .21) with a median follow-up of
68 months, although a retrospective subset analysis
suggested that the patients with more advanced disease (T3 or T4) may have benefited from treatment.
Indeed, few adjuvant trials for gastric cancer have
entered enough patients within discrete disease
stages to allow for more than a hypothesis-generating analysis of which patients within a trial may
have benefited or not. A different study of doxorubicin randomized 125 patients who had undergone
potential curative resection to treatment with 5-FU
plus doxorubicin or to observation alone. The two
groups showed almost identical 5-year survival rates
(32% in the treatment arm and 33% in the control
arm).9 In a small study combining epirubicin with 5FU/leucovorin as adjuvant treatment for patients with
node-positive gastric cancer,10 48 patients were randomized to the chemotherapy arm, and 55 patients
were randomized to the observation arm. The median
survival rate was 20.4 months for patients in the
chemotherapy arm but only 13.6 months for the
patients having only surgery (p = .01). However, this
study had a small sample size, and larger trials would
be required to confirm the benefit observed. An Italian Trials in Medical Oncology (ITMO) study suggested a small benefit from postoperative adjuvant
chemotherapy with etoposide, doxorubicin, and cisplatin followed by 5-FU and leucovorin in the subset
of gastric cancer patients with widespread node
involvement. For those patients with 7 or more
279
involved nodes, 5-year overall survival rates were 42
percent in the treatment arm and 22 percent in the
observation arm.11
Several meta-analyses of adjuvant chemotherapy
for gastric cancer have been undertaken. A metaanalysis of randomized trials (published since 1980)
of adjuvant 5-FU–based chemotherapy following
curative resection for localized gastric cancer did not
demonstrate a survival benefit, with an odds ratio of
0.88 (95% confidence interval [CI], 0.78 to 1.08).12
This meta-analysis has been criticized for lacking
sufficient power to detect a clinically relevant difference in survival.13 A second meta-analysis (including
13 randomized controlled trials of adjuvant chemotherapy versus observation following curative resection for gastric cancer in non-Asian patients) has also
been performed.14 These results suggest that adjuvant
chemotherapy may produce a small survival benefit
of borderline statistical significance in patients with
curatively resected gastric cancer (Figure 14–1). The
odds ratio for death in the treated group was 0.80
(95% CI, 0.66 to 0.97), corresponding to a relative
risk of 0.94 (95% CI, 0.89 to 1.00). A larger magnitude of the effect appeared when the analysis was
restricted to trials in which at least two-thirds of
patients had node-positive disease (odds ratio of 0.74
[95% CI, 0.59 to 0.95]). A small survival benefit of
adjuvant chemotherapy after curative resection for
gastric cancer has been demonstrated from a recently
published third meta-analysis, which included 20
randomized trials (3 trials of a single agent, 7 trials of
5-FU with an anthracycline, and 10 trials of 5-FU
combinations without an anthracycline).15 The study
collected information on 3,658 patients and 2,180
deaths, using death from any cause as the end point.
The result showed that chemotherapy reduced the
risk of death by 18 percent (a hazard ratio of 0.82
[95% CI, 0.75 to 0.89, p < .001]), which translates to
an absolute survival advantage of 2 to 4 percent,
depending on the stage of the disease. The use of
chemotherapy alone in a routine fashion cannot be
supported by the results of single trials or from these
meta-analyses. The meta-analyses do, however, suggest that chemotherapy could play a role in adjuvant
treatment. This seems quite reasonable, given the
activity of chemotherapy in gastric cancer and given
the benefits of adjuvant chemotherapy in other solid
280
CANCER OF THE UPPER GASTROINTESTINAL TRACT
Figure 14–1. Forrest plot of a meta-analysis of randomized trials comparing adjuvant chemotherapy with observation after curative resection of gastric cancer. (z = degree of freedom; 2P = two-sided p value; nPts = number of patients.) (Reproduced with
permission from Earle CC, Maroun JA. Adjuvant chemotherapy after curative resection for gastric cancer in non-Asian patients: revisiting a meta-analysis of randomized trials. Eur J Cancer 1999;35:1059–64.)
tumors. Appropriately designed and statistically
powered studies will be required to accomplish this.
