日本胆囊癌研究进展

Recent Trends of Gallbladder Cancer in Japan
An Analysis of 4770Patients
Masato Kayahara,MD,PhD Takukazu Nagakawa,MD,PhD
Department of Gastroenterological Surgery,Divi-sion of Cancer Medicine,Graduate School of Medical Science,Kanazawa University,Kanazawa,Japan.
BACKGROUND.Gallbladder cancer is the most common cancer of the biliary tract
and has a particularly high incidence in Chile,Japan,and northern India.Many Japanese surgeons have reported that aggressive surgery improves the outcome of patients with gallbladder cancer.Differences in survival rates between Japan and other countries have been noted.The objective of this study was to deter-mine whether there were any changes over time in the incidence,therapeutic approach,stage at diagnosis,or prognosis of gallbladder cancer in an unselected,community-based series of patients in Japan.
METHODS.In total,4774patients with gallbladder cancer were analyzed between
1988and 1997based on data from the Biliary Tract Cancer Registration Commit-tee of the Japanese Society of Biliary Surgery.
RESULTS.Survival was related closely to surgical stage,with 5-year survival rates
of 77%for patients with stage I disease,60%for patients with stage II disease,29%for patients with stage III disease,12%for patients with stage IVA disease,and 3%for patients with stage IVB disease.Patient age also affected survival.The survival rate for patients aged \49years was significantly better compared with the survival rate for patients in the other groups (P <.05).The 5-year survival rate for patients aged <49years was 38%.The survival rate for patients aged >79years was significantly worse compared with the survival rate for patients in the other 4groups (P <.01).The 5-year survival rate for patients aged >79years was 21%.Stratifying patients by stage according to the Japanese Society of Biliary Surgery classification showed that women maintained a survival advantage over men among patients with stage I and II disease.Adjuvant chemotherapy did not pro-vide a survival benefit.There were no apparent changes in patient demographics between the period from 1988to 1992and the period from 1993to 1997.
CONCLUSIONS.For this study,the authors evaluated the gallbladder cancer trends
in Japan.The Classification of Biliary Tract Carcinoma proposed by the Japanese Society of Biliary Surgery reflected the prognosis of patients with gallbladder cancer.
Patient outcomes were affected by patient age and sex.No substantial differences in patient survival were apparent over the 10-year study period.The data did not support any advantage for aggressive surgical resection and adjuvant chemo-therapy.Further analysis of operative procedures will be necessary to determine conclusively whether there is any survival advantage from aggressive surgery in patients with advanced gallbladder cancer.Cancer 2007;110:572À80.Ó2007American Cancer Society.
KEYWORDS:gallbladder cancer,Japanese Society of Biliary Surgery,statistic registry,surgical stage.
I
n Japan,the number of cancer deaths in 1997was 275,143,and the death rate per 100,000was 220.4.1Gallbladder cancer (GBC)was responsible for 1.25%and 3.49%of the cancer deaths among men and women,respectively,in Japan.It has been reported that
Address for reprints:Masato Kayahara,MD,PhD,Department of Gastroenterological Surgery,Divi-sion of Cancer Medicine,Graduate School of Medical Science,Kanazawa University,13-1Takaramachi,Kanazawa,920-8641,Japan;Fax:(011)81-76-234-4260;E-mail:masatok@surg2.m.kanazawa-u.ac.jp
Supported in part by Grants-in Aid for Cancer Research Ministry of Health Labor and Welfare of Japan.
We thank the 158institutes and hospitals that participated in this study and those that supplied other necessary information.
Received December 19,2006;revision received March 28,2007;accepted April 6,2007.
ª2007American Cancer Society
DOI 10.1002/cncr.22815
Published online 26June 2007in Wiley InterScience ().
572
women have a2to6times greater incidence of GBC compared with men.2GBC has a striking geographic and ethnic variation,with pockets of high prevalence scattered throughout the world.2Bolivia and Chile have the highest incidence rates in the world com-pared with other countries.3Low incident rates have been reported in New Zealand,the United Kingdom, and Spain.4Japan is one of the countries with the highest incidence rates of GBC in the world.
