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Section of Health Services Research, Houston Veterans Affairs Medical Center, Baylor College of Medicine, Houston, TX, USA
2
Section of Gastroenterology, Houston Veterans Affairs Medical Center, Baylor College of Medicine, Houston, TX, USA
3
Division of Cancer Epidemiology and Genetics, NCI/DHHS, Columbia University College of Physicians and Surgeons, New York, NY, USA
4
Department of Medicine and the Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians
and Surgeons, New York, NY, USA
5
Mailman School of Public Health, Columbia University College of Physicians and Surgeons, New York, NY, USA
6
Corresponding author. Address: The Houston Veterans Affairs Medical Center, 2002 Holcombe Boulevard (152), Houston, TX 77030, USA
Received 17 April 2005; received in revised form 27 September 2005; accepted 11 October 2005; available online 2 November 2005
* Corresponding author. Tel.: C1 713 794 8640; fax: C1 713 748 7359.
E-mail address: hasheme@bcm.tmc.edu (H.B. El-Serag).
Abbreviations: HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; SEER, surveillance epidemiology and end-results
Program.
0168-8278/$30.00 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
doi:10.1016/j.jhep.2005.10.002
159
the group with no treatment (58 days). In the survival analysis, transplantation led to the longest survival, followed by
resection. Neither ablation nor TACE yielded prolonged survival (3 year survival was less than 10%).
Conclusions: In this predominantly 65 years and older Medicare population, there are marked geographic variations
in the management of HCC that seem to be at least as important as clinical and tumor-related features in determining
the extent and type of HCC therapy. There is underutilization of potentially curative therapy, even among those with
favorable tumor features.
Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
Keywords: Outcomes; SEER-Medicare; Resection; Transplant; Treatment; HCC
1. Background
The incidence of hepatocellular carcinoma (HCC) has
doubled over the last 20 years, with a substantial proportion
of this increase attributed to hepatitis C [1]. The overall
prognosis of patients with HCC in the US is poor, especially
for patients who do not receive specific therapy [2].
Potentially curative therapy for HCC includes surgical
resection, liver transplantation, and possibly local ablation
with alcohol and radiofrequency [3]. These therapies have
been shown in uncontrolled series to be associated with
longer survival than expected without therapy, particularly
among patients with smaller tumor size, fewer lesions, and
less severe liver disease [4]. In addition, some forms of
palliative therapy such as trans-arterial chemoembolization
(TACE) have also been shown in a recent meta-analysis of
randomized controlled trials to be associated with longer
survival in patients with relatively preserved liver function
[5]. However, most of these studies evaluated a small number
of patients, and focused on selected patient populations.
The outcomes of HCC in the US population are unclear
due to the lack of population-based data on HCC therapy.
These outcomes depend on the effectiveness of therapy but
also on the extent of using these therapies for HCC.
Establishing estimates of the extent of diffusion of therapies
is important in determining the effectiveness of treatment
and in identifying gaps in the equity of care. The registries
of the Surveillance, Epidemiology, and End Results (SEER)
Program collect population-based cancer incidence and
survival data from different sites across the country [6]. The
SEER-Medicare database merges SEER and Medicare, and
contains demographic, clinical and medical claims data
including treatment on cancer patients mostly over age 65 at
diagnosis [7]. It has been extensively used to examine the
outcomes of therapy for several cancers but not liver cancer.
Using SEER-Medicare, we examined the extent and
potential determinants of receiving (and type) of treatment,
and the effects of receiving different modalities on survival
of patients with HCC.
