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com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Original Article

Pegylated Liposomal Doxorubicin and

Gemcitabine in Patients With Advanced
Hepatocellular Carcinoma
Results of a Phase 2 Study

Giuseppe Lombardi, MD1; Fable Zustovich, MD1; Fabio Farinati, MD, PhD2; Umberto Cillo, MD, PhD3;
Alessandro Vitale, MD3; Giacomo Zanus, MD3; Martin Donach, MD1; Miriam Farina, MD1;
Stefania Zovato, MD1; and Davide Pastorelli, MD1

BACKGROUND: Over the years, doxorubicin and gemcitabine have been among the most widely used drugs for he-
patocellular carcinoma (HCC), with relative efficacy. The authors report the results of a phase 2 study of the combina-
tion of gemcitabine plus pegylated liposomal doxorubicin. METHODS: Patients with advanced HCC received
combination chemotherapy with gemcitabine 1000 mg/m2 on Days 1 and 8, followed by pegylated liposomal doxoru-
bicin 30 mg/m2 on Day 1. Treatment was repeated every 4 weeks to a maximum of 8 cycles. Primary endpoint was
overall response rate, and secondary endpoints were time to disease progression (TTP), overall survival (OS), and
toxicity. RESULTS: Forty-one patients were enrolled and were evaluable for response, toxicity, and survival. A total of
194 cycles of treatment were administered. Three (7%) patients had a complete response, and 1 of these patients
underwent liver transplantation. Seven (17%) patients had a partial response and, among these patients, 1 patient
underwent surgical resection. Among the 31 patients who had initial alpha-fetoprotein levels >400 ng/mL, 20
(64.5%) had a >20% decrease after 2 cycles of treatment. The median TTP and OS were 5.8 and 22.5 months, respec-
tively. Hematologic toxicity was the most common side effect, including neutropenia (17%) and anemia (7%).
CONCLUSIONS: The combination of gemcitabine plus pegylated liposomal doxorubicin was active and safe in
advanced HCC. Moreover, this treatment induced some complete responses and converted some untreatable HCCs
into lesions eligible for resection or transplantation. Cancer 2011;117:125–33. V
C 2010 American Cancer Society.

KEYWORDS: hepatocellular carcinoma, pegylated liposomal doxorubicin, gemcitabine, chemotherapy, liver, sorafenib.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer mortal-
ity worldwide.1 The highest incidence rates are found in East Asia and in the United States; the incidence rates of HCC
tripled between 1975 and 2005.2 The only curative treatments for HCC are surgical resection and liver transplantation;
however, only about 15% of patients are eligible for these treatments, because of the coexistence of the advanced stage of
the disease and cirrhosis at presentation.3 Over the years, numerous cytotoxic agents have been tested with rather disap-
pointing results.4 Underlying cirrhosis, impaired liver function, portal hypertension, and thrombocytopenia make sys-
temic chemotherapy difficult.
Gemcitabine is a pyrimidine antimetabolite with demonstrated activity against HCC,5 exhibiting cell phase specificity,
primarily killing cells undergoing DNA synthesis. Moreover, the favorable nonhematologic toxicity spectrum and the mild
and reversible hematological toxicity profile have made this agent an attractive and ideal drug for combination regimens.
Doxorubicin, a topoisomerase II inhibitor, is another of the most widely used and active agents in HCC, with a
response rate between 0 and 44%,6 although in more recent studies this has not exceeded 25%7; however, its use is limited
by elevated toxicity. In contrast to free doxorubicin, pegylated liposomal doxorubicin, which avoids uptake by the reticu-
loendothelial system, has shown longer circulation times, higher tumor selectivity, greater antitumor activity, and reduced

