| Hepatocellular carcinoma
(HCC) is a highly malignant tumor with
a very high morbidity and mortality worldwide,
carrying a poor prognosis and presenting
considerable management due to its rapid
infiltrating growth and complicating liver
cirrhosis. The treatment of patients with
HCC has been evolving in the past years.
Selection of the best treatment modality
for HCC
Liver resection remains a good treatment
for HCC in patients with cirrhosis. The
best results are obtained in patients
with small, non-invasive tumors. However,
only a small number of patients are suitable
for curative resection due to many factors
such as multicentric tumors, extrahepatic
metastases, early vascular invasion, coexisting
advanced liver cirrhosis and comorbidities.
Liver transplantation seems to be the
choice for monofocal HCC less than 5 cm
in diameter and in selected cases of plurifocal
HCC, but may be limited by availability
of donor organs and a long waiting time.
Local methods for tumor ablation, which
include transarterial chemoembolization
(TACE), percutaneous ethanol injection
(PEI), radiofrequency ablation (RFA),
microwave coagulation therapy (MCT), laser-induced
thermotherapy (LITT), and Cryoablation,
are promising extensions of tumor therapy,
especially in patients with limited liver
function, unresectable tumors, or multifocal
tumors.
Since TACE was introduced as a palliative
treatment in patients with unresectable
HCC, it has become one of the most common
forms of interventional therapy. TACE
has been shown to reduce systemic toxicity
and increase local effects and thus improve
the therapeutic results. Its therapeutic
effect is also limited by the lack of
appropriate and reliable embolic agents
and when the tumor is infiltrative in
nature or is hypovascular, too large or
too small.
PEI is widely used with excellent results
for small, encapsulated tumors in livers
with less than three HCCs, but it is not
suitable for patients having coagulopathy
or ascites.
While RFA results in a higher rate of
complete necrosis and requires fewer treatment
sessions than PEI, the complication rate
is higher with RFA than with PEI.
MCT under local anaesthesia is a minimally
invasive and effective therapy when carried
out on a single occasion to treat HCC
located near the liver surface. MCT may
be superior to PEI for the local control
of moderately or poorly differentiated
small HCC.
MR-guided LITT is another local effective
therapy with low morbidity in malignant
liver tumors with a maximum quantity of
5 and a size of < or = 5 cm, but local
recurrence can occur even in small HCC,
while this drawback is infrequent. Biotherapy
will play a certain role in the treatment
of HCC, however, the results are still
controversial.
Cryoablation is a method of in situ tumor
ablation. Cryosurgery destroys neoplastic
tissue by application of cold and affords
a better chance of cure because of predictable
necrosis even for HCC larger than 3 cm.
The cryoablation was performed with the
Cryocare System (Endocare, Irvine, CA,
USA) by using Argon gas as a cryogen.
Cryoprobes (3,5,or 8mm) were inserted
into the center of tumor mass under ultrasonographic
guidance, and two freeze-thaw cycles were
performed, each reaching a temperature
of –180? C at the tip of the probe. The
time of freezing was dependent on the
achievement of an “ice ball”, visible
as a hypoechoic region by ultrasonography.
Generally, the tumor were frozen at maximum
flow rate for about 15 minutes, and then
were thawed for 5 minutes and then refrozen
for another 15 minutes. A margin of at
least 1cm normal hepatic tissue was frozen
circumferentially around tumor. For mass
larger than 5 cm, two or three cryoprobes
were placed within the center and periphery
of tumor respectively, to insure freezing
of entire tumor. Lastly, the cryoprobe
was removed when the tip temperature reached
0?C and the tract formed was sealed off
with fibrin glue immediately after removal
of the cryoprobe to ensure haemostasis.
Tumor cell death is caused by both direct
and indirect mechanisms. The direct cellular
damage is a result of intra- and extra-cellular
ice crystal formation and solute-solvent
shifts, which induce cell dehydration
and rupture. The indirect effect results
from vessel obliteration with resulting
ischemic hypoxia.
