[Chinese Journal of Cancer 28:1, 45-48; January 2009]; ©2009 Sun Yat-Sen University Cancer Center
Clinical Research Paper
Efficacy of argon-helium cryosurgical ablation on primary hepatocellular
carcinoma
A pilot clinical study
Lin Zhou,1,2 Yong-Ping Yang,2,* Yong-Yi Feng,2 Yin-Ying Lu,2 Chun-Ping Wang,2 Xin-Zhen Wang,2 Lin-Jing An,2 Xin Zhang2
and Fu-Sheng Wang2
1PLA
Postgraduate Medical School; Beijing P.R. China; 2Liver Carcinoma Therapy and Research Center; PLA 302 Hospital; Beijing P.R. China
Key words: liver neoplasm, cryosurgery, efficacy, complication, survival
Background and Objective: Recent years, great progression has
been made in treating primary hepatocellular carcinoma (HCC)
with argon-helium cryosurgical ablation. This study was to evaluate
its efficacy on unresectable primary HCC. Methods: A total of 124
primary HCC patients were divided into early stage, middle stage
and advanced stage groups according to BCLC staging classification.
Clinical symptoms, tumor size, serum level of alpha-fetoprotein
(AFP), complications, and survival time were analyzed. Results:
After cryoablation of the tumors, serum level of AFP was reduced
in 76 (82.6%) patients, 205 (92.3%) of the 222 tumor lesions were
diminished or unchanged. Untill April 2008, 14 patients survived
and 110 died. The median survival time was 31.25 months in early
stage group, 17.41 months in middle stage group and 6.82 months
in advanced stage group. Conclusion: For the patients with unresectable HCC, argon-helium cryosurgical ablation has the advantages
of few complications and certain ­efficacy.
In recent years, the therapeutic efficacy on primary h­epatocellular
carcinoma (HCC) has been greatly enhanced. Hepatectomypredominant surgical treatment is still the first choice for HCC.
However, due to occult onset, the majority of HCC patients are
definitely diagnosed at middle and late stages. Thus, only 10–20%
of HCC patients could be treated with radical resection. For those
patients with unresectable HCC, treatment under the guidance of the
principle “survival with tumor” using minimally invasive approaches,
such as interventional therapy, radiofrequency ablation, microwave
coagulation therapy and argon-helium cryosurgical ablation (CSA),
*Correspondence to: Yong-Ping Yang; Liver Carcinoma Therapy and Research Center;
PLA 302 Hospital; Beijing 100039 P.R. China; Tel.: 86.10.66933429; Email: yongpingyang@hotmail.com
Submitted: 07/21/08; Revised: 09/04/08; Accepted: 10/15/08
This paper was translated into English from its original publication in Chinese.
Translated by: Wei Liu on 12/15/08.
The original Chinese version of this paper is published in: Ai Zheng
(Chinese Journal of Cancer), 28(1); http://www.cjcsysu.cn/cn/article.asp?id=15205
Previously published online as a Chinese Journal of Cancer E-publication:
http://www.landesbioscience.com/journals/cjc/article/8457
www.landesbioscience.com
shows good efficacy. Argon-helium cryosurgical ablation, a new cryosurgical approach, is a kind of mini-invasive surgery. It can induce the
formation of extracellular and intracellular ice crystals and cause cell
dehydration via rapid freezing ( < -140°C) lsion tissues with argon
gas as well as induce the necrosis of tumor cells via rapid thawing
(20–40°C) with helium gas. In this study, we retrospectively analyzed
the therapeutic efficacy of argon-helium cryosurgical ablation on 124
patients with unresectable primary HCC, which are summarized
below.
Materials and Methods
Clinical data. Clinical data of 124 HBsAg-positive patients with
unresectbale primary HCC, treated at PLA 302 Hospital from
December 2003 to December 2006, were analyzed. According to
the Barcelona Clinic Liver Cancer (BCLC) staging classification,1
16 patients (seven refused surgical resection, four were classified as
Child-Pugh Class B, and five had multifocal small HCC) had early
stage disease, 42 had middle stage disease, and 66 had advanced stage
disease (Table 1). End-stage HCC patients were not included since
only symptomatic treatment could be given to them. The following
patients were excluded: (i) those who previously underwent treatments, such as surgical resection and interventional therapy, due to
HCC; (ii) those who underwent other treatments such as interventional therapy (excluding argon-helium cryosurgical ablation) during
follow-up; (iii) end-stage HCC patients with hepatic function classified as Child-Pugh Class C.
Argon-helium cryosurgical ablation. After the patients were
admitted to the hospital, routine preoperative examinations were
performed. All patients were locally anaesthetized with 0.5% lidocaine and subjected to operation under B-ultrasound guidance.
