Cryotherapy for Liver Tumors

Cryotherapy for Liver Tumors

ABSTRACT: The curative management of primary and metastatic liver tumors has traditionally relied on surgical resection. Unfortunately, fewer than 10% of newly diagnosed patients have tumors that are considered to be surgically resectable. Limitations that often preclude a safe surgical resection include bilobar or centrally located tumors, insufficient hepatic reserve, cirrhosis, and/or associated comorbid medical conditions. For individuals with unresectable hepatic tumors, the treatment options are few, and the prognosis is uniformly poor. However, cryosurgery is a promising therapeutic alternative for these patients. This rapidly emerging technology allows for image-guided in situ tumor eradication using subzero temperatures, while selectively sparing most normal hepatic tissue. Tumor death occurs by direct cellular freezing and indirectly through vascular thrombosis and tissue anoxia. Accumulating data suggest that cryosurgery is a safe, effective treatment option for patients who would otherwise fair quite poorly, and that it may achieve long-term survival rates similar to those observed with formal surgical resection. This article summarizes the role cryosurgery may play in the management of patients with surgically unresectable primary and metastatic liver tumors. [ONCOLOGY 12(7):979-987,1998]


Primary and metastatic liver tumors are a common cause of
cancer-related mortality worldwide. In 1997, the estimated annual
incidence of primary liver tumors in the United States was 13,600,
with an estimated mortality of 12,400.[1] Although the relative
incidence of primary liver tumors in the United States is low (2.5%
of all new cancers), hepatocellular carcinoma constitutes one of the
most common cancers in other parts of the world, including certain
areas of Asia and Africa. Overall, however, the incidence of
malignant hepatic tumors is dominated by metastatic disease.

The estimated annual incidence of colorectal cancer in the United
States during 1997 was 131,200.[1] As many as 75% of patients with
colorectal cancer will develop synchronous or meta-
chronous liver metastases, and about 25% of these, or approximately
25,000 to 30,000 patients, will have disease limited to the liver.
Moreover, of the estimated 70,000 patients who succumbed to
colorectal cancer in 1997, approximately 25% had metastases confined
to the liver.

The natural course of untreated primary liver cancer is characterized
by rapid progression, with median survival times of 2 to 4 months and
few long-term survivors (Table 1).[2-4]
Most patients have disease limited to the liver at diagnosis, and
approximately 90% will have isolated hepatic disease at the time of death.[5]

Historically, complete surgical resection has been the only form of
curative therapy available for patients with hepatic carcinoma,
resulting in 5-year survival rates of 10% to 40% (Table
). Unfortunately, underlying hepatic disease, including
cirrhosis, hepatitis B, hemochromatosis, and alpha-1-anti-trypsin
deficiency, is common and can markedly complicate surgical resection
or render resection impossible. In fact, 70% to 90% of primary liver
cancers are surgically unresectable.

Although hepatic transplantation has been associated with 5-year
survival rates of 20% to 40%, it is contraindicated in many patients
and unavailable to most. Other treatment options, including
palliative resection and regional or systemic chemotherapy, have had
little impact on overall survival. Clearly, the prognosis for
patients with unresectable primary liver tumors has been dismal.

The natural history of patients with hepatic metastases depends on
several factors, including tumor histology,the extent of metastases,
and the presence or absence of extrahepatic disease (Table
). A collective review of 673 untreated patients with
colorectal liver metastases cited a median survival duration of 6 to
13 months.[6] When only 142 untreated patients with isolated liver
metastases (defined as unilobar, localized disease consisting of
fewer than four lesions) were considered, the median survival time
was 18 months with a 5-year survival rate of 1%.

Systemic chemotherapy generally achieves response rates of 20% to 30%
in patients with liver metastases but offers no significant survival
advantage compared to the natural course of untreated disease.[7] In
addition, regional chemotherapy, delivered via hepatic artery
infusion, results in a prolonged disease-free interval but has not
improved overall survival compared with systemic fluorouracil alone.[8-11]

Again, complete surgical resection offers the only potentially
curative therapy for patients with colorectal liver metastases. The
Hepatic Registry Group data of 859 patients treated with surgical
resection indicate a 5-year overall survival of 33%.[7] Several other
series report 5-year survival rates of 25% to 40% in patients with
surgically resected colorectal metastases (Table

Other less frequent, yet potentially still curable, tumors that
metastasize to liver include neuroendocrine, renal, adrenal, uterine,
ovarian, and cervical cancers; sarcoma; melanoma; and, perhaps,
breast cancer. Surgical resection of these noncolorectal liver
metastases has resulted in 5-year survival rates of 10% to 40% (Table
).[12-15] Unfortunately, 70% to 90% of patients diagnosed with
isolated hepatic metastases have surgically unresectable lesions.

