Liver Cancer Open Access
Copyright ©The Author(s) 2003. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 15, 2003; 9(6): 1212-1215
Published online Jun 15, 2003. doi: 10.3748/wjg.v9.i6.1212
Changes in survival patterns in urban Chinese patients with liver cancer
Xi-Shan Hao, Ke-Xin Chen, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin 300060, China
Peizhong Peter Wang, Department of Public Health Sciences, University of Toronto, Toronto, Canada
Tom Rohan, Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, Bronx, U.S.A
Author contributions: All authors contributed equally to the work.
Correspondence to: Dr. P. Peter Wang, ACREU, Toronto Western Hospital Research Institute, University Health Network, MP 10-327, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada. wang@uhnres.utoronto.ca
Telephone: +1-416-603-5800 Ext: 3174 Fax: +1-416-603-6288
Received: February 26, 2003
Revised: March 4, 2003
Accepted: March 16, 2003
Published online: June 15, 2003

Abstract

AIM: To examine the survival patterns and determinants of primary liver cancer in a geographically defined Chinese population.

METHODS: Primary liver cancer cases (n = 13685) diagnosed between 1981 and 2000 were identified by the Tianjin Cancer Registry. Age-adjusted and age-specific incidence rates were examined in both males and females. Proportional hazards (Cox) regression was utilized to explore the effects of time of diagnosis, sex, age, occupation, residence, and hospital of diagnosis on survival.

RESULTS: Crude and age-adjusted incidence rates in the study period were: 27.4/100000 and 26.3/100000 in males; and 11.5/100000 and 10.4/100000 in females, respectively. Cox regression analyses indicated that there was a significant improvement in survival rates over time. Industrial workers and older people had relatively poor survival rates. The hospital in which the liver cancer was diagnosed was a statistically significant predictor of survival; patients diagnosed in city hospitals were more likely to have better survival than those diagnosed in community/district hospitals.

CONCLUSION: Patients diagnosed in recent years appeared to have a better outcome than those diagnosed in early times. There were also significant survival disparities with respect to occupation and hospital of diagnosis, which suggest that socioeconomic status may play an important role in determining prognosis.




INTRODUCTION

Liver cancer is a fairly common malignancy world wide[1-5], especially in developing countries[6-9]. In China, primary liver cancer is the third and fourth most common cancer in men and women with the age-adjusted incidence rates of 28.2/100000 and 9.8/100000 respectively in Shanghai[10]. Population-based survival data on cancer are indispensable in providing real, unbiased, average outcome of cancer patients. While liver cancer is a major cause of cancer-related mortality in China, little is known about its survival patterns over time. The objective of this study was two-fold: (1) to examine a specific hypothesis regarding the survival patterns of liver cancer in the studied urban Chinese population; (2) to examine the factors affecting such survival patterns. The objectives were achieved by analysing the data from the Tianjin Cancer Registry. The Tianjin Cancer Registry Centre is one of the members of the International Agency for Research on Cancer (IARC) of the World Health Organization. The cancer incidence data from Tianjin have been included in IARC official publications: "Cancer Incidence in Five Continents" since 1981. As Tianjin Cancer Registry is one of the few internationally accredited cancer registries in China, the results have important implications.

MATERIALS AND METHODS
Data

Tianjin, the third largest city in China, has a population about 10 million, of which about 98% belongs to the Han ethnic group. The Tianjin Cancer Registry was established in 1978 and became operational in 1981[11-13]. While the registry covers the whole city, data from six urban districts, which include approximately 4-million people, have been computerized and evaluated here. A city by-law requires that all physicians are responsible for filling out a report form for each new diagnosis of cancer. Practically, the task of cancer reporting is delegated to the medical record unit at each hospital. Thus, cancer cases are normally reported when patients are discharged from or die in the hospital. Information collected on the cancer reporting card includes name, sex, current age or date of birth, address, reporting hospital or medical institute, date (month and year) of diagnosis, four digit ICD-9 codes, and occupation. The Centre for Disease Control in Tianjin performs an annual quality control examination in at least 20 randomly selected hospitals in Tianjin to ensure that each hospital meets the standard cancer case reporting protocol. The evaluation results are used as part of the overall hospital report card, which is further used for hospital excellence ranking. A monetary incentive is offered for each cancer case reported, which is normally paid to the medical record unit rather than to individual physicians. Patients from other parts of China or those without permanent residence in Tianjin are not reflected in the current registry data.