As a local therapy, cryoablation carries
certain advantages over other forms of
HCC treatment. First, it is able to destroy
only the tumor tissue in liver while sparing
more noninvolved tissues, which is of
important significance to HCC patients,
because the majority of these patients
have cirrhosis and decreased reserve of
liver function. Second, because of the
warming effect of flowing blood, large
blood vessels, such as inferior vena cava
and portal vein, are somewhat imperious
to the effect of freezing. Therefore,
tumors close to these venous system can
safely undergo cryoablation, whereas resection
of tumors close to large vascular structures
is very difficult. Third, it is known
that liver cirrhosis is a basis of HCC
development,if the entire liver is cirrhotic,
any part of the liver can develop new
tumors. Liver cryoablation is more effective
than surgical resection in treating multiple
new tumors. Forth, in contrast with other
local ablations, such as radiofrequency,
which is difficult to reliably destroy
tumors greater than 5 cm in diameter,
cryoablation is a promising means in the
treatment of this larger form of tumor.
Lastly, the rapid freeze-thaw process
enhances necrosis and helps induce an
immune response against the surviving
tumor cells.
How to increase therapeutic efficiencies
and prevent recurrence
It is well known that improving the overall
therapeutic effects of liver cancer depends
on the combined therapies. The purpose
of combined interventional therapies for
HCC is to give full play to the merits
of various therapeutic schemes, to overcome
their shortcomings and to get combined
effects that are impossible to obtain
from any single therapeutic regimen. The
general principles of combined therapies
for HCC are to destroy the tumor as completely
as possible, to increase their therapeutic
efficiencies but not the side effects
and complications, to keep the liver function
and immunity of patients in a better condition,
and to choose the suitable combined therapeutic
plan individually.
First Step:
Do Pre-operative TACE
TACE is a combination of target chemotherapy
and arterial embolization that has both
selective ischemic and chemotherapeutic
effects on HCC. TACE is an excellent debulking
procedure. Surgically resected specimens
showed that TACE effectively destroyed
malignant cells, not only in the main
tumors, but also in daughter tumors, extracapsular
invasion, and intraportal neoplastic thrombi.
TACE was proved to be effective in treating
HCC, and has been widely used for patients
with unresectable HCC in Asia. TACE application
to HCC has demonstrated good results in
reducing the size of tumor and improving
survival. It was even found that the effects
of TACE was comparable to that of resection
in some subpopulations of patients with
operable HCC. However, TACE is not a curative
method. Tumor cells remain viable, especially
in and around the capsule, and tumors
may recur by the blood supply from the
collateral circulation or portal vein.
The long-term efficacy of TACE was disappointing.
1, 3, and 5 year survival rates were around
50 %, 20 %, and 6 %, respectively. In
the present study, the RR and 5 year survival
rate in the TACE control group were 28.1
% and 7.2 %, respectively, which were
approximate to the results in the literature.
Nevertheless, in some prospective randomized
trials, TACE therapy failed to improve
the survival of patients significantly.
Segmental TACE has been shown to yield
5 year survival rate (30 %) for patients
with lesions less than 5 cm, but it is
suitable only for small tumors. Thus,
multimodality treatments are necessary,
especially for large HCC. We have found
in a clinical trial that TACE combined
with other therapies may be a good method
for large unresectable HCC.
Fig.1 Modern Model for Treatment of HCC
Second Step:
Choice one: If resectable, do Cryohepatectomy
If tumor shrinkage after TACE allowed
the use of hepatectomy, we combined TACE
with cryohepatectomy (cryosurgery with
liquid nitrogen (-196 degrees C) followed
by the resection of the frozen tumor by
conventional technique for HCC), and found
that it may remedy the limitation of each
alone and have synergistic effects. Combination
therapy also serves the purpose of eliminating
residual cancer cells after TACE. Furthermore,
the anticancer drug retained in the tumor.