2. Methods
2.1. Data source
The SEER-Medicare dataset contains Medicare claims data dating back
to 1991 for all Medicare-enrolled patients identified by SEER registries
160
3. Results
There were 2963 patients with HCC diagnosed between
1992 and 1999 who fulfilled our inclusion and exclusion
criteria. The method of diagnosis was histology in 63%,
cytology in 20%, abnormal lab test in 2%, direct
visualization in 1% or radiology tests in 14%. Approximately, two-thirds of patients (62.5%) had codes indicative
of cirrhosis or its complications. The median age of patients
was 74 (range: 32105), and most patients (91%) were older
Table 1
Sociodemographic characteristics of SEER-Medicare patients with HCC (nZ2963) by therapy received, 19921999
Total
(nZ2963)
Year of diagnosis
19921995
19961999
Age
!65
6574 years
75C years
Gender
Female
Male
Race
White
Non-White
SEER Registry
Atlanta
Connecticut
Detroit
Hawaii
Iowa
Los Angeles
New Mexico
San Francisco
San Jose
Seattle
Utah
No. comorbidities
0
1
2C
Historic stage
Localized
Regional
Distant
Unstaged
Medicare/Medicaid
dual enrolment
Transplant
(nZ27)
Resection
(nZ243)
Ablation
(nZ122)
TACE
(nZ131)
Rest
(nZ2440)
P-value*
1414
1549
9
18
33.3
66.7
115
128
47.3
52.7
36
86
29.5
70.5
52
79
39.7
60.3
1202
1238
49.3
50.7
0.0001
270
1351
1342
4
23
0
14.8
85.2
0.0
16
139
88
6.6
57.2
36.2
12
74
36
9.8
60.7
29.5
17
77
37
13.0
58.8
28.2
221
1038
1181
9.1
42.5
48.4
!0.0001
939
2024
12
15
44.4
55.6
92
151
37.9
62.1
36
86
29.5
70.5
40
91
30.5
69.5
759
1681
31.1
68.9
0.1340
2028
935
22
5
81.5
18.5
147
96
60.5
39.5
71
51
58.2
41.8
67
64
51.2
48.8
1721
719
70.5
29.5
!0.0001
142
329
461
146
263
640
158
337
143
275
69
4
3
1
0
2
11
1
2
0
3
0
14.8
11.1
3.7
0.0
7.4
40.7
3.7
7.4
0.0
11.1
0.0
11
15
40
14
24
56
10
28
12
21
12
4.5
6.2
16.5
5.8
9.9
23.1
4.1
11.5
4.9
8.6
4.9
10
11
11
16
5
38
12
7
3
9
0
8.2
9.0
9.0
13.1
4.1
31.2
9.8
5.7
2.5
7.4
0.0
8
12
10
18
6
30
3
16
14
12
2
6.1
9.2
7.6
13.7
4.6
22.9
2.3
12.2
10.7
9.2
1.5
109
288
399
98
226
505
132
284
114
230
55
4.5
11.8
16.4
4.0
9.3
20.7
5.4
11.6
4.7
9.4
2.3
!0.0001
1461
810
692
14
8
5
51.9
29.6
18.5
130
70
43
53.5
28.8
17.7
50
36
36
41.0
29.5
29.5
55
44
32
42.0
33.6
24.4
1212
652
576
49.7
26.7
23.6
0.1310
984
700
544
735
746
17
3
1
6
8
63.0
11.1
3.7
22.2
29.6
182
36
15
10
66
74.9
14.8
6.2
4.1
27.2
59
36
10
17
30
48.4
29.5
8.2
13.9
24.6
51
46
8
26
8
38.9
35.1
6.1
19.9
6.1
675
579
510
676
602
27.7
23.7
20.9
27.7
24.7
!0.0001
0.0305
161
Table 2
Risk factors and severity of liver disease in 2963 patients with HCC identified in SEER-Medicare between 1992 and 1999
Total
(nZ2963)
Risk factors
Alcoholic liver disease
Yes
669
No
2294
HBV
Yes
262
No
2701
HCV
Yes
491
No
2472
Diabetes
Yes
1158
No
1805
Liver disease severity
Ascites
Yes
1213
No
1750
Encephalopathy
Yes
481
No
2482
Esophageal varices
Yes
423
No
2540
Hepatorenal syndrome
Yes
100
No
2863
Child C score
Yes
395
No
2568
Transplant
(nZ27)
Resection
(nZ243)
Ablation
(nZ122)
n
TACE
(nZ131)
9
18
33.3
66.7
38
205
15.6
84.4
30
92
24.6
75.4
7
20
25.9
74.1
34
209
14.0
86.0
29
93
21
6
77.8
22.2
45
198
18.5
81.5
11
16
40.7
59.3
78
165
18
9
66.7
33.3
15
12
Rest
(nZ2440)
P-value*
43
88
32.8
67.2
549
1891
22.5
77.5
0.0023
23.8
76.2
30
101
22.9
77.1
162
2278
6.6
93.4
!0.0001
39
83
32.0
68.0
45
86
34.4
65.6
341
2099
14.0
86.0
!0.0001
32.1
67.9
51
71
41.8
58.2
67
64
51.2
48.8
951
1489
39.0
61.0
0.0095
78
165
32.1
67.9
52
70
42.6
57.4
58
73
44.3
55.7
1007
1433
41.3
58.7
0.0029
55.6
44.4
20
223
8.2
91.8
26
96
21.3
78.7
31
100
23.7
76.3
389
2051
15.9
84.1
!0.0001
10
17
37.0
63.0
16
227
6.6
93.4
21
101
17.2
82.8
26
105
19.9
80.1
350
2090
14.3
85.7