ADJUVANT RADIATION THERAPY
Based on the high likelihood of local and regional
recurrence after surgery for gastric cancer, there
may be a role for adjuvant radiation. However, the
position of the stomach limits the radiation dose that
can be safely delivered, owing to the location of the
spinal cord, kidneys, small bowel, and liver. After
partial gastrectomy, the residual stomach is also a
radiation-sensitive organ; thus, adjuvant radiation
may result in significant ulceration and bleeding.
Acute side effects including nausea, fatigue, and
weight loss may occur when the upper abdomen is
irradiated, which may make postoperative treatment
difficult in a recovering patient.
Most reports of adjuvant radiation as a single
modality have been of intraoperative radiation used
alone or in combination with external beam radiation. A phase II study reported by the Radiation
Therapy Oncology Group combined intraoperative
radiation (12.5 to 16.5 Gy) and postoperative 45-Gy
external beam radiation.16 Twenty-seven patients
received intraoperative radiation, and 23 of those
also received external beam radiation. Eighty-three
percent of the patients had serosal involvement, and
70 percent had lymph node metastases. The actuarial 2-year survival was 47 percent, and there was
local recurrence of disease in 15 percent of patients.
Three small phase III trials using intraoperative radiation and/or external beam radiation postoperatively
have also been reported. A survival advantage of a
single dose of intraoperative radiation (20 to 25 Gy)
after resection for patients with stages II, III, and IV
disease (gross residual disease without metastases)
was reported by Japanese researchers.17 Unfortunately, these patients were randomized without
regard to stratification criteria. A small randomized
trial conducted by the National Cancer Institute
compared external beam radiation (45 Gy) alone to
intraoperative radiation plus external beam radiation
following gastrectomy.18 No survival difference was
demonstrated, but the group that received intraoperative radiation plus external beam radiation had a
lower local recurrence rate. A three-arm randomized
Adjuvant Therapy for Gastric Cancer
trial from Britain compared gastrectomy alone to
gastrectomy followed by 5-FU, doxorubicin, and
methotrexate or postoperative radiation (45 Gy in 25
fractions).20 There was no survival benefit for either
adjuvant chemotherapy or the radiation. The second
prospective randomized trial by the British Stomach
Cancer Group also failed to demonstrate a survival
benefit for postoperative adjuvant radiation; however, there was an apparent decrease in the rate of
locoregional failure, from 27 to 10 percent.20
ADJUVANT CHEMORADIATION THERAPY
In a series of early trials at the Mayo Clinic, there was
evidence of the superiority of 5-FU plus external
beam radiation over radiation alone in a small randomized controlled trial involving patients with
unresectable gastric cancer.21 Based on these encouraging results, clinical investigators have considered
the use of such therapy (which has been applied in
patients with pancreatic, esophageal, and rectal
tumors) in patients with resectable disease as well.
Several single-institution phase II studies have suggested an improved survival for patients given postoperative adjuvant chemoradiation (Table 14–1).22–25
A study done at the Massachusetts General Hospital
reported a 4-year survival rate of 43 percent for 14
patients with poorly differentiated disease (80% of
Table 14–1. PHASE II TRIALS OF ADJUVANT
CHEMORADIATION
No.
of
Patients
Median
Survival
(mo)
5-Year
Survival
(%)
110
NR
Surgery → 5-FU + XRT
14
24
38 (node –);
15 (node +)
43*
Gez et al (24)
Surgery → 5-FU + XRT
25
33
40
Regine et al (25)
Surgery alone
Surgery → chemo + XRT
70
20
12
19
13
21
Whittington et al (26)
Surgery alone
Surgery → XRT
Surgery → chemo + XRT
40
17
20
16
15
21
31
50
55
Study (Reference No.)
Gunderson et al (23)
Surgery alone
chemo = chemotherapy; NR = not recorded; 5-FU = 5-fluorouracil;
XRT = radiation therapy.
*4-year survival rate.