All death certificates, which are the second source of cancer registration, are registered both at the district public health unit (DPHU) and the local police station. The DPHU routinely reviews all death certificates and identifies deaths, which are directly or indirectly caused by cancers. All cancer cases identified through death certificates are checked against the existing database at the Tianjin Cancer Institute for possible double or multiple reporting. In this study, we included all primary liver cancer patients (ICD-9 codes 155.1, 155.2). Numbers in each age-sex specific population for the six urban districts were obtained from the Tianjin Police Head Office, which enumerates the Tianjin urban population based on people's unique resident cards.

Analyses

Univariate and bivariate descriptive analyses were performed prior to multivariate analyses. Proportional hazards regression (Cox model)[14-20] was used to examine the effects of various factors on survival time for the study population. The proportional hazards model can be expressed as:

h(t;X) = h0(t)exp(β'X)

where h(t; X) is the hazard function of T at time t given a regression vector X; h0 is the unspecified baseline hazard function. The SAS PROC PHREG procedure was used to examine the specified survival model. The time variable (in days) was defined as the interval between the date of diagnosis and date of death. The covariates included in the survival analyses were age, sex, occupation, year of diagnosis, and residence. To best capture the impact of age on survival time, we explored different ways to categorize it in our regression models. As the incidence rates of liver cancer are very low in children, in our final model, we used ages 0-19 years as one group (baseline) and 10-year intervals thereafter to get stable estimates for the regression coefficients. Treating age categories as dummy variables in the model did not result in a better goodness of fit than simply introducing age as an ordered categorical variable with one degree of freedom.

Residence was introduced as a binary variable. As Hexi district is generally regarded as the best neighbourhood in Tianjin, it was used as a reference group and coded as "0". Other districts were coded as "1" and compared to Hexi district. Self-reported occupations were collapsed into 4-broad mutually exclusive categories: professionals and managers (such as teachers, medical doctors), service industry workers (such as salespeople), industry workers, and others. The professional and manager group was treated as the reference category. Year of diagnosis was treated as single year in Poisson regression and grouped into four categories in Cox regression analysis: 1981-1985 (reference category), 1986-1990, 1991-1995, and 1996-2000. Hospital of diagnosis was dichotomized to community/district hospitals (reference category) and city hospitals. Community hospitals normally provide walk-in service in their districts but do not provide surgical operations. District hospitals provide in-patient service and day-surgery operations in their districts. City general hospitals and speciality hospitals, which normally have advanced technology and research programs, provide a wide range of service to all Tianjin residents referred by community or district hospitals and sometimes patients from other parts of China.

RESULTS

In total, 13685 cancer cases were identified during the study period (1981-2000) and 70.6% occurred in males. The mean age at diagnosis for the study population was 62.2 years (61.3 and 64.3 years for males and females, respectively) with a median survival time of 151 d. As shown in Table 1, diagnosis based on death certificate only (DCO) was less than 1%. Most cancer cases were reported from city (75.1%) or district hospitals (15.5%) and most cases were diagnosed based on either medical imaging (60.6%) or histology (28.4%). While there are few gender differences with respect to the age at diagnosis and types of hospitals of diagnosis, males were more likely than females to be administrators or professionals.

Table 1 Characteristics of liver cancer cases diagnosed during 1981 to 2000, Tianjin, China.
VariableCategoryMale
Female
Total
n%n%n%
SexMale----966670.63
Female----401929.37
Age0-19190.20180.45370.27
20-29640.6624v0.60880.64
30-393603.721192.964793.50
40-49111811.572847.07140210.24
50-59244325.2772818.11317123.17
60-69315532.64139534.71455033.25
70-79200920.78112928.09313822.93
80+4985.153228.18205.99
Type ofClinical only98110.1547311.77145410.62
diagnosisMedical imaging only593461.39235358.55828760.56
Histology at local site271028.04117629.26388628.40
Surgical examination or autopsy140.1480.20220.16
Death certificate only10.0110.0220.01
Unknown260.2780.20340.25
OccupationProfessionals and administrators319333.033909.7358326.18
Service industry workers122012.623348.31155411.36
Industry workers393740.7398924.61492636.00
All others131613.62230657.38362226.46
Type of reportingCity general or specified hospitals730675.58296873.851027475.07
hospitalDistrict general hospital149515.4762415.53211915.48
Community hospital8658.9542710.6212929.44

The crude and age-adjusted incidence rates for the entire study period were 27.4/100000 and 26.3/100000 respectively for males. The corresponding rates were 11.5/100000 and 10.4/100000 for females.