Corresponding author: Giuseppe Lombardi, MD, Istituto Oncologico Veneto-IRCSS, via Gattamelata, 64, 35128 Padova, Italy; Fax: (011) 390498215904; lombardi.
giuseppe.lg@gmail.com
1
Department of Medical Oncology 1 Unit, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy; 2Department of Surgical and Gastroenterological Sciences, Uni-
versity of Padua, Padua, Italy; 3Hepato-Biliary and Transplantation Unit, University of Padua, Padua, Italy
DOI: 10.1002/cncr.25578, Received: May 24, 2010; Revised: July 7, 2010; Accepted: August 19, 2010, Published online August 31, 2010 in Wiley Online Library
(wileyonlinelibrary.com)

Cancer January 1, 2011 125


Original Article
toxicity.8 Neutropenia, stomatitis, and palmoplantar
erythrodysesthesia (PPE) were found to be the major
dose-limiting adverse effects of pegylated liposomal dox-
orubicin. Regarding its activity in advanced HCC, various
studies have shown response rates of 10% to 14%,9 with a
favorable toxicity profile.
Since 2008, sorafenib has become the standard first-
line treatment for advanced HCC, on the basis of the
results of the SHARP trial; this study showed an increased
median time to progression (TTP) and overall survival
(OS) of about 3 months when compared with placebo10;
despite the significant survival benefit obtained, further
improvement in the treatment of advanced HCC remains
mandatory.
For all these reasons, in particular for the demon-
strated single-agent cytotoxic action, the different mecha-
nisms of action, the lack of cross-resistance, and
nonoverlapping toxicity, a phase 2 study was undertaken
to examine the efficacy and safety profiles of a combina-
tion chemotherapy with gemcitabine plus pegylated lipo-
somal doxorubicin. In our study, gemcitabine was
administered before pegylated liposomal doxorubicin,
because various studies11,12 have demonstrated that gem-
citabine induces an increase in topoisomerase II expres-
sion; thus, a subsequent pegylated liposomal doxorubicin-
mediated antitopoisomerase effect may cause a more sig-
nificant cytotoxicity. Moreover, because in a prior phase 2
study13 of pegylated liposomal doxorubicin at a dose of
50 mg/m2 in refractory ovarian cancer significant skin
toxicities and mucositis were been reported, whereas a
subsequent study14 demonstrated that pegylated liposo-
mal doxorubicin at a dose of 30 mg/m2 in advanced HCC
had low systemic toxicity, it was decided to use pegylated
liposomal doxorubicin at a dose of 30 mg/m2.
MATERIALS AND METHODS
Patient Selection
This study was a phase 2, open-label, single-arm, single-
institution trial. All patients were required to provide
written informed consent before study participation.
Patients were eligible for the study if they met the follow-
ing criteria: pathologically proven HCC or an alpha-feto-
protein (AFP) level >400 ng/mL associated with imaging
evidence on computed tomography (CT) scan or nuclear
magnetic resonance (NMR) of HCC and inoperable or
metastatic HCC. Inoperable disease was defined as either
lesion too large for resection, regional lymph node
involvement, presence of multifocal disease, or invasion of
126
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major blood vessels. Other inclusion criteria were as fol-
lows: measurable disease according to the Response
Evaluation Criteria in Solid Tumors (RECIST)15 on CT
or magnetic resonance imaging; no previous systemic
chemotherapy regimens for HCC; age >18 years; Eastern
Cooperative Oncology Group performance status
(ECOG PS) of 0 to 2; compensated Child-Pugh stage A
or B cirrhosis; adequate renal function (creatinine <120
lmol/L), adequate blood cell counts (neutrophil count
>1.5
109/L, platelet count >100
109/L), and
adequate hepatic function (bilirubin 3 mg/dL, alanine
aminotransferase and aspartate aminotransferase levels up
to 7
the institutional normal limits). Prior allowed treat-
ments included surgery, transarterial chemoembolization,
percutaneous ethanol injection, and radiofrequency abla-
tion. Exclusion criteria included concurrent malignancy,
known central nervous system metastases, significant
medical comorbidities, clinically significant cardiovascu-
lar disease, and any evidence of hepatic encephalopathy.
Treatment Protocol
Treatment consisted of gemcitabine 1000 mg/m2 diluted
in 250 mL normal saline infused over 30 minutes on Days
1 and 8, followed by pegylated liposomal doxorubicin 30
mg/m2 in 500 mL 5% dextrose intravenously over 1 hour
on Day 1. Each cycle was given every 4 weeks.
The pretreatment evaluation included a medical his-
tory, physical examination, serum hepatitis B and C serol-
ogy, blood chemistry including AFP level, and hepatic
and renal function tests. Required radiologic studies
included chest x-ray, cardiac echocardiogram, abdomen
CT, or NMR imaging scan.
Physical examinations, full blood counts, serum bili-
rubin, and AFP assay were recorded before the beginning
of each cycle; CT or NMR imaging scans were performed
every 3 cycles. Follow-up evaluations included physical
examination, blood chemistry, and CT or NMR imaging
scans every 2 months. Response and progression were
evaluated using the RECIST system.15 Treatment was
continued until disease progression, chemotherapy delay
for >3 weeks, unacceptable toxicity, patient refusal, or
completion of 8 courses of therapy. Salvage chemotherapy
was allowed for patients who were refractory to this treat-
ment and was left to the discretion of the investigators.
Premedication included ranitidine 150 mg, hydro-
cortisone 125 mg, chlorphenamine 10 mg, and ondanse-
tron 4 mg. Granulocyte colony-stimulating factor was not
recommended for prophylaxis of neutropenia.
Cancer January 1, 2011
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Gemcitabine and Doxorubicin in HCC/Lombardi et al