The symptoms and signs of GBC are not specific and often appear late in the clinical course of the dis-ease.For this reason,the diagnosis generally is made when the cancer already is at an advanced stage.GBC in Japan is relatively rare among the gastrointestinal tract cancers but often is a fatal disease characterized by a poor prognosis and the lack of any effective ther-apy.The Japanese Society of Biliary Surgery(JSBS) established the General Rules for Surgical and Patho-logical Studies on Cancer of the Biliary Tract in1981 as a means of assessing data on the basis of common criteria.Since1988,the Biliary Tract Cancer Registra-tion Committee(BTCRC)of the JSBS has been con-ducting a nationwide survey of patients with biliary tract cancer to evaluate its epidemiologic and clinical characteristics,histopathologic features,diagnosis, treatment modalities,and outcome.The most recently available data from the cancer registry for GBC are reviewed in this article.It is our hope that this information will be useful for evaluating future studies that use population-based data sets or large, hospital-based samples.The objective of this study was to determine whether there were any changes over time in the incidence,therapeutic approach, stage at diagnosis,and prognosis of GBC in an un-selected community-based series of patients in Japan. MATERIAL AND METHODS
The BTCRC of the JSBS registered a total4774patients with GBC from158major hospitals between1988and 1997.A questionnaire covered approximately150 items,including age,clinical characteristics,gross anatomic and histologic features of the tumors,diag-nosis,treatment modalities,outcome,etc.These patients were included in the analysis of the basic pat-terns of care and trends overtime presented in this report.Cancer extension was classified according to the2001version of the Classification of Biliary Tract Carcinoma proposed by the JSBS.5The macroscopic (surgical)classification of primary tumor extension (T)was divided into4degrees according to the pre-sence or absence and extent of serosal invasion(S), hepatic and bile duct invasion(Hinf and Binf,respec-tively),and portal vein and hepatic artery invasion (PV and A,respectively).The surgical stage was classi-fied into1of5stages in accordance with the T cate-gory,lymph node involvement(N),liver metastasis (H),and peritoneal dissemination(P).
The tumor categories were classified as follows:
T1:S0,Hinf0,Binf0,PV0,A0
T2:S1,Hinf1,Binf1,PV0,A0
T3:S2,Hinf2,3,Binf2,PV1,A1
T4:S3,any Hinf,Binf3,PV2,3,A2,3.
The grade of serosal invasion was classified as fol-lows:
S0:No invasion of serosa
S1:Doubtful invasion of serosa
S2:Definite invasion of serosa
S3:Invasion of other organs or structures.
The grade of hepatic invasion was classified as fol-lows:
Hinf0:No direct invasion of the liver
Hinf1:Doubtful direct invasion of the liver
Hinf2:Definite direct invasion of the liver and invasion around the gallbladder bed
Hinf3:Mass formation because of direct invasion of the liver.
The grade of hepatoduodenal ligament(bile duct) invasion was classified as follows:
Binf0:No invasion of the hepatoduodenal ligament Binf1:Doubtful invasion of the hepatoduodenal ligament
Binf2:Definite invasion of the hepatoduodenal liga-ment
Binf3:Severeinvasionofthehepatoduodenalligament.
The grade of portal vein invasion was classified as follows:
PV0:No invasion of any of the portal veins
PV1:Doubtful invasion of the portal veins
PV2:Definite invasion of the portal veins
PV3:Severe invasion of the portal veins(narrowing or constriction).
The grade of hepatic artery invasion was classified as follows:
A0:No invasion of any of the hepatic arteries
A1:Doubtful invasion of the hepatic arteries Gallbladder Cancer in Japan/Kayahara and Nagakawa573
A2:Definite invasion of the hepatic arteries
A3:Severe invasion of the hepatic arteries(nar-rowing or constriction).
Lymph node involvement was classified into1of5 groups:
N0:No evidence of lymph node metastasis
N1:Lymph node involvement in a primary lymph node group close to the tumor
N2:Lymph node involvement in a secondary lymph node group
N3:Lymph node involvement in a tertiary lymph node group
N4:Lymph node involvement in the fourth lymph node group.
