Disparities in Hepatocellular Carcinoma Survival among Californians of Asian ancestry, 1988–2007

Abstract

Background

Hepatocellular carcinoma (HCC) represents a significant health disparity affecting Asian Americans, a population comprised of distinct ethnic groups. The purpose of this paper is to analyze Californians of Asian ancestry with HCC with respect to socioeconomic status, demographic factors, stage of disease, treatment received, and survival.

Methods

To investigate ethnic differences in survival, we analyzed ethnically disaggregated data from 6068 Californians of Asian ancestry with hepatocellular carcinoma (HCC) diagnosed in 1988–2007 and reported to the California Cancer Registry.

Results

Compared to the average of all ethnic groups, cause-specific mortality was significantly higher among Laotian/Hmong (hazard ratio (HR) =2.08, 95% confidence interval (CI) 1.78–2.44) and Cambodian patients (HR=1.26, 95% CI 1.06–1.51), groups with higher proportions of their populations at low levels of socio-economic status; in addition, Laotian/Hmong patients disproportionately presented at later stages of disease, with only 3% receiving local surgical treatment, resection, or liver transplantation.

After adjustment for time period of diagnosis, age at diagnosis, gender, geographic region, stage at diagnosis, type of surgery, and socio-economic status, survival disparities remained for both groups (Laotian/Hmong: HR=1.51, 95% CI 1.28–1.79; and Cambodian: HR=1.23, 95% CI 1.05–1.44).

Conclusions

Our hypothesis that survival outcomes would differ by ethnicity was verified.

Impact

Research is needed not only to develop more effective treatments for HCC, but also to develop community-based interventions to recruit Asian Americans, particularly Laotian/Hmong and Cambodians, for hepatitis B screening and into medical management to prevent or detect this tumor at an early stage.

INTRODUCTION

Background

Hepatocellular carcinoma (HCC) experienced the highest average annual percent (AAPC) increase in mortality of all cancers for both men and women in the U.S (1) and is among the lowest in its amenability to medical intervention (2). Though liver cancer is less common in the U.S. compared to other parts of the world, incidence and mortality rates have been rising, and HCC is a cancer that disproportionally affects all U.S. racial/ethnic minority populations (3–5, 1).

The incidence rate for liver cancer is highest among male Asian Americans and Pacific Islanders (API) with rates almost twelve times the incidence rates for non-Hispanic White men (6). Based on data from fourteen Surveillance Epidemiology and End Results (SEER) regions for the years 1998–2002, liver cancer incidence is ranked among the top five cancers among male Cambodians, Chinese, Filipinos, Koreans, Laotians, and Vietnamese and female Cambodians, Koreans, Laotians, and Vietnamese (6). Liver cancer incidence among these Asian American ethnic groups is even more prominent in California. Male Californians of Laotian ancestry experienced liver cancer as the most common cause of new cancer cases for the years 2000–2004 (7)versus ranking second based on the SEER data (6) and it is the second most common cancer among Vietnamese men (7) versus ranking third based on the SEER data (6). Chronic hepatitis B, acquired through vertical transmission during childbirth or horizontal transmission in early childhood, is the most common cause of liver cancer among Asians (8). Based on the estimated maternal hepatitis B surface antigen prevalence rate of 8.9 per cent among foreign-born Asian Americans compared to 0.13 per cent for non-Hispanic Whites, a disparity rate of 68.5:1 was calculated (9). This disparity far exceeds that of any health disparity exemplified in the ten greatest health disparities based on the Healthy People 2010 Objectives (10) andrepresents the most significant cancer health disparity affecting Asian Americans (11–14).

However, Asian Americans are not all alike. Asian American ethnic groups differ in terms of their socioeconomic status, age distribution, duration of time since immigration to the U.S., and risk factors for the development of liver cancer (15–19). Due to this diversity, we hypothesized that there would be differences in survival outcomes among Asian American ethnic groups with HCC. California is an ideal location to undertake this study because, according to U.S. Census Bureau news releases, California is home to the largest population of Asian Americans in the USA and experienced the largest numerical increase of Asian Americans of any state. There are currently more than five million Asian Americans in California who constitute more than 14 percent of the state’s population (20–21). In order to monitor the incidence rates, risk factors, treatments and survival from cancer among the different ethnicities that make up this varied group, we used data from the California Cancer Registry (CCR) which comprises the world’s largest repository of high quality ethnically-specific cancer data for Asian Americans in a geographically contiguous jurisdiction (22). Most recently, ethnically-specific HCC survival data from the California Cancer Registry for the 20-year period, 1988–2007 have become available.

