DOI:10.2214/AJR.07.2879
AJR 2008; 190:608-615
© American Roentgen Ray Society
Chemoembolization of Hepatocellular Carcinoma: Patient Status at Presentation and Outcome over 15 Years at a Single Center
Daniel B. Brown1,2,3,4,
William C. Chapman2,3,
Ryan D. Cook1,
Jason R. Kerr1,
Jennifer E. Gould1,3,
Thomas K. Pilgram1 and
Michael D. Darcy1,2,3
1 Mallinckrodt Institute of Radiology, Washington University School of Medicine,
St. Louis, MO.
2 Department of Surgery, Washington University School of Medicine, St. Louis,
MO.
3 Siteman Cancer Center, Washington University School of Medicine, St. Louis,
MO.
4 Present address: Division of Cardiovascular and Interventional Radiology,
Thomas Jefferson University Hospital, Ste. 4200, Gibbon Bldg., 111 S 11th St.,
Philadelphia, PA 19107.
Received July 16, 2007;
accepted after revision September 18, 2007.
Address correspondence to D. B. Brown.
Abstract
OBJECTIVE. We report the outcome of the care of 209 patients with
hepatocellular carcinoma with a focus on relevant scoring systems for
predicting overall survival and time to progression and on changes in
presentation status and outcome from 1991 to 2006.
MATERIALS AND METHODS. Hepatic arterial chemoembolization was
performed on 209 patients in 375 sessions. Disease status was evaluated with
the Child-Pugh, Okuda, Cancer of the Liver Italian Program, and American Joint
Committee on Cancer (AJCC) systems. Changes in status at presentation from
1991 to 2006 and change in overall survival period and time to progression
were analyzed.
RESULTS. Median and mean overall survival periods for the entire
group were 376 and 574 ± 61 days. Median and mean times to progression
were 267 and 409 ± 54 days. Forty-nine patients underwent liver
transplantation a median of 143 days after chemoembolization. The median and
mean overall survival times among patients not undergoing transplantations
were 466 and 574 ± 61 days. Okuda score (p < 0.0001) and
AJCC stage (p = 0.014) were the best predictors of overall survival
and time to progression, respectively. Patients with disease with an Okuda I
score and in AJCC stage I or II had median and mean overall survival periods
of 667 and 992 ± 176 days and times to progression of 378 and 589
± 110 days. Clinical status at presentation, overall survival period
(p = 0.64), and time to progression (p = 0.44) were
unchanged from 1991 to 2006. The 30-day mortality was 3.2%.
CONCLUSION. Patients treated with hepatic arterial chemoembolization
for HCC in Okuda score I and AJCC stage I or II have more durable survival
than previously reported in a U.S. population.
Keywords: chemoembolization • hepatocellular carcinoma
Introduction
The incidence of hepatocellular carci noma (HCC) in the United States is
rapidly increasing, from approximately 10,000 cases per year in the 1980s to
an estimate of 34,000 cases per year by 2019
[1]. Optimal treatment of these
patients is liver transplantation or resection of the tumor
[2–4].
However, the number of organ donors is limited, and most patients present with
cirrhosis, limiting the potential for hepatectomy. Whereas small tumors can be
managed with alcohol or thermal ablation, the primary method of treat ment of
most patients is hepatic arterial chemoembolization
[5,
6]. This technique was
initially controversial because poorly con struct ed random ized trials did
not show a significant survival benefit
[7–10].
A number of factors led to limited outcomes in these trials, including poor
patient selection and suboptimal choice of embolic agent, such as coils. Later
studies [11] showed improved
survival by gauging the need for follow-up therapy based on imaging findings
rather than empirically treating patients on a calendar basis until death or
liver decompensation. As experience with chemoembolization increased and
patient selection improved after initial studies in the 1980s and early 1990s,
outcome improved. These modifications in technique led to separate prospective
randomized trials in Europe and Asia that showed the benefit of
chemoembolization [12,
13]. In most U.S. reports
[14–16],
survival has been notable but has lagged behind the outcome in European and
Asian randomized trials.