The surgical stages are listed in Table1.When possible,pathologic staging was used and was sup-plemented by clinical staging when the pathologic stage was not known.Kaplan-Meier survival calcula-tions and the corresponding log-rank tests were per-formed to determine differences in survival rates. The starting point for calculating survival was the date of surgery in the patients who underwent sur-gery.Observed survival was computed by using the actuarial method,compounding survival in1-month intervals from the date of diagnosis for patients who did not undergo surgery.The standard statistical soft-ware package SPSS(version 6.1;SPSS,Japan)was used to analyze the data.
Treatment procedures were classified into4 categories:surgical resection(including palliative cholecystectomy),biliary diversion,explorative lap-
arotomy,gastrointestinal bypass,and no surgery. Of3324patients who underwent surgical resection, 1231patients(37%)received postoperative chemo-therapy,which consisted mainly of oral antican-cer drugs.Radiotherapy was administered to only 5%of patients who underwent surgical resection. Therefore,the effects of radiotherapy were not evaluated.
RESULTS
Patient Demographics
There were no substantial changes between1988and 1997in patient sex or age in this study.The mean patient age was66years(range,16À98years).On average,68%of patients were between ages of60 years and79years.The ratio of men to women was 1:1.74.There was a slight increase in the proportion of men reported with GBC(from34.5%during 1988À1992to38.5%during1993À1997).Surgical Stage and Type of Surgery
The treatments implemented for patients with GBC over the10years of this study are listed in Table2. According to the treatment method,in total,there were3324registered patients who underwent resec-tion:One hundred forty-seven patients underwent palliative biliary diversion,304patients underwent ex-ploratory laparotomy,245patients underwent gastro-intestinal bypass,and750patients did not undergo surgery.Nearly70%of all patients who were included in the study underwent resection as their sole treat-ment.Almost all patients who did not have stage IVB or unknown disease underwent surgical resec-tion,including palliative primary tumor resection. However,only74%of patients underwent macro-scopic curative resection,including the patients who had stage IVA disease.Thirty-six percent of patients who had stage IVA disease underwent conservative resection.Only66%of patients who underwent surgical resection obtained negative surgical margins TABLE1
Staging System of Gallbladder Cancer of the Japanese Society
of Biliary Surgery
Stage I T1N0M0 Stage II T1N1M0
T2N0,N1M0 Stage III T1,T2N2M0
T3N0,N1,N2M0 Stage IVA T4N0,N1,N2M0
Any T N3M0 Stage IVB Any T N4M0
Any T Any N M1
T indicates primary tumor extension;N,lymph node involvement;M0,no distant metastasis;M1, distant metastasis(including hepatic metastasis and peritoneal dissemination).
TABLE2
Number of Patients by Selected Characteristics for Gallbladder Cancer Diagnosed From1988to1997
Characteristic
Surgical stage
I II III IVA IVB Unknown
Age,y
\501101*********
50À591796972122198151
60À69355112202249425341
70À79337125207208330352 [7911323321560145 Treatment
All resected patients1094344538635490223 Biliary diversion014111823 Exploratory laparotomy001028518 Gastrointestinal bypass000021827
No surgery00000750
574CANCER August1,2007/Volume110/Number3
in the resected specimens.Therefore,a detailed microscopic evaluation of the samples was not per-formed.
Younger patients,which we defined as those aged \50years,were diagnosed more frequently with stage I disease those older patients (aged [50years)(Table 2).Older patients,which we defined as patients aged [79years,were diagnosed frequently with stage I disease;however,because of the small numbers of these patients,there was no significant difference between the 2groups.In addition,the sur-gical stage distribution for men and women were similar in each study period (data not shown).
Differences in the treatment patterns by patient age were noted.Approximately 70%of patients aged \50years underwent surgical resection.Only 10%of the study patients who did not undergo surgery were aged \50years.Patients aged [79years underwent surgical resection less frequently than patients in the other 4groups (P <.05).Twenty-eight percent of all patients aged >79years did not undergo any surgical treatment (Fig.1).