The purpose of this paper is to analyze the 6068 Californians of Asian American ancestry with HCC in this database and determine the differences in survival (or mortality), both HCC cause-specific and overall, among the nine largest Asian American ethnic groups in California and who constitute more than 93 percent of all Californians of Asian ancestry. Furthermore, we want to assess the effects of variables such as age at diagnosis, gender, stage at diagnosis, type of surgery, and socio-economic status that may explain these differences.

METHODS

Data Source

The data source for our study is the California Cancer Registry, a population-based statewide registry funded in part through the National Cancer Institute’s SEER Program. The CCR covers the entire state of California and includes three SEER regions: the Greater San Francisco Bay Area, Los Angeles County, and the remainder of the state. The CCR has achieved the highest standards for cancer registry quality established by the North American Association of Central Cancer Registries (NAACCR) and the National Program of Cancer Registries (NPCR) for completeness and quality. Reporting of cancer cases to the CCR has been legislatively mandated in California since 1985. Currently, the CCR includes data from all cancer cases (except basal and squamous cell carcinoma of the skin and carcinoma in situ of the cervix) reported between 1988 through 2007. The completeness of the CCR is estimated to be 95% or greater.

The CCR follows standardized data collection and quality-control procedures in terms of racial/ethnic categorizations and cancer diagnoses (23). Race/ethnicity information for the HCC cases is primarily based on information contained in the patient’s medical record. This information may be based on self-identification by the patient, on the assumptions by an admissions clerk or other medical personnel, or by inference using race/ethnicity of parents, birthplace, maiden name, or last name. Asian race is further divided into twelve groups, the nine largest in California in rank order according to their 2000 U.S. Census populations are as follows: Chinese (including Taiwanese), Filipino, Vietnamese, South Asian (Asian Indian, Pakistani, Bangladeshi, Sri Lankan), Korean, Japanese, Hmong and Laotian, Cambodian, and Thai.

In addition to medical record reports, the CCR uses surname to identify persons of Vietnamese or Hmong ethnicity to compensate for the recognized underreporting of cancer cases for Vietnamese and Hmong ethnicity (24–25). In our study, Laotian and Hmong have been combined into one group because the majority of foreign-born Hmong were born in Laos (26), and older Hmong individuals may classify themselves as Laotian because they were formerly citizens of Laos (27).

South Asians, whose land of origin is the Indian subcontinent (28, 22), are comprised of Asian Indian, Pakistani, other South Asian, Bangladeshi, Bhutanese, Nepalese, Sikh, and Sri Lankan. Excluded from our analyses were 302 HCC cases from smaller Asian groups or with unspecified ethnicity. Also excluded are Native Hawaiians and other Pacific Islanders because the 2000 Census separated Pacific Islanders from the “Asian or Pacific Islander” category.

The analysis included all invasive hepatocellular carcinoma (HCC) cases diagnosed among the nine specified Asian ethnic groups, between January 1, 1988 and December 31, 2007 and reported to the CCR as of January 2010. We used the International Classification of Diseases for Oncology, Third Edition site code (C22.0) and histology code (8170) to identify patients with HCC among all patients with primary liver cancer. Eligibility was restricted to HCC as the first primary cancer in order to eliminate survival differences due to the effects of other cancers. Only cases with diagnostic confirmation of HCC were included in our study (92.9%). Diagnostic confirmation of HCC was defined as having positive histology (54.4%), positive radiological test (20.5%), cytology (13.7%), laboratory test/marker study (3.6%), or direct visualization (0.6%). A total of 6068 invasive HCC cases that met the above requirements were analyzed for this study.

