Meta analysis: underutilization and disparities of treatment among patients with hepatocellular carcinoma in the united states

Abstract

Background

Despite wide availability of treatment options for hepatocellular carcinoma (HCC), several studies have suggested underutilization in clinical practice.

Aims

To quantify utilization rates for HCC treatment among patients with HCC in the United States and summarize patterns of association between utilization rates and patient socio-demographic characteristics.

Methods

We performed a systematic literature review using the Medline database from January 1989 through March 2013. Two investigators independently extracted data on patient populations, study methods, and results using standardized forms. Pooled treatment rates for any treatment and curative treatment, with 95% confidence intervals, were calculated. Pre-specified subgroup analysis was performed to identify patient-level correlates of treatment utilization.

Results

We identified 24 studies that met inclusion criteria. The pooled rates of any treatment and curative treatment were 52.8% (95%CI 52.2-53.4%) and 21.8% (95%CI 21.4-22.1%) respectively. Among patients diagnosed at an early stage, the pooled curative treatment rate was 59.0% (95%CI 58.1-59.9%). Elderly, non-Caucasians and patients of low socioeconomic status had lower treatment rates than their counterparts.

Conclusions

Rates of HCC treatment in the United States, including curative treatment rates among patients detected at an early stage, are disappointingly low. Future efforts should focus on identifying appropriate intervention targets to increase treatment rates and reduce socio-demographic disparities.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide and is one of the leading causes of death among patients with cirrhosis¹. Its incidence in the United States is increasing due to the current epidemic of non-alcoholic fatty liver disease and hepatitis C virus (HCV) infection¹. Prognosis for patients with HCC depends on tumor stage, degree of underlying liver dysfunction, and patient performance status, with curative therapies only available for patients detected at an early stage. Patients detected at an early stage can achieve 5-year survival rates of 70% with transplant or resection, whereas those with advanced HCC are only eligible for palliative treatments and have a median survival of less than one year^{2, 3}.

HCC disproportionately affects disadvantaged populations, with the highest age-specific incidence occurring among minorities. HCC rates are two times higher in Asian Americans than African Americans, whose rates are two times higher than those in Caucasians¹. Elderly, African Americans and patients of low socioeconomic status (SES) have poorer survival rates than their counterparts^{4, 5}. The reasons for differences in survival are likely multi-factorial, involving a combination of medical, financial, and social factors. Several studies have reported lower rates of surveillance, whereas others have postulated biologic differences in tumor behavior, and others have reported differential rates of HCC treatment ^{4, 6-8}. The aims of our study were to 1) quantify utilization rates for any treatment and curative treatment among patients with HCC in the United States and 2) to summarize patterns of association between utilization rates and patient socio-demographic characteristics.

METHODS

Literature Search

We conducted a computer-assisted search with the Ovid interface to Medline to identify relevant published articles. We searched the Medline database from January 1, 1989 through March 1, 2013 with the following keyword combinations: [treat$ OR therap$ OR transplant$ OR resect$ OR surg$ OR ablat$ OR RFA OR chemo$ OR emboliz$ OR TACE OR nexavar OR sorafenib] AND [hepatocellular ca$ OR liver ca$ or HCC]. Given our focus on current utilization of treatment within the United States, our search was limited to human studies published in English after 1989. Manual searches of references from relevant articles were performed to identify studies that were missed by our computer-assisted search. Finally, consultation with expert hepatologists was performed to identify additional references or unpublished data.

Study Selection

One investigator (D.T.) reviewed all publication titles of citations identified by the search strategy. Potentially relevant studies were retrieved, and selection criteria were applied. The articles were independently checked for inclusion (D.T. and A.S.) and disagreements were resolved through consensus. Inclusion criteria included: (i) cohort studies that described receipt of HCC treatment in patients with HCC, ii) studies from the United States after 1989 so as to be representative of current delivery of care, and (iii) available data regarding socio-demographic information for patients who did and did not receive treatment. We excluded: i) clinical trials with a protocol and/or extra nursing support as they do not evaluate delivery of care in a real-world clinical setting, ii) studies conducted outside the United States, and iii) survey studies because of high rates of over-reporting by physicians. Additional exclusion criteria included non-English language, non-human data, and lack of original data. If publications used the same patient cohort, data from the most recent manuscript were included.