Registration Period and Surgical Staging
There was a marked improvement between 1988and 1997in the documentation of surgical stage.More patients with stage IV disease (stages IVA and IVB)were reported in the earlier period (1988À1992)than in the later period (1993À1997;50.1%vs 43.6%,respectively)among the patients with a recorded disease stage.Stage I disease was reported more frequently in the study period from 1993to 1997
(26.9%)than in the study period from 1988to 1992(31.8%).Conversely,stage IVB disease was reported less frequently in the study period from 1988to 1992than in the study period from 1993to 1997.The pro-portion of patients with stage II,III,and IVA disease remained largely unchanged between the 2study periods (Table 3).
Survival According to Stage
Figure 2demonstrates the 5-year survival curves by surgical stage (stage)for patients who underwent surgical resection.The length of survival after resec-tion was correlated significantly with stage.The cu-mulative survival rates for patients with GBC were 77%for stage I disease,60%for stage II disease,
29%
FIGURE 1.Treatment for gallbladder cancer according to age.In total,1774patients with gallbladder cancer who were registered between 1988and 1997
in a Japanese data base were evaluated.The patients were separated into 5age categories (ages \50years,50À59years,60À69years,70À79years,and [79years),and their types of surgery were recorded.
TABLE 3
Patient Distribution According to Japanese Society of Biliary Surgery Stage of Disease Diagnosis
JSBS stage 1988À1992
1993À1997
No.of patients %*%y No.of patients %*%y Stage I 49921.226.959524.631.8Stage II 163 6.98.81827.59.7Stage III 26211.114.128111.615Stage IVA 3291417.730712.716.4Stage IVB 60225.632.450921.027.2Unknown 49321.054822.6Total
2348
100
100
2422
100
100
JSBS indicates Japanese Society of Biliary Surgery.*The percentage of all reported patients.y
The percentage of only patients with known disease stage.
Gallbladder Cancer in Japan/Kayahara and Nagakawa 575
for stage III disease,12%for stage IVA disease,and 3%for stage IVB disease.There were only 12patients with stage IVA disease patients who lived for [5years.There were significant differences in survival between the groups (P <.01).
Survival by Stage According to Age,Treatment,Sex,and Period
The 5-year survival rates for the 4770patients who were diagnosed with GBC between 1988and 1997,based on JSBS disease staging at the time of diagno-sis,are shown in Table 4.Overall,for patients ages 50years to 79years,the survival rate varied between 30%and 27%.The survival rate for patients aged \49years was significantly better than that for patients in the other 4groups (P <.05).The 5-year survival rate for patients aged <49years was 38%;and the 5-year survival rates were 30%,27%,27%,
and 21%for patients ages 50to 59years,ages 60to 69years,ages 70to 79years,and aged !79years,respectively.The survival rate for patients aged >79years was significantly worse compared with that for patients in the other 4groups (P <.01).When all stages of disease were analyzed together,patient sur-vival for those who underwent surgical resection was superior to that for those who did not (Table 4).Thus,the results indicated that surgical resection is the only treatment capable of prolonging survival.
In patients with stage I disease,there was no sig-nificant difference in survival between those aged 49years and those ages 50to 59years.However,the prognosis for patients aged \49years was signifi-cantly better compared with the prognosis for patients ages 60to 69years (5-year survival rate:87%vs 78%;P <.01).In addition,patients aged >79years had a significantly worse prognosis compared with the prognosis for patients in the other 4groups (P <.01).Patients aged >79years who had stage II disease also had a significantly worse prognosis com-pared with the prognosis for patients in the other 4groups (P <.01),but there was no significant differ-ence in survival between the other 4groups.Patients aged >79years who had stage III disease had a sig-nificantly worse prognosis compared with the prog-nosis for patients ages 60to 69years (P <.01).No patient aged >79years lived for >5years (Table 4).
