Gastric cancer is more prevalent in East Asia,
Eastern Europe and Central and South America than in other
countries. Worldwide, gastric cancer ranks second among all causes
of death from cancer, with about 7,000,000 confirmed deaths
annually (1). In Japan, it is one
of the most frequent causes of cancer mortality, despite notable
advances in diagnosis and treatment (2). Outcomes are extremely poor in patients
with unresectable gastric cancer, with the median survival ranging
from 3–5 months even with the best supportive care (3,4).
Numerous randomized controlled trials of various
treatment regimens have previously been reported, including
5-fluorouracil, doxorubicin and mitomycin (5), epirubicin and cisplatin (CDDP) in
combination with continuous infusion of 5-fluorouracil (6) and 5-fluorouracil and cisplatin
(7). However, the trials produced
median survival rates of less than 1 year. Recently, two randomized
controlled trials were reported from Japan (8,9). One
was the JCOG9912 trial, which showed S-1 to be non-inferior to
continuous infusion of 5-fluorouracil with respect to overall
survival (OS). The other was the SPIRITS trial, which noted that
S-1 plus CDDP has been identified as the standard chemotherapy
regimen for advanced or recurrent gastric cancer in Japan (8).
Docetaxel has shown promising activity in gastric
cancer, both as a monotherapy (10)
and in combination with other agents (11–13).
Phase I and II studies of combination therapy were performed with
docetaxel and S-1 for patients with advanced or recurrent gastric
cancer (14,15). In the phase II study, the overall
response rate was 56.3% (95% confidence interval [CI], 38–66%) and
the median survival time period was 14.3 months (95% CI, 10.27–20.3
On the basis of these results, a phase III study
(JACCRO GC-03 study) comparing S-1 alone with the combination
therapy (docetaxel and S-1) was launched. This is a prospective,
multicenter (Korea and Japan), multinational, randomized study of
patients with advanced gastric cancer. In total, 638 patients were
recruited, and the final results are anticipated in 2010. Previous
studies reported that the docetaxel and S-1 combination has good
clinical efficacy with acceptable toxicity when administered as the
first-line treatment for patients with advanced gastric cancer
Systemic chemotherapy is the key treatment for
patients with stage IV gastric cancer. In some cases, combination
chemotherapy (CDDP plus S-1 and docetaxel plus S-1) results in
long-term survival in clinical practice. In selected cases,
additional (adjuvant) surgery may result in further long-term
survival. Surgical resection was classified as curative (no
evidence of remaining disease after surgery) or palliative
(remaining disease after surgery). In this context, adjuvant
surgery aimed to be curative, as opposed to palliative, after the
response to chemotherapy. Following adjuvant surgery, chemotherapy
This study therefore aimed to evaluate the efficacy
of adjuvant surgery after response to the chemotherapy for advanced
Materials and methods
The study included 20 advanced gastric cancer
patients treated between September 2003 and December 2008 at
Hiroshima University Hospital. Patients were diagnosed with
unresectable advanced gastric cancer and had undergone
gastrectomies following the response to chemotherapy with docetaxel
S-1 (80 mg/m2) was administered orally
after morning and evening meals for 2 weeks, followed by a
drug-free interval of 1 week (one cycle). Docetaxel (40
mg/m2) was diluted in 100 ml of 0.9% saline and
administered as a 1-h infusion on the morning of day 1 of each
cycle (i.e., every 3 weeks). The docetaxel infusion was started
simultaneously with the S-1 administration. Dexamethasone (8 mg)
was infused 1 h before the docetaxel administration. Responses were
classified according to the Response Evaluation Criteria in Solid
Tumors (RECIST) guidelines (18)
and the guidelines of the Japanese Gastric Cancer Association
(19). To assess responses every
4–6 weeks, the tumor area was measured using a 5-mm slice computed
tomography scan for all measurable lesions. Toxicity was graded
according to the Common Terminology Criteria for Adverse Events
(CTCAE) version 3.0 (20).
Indications for adjuvant surgery
The indications for adjuvant surgery (after the
response to chemotherapy) are that curative resection (not
palliative) is anticipated based on the response to chemotherapy.
Thus, indications such as the absence of other distant metastases,
including peritoneal dissemination, extensive lymph node metastases
or lung metastasis and feasible macroscopically complete removal of
liver deposits are considered. Other indications include curative
resection which is anticipated despite a poor response to
chemotherapy (stable disease).
OS was calculated from the date of chemotherapy
initiation to the date patients succumbed to all causes or the
latest follow-up. The median OS was estimated using the
Kaplan-Meier method. Multivariate analysis of prognostic factors
was performed by the Cox proportional method to evaluate the
effects of prognostic factors on patient survival. P<0.05 was
considered to indicate a statistically significant difference.