Data Extraction

Two reviewers (D.T. and A.S.) independently extracted required information from eligible studies using standardized forms. A third investigator (A.Y.) was available to resolve any discrepancies. Data were collected on study design, geographic location and date of the study, number of patients with cirrhosis, number of HCC patients, and number of patients with early stage HCC in each study. We recorded definitions of any treatment, curative treatment, and early stage HCC for each study. Finally, data were collected on age, gender, race/ethnicity, and SES (insurance status and income) for those who received treatment and those who failed to receive treatment. Authors were contacted as necessary for missing information.

Clinical End Point and Statistical Analysis

Our primary study outcomes were rates of any treatment and rates of curative treatment among patients with HCC. Rates of any treatment included curative treatments (transplant, resection, or radiofrequency ablation) and non-curative treatments (chemoembolization, radiation-based therapy, or systemic therapy). Studies that only reported rates of transplantation, resection, and/or radiofrequency ablation were included in analyses for receipt of curative treatment but not those for receipt of any treatment.

The proportion of patients who received treatment was derived for each study, and 95% confidence intervals were calculated using the adjusted Wald method. A weighed pooled estimate of treatment rates was computed by multiplying the point estimate for each study by the proportion of individuals in that study relative to the number of individuals in all included studies. Sensitivity analyses were planned for the following predefined variables: 1) the study cohort (single-center vs. multi-center administrative database), 2) the proportion of patients with early stage HCC, 3) the definition of curative treatment, and 4) introduction of the Milan criteria for liver transplantation in 1996. All data analysis was performed using Stata 11 (StataCorp, College Station, TX).

RESULTS

Literature Search

The computer-assisted search yielded 22280 potentially relevant articles. After initial review, 264 titles were potentially appropriate, and these abstracts were reviewed. Fifty-seven publications underwent full-text review, and 34 were excluded. Sixteen of these articles were excluded as they were repeat analyses using the same cohort as other studies, eleven were not related to receipt of HCC treatment, four did not have extractable data, and three did not have any original data. One additional relevant article was identified through recursive literature searches. The remaining twenty-four studies met all inclusion criteria^9-32 (Supplemental Figure, Table 1).

Table 1.

Characteristics of Studies Assessing Hepatocellular Carcinoma Treatment Utilization

Author, Year	Study Setting	Mean Age (Years)	Gender (% Male)	Race (% Caucasian)	Cirrhosis (%)
Altekruse 20129	SEER-Medicare Database	NR	74	49	NR
Cance 200010	National Cancer Database	60-69	71	60	NR
Harrison 200411	University of Medicine and Dentistry, New Jersey	59	80	61	93
Jan 201212	Tulane University	64	76	67	94
Jou 201013	Duke University	NR	80	68	100
Kanwal 201232	Liver Cancer Research Network	59	76	77	100
Kemmer 200814	University of Cincinnati	57	80	64	100
Kitisin 201115	University of Pittsburgh	62	75	87	84
Kooby 200816	Emory University	60	72	71	82
Kozyreva 201117	Tufts University and Massachusetts General Hospital	62	79	77	90
Leykum 200718	South Texas VA hospitals	55	100	40	79
Sanyal 201019	Marketscan Claims Research Database	63	66	NR	NR
Sarkar 201220	University of California, San Francisco	50-64	78	0	100
Schwartz 199521	Mount Sinai Medical Center	NR	NR	NR	100
Shah 201122	SEER-Medicare Database	75	67	74	55
Stravitz 200823	Virginia Commonwealth University	57	86	63	100
Stuart 199624	Deaconess Health System	64	78	NR	68
Theodoropoulos 201125	Hahnemann University	55	80	47	83
Tong 201026	University of California, Los Angeles	62	78	0	73
Wong 201227	Hawaii Medical Center	62	75	19	74
Yang 201128	Mayo Clinic	62	72	83	83
Yu 201029	Columbia University	60	80	40	NR
Zak 201130	California Cancer Registry	55-64	71	37	NR
Zaydfudim 201031	Tennessee Cancer Registry	61	74	78	NR

NR-Not Reported; SEER- Surveillance, Epidemiology, and End Results; VA-Veterans Administration