Appropriate body position was maintained to meet the needs of
the operation. Depending on the size of tumors, different argonhelium cryoprobes (the third-generation CryocareTM surgical system
equipped with 2-, 3- and 5-mm insertable cryoprobes, manufactured
by Endocare, USA), puncturing site and orientation were selected.
Following routine sterilization and draping, the skin at puncturing
site was cut open and punctured with an 18-G inner core needle.
After B-ultrasound examination proved that the needle reached the
predetermined site of tumors, the inner core was removed and a
Chinese Journal of Cancer
45
Efficacy of argon-helium cryosurgical ablation on primary hepatocellular carcinoma: A pilot clinical study
Table 1
Clinical data of the 124 primary hepatocellular carcinoma (HCC) patients
that, the argon-helium cryoprobe was pulled out. Stanching satin was
used to fill the puncture wound, and a pressure dressing was applied.
After the operation, hemostatic drugs and antibiotics were applied
routinely. One to two weeks after the initial operation, the patients
with large-size tumors often underwent argon-helium cryosurgical
ablation again. Postoperatively, routine hepatic function test, alphafetoprotein (AFP) detection and CT scan were performed.
Therapeutic outcome observation. Therapeutic outcomes were
evaluated based on postoperative clinical manifestations, changes in
local lesions revealed by CT scan, AFP level, occurrence of postoperative complications, survival rate and average survival duration. The
follow-up was conducted by telephone untill April 2008, and the
follow-up rate was 100%.
Statistical analysis. Statistical analysis was conducted using the
CHISS software. Measurement data basically obeying the normal
distribution were analyzed using the t-test while the data not obeying
the normal distribution were analyzed using the rank sum test.
Results
Clinical manifestations. Most patients developed low fever,
wound pain, cough, and so on, but these symptoms usually eased
or disappeared two to three days later. Preoperative hepatalgia in
patients with large tumors was often significantly alleviated after
operation, which may be due to tumor size shrink caused by absorpAFP, alpha-fetoprotein; HBV, hepatitis B virus; HBVM, hepatitis B virus marker.
tion of necrotic tumor tissues.
Changes in local lesions. Contrast-enhanced abdominal CT
scans were performed at 4–6 weeks after
operation. A total of 186 ablations were
given to 222 lesions in 124 patients. Tumor
lesion necrosis was seen postoperatively in
all patients. Of the 222 lesions, 165 was
shrank, 40 had no significant changes,
and 17 showed increased size. The total
response rate was 92.3%. Figure 1 shows
complete tumor tissue necrosis in a small
HCC patient after operation.
Hepatic function and AFP level.
Postoperatively, the aminotransferase and
bilirubin levels in all patients showed varying
degrees of elevation. After liver-protecting
treatment, aminotransferase and bilirubin
levels returned to preoperative levels within
2 weeks in 87 (70.1%) patients and within
Figure 1. CT images of a small hepatocellular carcinoma before and after argon-helium cryosurgical
ablation. (A) Enhanced CT image shows a small hepatocellular carcinoma in the right lobe; (B) The tumor four weeks in 25 (20.2%) patients. In
was destroyed at four months after argon-helium cryosurgical ablation.
contrast, 12 (9.7%) patients showed no
improvement in hepatic function, of which
guide wire was introduced. The puncture needle was then pulled eight had HCC at advanced stage and four had HCC at middle stage.
out. Subsequently, a dilatation catheter with an outer sheath was All these 12 patients had hepatic function classified as Child-Pugh
introduced along the guide wire. When the catheter reached the Class B before operation. Among the 92 patients with preoperative
predetermined site, the catheter and guide wire were pulled out, and AFP elevation, the examination at four weeks after operation showed
the argon-helium probe was introduced along the outer sheath. The that 76 (82.6%) had AFP level significantly decreased, while 16
gas regulator was then switched on to permit argon gas flow to the (17.4%) had AFP level elevated.
Occurrence of postoperative complications. Argon-helium cryocryoprobe. When argon gas reached the cryoprobe tip, it caused a
sharp temperature drop to -140°C within 30 s. After holding at this surgical ablation only induced few and slight complications in HCC
temperature for 15–20 min, argon gas flow was shut off, and helium patients, of which hepatic function impairment, subcutaneous
gas was introduced for 3–5 min to enable the temperature back to and abdominal hemorrhage as well as pleural effusion were most
20–40°C. Two or three freezing-thawing cycles were repeated. After commonly seen but disappeared rapidly after treatment. No bile
46
Chinese Journal of Cancer
2009; Vol. 28 Issue 1
Efficacy of argon-helium cryosurgical ablation on primary hepatocellular carcinoma: A pilot clinical study
Table 2
Complications in the 124 HCC patients
duct fistula, perihepatic abscess and coagulation disorder were seen
(Table 2).