The anticancer drug, when it is mixed
with lipiodol, has been reported to maintain
relatively high concentrations in tumors
as long as 27 days and decrease to a trace
level after 47 days. Yoshikawa et al.
reported that the combination therapy
was more effective than TACE or cryohepatectomy
alone in a preliminary study encompassing
a small number of cases. From then on,
this combination regimen was carried out
to treat HCC by more investigators, and
was found to be an effective method for
HCC. The results of our study also suggested
that TACE followed by cryohepatectomy
was a promising approach for large HCC.
The RR and 5 year survival rate were 47.4
% and 19.3 %, respectively, in 76 patients
with very large tumors (≥5 cm in all cases,
>10 cm in 38.2 % of the cases, while
two hepatic lobes were involved in 31.6
% of the cases).
We once did a research which included
84 patients who underwent cryohepatectomy
for HCC and were closely follow-up after
surgery. Recurrence and survival rates
were calculated by the life-table method.
We found that the postoperative course
of cryohepatectomy in all of the 84 patients
was uneventful, there being no operative
mortality or severe complications. The
1-, 3-, and 5-year survival rates after
cryohepatectomy were 98.7%, 83.9% and
64.0%, respectively. The 1-, 3-, and 5-year
recurrence rates after cryohepatectomy
were 15.1%, 30.1% and 39.0%, respectively.
It was proved that cryohepatectomy for
HCC was a safe procedure and may be potentially
beneficial in reducing recurrence and
prolonging survival. More time is needed
to further define whether this procedure
will improve long-term survival as compared
with conventional resection.
Choice two: If unresectable, do
Cryoablation or in combination with PEI
Prognosis of unresectable HCC is very
poor. In Japan, the median survival for
229 patients received no specific treatment
was 1.6 months. Although chemoembolization
is associated with good objective responses
in the tumor, a recent controlled trial
showed that by itself, chemoembolization
offered no improvement in survival compared
with supportive therapy alone[6]. Cryoablation
after TACE yielded higher survival rates
at 1, 2, and 3 years than TACE alone did[32-37],
and it was suitable for larger tumors,
even >8 cm. The results of combination
therapy in the present study appeared
to be comparable to those in other reports
of multimodality therapy.
In order to evaluate the effectiveness
of sequential treatment of transarterial
chemoembolization (TACE)-percutaneous
cryoablation for unresectable primary
liver cancer (PLC). We did a research
and once reported that three hundred and
sixty patients with PLC were received
the therapy. Intrahepatic tumor masses
were larger than 5 cm in size. 220 patients
had single mass in liver and others had
multiple masses but which numbered less
than 5. The patients with thrombosis of
portal vein, hepatic failure (serum bilirubin
of more than 34 ?mol/L, prothrombin time
of more than 3s over the control) and
obvious ascites were excluded from the
treatment schedule. The tumors of all
patients were considered to be unresectable
through comprehensive comment. Transarterial
chemoembolization was completed according
to routine method. The branch of the hepatic
artery supplying the tumor is occluded
at the arteriography by injection lipiodol
mixed with chemotherapeutic agents (adrimycin,
cisplatin and mitomycin) and gelfoam.
Two weeks later, if CT scanning showed
good response, percutaneous cryoablation
should be given, otherwise, the chemoembolization
should be completed again (generally no
more than 3 times). The cryoablation was
performed with the Cryocare system (Endocare,USA)
by using argon gas as a cryogen. Temperature
in targeting tissue reached to under –160?
C for 10 to 15 min, and then, helium was
sended to increase the temperature to
20?C. Two freeze-thaw cycles were performed.
One month after cryoablation, the chemoembolization
of one or two times may be further performed
if necessary. Among the follow-up period
of median 21 months (6-36 months), ultrasound
and /or CT showed that a complete response
(CR) was seen in 30 cases (8.3%), partial
response (PR) in 228 cases (63.3%), no
change (NC) in 66 cases (18.3%), and progressive
disease (PD) in 36 cases (10.0%). Alpha-fetoprotein
(AFP) was significantly decreased and
decreased into normal range, in 86.9%
and 62.0%, respectively, of 229 patients
with pre-therapy elevation of serum levels
of this protein. Out of 258 patients with
CR and PR, 26.7 % had intrahepatic recurrence,
but only 15.9% developed a cryosite recurrence.
