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Adjuvant Therapy in Gastric Cancer: Can We Prevent Recurrences?

Adjuvant Therapy in Gastric Cancer: Can We Prevent Recurrences?

ABSTRACT: Despite a dramatic decline in the incidence of gastric carcinoma in the United States during the past century, treatment remains a challenging problem for oncologists. Surgery continues to be the primary modality for managing early-stage gastric cancer, but up to 80% of patients who undergo a "curative" resection develop locoregional or distant recurrence. Given these sobering statistics, there has been great interest in developing strategies to prevent recurrences after surgery and improve overall mortality. In this article, we review data on adjuvant treatment modalities for this disease, including radiotherapy, chemotherapy, combination chemotherapy and radiation, intraperitoneal treatment, and immunotherapy. We focus attention on the recent widespread acceptance of adjuvant chemoradiotherapy, based on the results of Intergroup trial 0116. Future strategies incorporating different modalities of treatment will be outlined.

In 2003, an estimated 22,400 individuals
in the United States will
be diagnosed with gastric cancer,
and 12,100 will die from the disease.[
1] The worldwide incidence is
approximately 550,000 cases per
year, with 405,000 deaths.[2] Despite
attempts at curative resection, survival
for this disease remains poor
(Table 1).[3] As a result, investigators
have been evaluating adjuvant
therapy to prevent recurrences and
improve on overall mortality.

Studies of the benefits of adjuvant
therapy for gastric adenocarcinoma
have yielded conflicting results. The
more favorable results reported in
Asian countries compared to Western
countries may relate to ethnicity
factors,[4] although differences in
tumor location, prevalence of earlystage
disease, and extent of preoperative
staging evaluation may also
account for some of these results.[5]
Such discrepancies make it difficult
to translate the results of studies in
one of these populations to the other.

Treatment OptionsAdjuvant and Neoadjuvant

Gastric cancer has generally been
considered a relatively radioresistant
carcinoma, with limited benefits in
symptom palliation for advanced disease.[
6] However, the high incidence
of locoregional recurrence after surgery
for early disease has sparked
interest in radiation as adjuvant or
neoadjuvant therapy. Among patients
who undergo a curative resection,
38% to 67% will develop a clinically
evident locoregional recurrence, with
nodal stage and number of positive
lymph nodes predictive of risk.[7]
Investigators have hypothesized that
radiotherapy may sterilize the local
bed and prevent the growth of presumed
residual microscopic disease
after surgery.

Few trials have studied the impact
of radiation alone as adjuvant therapy.
The British Stomach Cancer
Group randomized 436 patients who
had undergone curative resection to
no further therapy, adjuvant radiotherapy,
or adjuvant chemotherapy.
The 5-year overall survival for the
153 patients randomized to adjuvant
radiotherapy was 12%, compared to
20% for those assigned to surgery
alone (P > .2).[8]

In China, researchers randomized
370 patients with locally advanced
gastric cancer of the cardia to either
immediate surgery or preoperative
radiation (40 Gy) followed by surgery.[
9] Patients who received neoadjuvant
radiation had a significantly
improved 5-year overall survival
(30% vs 20%, P = .009) and a lower
local recurrence rate (39% vs 52%,
P < .025) compared to those who
were treated with surgery alone. Although
these results are intriguing,
the authors did not provide information
on preoperative staging, and the
study was limited to patients with
cardiac and gastroesophageal junction

Recently, Skoropad et al reported
on a trial of preoperative radiotherapy
with 20 years of follow-up.[10]
Of 152 patients who underwent exploratory
laporatomy for staging, 102
were randomized to a short course of
preoperative therapy (20 Gy over 5
days) followed by surgery, or surgery
alone. The authors did not find
any significant differences in survival
between the two treatment groups
(P = .56). Moreover, subset analyses
by tumor location or stage of disease
did not demonstrate any significant
survival differences between treatment
arms. Further studies with radiation
alone are unlikely, given the
renewed interest in the combination
of chemotherapy and radiotherapy in
the adjuvant setting.

Intraoperative Radiotherapy
Intraoperative radiotherapy (IORT)
may be an attractive option for
achieving local control in gastric cancer
due to its ability to deliver a single,
large fraction of radiation with
minimal damage to normal tissue.[9]
Although most studies of IORT have
been nonrandomized and conducted
by single institutions, several experiences
are notable.