!0.0001
3
24
11.1
88.9
8
235
3.3
96.7
2
120
1.6
98.4
7
124
5.3
94.7
80
2360
3.3
96.7
0.1027
19
8
70.4
29.7
17
226
7.0
93.0
21
101
17.2
82.8
20
111
15.3
84.7
318
2122
13.0
87.0
!0.0001
162
Table 3
Results from the multiple logistic regression analysis examining receipt
of potentially curative therapy (vs. TACE, other palliative therapy or
no therapy) and the effect of several potential determinants including
demographic, clinical, and tumor features; the model contained all the
variables listed in the table
Adjusted odds
ratio
95% confidence
interval
P-value
Year of diagnosis
19921995
19961999
1.00
1.21
0.941.54
Reference
Age (Years)
!65
6574
O75
1.00
1.83
0.85
1.182.86
0.531.36
Reference
Gender
Women
Men
1.00
1.25
0.961.62
Reference
Race
White
Black
Hispanic
Asian
Other
1.00
1.06
0.89
1.47
1.01
0.691.63
0.481.64
0.932.32
0.641.60
Reference
SEER registry
San Jose
Connecticut
Detroit
Hawaii
Iowa
Los Angeles
New Mexico
San Francisco
Atlanta
Seattle
Utah
1.00
2.41
1.77
2.02
2.15
2.47
2.85
1.47
3.24
1.24
3.65
1.125.18
0.863.61
0.944.36
1.014.55
1.284.74
1.296.29
0.733.00
1.467.19
0.602.59
1.419.42
Reference
0.81
0.591.60
0.180
1.00
0.35
0.16
0.17
0.270.46
0.100.26
0.110.27
Reference
Co-morbidity index
0
12
O2
1.00
1.21
0.83
0.901.61
0.511.35
Reference
1.00
0.70
0.22
0.530.93
0.160.31
Reference
0.014
!0.0001
1.20
2.18
0.68
0.881.63
1.483.22
0.490.95
0.246
!0.0001
0.022
0.73
0.540.99
0.041
0.671.34
0.531.13
0.7448
0.1865
Risk factors
HCV
HBV
Alcoholic liver
disease
Diabetes
0.134
0.007
0.496
0.092
0.800
0.711
0.100
0.971
0.024
0.119
0.072
0.047
0.007
0.010
0.287
0.004
0.565
0.008
!0.0001
!0.0001
!0.0001
0.204
0.459
95% confidence
interval
P-value
Year of diagnosis
19921995
19961999
1.00
0.47
0.280.81
Reference
Age (Years)
!65
6574
O75
1.00
1.51
2.40
0.554.13
0.797.27
Reference
Gender
Men
Women
1.00
1.28
0.742.21
Reference
Race
White
Black
Hispanic
Asian
Other
1.00
1.53
0.82
1.32
1.20
0.613.87
0.223.03
0.523.35
0.473.11
Reference
SEER registry
Atlanta
Connecticut
Detroit
Hawaii
Iowa
Los Angeles
New Mexico
San Francisco
San Jose
Seattle
Utah
1.00
2.02
6.25
1.10
4.70
1.27
1.44
5.21
4.52
2.48
7.10
0.557.48
1.8620.94
0.274.60
1.2218.15
0.443.64
0.365.79
1.3919.50
0.8224.92
0.708.74
1.2420.8
Reference
1.66
0.843.28
0.144
1.00
0.44
0.31
0.29
0.250.77
0.110.87
0.100.68
Reference
Co-morbidity index
0
12
O2
1.00
0.75
0.47
0.401.38
0.171.29
Reference
1.00
2.72
0.88
1.524.86
0.421.86
Reference
0.60
0.57
1.10
0.321.11
0.271.22
0.582.09
0.103
0.147
0.777
0.86
0.451.62
0.633
0.180.79
0.291.56
0.0101
0.3541
0.441.36
0.407.26
0.3723
0.4733
Risk factors
HCV
HBV
Alcoholic liver
disease
Diabetes
0.007
0.422
0.121
0.383
0.366
0.766
0.561
0.705
0.292
0.003
0.893
0.025
0.658
0.607
0.014
0.084
0.158
0.014
0.004
0.026
0.024
0.350
0.144
0.001
0.744
163
4. Discussion
This is the first population-based study of the extent and
determinants of HCC therapy in the United States and the
outcomes of these therapies. Three main findings indicate
potentially significant inappropriate management of HCC
during the years 19921999. First, the great majority of
patients with HCC did not receive potentially curative
therapy. More importantly, only a third of patients with
favorable tumor features who were most likely to benefit
received such therapy. Second, potentially inappropriate use
of curative therapy, mostly resection, was observed in
approximately a fifth of patients with unfavorable features
such as lesions O10 cm [3]. Lastly, there were remarkable
geographic variations indicative of wide practice variations
in the extent and type of curative, as well as palliative,
therapies.