There were 113 cases who died during the
follow-up period,and the death reasons
included widespread metastasis in 45 cases,
rupture of esophageal varices in 24 cases,
spontaneous peritonitis in 23 cases, hepatic
encephalopathy in 14 cases and other non-liver
cancer-related causes in 7 cases. We proved
that sequential treatment of TACE-percutaneous
cryoablation offers a safe and effective
treatment options and may result in a
shrinkage or eradication of tumor mass
and increase of survival for patients
with unresectable PLC.
During the past years, great efforts have
been made to improve the survival of the
patients with this disease. In this trial,
percutaneous cryoablation in combination
with PEI showed more satisfactory therapeutic
efficacy.
Cryoablation was performed with Endocare
cryosurgery system. The result shows forty
eight patients were followed-up for 6-20
months. The decreased volume of intrahepatic
tumor was seen in 81.3 percent of patients,
no change of tumor in 12.5 percent and
increased volume in 6.3 percent; decreased
levels of serum alpha-fetoprotein were
seen in 85.3 percent, no significant change
in 11.8 percent and increased levels in
2.9 percent; 87.5 percent of patients
were alive for 6-20 months and 12.5 percent
of patients died with life span of 4-17
months. According to Kaplan Meier method,
the survival rate was 89.6 percent in
6 months, 80 percent in 12 months and
66.6 percent in18 months. It was proved
by us the sequential therapy sequential
consisted of TACE)-cryoablation-PEI has
complementary value for HCC treatment
and may be an alternative modality in
selective patients.
We once did another interesting research.
TACE was given at first, followed by cryoablation
at 2-3 weeks later, and lastly PEI was
given. We treated unresectable HCC like
this way and had better results. In our
hospital, a total of 105 masses in 65
HCC patients, who were not suitable for
surgical resection, was underwent percutaneous
hepatic cryoablation. The cryoablation
was performed with the Cryocare system
by using argon gas as a cryogen. Two freeze-thaw
cycles were performed, each reaching a
temperature of –180? C at the tip of the
probe. PEI was used in was given in 36
patients with tumor mass larger than 6
cm in diameter, was given since 1-2 weeks
after cryoablation and then once per week
for up to 4 to 6 sessions. Absolute alcohol
(100%) was slowly injected into periphery
zone of cancerous tissue in liver. During
median follow-up duration of 14 months
with a range of 5 to 21 months,33patients(50.8
%) are currently free of tumor,22patients
(33.8 %) are alive with tumor recurrence:
two had bone metastases, three were found
to have lung metastases, and the remaining
17 recurrences occurred in the liver ,
of whom only 3 developed a cryosite recurrence.
Among 41 patients who were given followed
up more than one year, there was a total
of 32(78%) who are alive, despite of tumor
recurrence. Eight patients (12.3 %) have
died with their disease recurrence. Three
patients (4.6%) have died of noncancer-related
causes. Among 43 patients who had a CT
scan available for review, 38 (88.4%)
had a shrinkage of tumor mass. Among 22
patients received biopsies of cryoablated
tumor mass, all biopsies, except one,
showed only dead or scar tissue. 91.3%
of patients who had an increased serum
AFP pre-cryoablatively, had a decrease
of AFP to normal or nearly normal levels
during postoperative 3-6 months. Complications
of cryoablation included liver capsular
cracking in one patients, transient thrombocytopenia
in 4 patients and asymptomatic right-sided
pleural effusions in 2 patient. Two patients
developed liver abscess at the previous
cryoablation site at 2 and 4 months, respectively,
following cryoablation and was recovered
with antibiotics and drainage. We think
percutaneous cryoablation offers a safe
and possibly curative treatment options
for patients with HCC that cannot be surgically
removed, and its integration with PEI,
may be as an alternative to partial liver
resection in selective patients.
Among 65 HCC patients receiving this combined
therapy and followed up for an median
duration of 14 months, 50.8 % of patients
are currently free of tumor and 33.8 %
are alive with tumor recurrences. Among
the 41 patients who were followed up for
more than one year, 78% are alive despite
of tumor recurrence. Only 10.8 % died
from tumor recurrence with an overall
survival of the 13.2 months. Of the patients
who had CT scan available for review,
88.4% had some shrinkage of tumor masses.