Causes of death. Of all 124 patients, 14 were still alive and 110
died. Of the 110 dead patients, 40 (36.4%) died of liver failure,
32 (29.1%) died of systemic failure caused by tumor recurrence
and metastasis, 25 (23.6%) died of gastrointestinal hemorrhage,
eight (7.3%) died of HCC rupture, and four died of other causes
(Table 3). The maximal survival duration was 52 weeks (still alive by
the end of the follow-up).
Survival analysis. The patients were followed up for 1–52 months.
By the end of follow-up, six of the 16 patients in early stage group,
four of the 42 patients in middle stage group, and four of the 66
patients in advanced stage group were still alive. The average survival
duration was (31.3 ± 3.2) months in early stage group, (17.4 ± 0.9)
months in middle stage group, and (6.8 ± 0.3) months in advanced
stage group. The 1-, 2- and 3-year survival rates were 75.0%, 56.3%
and 37.5% in early stage group, 61.9%, 22.9% and 5.7% in middle
stage group; the 1- and 2-year survival rates were 12.1% and 6.1%
in advanced stage group.
Discussion
The incidence of primary HCC ranks the fifth among all malignant tumors in the world.2 China is a high prevalence country of
HCC. The mortality of HCC ranks the second among all malignant tumors in China.3 In recent years, the rise of mini-invasive
surgery and local tumor treatment has opened up new avenues for
the treatment of HCC. Argon-helium cryosurgical ablation has
gradually become a major local treatment approach for unresectable HCC at middle and late stages. Compared with conventional
surgical resection for HCC, argon-helium cryosurgical ablation has
advantages of minimal invasion, less impact on hepatic function and
high re­producibility. Compared with other mini-invasive surgeries,
such as radiofrequency ablation (RFA) and microwave coagulation
therapy (MCT), argon-helium cryosurgical ablation has significant
advantages in reducing tumor residue and metastasis, enhancing the
body’s immunity, prolonging survival duration and relieving postoperative pain.4-7
Clinical studies show that it is essential to achieve tumorfree margins to improve the therapeutic efficacy of argon-helium
cryosurgical ablation on HCC. Accurate puncture and complete
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ablation of tumors are preconditions for ensuring the therapeutic
efficacy. In this study, different argon-helium cryoprobes were used
depending on the size of tumors to ensure that the ablated area
could cover the whole tumor and leave a tumor-free margin 1-cm
wide. For single tumors less than 5 cm in diameter, a single argonhelium cryosurgical ablation was applied; for multiple tumors less
than 5 cm in diameter, a single ablation with multiple argon-helium
cryoprobes was applied; for multiple tumors more than 5 cm in
diameter, multiple ablations with multiple argon-helium cryoprobes
were applied.
The major complications of argon-helium cryosurgical ablation are similar to those of surgical resection of HCC,8, 9 including
hemorrhage, pleural effusion, bile duct fistula, perihepatic abscess
and hepatic function impairment. Moreover, some freezing-related
complications, such as coagulation disorder, renal function impairment, low temperature-induced shock and hepatic parenchymal
rupture, may occur. In this study, all patients developed varying
degrees of hepatic function impairment after argon-helium cryosurgical ablation, which is similar to the result reported by Wen et
al.10 The hepatic function of 90.3% of the patients was recovered
to normal within four weeks after ablation, and only 9.7% of the
patients showed no improvement, which may be associated with
preoperative hepatic reserve capacity, ablation area and the number
of freezing-thawing cycles.9 Among other major complications,
pleural effusion and hemorrhage occurred in 23.4% and 16.1%
of the patients, respectively. Pleural effusion occurs mostly in the
right side and is associated with freezing-induced stimulation to the
diaphragm while hemorrhage is mainly associated with the placement of cryoprobes during puncture and the rupture of small blood
vessels during freezing. Fortunately, hemorrhage and pleural effusion
were rapidly alleviated in most patients after active treatment. Mala
et al.11 reported that the occurrence rate of pleural effusion ranged
from 4% to 18%. In our study, the occurrence rate of pleural effusion was as high as 23.4%, which may be due to large tumors, more
freezing-thawing cycles and tumor locations close to the diaphragm
in most patients. Because of the preventive application of antibiotics
and strict sterile surgical conditions, the occurrence rate of intraabdominal infection was very low. One patient with a tumor larger
than 13 cm in diameter developed HCC rupture and hemorrhage
after operation, which was the most severe complication observed
in this study. After interventional embolization, the hemorrhage was
stopped. However, the patient died of liver failure seven days later.