Table 2 displays the results from the proportional hazard regression analyses. Older age and female gender were associated with poor survival rates, with relative risks of 1.06 (95%CI: 1.01, 1.11) and 1.08 (95%CI: 1.05, 1.09) respectively. Hospital of diagnosis was a statistically significant predictor of survival time. Patients diagnosed in city hospitals tended to live longer than those diagnosed in district or community hospitals, with relative risk of death of 0.76 (95%CI: 0.73, 0.79). The results showed that period of diagnosis was a statistically significant predictor of patients' survival time. Patients diagnosed in more recent years were likely to live longer than those diagnosed in earlier years with a relative risk of 0.85 (95%CI: 0.83, 0.86) for every 5-year increment.

Table 2 Proportional hazards analyses of liver cancer diagnosed between 1981 and 2000 in Tianjin urban districts.
VariableCategoryRelative risk95%CI
SexMale1
Female1.061.01, 1.11
Age0-191
Every 10-years increase1.081.05, 1.09
Period of1981-19851
diagnosisEvery 5-years increase0.850.83, 0.86
ResidenceHexi District (advantaged)1
Other districts1.020.97, 1.08
OccupationAdministrators1
Service industry workers1.060.99, 1.13
Industry workers1.081.03, 1.13
All others0.970.91, .102
HospitalDistrict or community hospitals1
City general or speciality hospitals0.760.73, 0.79
DISCUSSION

In this study, we described the survival patterns for primary liver cancer in a Chinese urban population over the last 20 years. To the best of our knowledge, this was the first study of its kind ever reported from China. Given the inconsistencies in the literature regarding liver cancer incidence trends[21-26] and survival patterns[27-32], this study provides another piece of useful information for this disease. As Tianjin has a first-class cancer treatment centre and facilities, patients from other parts of China often seek treatment in Tianjin. It is relatively uncommon that Tianjin residents travel to other parts of China for treatment. There is no conceivable reason that this pattern had changed during the study period. Moreover, regardless of where a Tianjin patient gets treated, his/her cancer status would eventually be reflected in the death certificates, which are one source of our cancer registration data.

Based on clinical patients in Qidong, which has the highest liver cancer incidence rates in China, Chen et al[31] reported that females had a more favourable prognosis than males. In this study, we found that females had slightly poor survival rate than males. As the magnitude of the reported survival difference was small, the results were unlikely to be conclusive. Nevertheless, the discrepancy between the two studies may be related to the differences in study population, such as, clinical setting versus population based or rural (Qidong) versus urban (Tianjin). The last four decades have seen a significant improvement in liver cancer treatment in China[33]. While the current study only had a span of 20 years, the improvement in survival was apparent. The changes may be explained by improvements in liver cancer clinical management in this city. For example, unpublished data indicate the proportion of liver cancer patients who undergo surgery for their condition has increased substantially in Tianjin.

This study has several limitations. First, we only included urban residents and were unable to compare the differences between rural and urban populations. Since China is a vast country with significant variations in economic conditions, the reported results may only be applicable to urban Chinese residents. Second, as the Tianjin Cancer Registry only records cancer related deaths (direct and indirect), it is possible that liver cancer patients who died from other causes, such as traffic accidents, were not reflected in our data bases. As a result, the observed survival time as reflected in the cancer registry data, might have been inflated. However, given that liver cancer is a fast progressive condition and a dominant majority of liver cancer patients die from it or its complications, it is unlikely that the problem related to non-liver cancer deaths would have altered the observed survival patterns greatly. Furthermore, since the possible artificially better survival caused by omission of non-liver cancer deaths would have been more in evidence for patients diagnosed in early periods, the true survival advantage for the patients diagnosed in recent years could be even greater. Third, we did not have information on cancer stage and treatment and were unable to estimate their impact on the observed survival pattern. It was possible that some of the observed survival advantage in later periods could be attributed to the cancer stage shift over time. Thus, studies on the changes in cancer stage and treatment over time are needed to address these questions.