Toxicity Evaluation and Dose Modification Table 1. Patient Characteristics

All patients who received at least 1 dose of treatment were
Characteristics No. (%)
considered evaluable for safety. Toxicity was evaluated
according to the National Cancer Institute Common Total 41
Toxicity Criteria version 2. Median age, y 63.2
On Day 1, the patient was required to have an abso-
Sex
lute neutrophil count 1500 and platelets 100,000 to Men 33 (80.5)
receive treatment. The dose of gemcitabine was reduced Women 8 (19.5)

by 50% in case of grade 1 thrombocytopenia or grade 2 ECOG PS

neutropenia; it was discontinued if patients developed 0 4 (9.8)
1 36 (87.8)
higher toxicity. Pegylated liposomal doxorubicin was 1 (2.4)
2
reduced by 25% or discontinued in case of grade 2 PPE.
Okuda stage
Treatment of common adverse effects seen with this I 22 (53.7)
regimen, such as anorexia, nausea, and emesis, was II 16 (39.0)
allowed using standard interventions. III 3 (7.3)
AFP >400 ng/mL 31 (75.6)

Child-Pugh classification
Statistical Analysis A 19 (46.3)
The primary endpoint was the overall response rate. Sam- B 22 (53.7)
ple size was calculated to reject a 10% response rate in Score 7 14
Score 8 6
favor of a target response rate of 30%, with a significance
Score 9 2
level of .05 and a power of 80% by using Simon 2-stage Metastatic disease 19 (46.3)
design.16 In the initial stage, a total of 12 assessable HBsAg positive 5 (12.2)

patients were evaluated for response. If >1 response was Anti-HCV positive 20 (48.8)

observed, then 20 additional patients were selected to Previous treatment 22 (53.6)