281
them with lymph node metastases) who received
adjuvant chemoradiation, a rate that was better than
that expected in patients who underwent surgery only
(38% survival for patients with negative lymph
nodes, 15% survival for patients with positive lymph
nodes).22 Similar results were reported from another
study with 25 patients who had locally advanced
gastric cancer and who received postresection
5-FU–based chemoradiation.23
A few phase III studies have been performed to
evaluate the benefit of adjuvant chemoradiation therapy for locally advanced gastric cancer.26,27 Dent and
colleagues conducted an early study comparing
surgery alone in 31 patients to adjuvant chemoradiation with 20 Gy of external beam radiation and 5-FU
in 35 patients.26 There was no significant difference
noted between the control and the treatment arms.
However, the Mayo Clinic conducted a prospective
randomized trial comparing gastrectomy alone with
gastrectomy followed by adjuvant external beam radiation (37.5 Gy in 24 fractions) plus 5-FU (15 mg/kg
bolus on days 1 through 3).27 The patients, including
those with scirrhous carcinomas, regional lymph
node metastases, or adjacent organ involvement, were
all considered to have poor prognoses. The 5-year survival rate in the adjuvant chemoradiation group was
23 percent, versus 4 percent in the surgery-only group
(p = .05). Fifty-five percent of those patients who
were treated by surgery alone had locoregional
relapse as the first clinical recurrence, compared to 39
percent of those who had with adjuvant chemoradiation. However, the results of this trial are confounded
by the fact that the study was done with a technique
known as prerandomization. Ultimately, 10 patients
who were randomized to adjuvant treatment refused
chemoradiation, and these patients did as well as
those patients who received adjuvant treatment.
In an attempt to clarify whether combinedmodality chemoradiotherapy following curativeintent resection may benefit patients with locally
advanced gastric cancer, a phase III intergroup study
(INT-0116) was conducted in the United States.28
For the first time, both disease-free survival (DFS)
and overall survival (OS) in high-risk resected
locally advanced adenocarcinoma of the stomach
and gastroesophageal (GE) junction were demonstrated by this well-designed prospective phase III
282
CANCER OF THE UPPER GASTROINTESTINAL TRACT
Figure 14–2. Radiation field for gastric cancer in an adjuvant setting. The areas enclosed by the proposed radiation fields encompass the majority of locoregional failure sites. (Reproduced with permission from Gunderson
LL, Sosin H. Adenocarcinoma of the stomach: areas of failure in a re-operation series [second or symptomatic
look] clinicopathologic correlation and implications for adjuvant therapy. Int J Radiol Biol Phys 1982;8:1–11.)
trial. In INT-0116, patients with complete resections
(ie, R0 resections), negative margins, and no evidence of residual disease were randomized to receive
surgery alone or surgery plus postoperative chemotherapy with 5-FU and leucovorin and concurrent
radiation therapy (Figure 14–2). The type of lymphadenectomy was not mandated by the study protocol although D2 resection was recommended. From
the analysis, it was observed that only 54 patients
(9.9%) underwent formal D2 dissections, 199
patients (36%) underwent D1 dissections (removal of
all N1 nodes), and the rest of the patients (54%)
underwent D0 dissections (ie, less than complete dissection of the N1 nodal stations). This has prompted
the criticism that more complete surgery should have
been performed and that the results of the study
would not be applicable if more D2 dissections had
been done. Randomization was performed between
20 and 40 days after surgery, with stratification based
on tumor stage (T1 to T2 vs T3 vs T4) and nodal sta-
tus (none vs 1 to 3 vs 4 or more positive). The treatment consisted of one cycle of 5-FU (425 mg/m2)
and leucovorin (20 mg/m2) in a 5-times-daily regimen (the Mayo Clinic regimen), followed by 45 Gy
(180 cGy/d) of radiation 28 days later, given with 5FU (400 mg/m2) and leucovorin (20 mg/m2) on days
1 through 4 and on the last 3 days of radiation. One
month after completion of radiation therapy, two
cycles of 5-FU (425 mg/m2) and leucovorin
(20 mg/m2) daily for 5 days were given at monthly
intervals. Doses of 5-FU were reduced in patients
experiencing grade 3 and grade 4 toxicity. Modified
schedules of 5-FU/leucovorin were given with radiation therapy. Based on the knowledge and experience
from previous studies in gastrointestinal tumors, specific attention was given to the designation and monitoring of radiation, to allow for optimal quality control. The therapy was designed in a “sandwich”
fashion to allow for the delayed start of radiation and
to allow for a prospective external review of radiation
Adjuvant Therapy for Gastric Cancer
283
Figure 14–3. Radiation port for treatment of gastric cancer. A, Anteroposterior view. B, lateral view. (Courtesy of Dr Richard Whittington, Professor of Medicine, Radiation Oncology, University of Pennsylvania.)