In Japan, a retrospective case-control
comparison in 242 patients demonstrated
that those with stage II-IV
disease who received IORT achieved
a 10% to 20% improvement in 5-year
survival.[11] In contrast, Sindelar and
colleagues at the National Cancer Institute
(NCI) randomized 41 gastric
cancer patients to either externalbeam
radiation or IORT after surgery.[
12] Although locoregional
failure was less common among patients
in the IORT arm (44% vs 92%,
P < .001), overall survival did not
differ between treatment arms. A randomized
trial in Germany compared
surgery alone to surgery with IORT
and also found no statistical differences
in overall survival or cancerrelated

Systemic Therapy
Approaches to adjuvant chemotherapy
for gastric cancer have been
based largely on the results of regimens
evaluated in the setting of metastatic
disease. Unfortunately, the use
of chemotherapy in patients with advanced
gastric cancer has produced
disappointing results. Complete
responses are rare, and partial responses
to single-agent therapies have
been limited, with results ranging
from 0% to 30%.[14] Fluorouracil
(5-FU) remains the most widely used
agent, with response rates to singleagent
therapy in previously untreated
patients ranging from 21% to
30%.[15,16] Other agents with activity
as single-agent therapy include
cisplatin, doxorubicin, epirubicin
(Ellence), docetaxel (Taxotere), paclitaxel,
and irinotecan (CPT-11,

Combination chemotherapy regimens
for metastatic gastric cancer
have been tested extensively. Initial
trials have often demonstrated striking
results, with the majority of patients
achieving a response. However,
confirmatory trials in larger populations
of patients have resulted in more
sobering findings.[17] Many combination
regimens have not been
shown to improve overall survival
compared to single-agent therapy
when tested in prospective, randomized

Recently, the combination of epirubicin,
cisplatin, and 5-FU (ECF) produced
improved response and overall
survival rates with lower toxicity,
compared to a prior standard of care,
FAMTX (5-FU, doxorubicin [Adriamycin],
methotrexate).[22] However,
the median overall survival among
patients treated with ECF was still only
8.7 months, with a 2-year survival rate
of 14%. Other promising combination
regimens include irinotecan or a taxane
and a platinum agent,[14] but randomized,
multicenter trials must be
conducted to discern the true efficacy
of these newer drugs in gastric adenocarcinomas.

Adjuvant Chemotherapy
The administration of chemotherapy
shortly after complete resection
of gastric tumors in patients at high
risk of recurrence has been assessed
as a means of treating clinically undetectable
micrometastases. A number
of studies have investigated
whether adjuvant chemotherapy can
reduce the incidence of the disease
recurrence and mortality following
a curative resection. To date, four meta-analyses have been published
that examined the impact of postoperative
adjuvant chemotherapy on
survival after surgical resection
(Table 2).[23-26]

Hermans et al analyzed 11 randomized
trials, with a total of over
2,000 patients, that compared postoperative
chemotherapy to surgery
alone.[24] Most of these trials used
older 5-FU-based regimens, including
FAM (5-FU/doxorubicin/mitomycin
[Mutamycin]), 5-FU/mitomycin,
and 5-FU/semustine (methyl-CCNU).
The investigators were not able to
demonstrate a significant survival
advantage for adjuvant chemotherapy
beyond that achieved with surgery
alone. However, the analysis was
later criticized for a lack of sufficient
statistical power and the studies chosen
for inclusion.

Earle and Maroun compiled a
similar meta-analysis, limited to non-
Asian studies and with stricter inclusion
criteria.[23] The authors
reported an odds ratio for death in
the treated group of 0.80 (95% confidence
interval [CI] = 0.66-0.97), corresponding
to a relative risk of 0.94
(95% CI = 0.89-1.00). They calculated
that in a group of patients similar
to those included in the analyzed
trials, 65% would have a recurrence
and die of gastric cancer following
treatment with surgery alone, compared
to 61% following treatment
with surgery and adjuvant chemotherapy.
This absolute risk reduction
of 4% indicates that 25 patients would
need to receive adjuvant therapy to
prevent one death (ie, the "number
needed to treat" = 25).

An Italian group led by Mari performed
a meta-analysis of 20 trials
published between 1982 and 1999.[25]
Using time-to-event data with censoring,
they found a favorable hazard ratio
of 0.82 (95% CI = 0.75-0.89) for
postoperative adjuvant chemotherapy
over surgery alone. In a subgroup analysis,
they did not detect any statistical
differences between trials, with or
without the use of anthracycline-based
therapy. Most recently, Panzini and
colleagues reported a meta-analysis
similar to that of Mari et al, although
trials that did not require complete resection
of disease were excluded.[26]
Of the 17 trials included, 14 overlapped
with those in the analysis
by Mari et al. The odds ratio for
death for patients receiving adjuvant
therapy in this analysis was 0.72
(95% CI = 0.62-0.94).