enter the second stage to achieve a sample size of at least
32 evaluable patients.
Secondary objectives included TTP, OS, safety, and
identification of the factors that influence TTP and OS
with this regimen. Follow-up was calculated from the out-
set of treatment.
TTP was calculated from the start of therapy until
tumor progression or death. OS was calculated from the
start of therapy to the date of death. The Kaplan-Meier
method was used to estimate survival. The analyses were
performed on an intent-to-treat basis.
Independent prognosticators for TTP and OS were
studied by forward stepwise approach in Cox regression
analyses. Variables with a P value <.25 in univariate anal-
ysis were included in the multivariate regression. P values
were based on 2-sided testing, and statistical analyses were
performed with SPSS 15 statistical software (SPSS Inc,
Chicago, Ill). Differences with a P.05 were considered
significant.
RESULTS
Patient Characteristics
Between November 2003 and May 2008, 41 patients
with advanced-stage HCC were enrolled in the study.
Surgical resection 12 (29.3)
Locoregional therapy
RF 6 (14.6)
PEI 10 (24.4)
TACE 13 (31.7)
ECOG indicates Eastern Cooperative Oncology Group; PS, performance
status; AFP, alpha-fetoprotein; HBsAg, hepatitis B surface antigen; HCV,
hepatitis C virus; RF, radiofrequency thermal ablation; PEI, percutaneous
ethanol injection; TACE, transarterial chemoembolization.
Patient and disease characteristics are shown in Table 1.
There were 33 (80.5%) men and 8 (19.5%) women. The
median age was 63.2 years (range, 44-78.1 years); the me-
dian ECOG PS was 1 (range, 0-2); 19 (46.3%) patients
and 22 (53.7%) patients, respectively, were in Child-
Pugh stage A and B; metastatic disease was present in
46.3% of patients; and 31 (75.6%) patients had an ele-
vated AFP level (>400 ng/mL) at the time of entry. Hepa-
titis B surface antigen was positive in 12.2% of patients,
and 48.8% of patients were hepatitis C virus seropositive.
Nineteen (46.3%) patients had stage II or III disease,
according to the Okuda system. Twenty-two (53.6%)
patients had received previous treatment, including surgi-
cal resection and/or locoregional therapy (transarterial
chemoembolization, radiofrequency thermal ablation,
and percutaneous ethanol injection). Regarding second-

Cancer January 1, 2011 127

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Original Article

Table 2. Response to Treatment

Response No. (%)

Complete response (CR) 3 (7.3)

Partial response (PR) 7 (17.1)
Overall response rate (CRþPR) 10 (24.4)
Stable disease 14 (34.1)
Progression disease 17 (41.5)

line treatment, this was left to the discretion of the investi-

gators; most patients were treated with oral capecitabine
or intravenous 5-fluorouracil.

Figure 1. The median time to disease progression was 5.8

months (95% confidence interval, 2.6-8.9 months).

Clinical Efficacy
Overall, 194 cycles of treatment were administered; the
median number of courses of pegylated liposomal doxoru-
bicin plus gemcitabine was 4 (range, 1-8). At the time of
analysis, 20 patients were still involved in the study. Me-
dian follow-up time was 8.2 months (range, 1.7-52.8
months). In the 20 patients who were still alive, the me-
dian follow-up time was 22.5 months (range, 2.3-52.8
months).
The primary study endpoint was objective response
(Table 2). All patients were evaluable for response. Three
(7.3%) patients had a complete response (CR) and, in
particular, complete pathologic remission by chemother-
apy alone was documented in 1 patient in the specimen
who underwent resection. Moreover, 1 of these patients
underwent liver transplantation after the response to Figure 2. The median overall survival was 22.5 months (95%
chemotherapy; to date he is still alive (52.8 months from confidence interval, 4.6-40.3 months).
the start of systemic treatment).
Seven (17.1%) patients had a partial response (PR)
and, among these patients, 1 patient underwent surgical Toxicity
resection; in this case the TTP was 18.9 months. All patients were assessable for toxicity. Adverse events
Of 31 patients who had an elevated AFP level related to the study drugs are listed in Table 3. The com-
(>400 ng/mL) at baseline, a decrease in AFP of >20% af- bination of gemcitabine plus pegylated liposomal doxoru-
ter 2 cycles of treatment was observed in 20 (64.5%) bicin was generally well tolerated, and no treatment-
patients. related death occurred; moreover, there was no significant
The overall response rate (CR þ PR) was 24.4%. difference in tolerance to chemotherapy between patients
The disease control rate (CR þ PR þ stable disease [SD]) with Child-Pugh stage A and B. Thirteen grade 3-4
was 58.5%. However, 17 (41.5%) patients had disease adverse events were observed. Hematologic toxicity was
progression. the most common severe toxicity and consisted of neutro-
The median TTP of the entire population was 5.8 penia (17%), anemia (7%), and thrombocytopenia (2%).
months (95% confidence interval [CI], 2.6-8.9 months) Nonhematologic grade 3-4 toxicity consisted of nausea/
(Fig. 1) and the median OS was 22.5 months (95% CI, vomiting in (2%) 1 patient and stomatitis in 1 (2%)
4.6-40.3 months) (Fig. 2). patient. Only 3 (7%) grade 1-2 hand-foot syndromes