Treatment Utilization

There were 16 studies, with a total of 24237 patients, which assessed receipt of any treatment, including both curative and non-curative treatments, among patients with HCC. Rates of treatment ranged from 28% to 85% among studies, with a pooled treatment rate of 52.8% (95%CI 52.2-53.4%) (Figure 1). We evaluated potential sources of heterogeneity through pre-planned subgroup analysis. The pooled treatment rate was 49.1% (95%CI 48.4 – 49.8%) among the 19489 patients in the three multi-center studies, which was significantly lower than the 72.0% (95%CI 70.7 – 73.3%) treatment rate among the 13 single-center studies, which contained a total of 4748 HCC patients (p<0.001). Among the multi-center studies, the study by Sanyal and colleagues reported substantially higher treatment rates than the other two studies. Given this study used insurance claims data, untreated patients who did not receive hospice may not have been fully captured. If this study was removed, the pooled treatment rate of the two remaining multi-center studies was only 38.5% (95%CI 37.7-39.3%).

Figure 1.

Treatment Rates for Hepatocellular Carcinoma

Utilization of Curative Treatment

There were 23 studies, with a total of 50769 patients, which assessed receipt of curative treatment among patients with HCC. Rates of curative treatment ranged from 14% to 51% among studies, with a pooled treatment rate of 21.8% (95%CI 21.4-22.1%) (Figure 2). Once again, we found substantial heterogeneity between studies, which was explored though sensitivity and subgroup analyses. We first performed a sensitivity analysis based on introduction of the Milan criteria for liver transplantation. When excluding the studies by Stuart and Cance, which both exclusively included cohorts prior to 1996, the pooled treatment rate was 22.5% (95%CI 22.1-22.9%). We next explored heterogeneity through subgroup analyses. The pooled curative treatment rate was 20.8% (95%CI 20.5 – 21.2%) among 45244 patients in the six multi-center studies, which was significantly lower than the 29.4% (95%CI 28.2 – 30.7%) curative treatment rate among the 17 single-center studies, which contained a total of 5525 HCC patients (p<0.001). We also performed a subset analysis, based on the definition of curative treatment. Studies that included transplant, resection, and RFA as curative treatments had a pooled curative treatment rate of 22.2% (95%CI 21.8-22.6%) compared to a pooled rate of 19.8% (95%CI 19.0-20.6%) among studies that only included surgical treatment (liver transplantation and/or resection) (p<0.001).

Figure 2.

Rates of Curative Treatment for Hepatocellular Carcinoma

Eighteen of the studies reported the number of patients with early HCC. Of the 32884 HCC patients in these studies, 12455 (37.9%) had early stage HCC. The pooled curative treatment rate among patients with early stage HCC was 59.0% (95%CI 58.1-59.9%) (Figure 3). When excluding the two studies by Stuart and Cance, the pooled treatment rate was 54.9% (95%CI 54.0-55.9%). Only three studies defined early stage with the Barcelona Clinic Liver Cancer (BCLC) staging system, while an additional 8 studies used Milan criteria. The other seven studies used a variety of definitions including the American Joint Committee on Cancer (AJCC) or Tumor Node Metastases (TNM) staging systems. The pooled curative treatment rate among studies using the BCLC or Milan criteria was 72.4% (95%CI 69.9-74.8%), which was significantly higher than the pooled curative treatment rate of 56.7% (95%CI 55.8-57.6%) among studies using other definitions (p<0.001).

Figure 3.

Curative Treatment Rates among Patients with Early Stage Hepatocellular Carcinoma

Correlates of HCC Treatment

Several patient factors are associated with higher utilization rates for HCC treatment, but heterogeneity in the reporting of these associations precluded pooling of the data.

Age

Older age was a consistent negative predictor of HCC treatment, with five studies reporting higher treatment rates in younger patients^{17, 19, 22, 29, 30}. Most studies lacked sufficient data to adjust for potential differences in tumor stage at presentation^{19, 22, 30}. However, Kozyreva and colleagues found patients older than 70 years were significantly less likely to receive any treatment than younger patients (36.8% vs. 22.9%, p=0.01) despite having similar tumor stage (p=0.95) and liver function as younger patients (Child A 57.9% vs. 56.7%)¹⁷.