Patient vital status was updated using both passive and active follow-up methods. Passive follow-up methods included annual record linkages with the California State death file, National Death Index, Social Security Death Master File, Medicare and Medicaid, California Department of Motor Vehicles, Voter Registration, and National Change of Address. Active follow-up methods required contacting physician’s offices, hospitals, patient’s relatives, and patients. While both passive and active follow-up methods were used, most information for follow-up was gathered through the passive follow-up methods. The follow-up period for this study began at HCC diagnosis and ended at the earlier of the date of death or last follow-up and December 31, 2007 (the end of the latest full year of case follow-up).

As a member of SEER, CCR must meet or exceed 95% follow-up on all eligible cases. No difference is seen in the distribution of follow-up dates by Asian ethnic groups. Only 161 cases distributed among the nine Asian ethnic groups had a follow-up date prior to 2007. With such a high follow-up percentage, survival results should not be impacted by loss to follow-up information.

The use of SEER and California Cancer Registry data on liver transplantation is well established (29–32). However, SEER began coding transplantation as a separate category of surgery in 1998. Therefore, we ran the multivariable analyses with resection and transplantation combined into one category, as others have done (33).

Statistical Analyses

We used chi-square tests to examine bivariate relationships between Asian American ethnic groups and the variables displayed in Table 1. These variables included time period of diagnosis divided into four consecutive five-year intervals; age at diagnosis (<50, 50–59, 60–69, 70–79, and 80 years or older); gender; geographical region (Los Angeles County, Greater San Francisco Bay Area, Central California, Northern California, and San Diego-Imperial-Orange Counties); stage of diagnosis (remote, regional, local, and unstaged); type of surgery (none, local, and resection or transplantation); and socioeconomic status (SES) on the basis of neighborhood income levels in quintiles. The index of SES (34) used in this analysis was a composite variable created by principal components analysis using a number of variables from 1990 and 2000 Census data at the block group level. The Census variables used in creating the aggregate SES measure included: education index, median household income, proportion below 200% of the poverty level, median rent, median house value, proportion with a blue collar job, and proportion older than 16 in the workforce without a job. The education index weights the proportion of people in a census block group with a given level of education by the number of years needed to attain that level of education (35). Block group quintiles based on statewide measurement of the SES variable were used in the analysis. Cases missing census block group due to incomplete address at time of diagnosis (26.2% of patients) were randomly allocated to census block groups within county of residence because excluding these cases has been shown to bias results (34).

Table 1.

Demographic and Tumor Characteristics by Asian American Ethnic Groups Among Patients with HCC between 1988–2007 in California (N = 6068)