128 Cancer January 1, 2011

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Gemcitabine and Doxorubicin in HCC/Lombardi et al

Table 4. Clinical Factors Associated With TTP

(%)

29

29
—
Univariate Multivariate

Toxicity
Analysis Analysis
Liver

No.
Clinical

12

12
—
Factors P HR CI 95% P HR CI 95%

(%) Sex .38 —

Age .60 —

—
7

7
ECOG PS .004a .04a
PS 0 Ref. Ref. Ref. Ref.
HFS

PS 1 .03 3.25 1.09-9.6 .03 1.7 1.07-5.2

No.

PS 2 .006 48.5 2.9-787.6 .02 27.8 1.7-453

3

Child-Pugh <.001a 4.8 2.0-11.6 .16

classification

Okuda staging <.001a <.001a

(%)

Okuda I Ref. Ref. Ref. Ref.

7
2
9
Stomatitis

Okuda II <.001 7.4 2.9-18.6 <.001 7.4 2.9-18.9

Okuda III .002 9.2 2.2-38.1 .002 9.2 2.4-45.0
Metastatic disease .15 .8
No.

HBV .77 —
3
1
4

HCV .78 —
RF .4 —
PEI .38 —
TACE .88 —
(%)

29

36
7

Surgical resection .38 —

AFP >400 ng/mL .04a 2.5 1.03-6.3 .21
Anemia

TTP indicates time to disease progression; HR, hazard ratio; CI, confidence
No.

interval; ECOG, Eastern Cooperative Oncology Group; PS, performance

12

15
3

status; Ref., reference; HBV, hepatitis B virus; HCV, hepatitis C virus; RF, ra-
diofrequency thermal ablation; PEI, percutaneous ethanol injection; TACE,
transarterial chemoembolization; AFP, alpha-fetoprotein.
a
Statistically significant.
(%)

19

21
2
cytopenia

were observed. Liver toxicity was only grade 1-2, and

Trombo-

the majority (61%) of patients had viral hepatitis at

No.

baseline.
8
1
9
(%)
Neutropenia

Predictive Factors
17
17
34

The results of univariate and multivariate analyses, carried

out to identify factors predicting TTP and OS, are given
in Table 4 and Table 5.
No.

14

ECOG PS (P ¼ .04) and Okuda staging (P<.001)

7
7

were found to be independent predictors for TTP on mul-

tivariate analysis.
(%)

10

12

Multivariate analysis indicates that OS was signifi-

HFS indicates hand-foot syndrome.
2
Vomiting

cantly longer in patients with good PS (P <.001), earlier

Nausea/

disease stage (P ¼ .002) and lower AFP (<400 ng/mL)

Table 3. Toxicity Profile

levels (P ¼ .02).
No.

4
1
5

Among the 31 patients with elevated serum AFP

(>400 ng/mL) before treatment, a decrease in AFP of
>20% after 2 cycles of chemotherapy was an independent
Grade 1-2
Grade 3-4
All grades
Profile

favorable predictor for TTP (P<.001) and OS (P ¼ .02)

(Table 6).