Several factors contribute to the difference in survival in studies in the
United States and those conducted in other areas of the world. One factor is
likely the restrictive selection criteria applied in the randomized controlled
studies outside the United States. In light of different causes of cirrhosis
in Asia and the United States, there are also questions regarding whether the
aggressiveness and biologic mechanisms of HCC vary in different parts of the
world [3,
17,
18]. Resectable HCC typically
presents in a later stage in the United States than it does in other countries
[3]. An additional factor that
may contribute to differences in outcomes is the limited sample size in
studies conducted in the United States. Although results for large patient
populations have been presented in Asia, in the United States only two
studies, to our knowledge, of chemoembolization outcome have included more
than 100 patients [15,
19,
20]. A primary limitation with
the smaller study groups in the United States is lack of subgroup analysis to
determine which groups of patients receive the greatest benefit from hepatic
arterial chemoembolization.
One reason for the limited sample sizes is that the increase in incidence
of HCC in the United States is a relatively recent phenomenon. The primary
purpose of our study was to determine survival time and time to progression as
well as factors predictive of outcome after chemoembolization of HCC in a
single-center cohort of more than 200 patients. Given the steady increase in
incidence of HCC, patients in any U.S. study are likely to have initiated
treatment over a relatively wide period of time. Improvements in outcome of
hepatic arterial chemoembolization for HCC in other populations have resulted
in the finding of substantial benefit in randomized prospective trials.
Therefore, the secondary intent of our study was to evaluate trends over time
in patient and tumor status at presentation and whether there have been
changes in treatment outcome.
Materials and Methods
Study Group
This study was approved by our institutional review board. The cases of all
patients undergoing hepatic arterial chemoembolization for HCC at our
institution from 1991 to 2006 were retrospectively reviewed through use of a
prospectively constructed database in our division. Before hepatic arterial
chemoembolization, patients underwent cross-sectional imaging with
contrast-enhanced CT or MRI and serum analysis of liver and renal function,
complete blood cell count, and evaluation of coagulation parameters. Available
imaging and laboratory parameters were used to calculate Child-Pugh class,
Okuda score, Cancer of the Liver Italian Program score, and American Joint
Committee on Cancer (AJCC) tumor stage at the time of first treatment.
Specific inclusion and exclusion criteria were not used given the aggressive
nature of our practice. Patients with Child-Pugh class C cirrhosis, portal
venous thrombosis, or an elevated bilirubin level were treated if subselective
therapy was feasible. Seven patients had undergone resection. None had
undergone ablative therapy.
Hepatic Arterial Chemoembolization Procedure
Patients received hydration with 100–200 mL/h of 5% dextrose
half-normal saline solution and were given premedication with 500 mg IV
metronidazole, 10 mg dexamethasone, and 16 mg ondansetron. Superior mesenteric
angiography was performed to evaluate portal vein status and evaluate for the
presence of anatomic variation. Celiac angiography was performed with
selection of the tumor-bearing artery before drug infusion. Use of
microcatheters was dependent on the treating physician. In general, the slurry
contained 50 mg cisplatin, 20–50 mg doxorubicin, and 10 mg mitomycin C
mixed with 10 mL of ethiodized oil (Ethiodol, Savage Laboratories). After
infusion of approximately one half of the chemotherapeutic
agent–ethiodized oil mixture, particle embolization was added with
300–500 µm polyvinyl alcohol (Ivalon, Cook) or absorbable gelatin
sponge (Gelfoam, Pfizer). Injection was continued until relative stasis was
identified in the feeding artery. Infusion and embolization were performed
with the catheter in a lobar or segmental artery. The volume of liver
embolized in any session was no greater than one-half the total volume. In
patients with bilateral tumors, the contralateral lobe was treated 4–6
weeks after the initial session. Follow-up imaging was performed 4–6
weeks after the entire tumor-bearing liver was treated. Whether therapy was
repeated was based on a combination of evidence of recurrent or residual
malignancy and synthetic hepatic function on follow-up scans obtained every
3–4 months.