Table 5shows the correlations between 5-year survival,clinical stage,and sex in the patients who underwent surgical resection.The total number of patients who could be evaluated for precise outcome was 3053of 3324patients who underwent surgical resection.To determine whether there were differ-ences between the sexes in the survival rate from GBC,we analyzed the available sex-specific survival
TABLE 4
Five-year Survival Rates by Selected Characteristics for 4770Patients With Gallbladder Cancer Diagnosed From 1988to 1997
Characteristic JSBS surgical stage
Total
I
II
III
IVA
IVB
Unknown
Age,y \5087633629303850À5983603014343060À6978673310142770À79755826121527[7957321600521Treatment
All resected patients 77
60
29
12
31540Biliary diversion
102Exploratory laparotomy 000Gastrointestinal bypass 1
12No surgery
1
1
JSBS indicates Japanese Society of Biliary Surgery.
TABLE 5
Five-year Survival by Japanese Society of Biliary Surgery Stage of Disease and Sex in Patients Who Underwent Surgical Resection
JSBS stage
5-Year survival
P Men
Women
No.of patients %No.of patients %Stage I 3697162779.8.0005Stage II 11456.920161.3.01Stage III 16127.834229.7NS Stage IVA 2129.137414.2NS Stage IVB 3752660 1.4NS Unknown 355 3.3582 4.4NS Total
1587
36.8
2787
41.1
.004
JSBS indicates Japanese Society of Biliary Surgery;NS,not significant.
FIGURE 2.Survival curves according to Japanese Society of Biliary Sur-gery (JSBS)stage.These curves illustrate the survival of Japanese patients who underwent surgery for gallbladder cancer between 1988and 1997.
576CANCER August 1,2007/Volume 110/Number 3
rates for both women and men.Without stratifying according to JSBS stage,the 5-year cumulative sur-vival rate for women was significantly better com-pared with that for men (P <.01).Stratifying by JSBS disease stage indicated that women maintained a survival advantage over men for stage I and II dis-ease (Figs.3,4)but fared no better than men when they were diagnosed with stage III,IVA,or IVB dis-ease (Table 5).The curative resection rate for both men and women with stage I disease was 92%.The curative resection rates for men and women with stage II disease were 87%and 88%,respectively;and the overall curative resection rates for men and women were 65.5%and 66.5%,respectively.
Table 6shows the correlations between chemo-therapy,sex,and 5-year survival in the group of patients who underwent surgical resection.There was no significant difference in the frequency of chemotherapy between men and women,and there
was no significant difference in survival with regard to the type of chemotherapy regiment among patients with same clinical disease stage.Without stratifying by JSBS stage,the 5-year cumulative sur-vival rate for patients who did not receive chemo-therapy was significantly better than that for patients who did receive chemotherapy (P <.05).The 5-and 10-year survival rates for patients who received chemotherapy in the group that underwent surgical resection were 33%and 28%,respectively;and the 5-and 10-year survival rates for patients who did not receive chemotherapy in the group that underwent surgical resection were 45%and 37%,respectively (Fig.5).The benefit of adjuvant chemotherapy was obtained only in patients who had stage IVA disease (Table 6,Fig.
6).
FIGURE 3.Sex and cumulative survival of patients with stage I gallbladder
cancer.The patients with stage I gallbladder cancer in the Japanese data base were divided according to sex,and their cumulative survival curves were
calculated.
FIGURE 4.Sex and cumulative survival of patients with stage II gallblad-der cancer.The patients with stage II gallbladder cancer in the Japanese data base were divided according to sex,and their cumulative survival curves were calculated.
TABLE 6
Chemotherapy,Sex,and 5-Year Survival by Japanese Society of Biliary Surgery Stage of Disease in Patients Who Underwent Surgical Resection
JSBS stage Chemotherapy rate,%
P 5-Year survival rate,%P Men Women Chemo(1)Chemo(2)Stage I 2325NS 7478NS Stage II 4345NS 5565.12Stage III 4148NS 3029NS Stage IVA 4240NS 1412\.05Stage IVB 4353NS 23NS Unknown 4929\.051417NS Total
36
38
NS
33
45
\.01
JSBS indicates Japanese Society of Biliary Surgery;Chemo(1),received chemotherapy;Chemo(2),did not receive chemotherapy;NS,not
significant.