Cancer January 1, 2011 129

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Original Article

Table 5. Clinical Factors Associated With OS onstrated a significant survival benefit for sorafenib.10 In
this study, median OS and median TTP were prolonged
Univariate Multivariate
Analysis Analysis by nearly 3 months in the sorafenib group compared with
Clinical
the placebo group; median OS was 10.7 months versus
Factors P HR CI 95% P HR CI 95% 7.9 months (P<.001), and median TTP was 5.5 months
versus 2.8 months (P<.001). Although sorafenib was
Sex .21 .8 shown to be effective, no patient had a CR, only 2% had a
Age .17 .07 PR, and 71% had SD according to RECIST criteria.
ECOG PS .003a <.001a Recently, despite its effect on survival and TTP, in a draft
PS 0 Ref. Ref. Ref. Ref.
guidance the National Institute for Health and Clinical
PS 1 .001 7.8 2.3-26.4 .001 7.8 2.3-26.5
PS 2 .005 33.4 2.8-394.2 .005 33.4 2.8-394.2 Excellence suggested that sorafenib would not be a cost-
Child-Pugh .03a 2.7 1.08-5.3 .1 effective first-line drug to treat advanced HCC.18 Also,
classification
the drug is indicated for treatment only in patients with
Okuda staging .001a .002a preserved liver function (Child-Pugh A), at least in Italy.
Okuda I Ref. Ref. Ref. Ref.
Okuda II <.001 42.8 5.2-347.9 <.001 51.1 5.6-460
Before the evidence of efficacy of sorafenib become
Okuda III <.001 114.3 9.8-1322 .001 70.6 5.4-916 available, conventional doxorubicin was among the most
Metastatic disease .08 2.1 2.3-26.4 .25 used and active agents in advanced HCC, with a response
HBV .5 —
HCV .9 —
rate of approximately 25%.7 In a randomized study,6 free
RF .6 — doxorubicin has been shown to be superior to palliative
PEI .6 — treatment of HCC, although a subsequent meta-analysis
TACE .6 —
Surgical resection .04a 0.28 0.08-0.9 .9
showed no efficacy of the drug in terms of survival.17
AFP >400 ng/mL .02a 10.9 1.4-83.6 .02a 16.9 1.4-204.2 Conversely, the clinical usefulness of doxorubicin is lim-
ited by unacceptable toxicity, such as cardiotoxicity and
OS indicates overall survival; HR, hazard ratio; CI, confidence interval;
ECOG, Eastern Cooperative Oncology Group; PS, performance status; myelosuppression, which may preclude adequate dosing.
Ref., reference; HBV, hepatitis B virus; HCV, hepatitis C virus; RF, radiofre- To decrease its toxicity, new formulations have been
quency thermal ablation; PEI, percutaneous ethanol injection; TACE, trans-
arterial chemoembolization; AFP, alpha-fetoprotein. created, including pegylated liposomal doxorubicin. This
drug has shown efficacy in advanced HCC, with a
Table 6. Decrease in AFP of >20% After 2 Cycles of response rate of 10% to 17% and a median OS of 6.5
Chemotherapy Associated With TTP and OS, Results by
Univariate and Multivariate Analyses months; in particular, median OS was 12 months in
patients responding to treatment. Regarding safety, it
TTP OS showed a well-tolerated profile even in the presence of
impaired liver function; hematologic toxicity and PPE
Analysis P HR CI 95% P HR CI 95% were the most frequently reported side effects.19,20
Another frequently used drug was gemcitabine,
Univariate analysis <.001 0.1 0.05-0.4 <.001 0.04 0.01-0.2
Multivariate analysis <.001 0.08 0.02-0.28 .02 0.06 0.009-0.41
which demonstrated activity against human hepatoma
cells in vitro21 and as a single agent or in combination
AFP indicates alpha-fetoprotein; TTP, time to disease progression; OS,
chemotherapy regimens for advanced HCC; phase 2 trials
overall survival; HR, hazard ratio; CI, confidence interval.
have reported a response rate of about 18%,5 with favor-
able toxicity (finding grade 3-4 hematological toxicity in
DISCUSSION only about 10% of patients).
HCC has been considered to be a chemotherapy-resistant In light of these observations, the present study
tumor, and until recently there were no effective treat- aimed at improving the efficacy of systemic chemotherapy
ments that significantly increased survival in prospective with a favorable toxicity by combining 2 relatively active
randomized trials.17 The median survival of such patients drugs in HCC with different mechanisms of cytotoxic
was from 6 to 8 months. action and potential synergistic activity, lack of cross-re-
Only with the advent of sorafenib was a significant sistance, and nonoverlapping toxicity.
increase in survival obtained; a randomized, prospective, In this study, we analyzed the association of pegy-
double-blind, placebo-controlled phase 3 trial (SHARP) lated liposomal doxorubicin and gemcitabine; in particu-
in patients with advanced HCC and Child-Pugh A dem- lar, all patients received gemcitabine, a pyrimidine