Statistical Evaluation
Changes in patient presentation over time were evaluated with contingency
table analysis by initial treatment year and review of evaluation criteria
(Child-Pugh class, Cancer of the Liver Italian Program score, Okuda score, and
AJCC tumor stage). Changes and trends in presentation were tested for
statistical significance with the chi-square test. Calendar subgroups were
evalu ated according to date of presentation. The Kaplan-Meier method was used
to follow patient survival and time to progression for the whole group from
date of first chemoembolization. Data on patients undergoing liver
transplantation were censored at the time of surgery. The Kaplan-Meier method
also was applied to determine overall survival time and time to progression by
subgroup for Child-Pugh class (A–C), Okuda score (I–III), Cancer
of the Liver Italian Program score (0–4), and AJCC tumor stage
(I–IV) at presentation. The Child-Pugh, Okuda, and Cancer of the Liver
Italian Program systems were used because the scores have been found
predictive of survival in previous smaller series of patients undergoing
various arterially directed therapies for HCC
[14,
15,
21–24].
The AJCC system was used because of relevance regarding liver resection and
trans plantation [4]. After
these determinations, Cox proportional hazards analysis, in which all scoring
systems were the independent variables and time to progression and overall
survival time were the dependent variables, was performed to measure the
contributions of the scoring systems in combination.
Results
Group Outcome
Review of the database yielded the evaluable cases of 209 patients. The
study group included 146 men and 63 women with a median age of 59 years
(range, 36–84 years). The 209 patients underwent 375 chemoembolization
procedures (median, two procedures; range, one to six procedures). Forty-six
patients were alive at the end of the study. Scores based on the available
parameters (lack of data prevented classification in some cases) are outlined
in Table 1. Kaplan-Meier
analysis showed the median and mean overall survival times for the whole group
were 376 and 574 ± 61 days (Fig.
1A). One hundred of the patients had progression of disease
identified at follow-up imaging with median and mean times to progression of
267 and 409 ± 54 days (Fig.
1B). Forty-four of the 100 patients with progression were treated
with further hepatic arterial chemoembolization. Sixty-eight patients needed
multiple procedures to control all tumors either because of the presence of
bilateral disease or because of subselection to limit damage to normal hepatic
parenchyma. During the study period, 49 patients treated with
chemoembolization underwent transplantation. The median and mean times between
chemoembolization andtransplantation were 143 and 224 ± 34 days. For
all patients not undergoing transplantation, the median and mean survival
times were 466 and 574 ± 61 days.
Twelve patients died within 30 days of the procedure, resulting in a 3.2%
risk of mortality from hepatic arterial chemoembolization on a procedural
basis. The cause of death was known for seven patients: tumor lysis syndrome
(n = 5), massive pulmonary embolus (n = 1), and variceal
bleeding (n = 1). Associated preprocedure scores are outlined in
Table 2. In two patients,
dissection of the tumor-supplying artery occurred during attempted
catheterization. Both procedures were stopped, and these patients underwent
successful hepatic arterial chemoembolization 4 weeks later. No other major
complications occurred.
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TABLE 2: Breakdown of Scores of Patients Who Died Less Than 30 Days After a
Session of Hepatic Arterial Chemoembolization
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Outcome by Classification Scheme
Breakdown of patients in subdivisions of the Child-Pugh, Okuda, Cancer of
the Liver Italian Program, and AJCC systems along with time to progression and
survival is provided in Table
3. Regarding overall survival, scores in all four systems were
strongly predictive of this outcome measure (Child Pugh, p = 0.0099;
Cancer of the Liver Italian Program, p = 0.0001; AJCC, p =
0.018). Okuda score (p < 0.0001) had the strongest direct
association (Fig. 2A). Cox
proportional hazards analysis to determine which scoring systems had the
greatest predictive value showed only the Okuda score was statistically
significant in prediction of survival (p = 0.015). Regarding time to
progression, both Cancer of the Liver Italian Program score (p =
0.048) and AJCC stage had a significant relation, AJCC stage (p =
0.014) having the strongest direct association with this outcome measure.