	Chinese (n=1924)		Vietnamese (n=1367)		Filipino (n=1016)		Korean (n=807)		Japanese (n=459)		Laotian/Hmong (n=171)		Cambodian (n=158)		South Asian (n=114)		Thai (n=52)		Total	P value
Time Period of Diagnosis
1988–1992 (n=881)	332	17.3	127	9.3	158	15.6	112	13.9	82	17.9	29	17.0	22	13.9	12	10.5	7	13.5	881	<.0001
1993–1997 (n=1263)	426	22.1	269	19.7	192	18.9	173	21.4	106	23.1	39	22.8	30	19.0	17	14.9	11	21.2	1263
1998–2002 (n=1780)	521	27.1	421	30.8	296	29.1	262	32.5	130	28.3	55	32.2	45	28.5	30	26.3	20	38.5	1780
2003–2007 (n=2144)	645	33.5	550	40.2	370	36.4	260	32.2	141	30.7	48	28.1	61	38.6	55	48.3	14	26.9	2144
Age at Diagnosis
<49	334	17.4	247	18.1	171	16.8	135	16.7	25	5.5	50	29.2	54	34.2	8	7.0	23	44.2	1047	<.0001
50–59	387	20.1	346	25.3	212	20.9	203	25.2	80	17.4	42	24.6	49	31.0	30	26.3	16	30.8	1365
60–69	539	28.0	398	29.1	230	22.6	260	32.2	169	36.8	45	26.3	36	22.8	37	32.5	6	11.5	1720
70–79	488	25.4	296	21.7	273	26.9	170	21.1	145	31.6	20	11.7	13	8.2	26	22.8	6	11.5	1437
≥80	176	9.1	80	5.8	130	12.8	39	4.8	40	8.7	14	8.2	6	3.8	13	11.4	*	*	499
Gender
Male	1479	76.9	1089	79.7	769	75.7	550	68.2	184	40.1	136	79.5	126	79.8	79	69.3	42	80.8	4454	<.0001
Female	445	23.1	278	20.3	247	24.3	257	31.8	275	59.9	35	20.5	32	20.2	35	30.7	10	19.2	1614
Region
San Francisco-Oakland	1039	54.0	440	32.2	356	35.0	139	17.2	114	24.8	19	11.1	21	13.3	34	29.8	8	15.4	2170	<.0001
Central California	53	2.8	71	5.2	72	7.1	49	6.1	37	8.1	51	29.8	19	12.0	15	31.2	*	*	371
Northern California	107	5.6	68	5.0	81	8.0	22	2.7	59	12.9	56	32.8	19	12.0	25	21.9	5	9.6	442
San Diego-Imperial-Orange	101	5.3	523	38.2	183	18.0	135	16.7	86	18.7	39	22.8	13	8.2	21	18.4	5	9.6	1106
Los Angeles	624	32.4	265	19.4	324	31.9	462	57.3	163	35.5	6	3.5	86	54.4	19	16.7	30	57.7	1979
Stage at Diagnosis
Local	740	38.5	547	40.0	373	36.7	314	38.9	175	38.1	41	24.0	65	41.1	50	43.9	13	25.0	2318	0.0002
Regional	407	21.2	322	23.6	233	22.9	174	21.6	94	20.5	27	15.8	34	21.5	25	21.9	13	25.0	1329
Remote	536	27.9	353	25.8	285	28.1	197	24.4	125	27.2	73	42.7	44	27.9	27	23.7	19	36.5	1659
Unstaged	241	12.5	145	10.6	125	12.3	122	15.1	65	14.2	30	17.5	15	9.5	12	10.5	7	13.5	762
Type of Surgery
None	1467	76.3	1050	76.8	845	83.2	604	74.8	342	74.5	166	97.1	133	84.2	90	78.9	43	82.7	4740	<.0001
Local	93	4.8	120	8.8	38	3.7	54	6.7	33	7.2	*	*	8	5.1	9	7.9	*	*	358
Resection or transplantation	364	18.9	197	14.4	133	13.1	149	18.5	84	18.3	*	*	17	10.7	15	13.2	9	17.3	970
Socioeconomic Status
1 - Low SES	259	13.5	214	15.7	152	15.0	148	18.3	31	6.8	91	53.2	85	53.8	11	9.6	6	11.5	997	<.0001
2	307	16.0	366	26.8	182	17.9	142	17.6	79	17.2	44	25.7	25	15.8	14	12.3	18	34.6	1177
3	327	17.0	296	21.6	256	25.2	118	14.6	109	23.7	20	11.7	21	13.3	22	19.3	12	23.1	1181
4	489	25.4	269	19.7	273	26.9	172	21.3	119	25.9	15	8.8	14	8.9	33	29.0	13	25.0	1397
5 - High SES	542	28.2	222	16.2	153	15.1	227	28.1	121	26.4	*	*	13	8.2	34	29.8	*	*	1316

^*Less than 5 cases

Kaplan-Meier methods were used to estimate cause-specific and overall survival curves for each of the Asian ethnic groups, and the log-rank test was used to assess ethnic differences in survival. Results were very similar and therefore, cause-specific survival curves are presented in Figure 1 and all cause cancer survival curves are presented in Figure 2. Median survival times with 95% confidence intervals (CI) are presented in Table 2. Cox proportional hazards models were used to evaluate the association between ethnicity and survival, before and after adjustment for the effects of time period of diagnosis, age, gender, geographic region, SES quintile, stage of diagnosis, and type of surgery. Both cause-specific and all cause hazard ratios were calculated.

Figure 1.

Cause-specific HCC survival curves by Asian American ethnic groups, California, 1988–2007

Figure 2.

All cause-specific HCC survival curves by Asian American ethnic groups, California, 1988–2007

Table 2.