130 Cancer January 1, 2011

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Gemcitabine and Doxorubicin in HCC/Lombardi et al

Median OS (95% CI)

ORR indicates overall response rate; CI, confidence interval; PFS, progression-free survival; TTP, time to disease progression; OS, overall survival; HBV, hepatitis B virus; NA, not available; PLD, pegylated lip-
nucleoside analogue, followed by the administration of
pegylated liposomal doxorubicin, a type 2 antitopoiso-

6.83 months (4.8-9.56)

11.5 months (8.5-14.3)
8.67 months (6.36-12)
merase. Various studies11,12 demonstrated that gemcita-

9.5 months (7.8-11)

9.6 months (8-NA)

10.7 months (NA)
68 weeks (48-78)
bine induces expression of all topoisomerase enzymes, and
4.6 months (NA)

8.9 months (NA)

3 months (NA)
the subsequent administration of pegylated liposomal
doxorubicin stabilizes the covalently bound topoisomer-
ase-DNA complex,22 resulting in massive DNA damage
and cell death.
With an overall response rate of 24%, a disease con-
PFS/TTP (95% CI)

trol rate of 58.5%, a progression-free survival of 5.8

6.3 months (4.3-10.1)
4.7 months (2.6-9.5)

5.3 months (3.7-8.7) months, and a median survival of 22.5 months, this com-
39 weeks (26-45)
2.5 months (NA)

5.5 months (NA)

2 months (NA)

bination regimen compares favorably with other systemic

Median

therapies for advanced HCC, including sorafenib and

other targeted agents (Table 7).
NA
NA
NA

In the past, the attractive combination of free doxor-

ubicin plus gemcitabine was analyzed by Yang et al.23
ORR, % (95% CI)

Unfortunately, they showed no CR, and PR was observed

in 11.8% of patients; the median OS was 4.6 months, and
20.9 (12.5-29.2)

osomal doxorubicin; PIAF, cisplatin/doxorubicin/5-fluorouracil/a-interferon; GEMOX, gemcitabine/oxaliplatin; HCV, hepatitis C virus.

11.8 (0.8-22-8)

the median TTP was 2.5 months. Likely, the lower clini-
10.5 (3.9-16.9)

20 (11-34)
10 (0-20)

18 (8-34)

cal efficacy of this combination may be because of the

26 (NA)

25 (NA)
20 (NA)

lower therapeutic index of free doxorubicin than pegy-

2 (NA)

lated liposomal doxorubicin. They found frequent grade

3-4 hematological toxicity, including neutropenia in
Metabolic syndrome (62.5)

51.4% of patients, anemia in 45.7% of patients, and

thrombocytopenia in 25.7% of patients. Also, Eastern
Predominant
Etiology (%)

patients recruited in these studies have worse clinical fea-

tures in general than those recruited in the Western
Alcohol (58)

world.24
HCV (30)
HCV (29)
HBV (84)
HBV (80)
HBV (94)
HBV (82)
HBV (80)
HBV (41)

In our study, we had 3 complete responses, and in 1

patient the complete remission was documented by histo-
logical examination. To our knowledge, only a few cases
Number
Patient

of complete response after systemic chemotherapy in

advanced HCC have been described in the literature25,26;
Table 7. Summary of Important Prospective Clinical Trials

50
40
50
94
94
32
55
40
30
299

1 case was reported using the gemcitabine-oxaliplatin

combination,26 and 4 patients had a complete pathologi-
Gemcitabine/doxorubicin

Bevacizumab/erlotinib
GEMOX/bevacizumab

cal remission with a cisplatin/doxorubicin/5-fluorouracil/

GEMOX/cetuximab

a-interferon regimen25; conversely, in this last chemo-

therapy regimen the toxicities were considerable; in fact,
Regimen

Doxorubicin

Sorafenib

there were also 2 treatment-related deaths.

