Cancer
Hepatocellular Carcinoma
Hepatocellular carcinoma is the most prevalent malignant disease
in the world, killing up to 1.25 million people per year. HCC
accounts for more than 80% of all primary liver tumors and has
a worldwide annual incidence of approximately 1 million new
cases, (136) with a male to female
ratio of about 3-8:1. (137) HCC
is a common malignancy in Africa and Asia, and it accounts for
approximately 4000 to 6000 cases per year in the USA. (138)
Eighty to ninety percent of patients with HCC have underlying
cirrhosis; alcoholic cirrhosis is the predominant type in Western
countries, whereas in southeast Asia, posthepatitis cirrhosis
is more common. There is a strong correlation between HCC and
chronic hepatitis B. High incidence rates in Africa and Asia
have been associated with high endemic HBsAg carrier rates.139
In these areas highly endemic for hepatitis B, an association
between HCC rates and mycotoxin contamination of food has been
detected. (138) One of the identified
mycotoxins is one of the most potent< natural chemical carcinogens
known: aflatoxin B1. This toxin, produced by Aspergillus flavus
and Aspergillus parasiticus, is usually associated with grains
and food products such as peanuts and rice. (140)
More recently, an association between HCC and chronic hepatitis
C has been determined. Antibodies to hepatitis C virus are found
in as many as 80% of patients with hepatocellular carcinoma
in countries including Japan, Spain, and Italy. (141)
HCC carcinogenesis has also been associated with radiation,
thorotrast, smoking, alpha-1 antitrypsin deficiency, hemochromatosis,
Budd-Chiari syndrome, porphyria, oral contraceptives, and anabolic
androgenic steroids.
When identified in its early stages, HCC can be treated with
surgical resection or liver transplantation, and some patients
may be cured. However, the disease is often not amenable to
surgical treatment, either because of tumor size or because
of poor liver function. In these situations, the prognosis is
dire.
Other treatment approaches have been tried when surgery or liver
transplantation are not feasible. Systemic chemotherapy results
are at best dismal. Conversely, a large number of reports have
provided encouraging perspectives for regional chemotherapy.
(138) Transcatheter arterial
chemoembolization (TACE) is a combination of regional chemotherapy
and some form of hepatic artery occlusion. Consistently higher
response rates have been reported for TACE when compared with
systemic chemotherapy. Combining immunomodulatory therapy with
TACE was expected to increase the efficacy level even higher.
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Italian trial of Zadaxin in HCC
(142)
This phase 2 trial examined the efficacy and safety of Zadaxin
for treatment of HCC.
| Patients and
protocol: |
| • |
12 patients |
| • |
11 patients with Child
class A or B cirrhosis, Okuda stage I or II tumors |
| • |
1 patient with Child class
C cirrhosis, Okuda stage III tumor |
| • |
Diagnosis based on ultrasonography
and histology |
| • |
6 months treatment with
0.9 mg/m2 Zadaxin (SC, BIW) |
| • |
TACE (40 to 60 mg of doxorubicin) |
•
 |
Historical control group matched for
gender, age, Okuda staging, Child score, a-fetoprotein
serum levels, and viral infection, treated with TACE alone |
| Results: |
| • |
Longer survival times
in Zadaxin-treated patients |
|
| – |
Statistical
significance achieved 7 months after end of treatment |
| – |
82% versus
41% survival |
| – |
P <
0.05 |
|
| • |
Significant increase in
cytotoxic T cells (CD8) in Zadaxin-treated patients at
3 months after end of treatment |
| • |
Significant increase in
NK cells (CD16 and CD56) in Zadaxin-treated patients at
1 month after end of treatment |
The delayed after-treatment effect of Zadaxin observed in this
study is concordant with studies in hepatitis B where it is
common to see patients respond to Zadaxin during the follow-up
period.
Chinese Trial of Zadaxin in HCC
This open-label, historically controlled trial evaluated the
efficacy and safety of adding Zadaxin therapy to TACE. (143)
| Patients and
protocol: |
| • |
32 patients |
| • |
TACE procedure |
| |
| – |
5 to
15 mL iodinized oil |
| – |
40 to
60 mg doxorubicin HCI |
| – |
100 to
200 mg carboplatin |
| – |
1 g
5-FU |
| – |
Zadaxin:
1.6 mg SC days 1 to 10 after TACE treatment |
|
| • |
26 historical controls |
| |
| – |
Matched
for gender, age, Okuda staging, Child’s score,
serum a-fetoprotein, viral hepatitis infection |
| – |
Treated
with TACE alone |
|
| • |
HCC tumor variants: massive, nodular,
diffuse |
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| Results (Figure
18) — Zadaxin + TACE: |
| • |
Significantly lowered AFP
levels from baseline
(512 ng/mL): |
| |
| – |
354 ng/mL
after treatment |
| – |
215 ng/mL
2 weeks post therapy |
|
| • |
Significantly increased
CD3 count and NK-cell activity 2 weeks post treatment
(P < 0.05) |
| • |
Significantly increased
CD4/CD8 ratio |
| |
| – |
1.07
ratio value before therapy |
| – |
1.55
ratio value 2 weeks post therapy |
|
 |
Figure 18.
Zadaxin+TACE: HCC survival. (143) |
| Results
— 3-month survival |
| • |
96% Zadaxin + TACE |
| • |
96% TACE |
|
| Results
— 9-month survival |
| • |
88% Zadaxin + TACE |
| • |
58% TACE |
| • |
P < 0.05 |
|
| Results
— 6-month survival |
| • |
91% Zadaxin + TACE |
| • |
77% TACE |
| • |
P < 0.05 |
|
| Results
— 12-month survival |
| • |
78% Zadaxin + TACE |
| • |
46% TACE |
| • |
P < 0.05 |
|
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|