After Cox multiple regression analysis, only the AJCC system maintained a
statistically significant value (p = 0.0045) in prediction of time to
progression (Fig. 2B).
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Fig. 3A —Evaluation of subgroup of patients with disease with both
Okuda score of I and in American Joint Committee on Cancer stage I or II.
Graph shows median and mean survival periods were 667 and 992 ± 176
days.
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Fig. 3B —Evaluation of subgroup of patients with disease with both
Okuda score of I and in American Joint Committee on Cancer stage I or II.
Graph shows median and mean overall times to progression were 378 and 589
± 110 days.
|
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On the basis of the foregoing predictors, we evaluated overall survival
period and time to progression for a subgroup of patients who had disease both
with an Okuda score of I and in AJCC stage I or II. Both AJCC stages were used
because the number of patients with stage I disease was limited (n =
5). Fifty-six patients met these qualifications. The median and mean overall
survival periods in this patient subgroup were 667 and 992 ± 176 days.
Median and mean times to progression in this subgroup were 378 and 589
± 110 days, and 25% of the patients were alive 28 months after
chemoembolization (Fig. 3A,
3B).
Changes in Patient Presentation Over Time
The number of new patient treatments on a year-by-year basis is represented
in Figure 4. Given the gradual
increase in referral of new patients through the 1990s, for further analysis,
patients from this decade were grouped as one unit. No significant changes in
status at presentation were found with any of the scoring systems (Fig.
5A,
5B,
5C,
5D). Although year-to-year
variation occurred, few changes were in the same direction over consecutive
periods.
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Fig. 5A —Changes in presentation status over time according to
standardized systems. Graph shows results for Child-Pugh class. Changes were
not significant when evaluated with Pearson coefficient (p =
0.14).
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Fig. 5B —Changes in presentation status over time according to
standardized systems. Graph shows results for Okuda score. Changes were not
significant when evaluated with Pearson coefficient (p = 0.14).
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Fig. 5C —Changes in presentation status over time according to
standardized systems. Graph shows results for Cancer of the Liver Italian
Program score. Changes were not significant when evaluated with Pearson
coefficient (p = 0.56).
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Fig. 5D —Changes in presentation status over time according to
standardized systems. Graph shows results for American Joint Committee on
Cancer stage. Changes were not significant when evaluated with Pearson
coefficient (p = 0.19).
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Changes in Outcome Over Time
Patients were similarly grouped for evaluation of changes in survival
period and time to progression (Fig.
6A,
6B). Kaplan-Meier analysis did
not reveal significant change in survival at any time point since 1991
(p = 0.64). Time to progression also remained unchanged (p =
0.44).
Discussion
The incidence of HCC is increasing. HCC is now the fourth most common
malignant tumor and the third leading cause of cancer deaths worldwide, with
more than 500,000 cases per year
[25]. The increasing incidence
of HCC in the United States and increasing referring clinician acceptance of
hepatic arterial chemoembolization were the most likely sources of increasing
patient referrals over the course of this study. Survival after hepatic
arterial chemoembolization is typically limited. In most studies conducted in
the United States
[14–16,
26], the average survival time
is approximately 18–24 months. This relative stability in outcome over
many reports with relatively small sample sizes led us to investigate whether
outcome had changed over time in a larger patient cohort. We also wanted to
determine whether patient status at presentation had changed, specifically
with the increasing use of screening of patients at high risk and the greater
awareness of the disease process of HCC.