Despite the modestly positive results
of more recent meta-analyses,
enthusiasm for adjuvant systemic chemotherapy
remains limited. These
analyses are tempered by the usual restraints,
including publication bias,
differences in patient populations and
entry criteria of the trials, and a nonrandomized
design. Indeed, no individual,
prospective randomized trial
has provided convincing evidence in
favor of adjuvant chemotherapy. In
addition, the authors of each of these
four meta-analyses argue that larger,
randomized trials are warranted and
that adjuvant chemotherapy after curative
resection for gastric cancer
should be considered investigational.

Neoadjuvant Chemotherapy
The use of neoadjuvant chemotherapy
to downstage locally advanced
disease and improve the resectability
of the primary tumor in gastric cancer
patients has attracted the attention
of researchers. Phase I/II studies have
demonstrated the feasibility of preoperative
chemotherapy, with downstaging
achieved in up to 50% of
patients and complete pathologic
responses in up to 10%.[27-30] In addition,
operative morbidity and mortality
were not increased with the use
of preoperative therapy. However,
prospective randomized trials have
not demonstrated a benefit for neoadjuvant

The Dutch Gastric Cancer Group
randomized 56 patients to preoperative
FAMTX or immediate surgery.[
31] In this small trial, 44% of
patients did not complete the planned
four cycles of FAMTX due to pro-

gressive disease, and a nonsignificant
improvement in resection rates was
seen in the surgery-only arm. Moreover,
patients randomized to preoperative
FAMTX did not experience
any survival benefit compared to those
receiving surgery alone. Preliminary
reports of neoadjuvant chemotherapy
trials conducted in Asia have also
failed to demonstrate improved survival
rates for preoperative therapy.[
32,33] Several large, randomized
trials are currently being conducted
in Europe to evaluate the role of neoadjuvant
chemotherapy in the treatment
of gastric cancer (Table 3).[14]

Adjuvant Chemoradiotherapy
Gastric adenocarcinoma has a tendency
to recur both locoregionally
and distantly following curative resection
(Table 4).[34-37] As a result,
many investigators have explored the
combination of chemotherapy and
radiotherapy to prevent tumor recurrence.
Several phase II trials have
demonstrated favorable long-term
survival with the use of chemoradiotherapy
after curative resection, with
5-year survival rates ranging from
21% to 55%.[38]

Previous randomized trials comparing
surgery alone to chemoradiotherapy
after surgery, however, were
fraught with design flaws and did not

convincingly support adjuvant treatment.[
39,40] Dent et al randomized
142 patients with all stages of gastric
cancer, including T4 and M1 disease,
to surgery alone or postoperative
therapy including 2,000 cGy of
radiotherapy delivered in eight fractions
and chemotherapy with either
5-FU or thiotepa.[39] No differences
in survival rates (P > .5) or quality of
life emerged between the control and
treatment arms. Of note, the radiation
and chemotherapy doses in this
trial would now be considered suboptimal.

Subsequently, Moertel and colleagues
randomized 62 patients with
resectable gastric cancer to surgery
alone or postoperative radiotherapy
with 3,750 cGy plus 5-FU.[40] Due
to a later-realized design flaw, informed
consent was obtained after
randomization and ~25% of patients
in the postoperative therapy arm re-

fused treatment. Intent-to-treat analysis
demonstrated an improvement
in 5-year survival in the adjuvant
therapy arm (23% vs 4%, P < .05).
However, when the treatment group
was subdivided according to those
who actually received treatment and
those who refused it, 5-year survival
rates between these subgroups and
the control group were not statistically
different. Of note, treatment
did reduce locoregional recurrences
(39% for treated patients compared
to 54% for those who received no
treatment). The authors concluded,
"this study does not establish 5-FU
plus radiation as effective surgical
adjuvant therapy for gastric cancer
but suggests this approach as a
possible fruitful area for continued

  • INT 0116
    -Ultimately, between
    1991 and 1998, a large, US intergroup
    adjuvant chemotherapy and
    radiation therapy trial (INT 0116)
    was initiated by the Southwest Oncology
    Group (SWOG).[37] Investigators
    randomized 556 patients with
    resected stage IB-IV, M0 gastric and
    gastroesophageal adenocarcinoma to
    either no further therapy or postoperative
    chemoradiotherapy to investigate
    the potential benefit of
    adjuvant chemoradiotherapy. Patients
    were stratified by tumor stage
    and nodal status. Those randomized
    to chemoradiotherapy received one
    course of 5-FU at 425 mg/m2/d and
    leucovorin at 20 mg/m2/d on days 1
    through 5, followed by 45 Gy of
    radiation (to the original tumor bed,
    regional lymph nodes, proximal and
    distal resection margins plus 2 cm)
    concurrently with bolus 5-FU at 400
    mg/m2 and leucovorin at 20 mg/m2
    on each of the first 4 and last 3 days
    of radiotherapy. Two additional cycles
    of 5-FU and leucovorin were
    administered 1 month after radiation