Of the 22 patients who received biopsies
of their cryoablated tumor masses, all
but one showed only dead tumor cells or
scar. Of the patients who had an increased
AFP preablatively, 91.3% had a decrease
of AFP to normal or nearly normal levels
during postablative 3-6 months.
Present result is comparable with those
by other authors. Crews et al reported
that forty patients with hepatic malignancy
underwent cryoablation and the estimated
18-month survival was 60% and 30% for
patients with HCC and with colorectal
metastasis, respectively. Lam et al treated
4 patients with recurrent HCC after previous
curative hepatectomy with cryoablation.
All their patients were still alive with
a survival after cryoablation ranging
from 12 to 23 months. Sheen et al have
demonstrated that the median survival
for HCC patients after cryoablation was
36 months. Zhou et al reported 1-, 3-
and 5-year survival rates of 78%, 54%
and 40%,respectively in 235 HCC patients
who received cryoablation .It should be
noted that the cryoablation reported by
those authors was mainly performed through
intraoperative approach with a large invasion,
while in the present trial, cryoablation
was performed percutaneously, being minimally
invasive and allowing for a rapid recovery.
During cryoablation, freezing occur in
three main areas:(1) the center of iceball
near the cryoprobe, where freezing is
rapid and the temperature is lowest;(2)
the middle of the iceball, where the tissue
experiences intermediate cooling rate;
and (3) the periphery of the iceball,
where slow rates of cooling occur.The
cytotoxic effect from rapid cooling is
the greatest in the center of the iceball,
while cells at the periphery of the iceball
may survive, particularly if the tumor
abuts a large intrahepatic blood vessel
that abrogates the effects of tissue cooling.
The surviving tumor cells result in the
recurrence of the disease.
PEI has been used extensively for treatment
of HCC. Ethanol diffuses into the tumor
cells and causes nonselective protein
denaturation and cellular dehydration,
leading to coagulated necrosis. Subsequent
fibrosis and small vessel thrombosis also
contribute to cellular death. Therefore,
after cryoablation which could destroy
much majority of tumors, PEI used at periphery
of tumor can destroy residue tumor tissues.
It is obvious that combination of cryoablation
and PEI had a complementary effects for
preventing recurrence. In this series,
PEI was given to 36 patients with tumor
mass larger than 6 cm in diameter 1-2
weeks after cryoablation, which may be
contributory to a better outcome. Moreover,
among the 17 patients who had recurrent
tumors, only 3 had recurrence at the original
cryosite, which suggests the effectiveness
of this combined therapy as well.
Third Step:
Do post-operative TACE and/or postoperative
trans-portal vein chemotherapy in combination
with IFN or others
Over the last two decades, the surgical
techniques and peri-operative care have
been improved, and the operative death
(within 30 days after operation) decreased
to 2.5 %, the 5-year overall survival
after curative resection of hepatocellular
carcinoma (HCC) increased to 25 % or 46.7
%. However, HCC is far from a curable
disease because of high recurrence rate,
the 5-year recurrence rate after curative
resection was 38 % to 61.5 %, the 5-year
disease-free survival was 16 % or 38.6
% after curative resection of HCC, and
the recurrence resulted in most deaths
after resection.
People have tried a number of approaches
to prevent recurrence, including post-operative
TACE however, only a few of them were
designed as randomized control trial (RCT),
which provide evidence-based results for
those treatment modalities.
The first RCT study on post-operative
TACE (postTACE) was reported by Izumi
et al in1994. The authors enrolled 50
patients after curative resection of HCC
with blood vessel involvement or intra-hepatic
spreadings. The results showed that both
DFS rate and DFS time were higher in postTACE
group than those in control group. However,
1 and 3-year OS rates were similar in
both groups (58.8 % vs 63.5 %; 30.5 %
vs 33.9 %, P=0.7647), the median survival
time in postTACE was shorter than that
in the control group (644.5±129.4 days
vs 759.9±137.5day, P<0.05). The authors
concluded that postTACE may postpone but
not eliminate the recurrence (60.9 % vs
81.5 %, P=0.106).