ACKNOWLEDGMENTS

Tianjin Cancer Registry is jointly funded by the Tianjin Health Bureau and the Tianjin Cancer Institute. All computations were prepared at Tianjin Cancer Institute and the responsibility for the use and interpretation of these data is entirely that of the authors. The authors thank the International Agency for Research on Cancer (IARC) for their technological support. We are grateful to Dr. Qi-Long Yi, University of Toronto, for his statistical advice.

Footnotes

Edited by Zhang JZ

References
1.  Benhamiche AM, Faivre C, Minello A, Clinard F, Mitry E, Hillon P, Faivre J. Time trends and age-period-cohort effects on the incidence of primary liver cancer in a well-defined French population: 1976-1995. J Hepatol. 1998;29:802-806.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 42]  [Cited by in F6Publishing: 46]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
2.  Anderson IB, Sørensen TI, Prener A. Increase in incidence of disease due to diagnostic drift: primary liver cancer in Denmark, 1943-85. BMJ. 1991;302:437-440.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 16]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
3.  Chiesa R, Donato F, Portolani N, Favret M, Tomasoni V, Nardi G. Primary liver cancer in a high-incidence area in north Italy: etiological hypotheses arising from routinely collected data. Eur J Epidemiol. 1995;11:435-442.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 10]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
4.  El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340:745-750.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2221]  [Cited by in F6Publishing: 2124]  [Article Influence: 85.0]  [Reference Citation Analysis (0)]
5.  Kobayashi M, Ikeda K, Saitoh S, Suzuki F, Tsubota A, Suzuki Y, Arase Y, Murashima N, Chayama K, Kumada H. Incidence of primary cholangiocellular carcinoma of the liver in japanese patients with hepatitis C virus-related cirrhosis. Cancer. 2000;88:2471-2477.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 3]  [Reference Citation Analysis (0)]
6.  Miyakawa Y, Yoshizawa H. Increasing incidence of hepatocellular carcinoma associated with hepatitis C virus infection in Japan. Indian J Gastroenterol. 2001;20 Suppl 1:C95-C96.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Parkin DM, Srivatanakul P, Khlat M, Chenvidhya D, Chotiwan P, Insiripong S, L'Abbé KA, Wild CP. Liver cancer in Thailand. I. A case-control study of cholangiocarcinoma. Int J Cancer. 1991;48:323-328.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 138]  [Cited by in F6Publishing: 139]  [Article Influence: 4.2]  [Reference Citation Analysis (0)]
8.  Srivatanakul P, Parkin DM, Khlat M, Chenvidhya D, Chotiwan P, Insiripong S, L'Abbé KA, Wild CP. Liver cancer in Thailand. II. A case-control study of hepatocellular carcinoma. Int J Cancer. 1991;48:329-332.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 66]  [Cited by in F6Publishing: 62]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
9.  Shea KA, Fleming LE, Wilkinson JD, Wohler-Torres B, McKinnon JA. Hepatocellular carcinoma incidence in Florida. Ethnic and racial distribution. Cancer. 2001;91:1046-1051.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
10.  International Agency for Reseach on Cancer. Cancer Incidence in Five Continents, Vol. VII. Lyon, IARC. 1997;.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Chen K, He M, Dong S, Wang J. [Incidence, mortality and survival rates of female breast cancer in Tianjin, China]. Zhonghua Zhongliu Zazhi. 2002;24:573-575.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Wang QS, Lin XP. [An approach to use cancer registration to assess cancer risks by occupation and industry]. Zhonghua Liuxingbingxue Zazhi. 1997;18:331-333.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Guo Z. [Mortality analysis of malignant neoplasms and cardiovascular diseases 1979-1983 in Tianjin]. Zhonghua Liuxingbingxue Zazhi. 1985;6:353-355.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Wang PP, Haines CS. Childhood and adolescent leukaemia in a North American population. Int J Epidemiol. 1995;24:1100-1109.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 7]  [Article Influence: 0.2]  [Reference Citation Analysis (0)]