Gender

The majority of studies that evaluated the impact of gender found no difference in treatment rates between males and females^{16, 22, 29, 30}. The study by Zaydfudim and colleagues was the only that suggested differential treatment rates by gender³¹. They found that females had a 1.78-odds (95%CI 1.15-2.76) of undergoing surgical treatment, after adjusting for age, race, insurance status, and tumor stage.

Race/Ethnicity

Five included studies demonstrated disparities in HCC treatment utilization, particularly that of curative treatments, according to race^{11, 22, 27, 29, 30}. Studies by Zak and Harrison reported lower treatment rates among African American patients but lacked sufficient data to adjust for differences in tumor stage and/or liver function^{11, 30}. Similarly, Shah and colleagues found higher treatment rates among Asian patients using the SEER-Medicare database, but it is unknown if this is related to differential rates of underlying cirrhosis²². Yu and colleagues found African Americans were significantly less likely to receive a transplant than Caucasian patients (OR 0.03, 95%CI 0.00 – 0.37) after adjusting for confounders including age, insurance status, and tumor stage but did not find a significant association with Hispanic ethnicity (OR 0.42, 95%CI 0.09 – 2.08)²⁹. Similarly, Wong and colleagues found that Pacific Islanders and Filipinos who were detected at an early stage were significantly less likely to undergo liver transplant than Caucasians (10.0% vs. 38.0%)²⁷.

Socioeconomic Status

The impact of SES on HCC treatment utilization has only been evaluated in four studies^{22, 29-31}. Several other studies evaluated patients with insurance or easy access to health care and therefore were unable to determine the impact of SES on treatment utilization^{9, 18, 19}. There was a consistent effect of higher treatment rates among patients with private insurance compared to patients without insurance or those with Medicare/Medicaid. In the Tennessee Cancer Registry, both uninsured patients (OR 0.05, 95%CI 0.01-0.37) and those with Medicaid (OR 0.32, 95%CI 0.15-0.69) were significantly less likely to receive surgical therapy than those with private insurance, after adjusting for age, gender, race, and tumor stage³¹. Yu and colleagues reported similar results, with privately insured patients significantly more likely to receive liver transplantation (OR 22.07, 95%CI 2.67-182.34), independent of tumor stage²⁹.

DISCUSSION

Despite strong evidence demonstrating HCC treatment significantly improves survival, our meta-analysis highlights that many patients with HCC fail to receive treatment in clinical practice. We found less than one-fourth of patients with HCC undergo curative treatment, and nearly 50% do not receive any treatment. The low rates of curative treatment are in part related to diagnoses at an advanced stage; however, more than one-third of patients diagnosed at an early stage do not receive curative treatment. Our study also highlights the presence of significant socio-demographic disparities, with the lowest treatment rates among non-Caucasians and patients of low SES.

The transition from diagnosis to treatment is a complex process, involving several steps and interfaces with multiple new providers³³. Providers must be aware of the cancer diagnosis, complete the staging work-up, determine the optimal treatment, and finally refer patients to the appropriate consultants³⁴. The complex array of potential treatment options, each delivered by a different type of provider, may make this process even more difficult for HCC. These treatment decisions for HCC have become increasingly complex with the availability of novel therapies and the growing use of multimodal and multi-provider treatments. Patients may be asked to make multiple transitions between several providers as various treatment options are considered. A breakdown at any step can result in treatment underutilization and/or treatment delays. Even in the setting of optimal processes, patients may choose to forgo therapy given disinterest, other barriers to care, or perceived excess risk from the treatment. Current studies fail to provide an in-depth analysis to clarify which factors mediate or moderate underutilization of HCC treatment. A multidisciplinary approach involving a team of hepatologists, surgeons, interventional radiologists, radiation oncologists, medical oncologists, and radiologists may improve communication and allow better delivery of optimal treatment³⁵. Further research is needed to evaluate the benefits of multidisciplinary care and identify other potential intervention strategies to increase appropriate HCC treatment³⁶.