    A single radiation protocol coordinator
    reviewed all radiotherapy
    treatment plans. Of note, more than
    one-third of the initial plans were
    revised upon review. Patients treated
    with postoperative chemoradiation
    achieved a significant improvement
    in both disease-free and overall survival
    at 3 years (Table 5). These
    results translated into a 52% improvement
    in relapse-free survival and a
    35% improvement in overall survival
    for patients in the intervention arm,
    after adjustment for extent of invasion
    through the stomach wall and
    nodal status.

  • INT 0116 Limitations
    these encouraging findings, the study
    has generated several criticisms.[41]
    First, many patients underwent a suboptimal
    examination for lymph node
    metastases; more than one-half (54%)
    had a D0 dissection (fewer than seven
    lymph nodes identified in the surgical
    specimen), whereas only 10%
    had a D2 dissection (extended lymphadenectomy).
    However, there is no
    definitive evidence that a D2 dissection
    offers any survival advantage
    over a less radical resection.[42] Furthermore,
    rates of D0, D1, and D2
    dissections in the intergroup trial are
    comparable to those in general practice,
    suggesting that the findings can
    be generalized to the population atlarge.[

    In addition, INT 0116 included
    patients with a wide variety of pathologic
    stages. This criticism questions
    the benefit of and need for adjuvant
    therapy in patients with the less-represented
    extreme stages of disease,
    particularly T1 and N0. Much of the
    benefit of chemoradiation in this trial
    appears to relate to improved local
    control rather than prevention of distant
    disease, and although patients
    treated with postoperative chemoradiotherapy
    experienced fewer
    locoregional recurrences, distant recurrences
    were equivalent between
    the two arms. Finally, postoperative
    adjuvant chemoradiotherapy after
    gastrectomy can be difficult to administer
    in full; in INT 0116, only
    65% of patients in the treatment arm
    completed all prescribed therapy.

  • Subsequent Research
    -Based on
    the results of INT 0116, curativeintent
    surgery followed by adjuvant
    chemoradiotherapy has become the
    standard of care for gastric cancer in
    North America. However, because the
    benefits associated with postoperative
    chemoradiotherapy were principally
    limited to improvements in
    locoregional control, investigators
    have examined the use of systemic
    regimens that are potentially more
    active than 5-FU/leucovorin.

    Fuchs and colleagues conducted a
    multicenter, pilot study of ECF plus
    continuous-infusion 5-FU administered
    during external-beam irradiation
    (Figure 1).[43] Among 21
    patients receiving therapy, the toxicity
    profile was tolerable and comparable
    to that of INT 0116. At a median
    follow-up of 8.1 months (range:
    1-27 months), only 14% of patients
    experienced a documented relapse.
    Because this pilot study demonstrated
    that postoperative ECF and continuous-
    infusion 5-FU with radiation
    was well tolerated, an NCI-sponsored
    trial was initiated that will randomize
    825 patients to this regimen or
    the INT 0116 regimen after a curative
    resection of gastric or gastroesophageal
    adenocarcinoma (Figure 2).

    In a similar effort, the Radiation
    Therapy Oncology Group (RTOG) is
    conducting a randomized, phase II
    trial of two cisplatin- and paclitaxelcontaining
    regimens for adjuvant
    treatment of gastric or gastroesophageal
    cancer. Patients with stage IB-
    IIIB cancer will be randomly assigned
    to one of two groups. Patients in
    group 1 will receive a 5-day continuous
    infusion of 5-FU and a 1-hour
    infusion of cisplatin once a day for
    5 days in weeks 1 and 5. They will
    also receive a 24-hour continuous infusion
    of paclitaxel during weeks 1
    and 5. At least 3 weeks later, patients
    will undergo radiation therapy 5 days
    per week and will receive a 5-day
    continuous infusion of 5-FU and a
    3-hour infusion of paclitaxel once per
    week for 5 weeks.

    Patients in group 2 will receive a
    3-hour infusion of paclitaxel and a
    1-hour infusion of cisplatin in weeks
    1 and 5. Between 3 and 6 weeks
    later, they will undergo radiation therapy
    plus a 96-hour continuous infusion
    of paclitaxel and a 1-hour
    infusion of cisplatin once per week
    for 5 weeks. The planned accrual of
    this trial is 94 patients. The results of
    this trial will help investigators determine
    which chemoradiation regimen
    is sufficiently efficacious and
    tolerable to warrant a phase III comparison
    with the INT 0116 regimen.


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