GEMOX

Moreover, our treatment was able to convert some

PIAF
PIAF
PLD

inoperable lesions into operable lesions, increasing their

overall survival; 1 patient with initially inoperable disease
Phase

underwent liver transplantation and was alive and free

I-II

from recurrence at 52.8 months from treatment.

III
III

III
II
II

II
II
II
II

Furthermore, the TTP obtained in our study was

Asnacios et al32
Thomas et al33

similar to that shown by sorafenib, despite the finding

Llovet 200810
Leung et al25

Louafi et al31
Hong et al14
Yang et al23

Zhu et al34

that in the sorafenib trial only 5% of patients had Child-

Yeo et al30
Yeo et al30
Study

Pugh B; indeed, the TTP with gemcitabine-pegylated lip-

osomal doxorubicin regimen was 5.5 months, and 53.7%

Cancer January 1, 2011 131


Original Article
had Child-Pugh B. Thus, our regimen may be an effective
treatment for patients not eligible for sorafenib treatment
because of altered liver function.
In the past, the combination of gemcitabine and
pegylated liposomal doxorubicin for advanced HCC was
also analyzed by Poh et al.27 They showed a poor clinical
efficacy of the treatment; no patient achieved a CR or PR,
with 2 (22%) patients with SD; the median OS was 2.8
months. In this study, the schedule was identical to that
used in our study, although the sequence of administra-
tion of the drugs is not reported; moreover, they evaluated
only 9 patients with advanced HCC, among whom there
were 4 (44%) patients already treated with prior systemic
chemotherapy (pegylated liposomal doxorubicin and
capecitabine) and 8 (89%) patients who had prior locore-
gional treatment. Furthermore, 8 (88%) patients had ex-
trahepatic metastases. Other differences from our study
were that all patients were from Asia and predominant eti-
ology of HCC was chronic hepatitis B virus infection
(90%). Thus, it is not possible to make a comparison with
our study, which used this combination in chemonaive
Western patients, only 46.3% of whom had metastases,
53.6% of whom had prior locoregional treatment, and in
whom predominant etiology was hepatitis C virus
(48.8%).
We also conducted an exploratory analysis of predic-
tive factors for TTP and OS. Independent predictors for
improved TTP and OS were good ECOG PS and earlier
stage disease, whereas lower serum AFP was an independ-
ent predictor only for improved OS. Moreover, our treat-
ment was effective independently of liver function,
demonstrating a low hepatotoxicity of the chemothera-
peutic combination.
Interestingly, a decrease in AFP of >20% after 2
cycles of chemotherapy was an independent favorable pre-
dictor for TTP and OS. Only 1 prior study showed AFP
response to be a predictive factor for survival in patients
undergoing systemic chemotherapy28; they analyzed 117
patients with elevated serum AFP (>20 ng/mL), showing
AFP responders had better survival than nonresponders.
Similar data were originally reported for tamoxifen treat-
ment in HCC.29
Nevertheless, the toxicity of this combination was
acceptable; the most severe adverse effects were neutrope-
nia (17%) and anemia (7%), whereas the expected PPE
appeared only in 7% of patients.
In conclusion, although our trial was a small phase 2
study, the combination of gemcitabine plus pegylated lip-
osomal doxorubicin proved effective and safe in patients
132
10970142, 2011, 1, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.25578, Wiley Online Library on [22/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
with advanced HCC, even in patients with impaired liver
function. In particular, patients with good ECOG PS,
early stage disease, and low serum AFP could derive the
greatest clinical benefit. In particular, this combination
may be useful in chemonaive patients not eligible for sora-
fenib treatment because of altered liver function. How-
ever, further randomized studies are needed, and it could
be useful to evaluate this combination alone or in associa-
tion with the newer targeted agents such as sorafenib, erlo-
tinib, and bevacizumab.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
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