Given the lack of population-based studies, the acceptable proportion of HCC patients in whom potentially
curative or palliative therapy should be applied is not
known. Estimates from non population-based large referral
centers such as the Barcelona Clinic Liver Center, indicate
that 28% of 2114 consecutive patients HCC presenting
between 1987 and 2002 were treated with potentially
curative therapy (resection 6%, transplantation 9%, ablation
13%) [10]. Data from the Cancer of the Liver Italian
Program (CLIP) on 650 patients diagnosed between 1990
and 1997 indicate that 41% received liver resection or local
ablation, and 16% received TACE/TAE [11]. In the CLIP
data, about 31% of patients 70 years and older received
potentially curative therapy. Neither study was a true
population-based study. Nevertheless, our results, with only
13% receiving potentially curative therapy suggest marked
underutilization of such therapy.
There are several possible explanations for this apparent
underutilization of HCC therapy. The severity of liver
164
Table 5
Observed survival in patients with HCC categorized by the type of treatment received
Median survival in
days (25th75th)
Transplant (nZ27)
Surgical resection (nZ243)
Ablation (nZ122)
TACE (nZ131)
None of the above (nZ2440)
852 (2971614)
568 (2001279)
458 (213772)
324 (151633)
82 (41202)
30-day mortality
Survival 1-year
Survival 2-year
Survival 3-year
No.
No.
No.
No.
0
17
1
7
384
0.0
7.0
0.8
5.3
15.7
20
150
73
58
318
74.1
61.7
59.8
44.3
13.0
14
105
35
24
135
51.9
43.2
28.7
18.3
5.5
11
75
12
8
63
40.7
30.9
9.8
6.1
2.6
0.9
0.8
0.7
0.6
transplant
0.5
resection
0.4
ablation
0.3
TACE
0.2
0.1
0
0.5
1.5
2
2.5
3
3.5
Follow up Duration (Years)
4.5
Hazard
ratio
95% CI
0.65
0.80
0.51, 0.83
0.60, 1.07
0.78
0.58, 1.04
0.90
Reference
0.66
1.23
0.71
0.81
Reference
0.45, 1.13
0.50, 1.31
0.91
0.68, 1.21
1.04
0.79, 1.37
0.45
0.64
0.77
0.50
0.61
0.58
0.71
0.57
1.12
1.34
Reference
0.21, 0.96
0.33, 1.24
0.45, 1.30
0.26, 0.96
0.33, 1.11
0.35, 0.98
0.36, 1.40
0.28, 1.20
0.62, 2.02
0.63, 2.84
1.44
1.09
Reference
1.08, 1.92
0.77, 1.54
1.14
2.24
0.96
Reference
0.34
0.78, 1.68
1.37, 3.66
0.56, 1.66
0.98
Reference
0.65, 1.49
0.12, 0.96
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Table 7
Risk of mortality in patients treated with local ablation or TACE:
Results of a Cox PH model
Hazard
ratio
95% CI
0.70
0.71
0.54, 0.91
0.54, 0.95
0.68
0.50, 0.91
0.92
Reference
0.63, 1.33
0.89
1.36
Reference
0.57, 1.39
0.84, 2.19
1.06
0.74, 1.52
1.11
0.81, 1.52
0.43
0.64
0.43
0.53
0.68
0.63
0.55
0.58
1.18
2.45
Reference
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0.29, 1.42
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0.31, 1.28
0.20, 1.51
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0.61, 2.29
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1.44
2.13
Reference
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1.20
3.52
1.02
Reference
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