Median survival for patients with hepatocellular carcinoma by Asian American ethnic groups, California, 1988–2007

	Cause-Specific Survival		All Cause Survival
	Median survival months	95% CI	Median survival months	95% CI
Chinese	10	9 – 11	6	6 – 7
Japanese	12	8 – 14	6	5 – 9
Filipino	7	6 – 9	4	3 – 5
Korean	11	9 – 13	7	6 – 9
South Asian	12	7 – 43	7	3 – 10
Vietnamese	12	9 – 14	6	6 – 8
Laotian/Hmong	2	1 – 2	1	1 – 2
Cambodian	6	3 – 8	3	2 – 5
Thai	4	2 – 9	4	1 – 5

Using the average of the nine Asian ethnic groups as the referent group for ethnicity, hazard ratios (HR) and 95% confidence intervals (CI) were calculated for death from HCC. When modeling the variation in survival among the ethnic groups, it seemed most appropriate to assess each group’s difference from the average of the groups, rather than to arbitrarily select a particular group as the reference. The use of centered hazard ratios has been recommended for evaluating the performance of institutions (36) We estimated the ethnicity terms of the log hazard rates using the EFFECT parameterization in SAS, which constrains the ethnicity effects to sum to zero over all groups (rather than setting the effect for one of the groups to zero); we then took the antilog of each estimate to obtain the desired hazard ratio.

Analyses were performed using PROC LIFETEST and PROC TPHREG in SAS version 9.1 (SAS Institute Inc, Cary, NC). Survival time was measured in months from the date of diagnosis to death or censoring. Because the outcome of interest was death due to HCC, HCC cases for people who did not die or died of other causes were coded as censored observations.

A competing risk analysis is indicated if the other causes of death produce informative censoring, that is, if they are related to the event of interest (37). Because few of the other causes of death were related to liver cancer (6.1% cases had unknown cause of death, which could be related, but otherwise we could not tell if other causes of death were related), we did not perform a competing risk analysis. The assumptions for our models include uninformative censoring and proportional hazards, that is, time invariant effects.

Results

During the 20-year period of our study, 1988 through 2007, there were 6068 cases diagnosed for the 9 largest Asian American ethnic groups in California. Table 1 shows the demographic, disease and treatment characteristics of each of the nine Asian ethnic groups, which differed significantly with respect to all variables tabulated (p<.0001).

Time period of diagnosis

Almost two-thirds of HCC cases were diagnosed in 1998 or later. Consistent with immigration patterns, the proportion diagnosed in this period was highest among South Asians (75%) and lowest among Japanese (59%), Laotian/Hmong (60%) and Chinese (61%).

Age at diagnosis

Less than 20% of HCC cases were diagnosed before age 50 in all Asian American groups except Laotian/Hmong (29%), Cambodian (34%), and Thai (44%).

Gender

The majority of liver cancer diagnoses were among men in all the groups except Japanese, where women made up 60% of cases. The ratio of male to female HCC cases was highest among Southeast Asians (approximately 4:1). This ratio is particularly pronounced because the ratio of males to females among Vietnamese and among Laotian/Hmong is 1:0; among Cambodians, 0.9; and Thai: 0.8.

Region

Most of the HCC cases came from the coastal regions of the Greater San Francisco Bay Area, Los Angeles County, and San Diego-Imperial-Orange Counties, reflecting where the respective ethnic populations predominantly reside. At the same time, among the Laotian/Hmong a higher proportion of HCC cases were from the primarily inland Central California and Northern California regions, where the greater proportion of Laotians and Hmong reside.

Stage at diagnosis and treatment

On average the groups had 27% of tumors staged in remote locations, but among Laotian/Hmong, 43% had disease spread to remote sites. Overall, 22% of Asian Americans with HCC, but only 3% of Laotian/Hmong patients, underwent local surgical treatment, resection, or liver transplantation.

Socioeconomic status

About two-thirds of Asian Americans with HCC lived in neighborhoods with SES in the 3^rd quintile or above, except in the Laotian/Hmong and Cambodian groups in which more than half were in the lowest quintile.

The nine ethnic groups differed significantly with respect to both cause-specific and all cause survival (p<.0001). The Kaplan Meier curves (Figure 1) and estimates of median survival (Table 2) show Laotian/Hmong patients having the worst survival, with a median of 2 months cause-specific and 1 month all cause; followed closely by Cambodians (6 months and 3 months, respectively) and Thai (both 4 months). Koreans and South Asians had the longest all cause survival, with a median of 7 months.