FIGURE 5.Survival curves according to the receipt of chemotherapy
among patients with gallbladder cancer who underwent surgical resection.The survival curve for patients who received chemotherapy (1)was signifi-cantly worse compared with that for patients who did not receive chemo-therapy (2).
Gallbladder Cancer in Japan/Kayahara and Nagakawa 577
Treatment Period and Survival
The 5-and 10-year survival rates for patients who underwent surgical resection in the earlier period were 38.2%and 31.6%,respectively;and the 5-and 10-year survival rates for patients who underwent surgical resection in the later period were 41.0%and 34.1%,respectively.There was no significant differ-ence in these survival rates between the 2groups (P 5.12)(Fig.7).Table 6shows the 5-year survival rates stratified by clinical stage.There was no signifi-cant difference between the 2groups even in patients who had the same clinical disease stage (Table 7).
DISCUSSION
GBC is more prevalent in Eastern countries than in Western courtiers.The incidence of GBC is increas-ing in the Western world.A recent French study 6reported a standardized annual incidence of 0.6
cases per 100,000men and 1.7cases per 100,000women.Most large studies of GBC have demon-strated only a 2.7%to 15%overall 5-year survival rate in the United States and European countries.6À8The reported 5-year survival rates differ dramatically between Japan and the United States.Most available reports are hospital based.Because of selection bias (such as age,stage at diagnosis,health status,social status,etc),these data cannot be used as reference values.One of the reasons for this reported differ-ence may be the more extensive resection routinely performed by Japanese surgeons,although patient selection bias,differences in pathologic staging,and other variables also are potential explanations for this difference in survival rates.9Therefore,in the current study,we analyzed the profile of treatment outcome of GBC in Japan from a registry.
The most notable changes in tumor stage during the study period were an increase in the frequency of patients who were diagnosed with stage I GBC and a decrease in stage IVB disease.The reason for the increase in the percentage of patients with stage I dis-ease probably was because of an improvement in diag-nostic methods.Even in Japan,the prognosis for patients with stage IVB GBC is miserable.Recent dra-matic improvements in diagnostic and therapeutic techniques,including stent insertion,have enabled surgeons to avoid unnecessary operative procedures.
According to the National Cancer Data Base Report,7the 5-year survival rate for patients with stage I GBC is 38.9%.According to the American Joint Committee on Cancer (AJCC)classification,stage I is defined as T1(tumor invades the mucosa or muscle layer),N0(no regional lymph node metas-tasis),and M0(no distant metastasis).Furthermore,even the patients with stage 0disease had a
58%
FIGURE 6.Survival curves according to the receipt of chemotherapy
among patients with stage IVA gallbladder cancer who underwent surgical
resection.
FIGURE 7.Survival curves in accordance with the period of resection.The
survival curves for patients who were entered into the data base between 1988and 1997and between 1993and 1997were calculated.There was no statistically significant difference between the 2groups.
TABLE 7
Five-year Survival by Japanese Society of Biliary Surgery Stage of Disease and Time Trend
JSBS stage 5-Year survival
P 1988À1992
1993À1997No.of patients %No.of patients %Stage I 48674.951078.4NS Stage II 1596215657.2NS Stage III 25128.124730NS Stage IVA 31512.227012.4NS Stage IVB 232 3.1226 2.5NS Unknown 10612.69417.7NS Total
1550
38.2
1503
41.1
.12
JSBS indicates Japanese Society of Biliary Surgery;NS,not significant.