The only curative treatment of patients with unresectable HCC is
transplantation. The number of donor organs available per year has remained
steady at approximately 6,000 while the number of patients on the United
Network for Organ Sharing waiting list has expanded, leading to an increase in
mortality among those waiting for an organ
[27]. Interventional
radiologic procedures, including transarterial and ablative therapies, already
play a large role in this patient population
[28]. Although the use of
wide-spread screening in western populations remains controversial, screening
is increasingly being used and is supported by the American Association for
the Study of Liver Diseases
[2]. As screening for early HCC
is increasingly used for high-risk patients, there will likely be a parallel
increase in the number of patients referred for treatment with hepatic
arterial chemoembolization or ablation. Screening has the potential to reveal
unifocal tumors at a markedly earlier stage, before portal vein invasion, than
was previously possible [29,
30]. In addition, the stigmata
of cirrhosis may be less pronounced when a significantly higher percentage of
cases are diagnosed when the disease is in Child-Pugh class A
[29].
Treatment of a higher percentage of screened patients has the potential to
result in treatment of more patients with optimal liver function and tumor
status and lead to marked improvement in the outcome of hepatic arterial
chemoembolization. A review of Medicare patients
[19] included an evaluation of
133 patients treated with hepatic arterial chemoembolization. This subgroup
survived a median of less than 11 months, and fewer than 20% of the patients
survived 2 years. Our study showed patients with well-compensated cirrhosis
and early-stage tumors had a median survival time of 667 days and that almost
one half of the patients were alive 992 days after chemoembolization. These
patients have the synthetic function to avoid liver decompensation after tumor
control with hepatic arterial chemoembolization.
Our study also showed that at presentation overall tumor and clinical
status is essentially unchanged from the 1990s. On a patient-by-patient basis,
individual status measured with Child-Pugh class, Okuda score, Cancer of the
Liver Italian Program score, and AJCC tumor stage is a predictor of survival
in all of the systems. In our patient group, Okuda score was found to be the
best predictor of survival in both Kaplan-Meier analysis and Cox multiple
regression analysis. Other investigators
[15] found Child-Pugh class to
be the best predictor of survival. A reason for the differing outcomes in the
two trials is difficult to ascertain. An important consideration regarding the
Child-Pugh system is that scores are determined only on the basis of hepatic
function without direct consideration of tumor burden. The three other grading
systems include tumor burden as part of the calculated score. Our results
suggest that survival is affected by both tumor burden and hepatic function.
This assertion is supported by the finding that Okuda score was the most
accurate predictor of survival in our population.
The AJCC system focuses only on factors directly related to malignancy
separate from liver function. This feature may explain why AJCC stage was the
best predictor of time to progression in both Kaplan-Meier analysis and Cox
multiple regression analysis. Other studies have shown that larger tumors are
more likely to progress and are more likely to exhibit incomplete coagulative
necrosis after hepatic arterial chemoembolization
[20,
31].
Other studies have shown that both ablative and arterial therapies can
lengthen survival in the setting of small HCC and well-compensated cirrhosis.
Lencioni et al. [5] found
significantly improved survival among patients with Child-Pugh A versus
Child-Pugh B disease with small HCC managed with thermal ablation. Patients
with Child-Pugh class A cirrhosis had a 51% 5-year survival rate. Similar
results have been reported with arterial embolization for HCC in patients with
well-compensated cirrhosis. Covey et al.
[21] treated a group of
patients with recurrent HCC after resection. Forty-two of the 45 treated
patients had disease with an Okuda score of I, and the actuarial 5-year
survival rate was 47%. Patients with solitary or small tumors survived longer
than their counterparts. When we studied a subgroup with an optimal survival
time and time to progression, we found the survival period approached that of
the highly selected populations in recent randomized trials
[12,
13]. It is clear that when
limited tumor burden is present in a patient with good hepatic reserve,
durable survival can be attained with arterial techniques, even among patients
not undergoing transplantation. However, when either the tumor burden or liver
function leads to a higher score in any of the classification systems used in
this study, survival suffers appreciably. For solitary tumors larger than
3–4 cm in diameter, arterial therapy and thermal ablation can be
combined to maximize necrosis in a minimal number of treatment sessions
[32].