Table 3 presents multivariable models of survival from HCC among the nine specified Asian groups in California. Compared to the average of all ethnic groups, cause-specific mortality was significantly higher among Laotian/Hmong (hazard ratio (HR)=2.08, 95% confidence interval [CI] 1.78–2.44) and Cambodian patients (HR=1.26. 95% CI 1.06–1.51). After adjusting for time period of diagnosis, age at diagnosis, gender, geographic region, stage at diagnosis, type of surgery, and socio-economic status, survival disparities remained for both groups (Laotian/Hmong: HR=1.51, 95% CI 1.28–1.79; Cambodian: HR=1.24. 95% CI 1.03–1.48). Cause-specific mortality was lower for more recent time periods of diagnosis vs. 1988–1992 (1993–1997: HR=0.79, 95% CI 0.72–0.87; 1998–2002: HR=0.66, 95% CI=0.63–0.74; 2003–2007: HR=0.57, 95% CI 0.51–0.64); ages 50–69 vs. under age 50 (50–59: HR=0.87, 95% CI 0.79–0.96; 60–69: HR=0.85, 95% CI 0.77–0.94); higher SES vs. the lowest quintile (quintile 3: HR=0.88, 95% CI 0.79–0.99; quintile 4: HR=0.89, 95% CI 0.80–0.98; quintile 5: HR=0.73, 95% CI 0.66–0.82); earlier vs. remote stage disease (regional: HR=0.58, 95% CI .49–0.69; local: HR=0.37, 95% CI 0.31–0.44; unstaged: HR=0.65, 95% CI 0.55–0.78); and surgery vs. no curative treatment (local: HR=0.40, 95% CI 0.33–0.47; resection or transplantation: HR=0.31, 95% CI 0.27–0.35;). Results were similar for all cause mortality, except that patients aged 80 and over had higher mortality, and those aged 50–69 had no survival advantage, compared with patients under age 50.

Table 3.

Multivariate Model of Survival from Hepatocellular Carcinoma, California, 1988–2007 (N=6068)

	Cause-Specific Survival				All Cause Survival
	Unadjusted HR	95% CI	Multivariate HR 95% CI		Unadjusted HR	95% CI	Multivariate HR 95% CI
Asian American Ethnic Groups
Chinese	0.83	0.77 –0.90	0.89	0.82 – 0.96	0.80	0.75 – 0.85	0.85	0.79 – 0.91
Vietnamese	0.83	0.76 –0.90	0.86	0.79 – 0.94	0.81	0.75 – 0.87	0.84	0.78 – 0.91
Filipino	0.91	0.83 –0.99	0.89	0.81 – 0.98	0.97	0.90 – 1.05	0.94	0.87 – 1.02
Korean	0.80	0.73 –0.89	0.90	0.82 – 1.00	0.77	0.71 – 0.84	0.86	0.79 – 0.94
Japanese	0.89	0.80 –1.00	0.99	0.87 – 1.11	0.85	0.77 – 0.95	0.93	0.83 – 1.03
Laotian/Hmong	2.08	1.78 –2.44	1.51	1.28 – 1.79	1.90	1.64 – 2.19	1.43	1.23 – 1.66
Cambodian	1.26	1.06 –1.51	1.24	1.03 – 1.48	1.25	1.07 – 1.46	1.23	1.05 – 1.44
South Asian	0.72	0.57 –0.92	0.81	0.64 – 1.03	0.84	0.69 – 1.02	0.92	0.76 – 1.11
Thai	1.17	0.87 –1.57	1.09	0.81 – 1.50	1.21	0.94 – 1.56	1.15	0.89 – 1.48
Time Period of Diagnosis
1988–1992			1.00				1.00
1993–1997			0.79	0.72 – 0.87			0.83	0.76 – 0.91
1998–2002			0.66	0.60 – 0.73			0.71	0.65 – 0.77
2003–2007			0.57	0.51 0.64			0.61	0.55 0.67
Age at Diagnosis
<49			1.00				1.00
50–59			0.87	0.79 – 0.96			0.95	0.87 – 1.04
60–69			0.85	0.77 – 0.94			0.93	0.85 – 1.02
70–79			0.93	0.84 – 1.03			1.03	0.94 – 1.13
≥80			0.97	0.85 – 1.12			1.17	1.04 – 1.32
Gender
Male			1.00				1.00
Female			1.03	0.96 – 1.11			1.05	0.98 – 1.12
Region
Los Angeles			1.00				1.00
San Francisco-Oakland			1.05	0.97 – 1.15			1.01	0.94 – 1.09
Central California			1.11	0.96 – 1.28			1.08	0.96 – 1.23
Northern California			1.05	0.92 – 1.20			1.03	0.92 – 1.16
San Diego-Imperial-Orange			1.12	1.01 – 1.24			1.10	1.01 – 1.20
Stage at Diagnosis
Remote			1.00				1.00
Regional			0.58	0.49 – 0.69			0.55	0.48 – 0.64
Local			0.37	0.31 – 0.44			0.37	0.32 0.43
Unstaged			0.65	0.55 – 0.78			0.62	0.53 – 0.72
Type of Surgery
None			1.00				1.00
Local			0.40	0.33 – 0.47			0.42	0.36 – 0.49
Resection or transplantation			0.31	0.27 – 0.35			0.34	0.31 – 0.38
Socioeconomic Status
1 - Low SES			1.00				1.00
2.00			0.99	0.89 – 1.10			1.00	0.91 – 1.10
3.00			0.88	0.79 – 0.99			0.93	0.85 – 1.03
4.00			0.89	0.80 – 0.98			0.88	0.80 – 0.97
5 - High SES			0.73	0.66 – 0.82			0.76	0.69 – 0.84