578CANCER August 1,2007/Volume 110/Number 3
5-year survival rate with nonradical surgery.Henson et al.10reported that the2-year survival rate was45% and the5-year rate was32%for patients who had tumors that were limited to the gallbladder at the time of surgery.The survival rate for patients with stage I GBC in a French study reportedly was58.6%6; however,that report was based on a small number of patients with stage I disease.In our current study, the5-year survival rate for patients with stage I dis-ease based on the JSBS classification was85%. According to the JSBS classification,stage I is the same as the AJCC classification.Many reports from Japanese surgeons have indicated an excellent sur-vival rate for patients with stage I disease.11À15What is responsible for this difference in the survival rate for patients with stage I GBC between Japan and other countries?Some possible explanations include the following:1)Multiple sections of the entire tu-mor were examined histopathologically to determine the precise depth of tumor invasion in Japan.Many investigators11,12,16have reported that the depth of tu-mor invasion is one of the most important prognostic factors;2)for[20years,many Japanese surgeons have advocated regional lymph node dissection for patients with GBC11,16;3)more extensive radiographic examinations are likely to be done under the medical insurance system in Japan;and4)in Japan,a laparo-scopic cholecystectomy is not undertaken if a patient has suspected GBC.However,some studies17,18indi-cated that patients who had stage0or stage I GBC found in their cholecystectomy specimens had a5-year survival rate from85%to100%.Although a sim-ple cholecystectomy is adequate treatment for carci-noma in situ and early-stage GBC,more extensive surgery,including the removal of adjacent liver paren-chyma and regional lymph nodes,is advocated for invasive GBC that appears to be localized.
There was no significant difference between the 2registration periods in the current study.In addi-tion,there was no significant difference in surgical procedures or clinical stage.Furthermore,during the study period,no new,effective anticancer drugs were developed.Conversely,in the French study,Manfredi et al.6reported that the5-year survival rates were [3-fold higher during the last decade than during the first decade;however,in multivariate analysis, the period of diagnosis had no effect on survival.In addition,there was a change in the management and staging of patients with GBC in the French study. Those authors also emphasized that there was an improvement in diagnostic methods,more aggressive surgery,and so forth,which may have contributed to the better prognosis.The Surveillance,Epidemiology, and End Results Program of the National Cancer Institute reported a similar incidence of metastatic disease and an increase in localized disease over the period from1973to1987.8,10Various nonexclusive explanations may be responsible for this trend:better technical performance of diagnostic methods,more widespread and earlier use of those methods,more aggressive surgery,or an increase in the rate of cholecystectomy.
Although the National Cancer Data Base report7 indicated that there was no noticeable difference in the survival outcomes according to patient age,the survival outcome for patients aged\49years was sig-nificantly better compared with the outcome for the other groups in our study.Manfredi et al.6also reported that the survival rates decreased with increasing age,especially after age75years,and the prognosis worsened with increasing disease stage. Our results indicated that the survival rate for patients aged[79years was significantly worse compared with the survival rate for the other4groups.Patient age is an important determinant of survival for most cancers.19One explanation for the variation in sur-vival by age is the more unfavorable stage distribution of tumors among the elderly.For many reasons,their diagnoses are likely to be delayed more often than among younger patients.There are various host char-acteristics among the elderly that favor more aggres-sive growth patterns and resistance to treatment.
The current results also suggest that women have better survival outcomes from GBC than men. In the current report,the enhanced survival among women was observed only for those with stage I and II disease,whereas there were no apparent differ-ences between the sexes in survival for those with stage III,IVA,and IVB disease.The percentage of patients who received chemotherapy was not differ-ent between men and women.In addition,adjuvant chemotherapy did not provide a survival benefit in our series.Only in the group of patients with stage IVA GBC was there a survival benefit from adjuvant chemotherapy(Table6).Conversely,it may be said that chemotherapy had a bad influence on the sur-vival of patients with nonadvanced GBC.However, our study was a historic,nonrandomized study between1988and1997.Over the more recent10-year period,various new anticancer drugs have been developed.Thus,a randomized controlled trial will be necessary to determine the benefit of adjuvant chemotherapy.
In general,there was no significant difference in prognosis with respect to sex.Kokudo et al.16re-ported that women had a slightly better prognosis than men(P5.24).The reasons for this difference in survival related to sex were not determined.The av-Gallbladder Cancer in Japan/Kayahara and Nagakawa579。