In another RCT reported by Lau et al,
the authors used 131I-Lipiodol instead
of conventional Lipiodol. The result showed
that postTACE improved DFS and OS, decreased
recurrence without major side-effects.
This is the only one RCT reporting a positive
result for postTACE treatment. The authors
suggested more effective agents should
be used in postTACE.
However, in Lai et al 's study of postTACE,
although the preventive treatment protocol
was more aggressive than Izumi's study,
the result was even worse. The recurrence
rate and extrahepatic metastasis rate
were higher in postTACE group (recurrence
rate: 23/30 vs 17/36, P=0.01) extrahepatic
metastasis rate: 11/30 vs 5/36, P=0.03);
3-year DFS in postTACE group was lower
than that in the control group (18 % vs
48 %, P=0.04). The OS in postTACE group
was worse than that in the control group,
especially in the first two years, but
the difference was not statistically significant.
Therefore, the authors concluded postTACE
is harmful to patients after curative
resection of HCC.
The reason of why conflicting results
came from different RCTs is the selection
of patients. Lai et al 's group of patients
was selected by a highly rigorous standard;
the rationale of preventive treatment
was not solid enough to protect this group
of patient with interventional treatment
like postTACE. However, in Izumi and Lau's
studies, the authors selected a group
of patients with more possibility of recurrence
(invasive cancer or large cancer), so
the results turned out to be effective.
In summary, postTACE is not only beneficial
to the patients with invasive HCC, but
also effective and useful to the patients
after treatment, especially for preventing
recurrence.
Further, we found that hapatectomy sequencing
two vessels therapy (Preoperative adjuvant
TACE and postoperative trans-portal vein
chemotherapy) in perioperative period
could be to increase disease-free survival
rate, which can prevent and delay the
incidence of recurrence and may improve
the effect of liver resection. We once
did further research. There were three
hundred and sixtee cases of operable hepatocellular
carcinoma who were divided into three
groups. Only hepatectomy were performed
in group one (218 cases). Preoperative
adjuvant TACE were done in group two (52cases).
Preoperative adjuvant TACE and postoperative
trans-portal vein chemotherapy were done
in group three (46cases), which is named
hepatectomy sequencing two vessel therapy.
We found disease-free survival rate of
1,3 and 5 year were 51.2%,30.0% and 20.5%
respectively in group one ,57.2%,43.0%
and 31.5% in group two ,84%,62.5% and
51.0% in group three. The disease-free
survival rate of postoperation in group
three was significantly higher than group
one and group two (p<0.05).
The rationale of post-operative IFN treatment
came from the several findings in HBV
or HCV related HCC. First, a lower incidence
of HBV or HCC was observed in many studies
when IFN was used to clear HBV or HCV
viremia; second, recurrence after curative
resection of HCC developed from multicentric
origin, which was closely related to the
HBV or HCC viremia status. Third, IFN
had anti-cancer effect on the early stage
tumors, like micrometastatic lesions.
The following is the summary of post-operative
IFN treatment (Table 1).
Table 1 Summary of RCTs to evaluate the
efficacy of pre- and post-operative TACE
on prevention of recurrence
|
Enter
criteria |
Method |
Case(IFN/CTL) |
Follow-up
time |
Comment |
| Ikeda Kubo |
Complete
resection
(operation or PEI)
complete
remove
(operation) |
IFNbeta 6 mu
imBIW 36 mons
IFN alpha 6mu
BIW 2wks
then TIW 14wks
then BIW 88 wks |
20(10/10)
30(15/15)
|
2-346 mons
1817 days
|
Beneficial
Beneficial |
L: lipiodol; M: mitomycin; A: adriamycin,
G: gelfoam; C: cis-platin; Tx: treatment;
Ctl: control; DFS: disease free survival;
OS: overall survival.
|
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Fuda cancer hospital Guangzhou