No bile duct fistula, perihepatic abscess, coagulation disorder and
acute renal failure were observed in our patients.
The therapeutic efficacy of argon-helium cryosurgical ablation on
unresectable primary HCC was evaluated based on tumor ablation
area, average survival duration, recurrence, decrease in AFP level,
and the occurrence of complications. Serum AFP level is currently
the most commonly used index for laboratory detection of primary
HCC. Our previous results had indicated that, of 320 primary HCC
patients, 71.7% had AFP elevation.12 Of the 124 patients included
in this study, 74.2% had AFP elevation. The results of these two
studies are basically consistent. For the patients with AFP elevation,
postoperative change in AFP level can be used as an effective index
for evaluating therapeutic efficacy and recurrence. In this study,
among the 92 patients with AFP elevation, 76 (82.6%) showed a
significant postoperative decline in AFP level while 16 (17.4%) had
an elevation. Postoperative decline in AFP level may be associated
with reduced AFP release by tumor tissues due to freezing-induced
Chinese Journal of Cancer
47
Efficacy of argon-helium cryosurgical ablation on primary hepatocellular carcinoma: A pilot clinical study
Table 3
Causes of death among the 124 HCC patients
Figure 2. Kaplan-Meier survival curves of HCC patients at different stages
after argon-helium cryosurgical ablation
necrosis. Because of inaccurate B-ultrasound-guided localization in
some patients, some normal liver tissues, besides tumor tissues, were
also frozen and became necrotic. Since neonatal hepatic cells can
release a large amount of AFP during regeneration process, elevated
AFP levels, usually accompanied by significant hepatic function
impairment and elevated aminotransferase level, are caused postoperatively. CT scans of 222 lesions in 124 patients at 4–6 weeks after
ablation showed tumor necrosis, manifesting as a decrease in CT gray
values, in all patients. On these CT scans, 165 lesions showed diminished size, 40 had no significant changes, and 17 showed increased
size. The total response rate was 92.3%.
In this study, after argon-helium cryosurgical ablation, the
median survival durations of patients with HCC at early, middle
and advanced stages were 31.25, 17.41 and 6.82 months, respectively. Zhou et al.13 treated 235 HCC patients with argon-helium
cryosurgical ablation and found that the 1-, 3- and 5-year survival
rates of the patients treated with argon-helium cryosurgical ablation
alone were 63.9%, 40.3% and 26.9%, respectively. However, they
did not compare the therapeutic efficacy of cryosurgical ablation
among patients with HCC at different stages. In our study, the 1-,
2- and 3-year survival rates of the patients with HCC at early stage
were 75%, 56.3% and 37.5%, respectively, while the 1- and 2-year
survival rates of the patients with HCC at advanced stage were
12.1% and 6.1%, respectively. Kerkar et al.14 reported that the 1-,
2-, 3- and 5-year survival rates of 98 malignant liver tumor patients
(56 had metastasis from rectal cancer, 28 had metastasis from nonrectal cancer, and 14 had HCC) after cryosurgical ablation were
81%, 62%, 48% and 28% (median survival duration of 33 months),
respectively, with a median survival of 33 months. These results
48
indicate that argon-helium cryosurgical
ablation not only has different therapeutic
efficacies on metastatic and primary HCC
but also results in significant difference
in the median survival duration among
patients with HCC at different stages.
In contrast to lung cancer, prostate
cancer and gastric carcinoma, HCC is
usually accompanied with liver cirrhosis
in addition to tumor invasion and oppression.12 Thus, liver cirrhosis-induced liver
failure and esophageal variceal hemorrhage
are also important death causes of HCC
patients. Of all dead HCC patients in our study, 60% die of liver
cirrhosis-induced liver failure and esophageal variceal hemorrhage,
and 36.4% die of tumor recurrence and metastasis-induced systemic
failure and HCC rupture-induced hemorrhage. Dong et al.15 found
that, of 396 dead primary HCC patients, 46.2% died of upper
gastrointestinal hemorrhage and 38.9% died of liver failure. These
results indicate that surgical resection-based combination therapy is
preferred for HCC, and liver-protecting treatment and esophageal
varices treatment are very important for prolonging the survival
duration and improving the life quality of HCC patients.
The above results indicate that, for patients with unresectable
HCC at middle and late stages, argon-helium cryosurgical ablation
can achieve satisfactory performance in safety, control of complications and improvement of postoperative life quality and average
survival duration. Furthermore, the attempts of combining argonhelium cryosurgical ablation with interventional therapy, ethanol
injection, and immunotherapy will open up new avenues for
combined treatment of HCC at middle and late stages. However, the
long-term efficacy remains to be observed.
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Chinese Journal of Cancer
2009; Vol. 28 Issue 1