ports before treatment commenced. Radiotherapy
consisted of 45 Gy in 25 fractions, 5 days per week,
to the original tumor bed, regional nodes, and proximal and distal resection margins plus 2 cm. The
designed size and coverage area for radiation were
based on the results of early studies of the locoregional patterns of recurrence of gastric cancer (Figure 14–3).29 The original tumor bed was defined on
the basis of preoperative computed tomographic
imaging, barium studies, and surgical clips. The
Japanese Research Society for the Study of Gastric
Cancer (JRSGC) definition of the extent of the
regional lymph node involvement was used.30 Perigastric, celiac, local para-aortic, splenic, hepatoduodenal, portahepatic, and pancreaticoduodenal lymph
nodes were included in the radiation fields (Figure
14–4). Patients with GE-junction tumors had the
additional inclusion of paracardial and paraesophageal nodes in radiation fields, but pancreaticodudenal radiation was not required. Splenic nodes
were excluded in patients with antral lesions if doing
so was necessary to spare volumes of the left kidney.
Dose limiting of radiation to structures was defined
as follows: for the liver, < 60 percent of hepatic volume exposed to > 30 Gy; for the kidneys, the equiv-
alent of at least two-thirds of one kidney spared from
the radiotherapy field; for the heart, < 30 percent of
the cardiac silhouette exposed to > 40 Gy.
At the initial radiotherapy quality control review,
prior to treatment implementation, 35 percent of
treatment plans were found to contain major or
minor deviations due either to critical-organ toxicity
or to failure to treat protocol-defined target volumes. The overwhelming majority of these errors
were corrected prior to the initiation of radiotherapy.
The final radiotherapy quality assurance review (following the delivery of radiation) for those with complete documentation revealed 6.5 percent major
deviations. The importance of nutrition was emphasized in the study, and careful attention was paid to
the patient’s nutritional status. Most of the patients
had appropriate nutritional support before and during treatment. Between August 1991 and July 1998,
603 patients were accrued, and 556 patients were eligible for the study. The surgery-alone observation
arm included 275 patients; 281 patients were in the
combined-modality arm. For all eligible patients, the
median follow-up was 5 years. The median survival
was 36 months for patients in the adjuvant-chemoradiation arm versus 26 months for patients in the
284
CANCER OF THE UPPER GASTROINTESTINAL TRACT
surgery-only arm (a hazard ratio of 1.35) (p = .005;
95% CI, 1.09 to 1.66) (Figure 14–5). The 3-year OS
rates were 50 percent for the treatment group and 40
percent for the observation group. The 3-year DFS
rates were 48 percent for the treatment group and 31
percent for the observation group. The median DFS
rates were 30 months for treated patients and 19
months for surgery-only patients, with a hazard ratio
of 1.52 (p < .001; 95% CI, 1.23 to 1.86) (Figure
14–6). The toxicities of the chemoradiation
appeared acceptable, with hematologic and gastrointestinal toxicities being the predominant adverse
events. Grade 3 and grade 4 toxicity occurred in 41
percent and 32 percent of cases, respectively, and
three patients (1%) died due to toxicities.