A total of 20 advanced gastric cancer patients were
treated from September 2003 to December 2008 at Hiroshima
University Hospital. Table I shows
the patient characteristics. The median age was 58.8 years (range
25–73). All 20 patients showed a performance status of 0 or 1. The
median number of cycles administered per patient was 4.4 (range
2–11). Patients were assessable for response. No complete response
was noted, while 17 patients (85%) had partial responses (PR) and 3
(15%) had stable disease (SD). The patients had been diagnosed as
resectable following chemotherapy. However, in 9 patients,
peritoneal dissemination or tumor cells in peritoneal fluid on
cytological analysis were found during surgery, resulting in
palliative surgery. At a median follow-up of 980 days, OS was 855
days (Fig. 1).
Overall survival. At a median
follow-up of 980 days, OS was 855 days.
Patient characteristics of the
adjuvant surgery for advanced gastric cancer.
Comparison of OS in patients between the
curative resection and palliative groups
A 2- and 3-year survival was observed in 80 and
54.9% of patients, respectively, following macroscopic curative
surgery. In the palliative group, the median OS was 510 days, but a
3-year survival was not observed (Fig.
Comparison of OS in patients between
the curative resection and palliative groups. A 2- and 3-year
survival was observed in 80 and 54.9% of patients, respectively,
following macroscopic curative surgery. In the palliative group,
the median OS was 510 days, but a 3-year survival was not
Comparison of OS in patients between the
partial response and stable disease group
In the partial response group, the median OS was 865
days and a 3-year survival was observed in 37% of patients.
One-year survival was not observed in the stable disease group. OS
in the partial response group was statistically more prolonged than
the stable disease group (Fig.
Comparison of OS in patients between
the partial response and stable disease groups. In the partial
response group, the median OS was 865 days and a 3-year survival
was observed in 37% of patients. One-year survival was not observed
in the stable disease group.
Comparison of OS in patients amonng the
various unresectable factors (liver metastasis, H factor;
peritoneal dissemination, P factor; lymph node metastasis, N
A comparison was made of OS among the various
unresectable factors. The median OS in patients with the H factor
was 865 days, while that in patients with the P factor was 510 days
Comparison of OS among the various
unresectable factors (liver metastasis, H factor; peritoneal
dissemination, P factor; lymph node metastasis, N factor). The
median OS in patients with the H factor was 865 days, while that in
patients with the P factor was 510 days.
Various treatment regimens have been developed
have improved the survival of patients with advanced or recurrent
gastric cancer (21). The rationale
for the design of the combination therapy of docetaxel and S-1 was
the significant laboratory and clinical anti-tumor activity of both
docetaxel and 5-fluorouracil in gastric cancer, their synergistic
activity in vivo and the relative lack of overlapping
toxicities (22). Takahashi et
al reported increased anti-tumor activity in combination
therapy with docetaxel and S-1 using gastric cancer xenografts
(23). Wada et al reported
that docetaxel and S-1 combination therapy showed synergistic
effects by modulating the expression of the metabolic enzymes of
5-fluorouracil, including thymidylate synthase, dihydropyrimidine
dehydrogenase and orotate phosphoribosyl transferase in human
gastric cell lines (24). In a
phase II study of docetaxel and S-1 combination therapy, the median
time to tumor progression was 7.3 months (95% CI, 4.3–10.0 months)
Although progress in chemotherapy has resulted in
long-term survival, a number of patients require treatment changes
or a reduction in dose levels due to drug resistance or adverse
events. Such patients are required to change to another regimen
(second- or third-line).
When chemotherapy has produced transient tumor
regression and curative surgery may be accomplished, curative
resection in selected patients is occasionally associated with
prolonged survival. This type of surgery is referred to as adjuvant
surgery. The difference between adjuvant surgery and neoadjuvant
chemotherapy is their respective indications.
Neoadjuvant (preoperative) chemotherapy is an
investigational option. Its rationale is based on the difficulty of
performing an R0 resection in patients with locally advanced tumors
and the high risk of micrometastatic disease in these patients.
Neoadjuvant treatments aim to: i) downstage the primary tumor,
resulting in a higher R0 resection rate, and ii) simultaneously
treat micrometastases at an early stage (25–28).
Although the basic treatment in cases of advanced
gastric cancer is chemotherapy, it is insufficient. Additionally,
adjuvant surgery is preferred for patients with a favorable
response to chemotherapy.
The timing of such surgery may occur at the point
when the tumor is reduced, but prior to the appearance of drug
resistance. Empirically speaking, in gastric cancer, metastasis
occurs immediately after surgery, at the time of drug
This study aimed to evaluate the efficacy of
adjuvant surgery after response to the chemotherapy for advanced
gastric cancer. The OS of patients in the partial response and
curative resection groups was prolonged. The survival of patients
with H or N factor was also prolonged, if they received curative
surgery. However, the survival of patients with P factor was not
prolonged. Adjuvant surgery is effective in gastric cancer patients
diagnosed as stage IV in the case of liver or distant lymph node
metastasis, but not peritoneal dissemination.
To prove the efficacy of adjuvant surgery, a
randomized controlled study is necessary. Numerous obstacles remain
to be addressed regarding the selection of combination drugs (S-1
plus CDDP, S-1 plus docetaxel and docetaxel plus CDDP plus
5-fluorouracil), the timing of adjuvant surgery and the selection
of chemotherapy after surgery.
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