It has become clear that primary and metastatic liver tumors
represent a significant therapeutic challenge and increasingly
important health-care problem. Driven by the low resectability rate,
limited treatment options, and correspondingly dismal prognosis,
recent emphasis has focused on regional ablative therapies, including
cryosurgery, alcohol or laser ablation, interstitial radiation,
hyperthermia, chemoembolization, and radiofrequency ablation. Of
these various modalities, accumulating data suggest that cryotherapy
is a safe, efficacious treatment alternative for many patients with
surgically unresectable tumors. In fact, cryoablation of selected
unresectable primary and metastatic liver tumors may result in
long-term survival rates similar to those reported in series of
surgically resected hepatic tumors.

History of Cryosurgery

Initial attempts at performing cryotherapy date back to the early
1800s. Simple techniques using iced saline solutions were employed to
try to alleviate pain in patients with advanced breast or cervical
cancer. Since then, significant advances in cryogenics have allowed
for the application of this technique to local tissues as a means of
controlling various cancers, including tumors of the skin, breast,
prostate, oropharynx, larynx ,and lung.[16-19]

However, it was not until 1963 that Irving Cooper, a neurosurgeon
using cryosurgery to treat Parkinson’s disease and other
neuromuscular disorders, suggested the possible use of this technique
for the management of primary and metastatic liver tumors.[20]
Although Cooper was instrumental in developing the cryosurgical
apparatus and delivery system for liquid nitrogen, limitations in the
accurate imaging of tumors prohibited the safe application of this
technique to deeper tissues, including the liver.

This obstacle was eventually overcome with the advent of
intraoperative ultrasound (IOUS). Today, liver tumors can be
accurately imaged and real-time monitoring of the freezing process
can be effectively achieved utilizing IOUS. Accordingly, hepatic
cryosurgery has now emerged as a viable therapeutic strategy for
unresectable liver tumors.

Principles of Cryotherapy

The fundamental effect of cryosurgery is based on in situ tissue
destruction using subzero temperatures. Cell death results from
complex physiologic mechanisms that rely on direct and indirect
mechanical effects. These effects include ice crystal formation and
cellular anoxia during the frozen state, followed by microvascular
thrombosis. Experimental evidence also suggests an adaptive
immunologic tumor response in the post-frozen state. The overall
results are cell membrane destruction, enzyme denaturation, osmotic
dehydration, anoxia, and cellular necrosis.[21]

Although the mechanism of cryo-ablation is tissue-nonspecific,
different tissues have inherently variable sensitivities to the
cryogenic effect. Similarly, within the liver itself, different cells
have varying degrees of sensitivity to subzero temperatures.
Hepatocytes, bile duct epithelial cells, and connective tissue cells
demonstrate resiliency to temperatures as low as -10 °C but are
completely destroyed at -40 °C. In contrast, larger blood
vessels seem to be resistant to temperatures of these extremes. This
effect, which may be due, in large part, to the thermal sink effects
of warm blood within the vessel itself, serves to protect the vessel
intima and media.

Experimental evidence suggests that complete perivascular and
intralesional tissue necrosis results following hepatic cryoablation
near large vessels.[22] Exploiting this phenomenon allows for the
application of this technique to the hepatic tissue surrounding these
vessels. By using IOUS guidance, malignant lesions can be completely
encompassed and ablated while the remaining liver tissue is
preserved. Thus, the fundamental principle of cryosurgery is the
ablation of malignant tumor deposits while selectively sparing normal
hepatic parenchyma that would otherwise require removal by formal
surgical resection.

Patient Selection

General indications for hepatic cryosurgery include the following:

  1.  A documented primary or metastatic liver tumor,

  2.  The absence of extrahepatic metastasis,

  3.  Surgically unresectable disease, and/or

  4.  Tumor involving surgically resected margins.

Following the diagnosis of a primary or metastatic liver tumor, a
careful preoperative evaluation and staging work-up are essential.
Preoperative liver imaging is important to determine the extent of
hepatic tumor involvement and to exclude the presence of extrahepatic disease.

Tumor markers are often measured preoperatively and may be important
in the postoperative follow-up period as well. These include
alpha-fetoprotein (AFP) for hepatocellular carcinoma,
carcinoembryonic antigen (CEA) for colorectal liver metastases,
and/or 5-hydroxyindoleacetic acid (5-HIAA) for metastatic carcinoid tumors.


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