This study was the first large well-controlled
study demonstrating a significant survival advan-
S
U
R
G
E
R
Y
*
Pathology staging
Stage IB to IV (M0)
with nagative margins
(stratification: tumor
stage nodal status)
*Surgery must have been done
with curative intent.
tage to adjuvant therapy for gastric cancer. Combined-modality treatment should therefore be considered the new standard of care in gastric cancer
when gastric resection has been performed with
curative intent. Although this therapy may be safely
delivered, it is important to emphasize that radiation
oncologists must be familiar with the proper techniques of delivering upper-abdominal radiation in
postgastrectomy patients, and care must be paid to
the maintenance of adequate nutrition during therapy. In this study, there was no compelling evidence
that more extensive surgery (ie, D2 dissection)
obviated the need for radiation and chemotherapy
postoperatively. However, some investigators have
questioned whether the more aggressive D2 dissection could eliminate the need for radiation therapy
in future trials.
R
A
N
D
O
M
I
Z
A
T
I
O
N
Arm I
(Observation)
Arm II
Treatment
Chemotherapy:
5-FU (425 mg/m2) and
LV (20 mg/m2) on
days 1–5
28 days
Radiation:
45 Gy in 25 fractions
Chemotherapy:
5-FU (400 mg/m2/d)
infusion on the first 4 days
and the last 3 days of radiation
28–35 days
Chemotherapy:
5-FU (425 mg/m2/d) and
LV (20 mg/m2) on
days 1–5
Repeat in 4 weeks
Figure 14–4. Schema of the INT-0116 study of adjuvant chemotherapy for gastric cancer. (5-FU = 5-fluorouracil; LV = leucovorin.)
Adjuvant Therapy for Gastric Cancer
285
Figure 14–5. Overall survival rates in the INT-0116 study, by treatment arm. (Obs = observation arm; RX = radiation arm; N = population size). (Data from Dr. John S. Macdonald.)
NEOADJUVANT CHEMORADIATION
AND CHEMOTHERAPY
It has been shown that neoadjuvant chemoradiation
therapy can down-stage gastric cancer and the
pathologic complete responses can be achieved, but
no obvious long-term survival benefit has yet been
proven in a randomized trial.31–33 Down-staging of
the tumor may benefit a subgroup of patients with
favorable tumor characteristics, but this has been difficult to prove clinically. Obvious down-staging benefits have been shown in several phase II studies. In
one study, three cycles of docetaxel (75 mg/m2 on
day 1) and cisplatin (75 mg/m2 on day 1) were given
as induction chemotherapy, with the support of prophylactic granulocyte colony–stimulating factor (G-
Figure 14–6. Relapse-free survival rates in the INT-0116 study, by treatment arm. (Obs =
observation arm; RX = radiation arm; N = population size.) (Data from Dr. John S. Macdonald.)
286
CANCER OF THE UPPER GASTROINTESTINAL TRACT
CSF).34 Radiation therapy (200 cGy/d, to a total of
50 Gy) with concurrent weekly docetaxel (20 mg/m2)
was given 3 to 4 weeks before surgery. Thirty-two
patients underwent surgical resection. Of these, 14
had pathologic complete responses and 10 had only
microscopic residual disease. In another study,
induction therapy of irinotecan (CPT-11) and cisplatin (75 mg/m2 and 25 mg/m2, respectively, four
times weekly every 6 weeks, delivered in two
courses) was given, followed by R0 gastric resection
in 10 patients.35 Out of 10 patients, 8 had objective
partial responses to the neoadjuvant therapy. With a
median follow-up of 6.8 months (5 to 12 months),
all 10 patients were free of the disease. In a third
study, continuous-infusion 5-FU (300 mg/m2) and
45 Gy of external beam radiation were given to
patients with gastric cancer, followed by a D2 gastrectomy with 10 Gy of intraoperative radiation.36 Of
34 patients who underwent resection, 5 had pathologic complete responses while 18 had partial
responses with evidence of down-staging. It is therefore clear that preoperative chemoradiation can
down-stage patients, but no data as to whether such
Table 14–2.
Trial
No. of
Patients
treatment affects the ultimate curability of such
patients are yet available.