HR indicates hazards ratio; 95% CI indicates 95% confidence interval.

Each value provides independent risk of death after adjusting for all other factors presented in the table.

DISCUSSION

This paper focuses on 6068 HCC cases among Californians of Asian ancestry that were diagnosed from 1988 through 2007. To our knowledge, these data represent the largest number of HCC cases focused solely on Asian Americans collected in a population-based Gold Certification (highest award) North American Association of Central Cancer Registries. Previously published reports focusing on HCC survival among Asian Americans in California were more limited in number, geographical scope, time period covered, and included fewer ethnic groups such as by Barazani et al. (38). Thus, the value of our study is both the quality and size of the database and the vantage point of examining the data disaggregated by ethnic group.

This large database with detailed demographic data and other selected variables along with survival outcomes allowed us to verify that the HCC patterns differ among the nine Asian American ethnic groups. Substantial differences in HCC survival outcomes exist among the nine largest Asian American populations in California. Cancer survival for Asian American groups is markedly different when their data are disaggregated than when viewed in the aggregate. In our study, among the most striking differences were the percentages younger than age 50 at diagnosis among the Laotian/Hmong (29%), Cambodian (34%), and Thai (44%). We acknowledge there were fewer than 100 deaths in 2 of the groups. Therefore, our power may have been inadequate to detect survival disparities for the smallest groups, South Asian and Thai. The ethnic-specific sample sizes were not large enough to assess whether the effects of socio-demographic, disease, and treatment-related variables on survival differed by ethnicity. However, our sample sizes were sufficient to detect substantial survival disadvantages among Laotian/Hmong and Cambodians. Although Laotian/Hmong patients disproportionately presented at later stages, and were therefore at a survival disadvantage for that reason, very few at any stage of diagnosis received curative treatment. If patients diagnosed at remote stage are excluded, 28% of the entire sample, but only 5% of Laotian/Hmong, underwent local treatment, resection, or transplantation. Laotian/Hmong and Cambodian patients came from the lowest socioeconomic groups, and Laotian/Hmong presented at a much later stage compared to all other Asian American ethnic groups. The reasons for this disparity and why so few Laotian/Hmong received any type of treatment strongly suggests the presence of barriers to detection and treatment such as cultural, linguistic, or socio-economic factors (27, 39–40). However even after controlling for age, gender, socioeconomic status, stage and treatment, Laotian/Hmong and Cambodians did poorly compared to the average. Unfortunately these data are unable to completely explain this finding. Unlike many other tumors, the treatment of liver cancer is strongly influenced by the underlying condition of the patient in regards to their liver disease as well as specific size, number and location of tumors, which play a major role in overall survival and candidacy for the various treatments. It is likely that the underlying patient condition played a role in explaining the lack of treatment for all Asian Americans as well as among the Laotian/Hmong and Cambodian patient population. In the future these data should be collected in addition to MELD score, CLIP scores and Okuda classification data, which are important predictors of survival (41). The model for end-stage liver disease (MELD) score has been shown to be an important predictor of survival from end stage liver disease (41)) and would provide accurate information about the patient’s overall long term prognosis from their liver disease. Although there is an overall lack of consensus upon the most accurate way to stage patients with HCC, the one most accepted by experts and takes into account the patient’s clinical status, tumor characteristics and treatment rendered is the Barcelona-Clinic-Liver-Cancer staging system (BCLC) (42) The BCLC stage should also be included in the registry because it is a more accurate predictor of survival than the current TNM staging (43–44)