15.  Contal C, Mallet A. [Checking the Cox model in a real situation]. Rev Epidemiol Sante Publique. 2000;48:490-501.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Fu JH, Rong TH, Li XD, Ma GW, Hu Y, Min HQ. [Cox regression analysis of the prognostic factors of unresectable esophageal carcinoma after stenting]. Ai Zheng. 2003;22:91-94.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Averbook BJ, Fu P, Rao JS, Mansour EG. A long-term analysis of 1018 patients with melanoma by classic Cox regression and tree-structured survival analysis at a major referral center: Implications on the future of cancer staging. Surgery. 2002;132:589-602; discussion 602-604.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 33]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
18.  Steinbach D, Hermann J, Littlewood T, Zintl F. Risk group definition in children with acute myeloid leukemia by calculating individual risk factors on the basis of a multivariate stepwise Cox regression analysis. Leuk Lymphoma. 2001;42:1289-1295.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 1]  [Article Influence: 0.0]  [Reference Citation Analysis (0)]
19.  Boberg KM, Rocca G, Egeland T, Bergquist A, Broomé U, Caballeria L, Chapman R, Hultcrantz R, Mitchell S, Pares A. Time-dependent Cox regression model is superior in prediction of prognosis in primary sclerosing cholangitis. Hepatology. 2002;35:652-657.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 71]  [Cited by in F6Publishing: 72]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
20.  de Bruijne MH, le Cessie S, Kluin-Nelemans HC, van Houwelingen HC. On the use of Cox regression in the presence of an irregularly observed time-dependent covariate. Stat Med. 2001;20:3817-3829.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 29]  [Cited by in F6Publishing: 29]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
21.  Law MG, Roberts SK, Dore GJ, Kaldor JM. Primary hepatocellular carcinoma in Australia, 1978-1997: increasing incidence and mortality. Med J Aust. 2000;173:403-405.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Saracci R, Repetto F. Time trends of primary liver cancer: indication of increased incidence in selected cancer registry populations. J Natl Cancer Inst. 1980;65:241-247.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Yu MC, Yuan JM, Govindarajan S, Ross RK. Epidemiology of hepatocellular carcinoma. Can J Gastroenterol. 2000;14:703-709.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Bosch FX, Ribes J. Epidemiology of liver cancer in Europe. Can J Gastroenterol. 2000;14:621-630.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Bosch FX, Ribes J, Borràs J. Epidemiology of primary liver cancer. Semin Liver Dis. 1999;19:271-285.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 671]  [Cited by in F6Publishing: 722]  [Article Influence: 28.9]  [Reference Citation Analysis (0)]
26.  Taylor-Robinson SD, Foster GR, Arora S, Hargreaves S, Thomas HC. Increase in primary liver cancer in the UK, 1979-94. Lancet. 1997;350:1142-1143.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 383]  [Cited by in F6Publishing: 367]  [Article Influence: 13.6]  [Reference Citation Analysis (0)]
27.  Lee CL, Ko YC. Survival and distribution pattern of childhood liver cancer in Taiwan. Eur J Cancer. 1998;34:2064-2067.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 29]  [Cited by in F6Publishing: 31]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
28.  Tang ZY, Yu YQ, Zhou XD, Chen QM. Factors influencing primary liver cancer resection survival rate. Chin Med J (Engl). 1981;94:749-754.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Walker AR, Walker BF, Serobe W, Paterson A, Isaacson C, Segal I. Survival of blacks with liver cancer in Soweto, Johannesburg, South Africa. Trop Gastroenterol. 1986;7:169-172.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Zhou X, Tang Z, Yu Y. [Changing prognosis of primary liver cancer: some aspects to improve long-term survival]. Zhonghua Zhongliu Zazhi. 1996;18:211-213.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Chen J, Sankaranrayanan R, Li W. [Population-based survival analysis of primary liver cancer in a high-incidence area-Qidong, China during 1972-1991]. Zhonghua Yufang Yixue Zazhi. 1997;31:149-152.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Faivre J, Forman D, Estève J, Obradovic M, Sant M. Survival of patients with primary liver cancer, pancreatic cancer and biliary tract cancer in Europe. EUROCARE Working Group. Eur J Cancer. 1998;34:2184-2190.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 60]  [Cited by in F6Publishing: 69]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
33.  Wu M. Clinical advances in primary liver cancer in China. Hepatogastroenterology. 2001;48:29-32.  [PubMed]  [DOI]  [Cited in This Article: ]