Therapeutic choices for HCC are dependent on tumor stage, liver function and performance status². Although there is not one universally accepted staging system, the BCLC staging system has been incorporated into guidelines and is the most widely used, given that it combines all three features^{37, 38}. However, it is important to note that most studies, particularly those from large administrative databases, provide limited data regarding liver function or patient performance status. This lack of data precludes an accurate assessment of the appropriateness of lack of treatment. For example, it would be appropriate to not treat a patient with poor functional status, but this would be regarded as treatment underutilization in several studies included in this meta-analysis. Automated data has been demonstrated to underestimate quality of care in other areas, such as HCV-related care, for similar reasons³⁹. It is crucial that future studies provide data regarding liver function and patient performance status to better interpret treatment utilization rates.

The low curative treatment rates appear to be related to high rates of late stage diagnosis, as only 40% of patients are diagnosed at an early stage despite the availability of efficacious surveillance tools⁴⁰. When examining the subgroup of patients detected at an early stage, curative treatment rates are closer to 57-73%, depending on the definition of early stage HCC. The low rates of early tumor detection are multi-factorial, with surveillance underuse and suboptimal effectiveness of surveillance tools in clinical practice both playing a large role^41-44. Patients diagnosed incidentally or symptomatically are significantly more likely to be diagnosed at an advanced stage, when curative options are no longer an option^{23, 45}. Interventions are needed to improve surveillance rates, which can increase early tumor detection, facilitate higher rates of curative treatment, and thereby improve overall survival^{36, 46}.

Racial and socioeconomic disparities have been well described in the survival of patients with HCC⁴. Although prior studies have suggested difference in tumor biology and/or surveillance rates, our meta-analysis highlights the importance of socio-demographic disparities in treatment utilization. Patients who are elderly, non-Caucasian, and of low SES suffer from significantly lower HCC treatment rates than their counterparts. While current studies suggest an association between socio-demographic factors and HCC treatment, none have explored why treatment is not being performed in these subgroups. The roles of patient attitudes, co-morbid conditions, and barriers to accessing care have not been clearly evaluated. For example, elderly patients and patients of low SES may have lower treatment rates due to difficulty accessing medical care or a higher rate of co-morbid conditions. Similarly, race and SES are often highly correlated so independent causal effects can be difficult to identify.

The primary limitation of our meta-analysis was our inability to identify specific reasons for underutilization of HCC treatment. Current studies did not distinguish cases in which physicians failed to order treatment, cases in which treatment was not appropriate (e.g., patients with significant co-morbidities or those with Child C cirrhosis who were not transplant candidates), and those in which patients were non-adherent after treatment was recommended. Studies evaluating the reasons behind treatment under-utilization are necessary to identify intervention targets that can increase treatment rates.

Our meta-analysis was also limited by clinical heterogeneity among studies, such as the different operational definitions used for early stage disease and/or curative treatment. This variability in definitions makes it difficult to compare treatment rates across studies. Clear consistent definitions and measures are necessary to better quantify and interpret HCC treatment rates⁴⁷. This clinical heterogeneity may also relate to other etiologies such as inter-center variation in treatment rates, similar to what has been reported for HCC surveillance⁴³. Inter-center variation in treatment rates may be even larger given the selected availability of some treatments, such as liver transplantation. Another possible explanation for clinical heterogeneity is changes in treatment expertise over time; however, we did not see any evidence of a time trend on subgroup analysis.

In summary, HCC treatment is underutilized nationally, with nearly 50% failing to receive any treatment and less than 25% receiving curative treatment. Even among patients diagnosed at an early stage, more than 1 in 3 fail to receive curative treatment. There are also significant socio-demographic disparities with the lowest treatment rates in non-Caucasians and patients of low SES. Further studies are needed to explore reasons for the underutilization of treatment, particularly in these disadvantaged subgroups. These studies will be the first crucial step in identifying appropriate intervention targets to increase HCC treatment rates and reduce socio-demographic disparities.

Table 2.