As expected, and consistent with others (33), we found survival to be positively associated with more recent diagnosis, as well as earlier stage of disease and receipt of curative treatment; however, we did not find a survival advantage for females. In smaller, clinically based studies of hepatocellular carcinoma survival in Asian Americans, one (45) found higher mortality in males, but another (46) did not. The latter study did not find differences in survival among Asian American ethnic groups, but was not population based and only included Chinese, Vietnamese, Japanese, and Koreans. Our findings regarding a survival advantage among persons with higher SES are consistent with those of Artinyan et al. (29), who also found that racial and ethnic differences in survival remained after accounting for SES, tumor characteristics, and treatment.

Consistent with others (47), we found that while HCC is a disease that is more commonly found in men, this finding was not apparent among Japanese Americans, where there was an observed predominance of female HCC cases. The reasons for this are unknown, but are presumed to be related to the etiology of HCC among Japanese patients. In contrast to other Asian groups who develop HCC due to hepatitis B, patients of Japanese ancestry are at higher risk for HCC due to infection with hepatitis C (HCV) related to “unsterilized medical practices” in the 1920’s to 1940’s (48). Japanese with HCC who migrated to California would be expected to fall into this category of those who were infected with HCV during this time period. It is unclear why this group had a predominance of women. One possible explanation is that because HCC in Japanese Americans is found in patients who were infected with HCV in the 1920’s to 1940’s, the men may be more likely to die at an earlier age from other causes such as cardiovascular disease or other forms of cancers.

Despite having access to the largest known cancer registry in a geographically contiguous jurisdiction with a large number of diverse Asian ethnic groups, we recognize several methodological challenges. Racial misclassification has been documented to exist in the CCR database (49), although this limitation exists in most population-based registry research (24). Gomez et al. reported differential completeness rates of birthplace information across race/ethnicity, hospital type, and language (50), and therefore, birthplace was not used as a proxy for acculturation. Lastly, the aggregate SES variable is not a measure of the individual’s SES level but rather that of his or her block group or neighborhood (34).

Nevertheless, the patterns that emerge from these data appear clear. In conclusion, our data and analyses support the finding that not all Asian Americans are the same; disaggregating the HCC data by ethnicity has elucidated Laotian/Hmong as the ethnic group with the worst survival outcomes. However, as our data indicate, none of the Asian Americans with HCC have favorable survival outcomes, and HCC by comparison with other cancers is almost invariably fatal (19, 33, 51). Viral hepatitis especially hepatitis B among Asian Americans was likely a major contributor to the development of liver cancer in this population (19) and unless one’s hepatitis status is known, proper medical management cannot occur. Unfortunately a large proportion of Asian Americans as well as others from HBV-endemic areas are unaware of their HBV status and have never been screened (52–53, 13). Less than one-third of HCC patients were screened prior to their diagnosis (54). Therefore, research is needed not only to better to develop more effective treatments, but also to develop community-based interventions to recruit Asian Americans, particularly Laotian/Hmong and Cambodians, for hepatitis B screening (14) and into medical management to prevent or detect this tumor at an early stage. In ongoing community-based research (54–56), we are learning that cultural inhibitions to screening among Californians of Asian ancestry, despite awareness of liver cancer, is not sufficient to assure screening. Much more research is needed in overcoming cultural barriers to screening and earlier medical management among Asian Americans.