To further explore the contribution of perioperative chemotherapy, a large randomized study of
neoadjuvant chemotherapy for esophageal cancer was
conducted by the United Kingdom Medical Research
Council (MRC) Upper GI Tract Cancer Group and
has shown encouraging results. These results may
also apply to patients with gastric cancer, since 67
percent of the patients had adenocarcinomas and 64
percent had lower-third esophageal tumors.37 Eight
hundred and two patients were randomized to two
cycles of neoadjuvant chemotherapy before surgery
(cisplatin, 80 mg/m2 for 4 hours; 5-FU, 1 g/m2 by continuous infusion for 4 days) or to surgery alone.
Resectability was significantly higher in the treatment
arm (78% vs 70% [p < .001]), as was the overall survival (p = .003). The European Organization for the
Research and Treatment of Cancer (EORTC) initiated
a phase III randomized multicenter study to compare
surgery alone to preoperative chemotherapy with cisplatin, leucovorin, and 5-FU followed by surgery in
patients with locally advanced gastric carcinoma
PHASE III NEOADJUVANT CHEMOTHERAPY TRIALS
Neoadjuvant
Treatment Arm
Control
Arm
Postsurgery
Treatment
Other Tests
EORTC 40954
360
Cisplatin IV over
1 h on days 1, 15, 29
Leucovorin IV over
2 h, followed by
5-FU IV over
24 h on days 1, 8, 15,
22, 29, 36
Repeat the treatment
in 2 wk
—
See “Other Tests”
QOL is assessed
before randomization,
every 3 mo for 1 yr,
and at 2 yr
FRE-FNCLCC9012
250
5-FU CI IV on
days 1–5
Cisplatin IV on
days 1, 2, for 2 cycles
3 cycles (for patients
with response and
without serious toxicity)
—
3–4 courses of same
chemotherapy to
patients who
responded to
neoadjuvant
chemotherapy
R2 resection with at
least 8 nodal groups
recommended
MRCST02
500
5-FU CI IV for 3 wk
Cisplatin IV over 4 h
(4 h after 5-FU
initiated) on day 1
Epirubicin IV on day 1
(ECF) for 3 cycles
—
3 additional ECF
cycles for patients in
neoadjuvant arm
QOL is assessed at
baseline, at completion
of study therapy, then
every 6 mo for 2 y
EORTC = European Organization for Research and Treatment of Cancer; FRE-FNCLCC = French-Federation Nationale des Centres de Lutte Contre le Cancer;
MRC = Medical Research Council; CI = continuous infusion; 5-FU = 5-fluorouracil; QOL = quality of life; IV = intravenous; ECF = epirubicin/cisplatin [CDDP]/5FU; wk = weeks.
Adjuvant Therapy for Gastric Cancer
(Table 14–2). A similar phase III study (surgery alone
vs neoadjuvant fluorouracil/cisplatin plus surgery for
the lower third of esophagus or cardia adenocarcinoma) is now being performed by the French-Federation Nationale des Centres de Lutte Contre le Cancer
(FRE-FNCLCC). The MRC is currently conducting a
phase III randomized study of perioperative chemotherapy with epirubicin/cisplatin/5-FU (ECF) versus
surgery alone for resectable gastric adenocarcinoma.
OTHER TREATMENTS
IN THE ADJUVANT SETTING
Intraperitoneal Chemotherapy
and Intraperitoneal Hyperthermic
Chemoperfusion
The rationale of intraperitoneal chemotherapy is that
locoregional failure occurs in 40 to 65 percent of
patients who relapse after curative gastric resections.29,38 Reports from autopsy and second-look
laparotomy have revealed that up to 50 percent of
patients have peritoneal carcinomatosis as a site of
failure. Significantly higher drug concentrations
within the peritoneal cavity can be achieved by
intraperitoneal delivery than by intravenous or oral
administration. Results of intraperitoneal chemotherapy in other cancers, such as ovarian cancer,
support its use in gastric cancer. Intraperitoneal
chemotherapy may be delivered intraoperatively or
after surgery; the most commonly used procedure
involves intraperitoneal treatment (with or without
hyperthermia) following surgery. Mitomycin-C, 5FU, floxuridine (FUDR), and cisplatin have all been
used, but no difference in overall survival is apparent among these agents.39,40
Most of the studies of intraperitoneal hyperthermic chemoperfusion (IHCP) have been conducted
by Japanese investigators. For those patients with
peritoneal disease or a high risk of developing carcinomatosis, IHCP has been administered during
exploratory laparotomy.41,42 The efficacy of prophylactic or therapeutic IHCP with mitomycin-C (with
or without cisplatin) administered immediately after
resection for gastric cancer has been evaluated in
several multiarm studies, mainly in Japan.43–45 Suggestions of survival benefit have been reported from
287
these relatively small trials.46 The feasibility of
IHCP is currently being evaluated at several centers
in the United States and Europe.