Treatment Utilization Rates for Hepatocellular Carcinoma

Author, Year	Study Years	Number of HCC Patients	Rates of any HCC Treatment (%)
Altekruse 20129	1998 – 2008	21390	NR
Cance 200010	1985 – 1996	6353	3213 (50.6%)
Harrison 200411	1997 – 2003	264	190 (72.0%)
Jan 201212	2003 – 2011	206	145 (70.4%)
Jou 201013	2002 – 2008	319	207 (64.9%)
Kanwal 201232	2001 – 2007	267	NR
Kemmer 200814	2000 – 2005	169	NR
Kitisin 201115	2000 – 2009	1010	841 (83.3%)
Kooby 200816	1990 – 2004	501	307 (61.3%)
Kozyreva 201117	1998 – 2008	335	245 (73.1%)
Leykum 200718	2000 – 2005	72	20 (27.8%)
Sanyal 201019	2002 – 2008	4406	3757 (85.3%)
Sarkar 201220	1997 – 2008	31*	NR
Schwartz 199521	1998 – 1994	115	NR
Shah 201122	1991 – 2005	8730	2595 (29.7%)
Stravitz 200823	1997 – 2005	297	233 (78.5%)
Stuart 199624	1986 – 1995	314	233 (74.2%)
Theodoropoulos 201125	2001 – 2007	81	63 (77.8%)
Tong 201026	2000 – 2007	278	236 (84.9%)
Wong 201227	1992 – 2009	618	427 (69.1%)
Yang 201128	2007 – 2009	453	271 (55.2%)
Yu 201029	2002 – 2008	462	NR
Zak 201130	1996 – 2006	12148	NR
Zaydfudim 201031	2004 – 2006	680	NR

NR-Not Reported

^*Subset of total population with cirrhosis

Table 3.

Rates of Curative Treatment for Hepatocellular Carcinoma

Author, Year	Number of Early HCC	Definition of Early HCC	Curative Treatment (%)	Definition Curative Treatment
Altekruse 20129	8940 (41.8%)	Localized	4727 (22.1%)	Resection, OLT and RFA
Cance 200010	1252 (19.7%)	AJCC Stage I-II	1088 (17.1%)	Surgery
Harrison 200411	108 (40.9%)	AJCC Stage I-II	68 (25.8%)	Resection and OLT
Jan 201212	NR	NR	51 (24.8%)	OLT
Jou 201013	151 (47.3%)	BCLC Stage A	113 (35.4%)	Resection, OLT and RFA
Kanwal 201232	76 (28.5%)	BCLC Stage A	135 (50.6%)	Resection, OLT and RFA
Kemmer 200814	82 (48.5%)	Milan Criteria	24 (14.2%)	OLT
Kitisin 201115	NR	NR	302 (29.9%)	Resection, OLT and RFA
Kooby 200816	232 (46.3%)	Milan Criteria	224 (44.7%)	Resection, OLT and RFA
Kozyreva 201117	197 (58.8%)	CLIP Stage I-II	104 (31.0%)	Resection and OLT
Leykum 200718	28 (38.9%)	Milan Criteria	16 (22.2%)	Resection, OLT and RFA
Sanyal 201019	NR	NR	932 (21.2%)	Resection, OLT and RFA
Sarkar 201220	16 (51.6%)	Milan Criteria	15 (48.5%)	Resection, OLT and RFA
Schwartz 199521	NR	NR	33 (28.7%)	Resection and OLT
Shah 201122	3197(36.6%)	AJCC Stage I-II	NR	Resection, OLT and RFA
Stravitz 200823	135 (45.5%)	Milan Criteria	60 (20.4%)	OLT
Stuart 199624	73 (23.2%)	TNM Stage I-II	63 (20.1%)	Resection and OLT
Theodoropoulos 201125	27 (33.3%)	BCLC Stage A	16 (19.8%)	Resection and OLT
Tong 201026	158 (56.8%)	Milan Criteria	141 (50.7%)	Resection, OLT and RFA
Wong 201227	237 (38.3%)	Milan Criteria	187 (30.3%)	Resection and OLT
Yang 201128	139 (30.7%)	Milan Criteria	79 (17.4%)	Resection, OLT and RFA
Yu 201029	246 (53.2%)	AJCC Stage I-II	130 (28.1%)	OLT
Zak 201130	NR	NR	2390 (19.7%)	Resection, OLT and RFA
Zaydfudim 201031	358 (52.6%)	AJCC Stage I-II	158 (23.2%)	Resection, OLT and RFA

AJCC – American Joint Committee on Cancer; BCLC – Barcelona Clinic Liver Cancer; HCC – hepatocellular carcinoma; NR-Not Reported; OLT – Orthotopic liver transplantation; RFA – radiofrequency ablation; TNM – Tumor, Node, Metastases