Most existing series in the United States are patient populations with
limited sample sizes (typically fewer than 100 patients) compared with trials
from areas of the world where HCC is more common
[15,
20,
31,
33]. Small sample sizes have
limited the type of subgroup analysis performed in our study. In addition,
retrospective reports from the United States typically have focused on most or
all patients referred to a given center who were determined to be eligible for
treatment
[14–16,
26]. In contrast, patients
treated in prospective randomized trials have been highly selected from
referral pools much larger than in the typical interventional oncology
practice in the United States. Lo et al.
[13] conducted a study with 80
patients of 279 referred over the enrollment period. In another prospective
randomized trial, Llovet et al.
[12] included 112 patients of
903 patients evaluated. This high level of selectivity likely contributes to
differences in survival between studies in Hong Kong, China
[13]; Barcelona, Spain
[12]; and the United States.
Other authors [3,
17,
18] have questioned whether
HCC in differing geographic areas represents different forms of the disease. A
comparison of surgical candidates from treatment centers in the United States,
Europe, and Asia showed that patients from the United States typically
presented with significantly larger tumors than patients in the other areas.
Patients in the United States also were significantly less likely to have
hepatitis C than their cohorts from other countries. Of note, 30-day, 1-year,
and 5-year survival rates for all surgically treated groups were similar.
Given their eligibility for surgery, this group of patients clearly represents
a healthy minority of all those with HCC. A comparison of nonsurgical
candidates from different geographic areas has not been performed, to our
knowledge. As the number of patients presenting with HCC in the United States
continues to escalate, such comparisons may be feasible.
In this study, 12 patients died within 1 month of treatment. All 12
patients died after their initial session of hepatic arterial
chemoembolization. Evaluation of available pretreatment laboratory and imaging
values showed a relatively high frequency of AJCC stage IV disease. The cause
of death was known in seven of the cases and was judged tumor lysis syndrome
in five of the seven patients on the basis of characteristic electrolyte
abnormalities (elevation of serum potassium, uric acid, and phosphorus levels
with a simultaneous decrease in serum calcium concentration). Given the larger
tumors in these patients, it is logical that they would be at greater risk of
tumor lysis syndrome. Only two of the patients had tumors that occupied more
than 50% of the liver, and only two patients had a bilirubin concentration
greater than 2 mg/dL. No patient had disease in Child-Pugh class C, and only
one patient had disease with an Okuda score of III. Although they appear
predictive of long-term outcome, the values assigned with the scoring systems
in this trial are not precisely predictive of high risk of short-term
mortality.
A limitation of this trial was the retrospective construction with a
nonrandomized patient population. The population, however, represented the
cross-section of all patients referred to our center. Although the sample size
was limited in comparison with the sample sizes in trials from areas where HCC
is endemic, the population is the largest from the United States, to our
knowledge, to be described. Although there was variation in the choice of
embolic agent, a previous report showed that a similar approach did not affect
survival [26]. Finally,
although we treated patients relatively recently, the overall number of
patients in the trial allowed us to assess differences in outcome with the
different grading systems.
The results of this study show that overall patient status and tumor stage
at presentation for hepatic arterial chemoembolization have not changed
significantly since the early 1990s. Overall survival period and time to
progression in this static patient population have remained unchanged as well.
The principal determinant of outcome of hepatic arterial chemoembolization for
HCC remains individual patient and tumor status at the time of progression.
The key to improving survival after hepatic arterial chemoembolization as it
is currently performed is to identify which patients have early-stage disease
and well-compensated cirrhosis. The survival among patients presenting with
the combination of well-compensated cirrhosis and limited tumor burden is
superior to that of patients presenting with advanced liver dysfunction or
more advanced tumors. Capturing more patients with less-severe disease may
result in an outcome approximating that in the randomized controlled trials
performed in Europe and Asia.
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Abstract
Introduction