Immunochemotherapy
Immunochemotherapy has also been used as adjuvant treatment following the resection of gastric cancer; most trials of such treatment have been conducted in Japan and Korea. Japanese investigators
conducted studies of the administration of proteinbound polysaccharide (PSK) in the adjuvant setting,
either alone or combined with 5-FU and/or mitomycin-C after gastrectomy.47 One study randomized
postresection gastric cancer patients to weekly
chemotherapy with mitomycin and 5-FU or to PSK
plus the same chemotherapy. The 5-year DFS rate
was 70.7 percent in the PSK-plus-chemotherapy
group versus 59.4 percent in the standard-treatment
group (p = .047). The 5-year survival rates were 73
percent and 60 percent, respectively (p = .044).48
Korean investigators reported a trial that compared
FAM to intradermally administered OK-432 (a
Streptococcus progenes preparation) plus the standard FAM regimen in patients with gastric carcinoma
who underwent curative resection.49 Fifty patients
received chemotherapy only, and 49 patients had
chemotherapy with OK-432 as an immunostimulant.
A significant improvement in survival with chemotherapy plus immunotherapy over chemotherapy
alone was reported (respective 5-year survival rates
of 62 percent and 52 percent [p = .04]). The prognostic advantage of preoperative intratumoral injection of OK-432 for patients with gastric cancer has
also been suggested by a Japanese study.50 These data
suggest that it is possible that immunotherapy or
immunochemotherapy may benefit the outcome for
those gastric cancer patients who have had potentially curative gastrectomy. However, these trials
were small and were without sufficient statistical
power to convincingly demonstrate a clinical benefit.
CONCLUSION
The use of adjuvant treatment in gastric cancer is
dictated by the high rate of recurrence in optimally
resected patients. The risk of recurrence is even
288
CANCER OF THE UPPER GASTROINTESTINAL TRACT
higher in patients with serosal extension, positive
lymph nodes, or positive surgical margins. The
result of the large and well-controlled intergroup
INT-0116 study demonstrated a survival advantage
for chemoradiation therapy with acceptable toxicity;
in the United States, this therapy is the standard
adjuvant treatment today for gastric cancer, following curative intent-resection. From the conduct of
the study, it must be stressed that radiation oncologists must be well trained in the proper techniques of
delivering upper-abdominal radiation in postgastrectomy patients, and attention must also be paid to the
maintenance of adequate nutrition during therapy.
Whether such treatment is appropriate in other countries, where surgical treatments and tumor biology
may be different, is open to question. Of particular
interest is the question of whether a large properly
controlled program of adjuvant chemotherapy would
be as effective as the chemoradiation administered
in the INT-0116 study, particularly when a D2 dissection is performed. Neoadjuvant chemotherapy or
chemoradiation is under active study to ascertain
whether an increase in the number of patients undergoing potentially curative operations will translate
into a survival benefit. More information from large
well-controlled studies is necessary to evaluate
intraperitoneal chemotherapy (including IHCP),
immunochemotherapy, and other biologic treatments. More studies are also needed to assess molecular prognostic risk factors for gastric cancer (eg,
loss of heterozygosity of chromosome 5q, p53, ras,
E-cadherin, microsatellite instability, HER-2/neu,
epidermal growth factor receptor [EGFR], and
cyclooxgenase-2 [COX-2]) and to assess target-oriented treatments for these molecular alterations.
ACKNOWLEDGMENT
The author would like to thank Dr. Richard Whittington, Dr. John S. Macdonald, Dr. Leonard Gunderson, and Dr. Craig Earle for their support.
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