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. 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. 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.
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
2). 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
1). A collective review of 673 untreated patients with
colorectal liver metastases cited a median survival duration of 6 to
13 months. 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. 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%. 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
2).[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.
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 Parkinsons disease and other
neuromuscular disorders, suggested the possible use of this technique
for the management of primary and metastatic liver tumors.
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.
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.
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. 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
General indications for hepatic cryosurgery include the following:
A documented primary or metastatic liver tumor,
The absence of extrahepatic metastasis,
Surgically unresectable disease, and/or
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.
1. Parker SL, Tong T, Bolden S, et al: Cancer statistics, 1997 CA
Cancer J Clin 47(1):5-27, 1997. (Published erratum appears in CA
Cancer J Clin 47(2):68, 1997.)
2. Okuda K, Obata H, Nakajima Y, et al: Prognosis of primary
hepatocellular carcinoma. Hepatology 4(1;suppl):3S-6S, 1984.
3. Nagasue N, Yukaya H, Hamada T, et al: The natural history of
hepatocellular carcinoma: A study of 100 untreated cases. Cancer
4. Falkson G, Cnaan A, Schutt AJ, et al: Prognostic factors for
survival in hepatocellular carcinoma. Cancer Res 48(24; pt
5. Chen MF, Hwang TL, Jeng LB, et al: Postoperative recurrence of
hepatocellular carcinoma: Two hundred five consecutive patients who
underwent hepatic resection in 15 years. Arch Surg 129(7):738-742, 1994.
6. Hughes KS, Simon R, Songhorabodi S, et al: Resection of the liver
for colorectal carcinoma metastases: A multi-institutional study of
patterns of recurrence. Surgery 100(2):278-284, 1986.
7. Arbuck SG: Overview of clinical trialsusing 5-fluorouracil and
leucovorin forthe treatment of colorectal cancer. Cancer
8. Chu DZ, Hutchins L, Lang NP: Regional chemotherapy of liver
metastases from colorectal carcinoma: Hepatic artery or portal vein
infusion? Cancer Treat Rev 15(4):243-256, 1988.
9. Hohn DC, Stagg RJ, Friedman MA, et al: A randomized trial of
continuous intravenous versus hepatic intraarterial floxuridine in
patients with colorectal cancer metastatic to the liver: The Northern
California Oncology Group trial. J Clin Oncol 7(11):1646-1654, 1989.
10. Martin JK Jr, OConnell MJ, Wieand HS, et al: Intraarterial
floxuridine vs systemic fluorouracil for hepatic metastases from
colorectal cancer: A randomized trial. Arch Surg 125(8):1022-1027, 1990.
11. Wagman LD, Kemeny MM, Leong L, et al: A prospective, randomized
evaluation of the treatment of colorectal cancer metastatic to the
liver. J Clin Oncol 8(11):1885-1893, 1990.
12. Harrison LE, Brennan MF, Newman E, et al: Hepatic resection for
noncolorectal, nonneuroendocrine metastases: A fifteen-year
experience with ninety-six patients. Surgery 121(6):625-632, 1997.
13. Foster JH: Survival after liver resection for secondary tumors.
Am J Surg 135(3):389-394, 1978.
14. Morrow CE, Grage TB, Sutherland DE, et al: Hepatic resection for
secondary neoplasms. Surgery 92(4):610-614, 1982.
15. Iwatsuki S, Starzl TE: Personal experience with 411 hepatic
resections. Ann Surg 208(4):421-434, 1988.
16. Miller D: Does cryosurgery have a place in the treatment of
papillomata or carcinoma of the larynx? Ann Otol Rhinol Laryngol
17. Onik GM, Cohen JK, Reyes GD, et al: Transrectal ultrasound-guided
percutaneous radical cryosurgical ablation of the prostate. Cancer
18. Rand RW, Rand RP, Eggerding FA, et al: Cryolumpectomy for breast
cancer: An experimental study. Cryobiology 22(4):307-318, 1985.
19. Gage AA: Cryosurgery for oral and pharyngeal carcinoma. Am J Surg
20. Cooper IS: Cryogenic surgery. N Engl J Med 268(14):743-749, 1963.
21. Rubinsky B, Lee CY, Bastacky J, et al: The process of freezing
and the mechanism of damage during hepatic cryosurgery. Cryobiology
22. Weber SM, Lee FT, Chinn DO, et al: Perivascular and intralesional
tissue necrosis after hepatic cryoablation: Results in a porcine
model. Surgery 122(4):742-747, 1997.
23. Yamaguchi A, Ishida T, Nishimura G, et al: Detection by CT during
arterial portography of colorectal cancer metastases to liver. Dis
Colon Rectum 34(1):37-40, 1991.
24. Fortunato L, Clair M, Hoffman J, et al: Is CT portography (CTAP)
really useful in patients with liver tumors who undergo
intraoperative ultrasonography (IOUS)? Am Surg 61(7):560-565, 1995.
25. Soyer P, Levesque M, Caudron C, et al: MRI of liver metastases
from colorectal cancer vs CT during arterial portography. J Comput
Assist Tomogr 17(1):67-74, 1993.
26. Moffat FL Jr, Pinsky CM, Hammershaimb L, et al: Clinical utility
of external immunoscintigraphy with the IMMU-4 technetium-99m
Fab¢ antibody fragment in patients undergoing surgery for
carcinoma of the colon and rectum: Results of a pivotal, phase III
trial: The Immunomedics Study Group. J Clin Oncol 14(8):2295-2305, 1996.
27. Hughes K, Pinsky C, Petrelli N, et al: Use of carcinoembryonic
antigen radioimmunodetection and computed tomography for predicting
the resectabitily of recurrent colorectal cancer. Ann Surg
28. Sirisriro R, Podoloff DA, Patt YZ, et al: 99mTc-IMMU4 imaging in
recurrent colorectal cancer: Efficacy and impact on surgical
management. Nucl Med Commun 17(7):568-576, 1996.
29. Dresel S, Kirsch CM, Tatsch K, et al: Detection of hepatocellular
carcinoma with a new alpha-fetoprotein antibody imaging kit. J Clin
Oncol 15(7):2683-2690, 1997.
30. Dutta P, Montes M, Gage AA: Large volume freezing in experimental
hepatic cryosurgery: Avoidance of bleeding in hepatic freezing by an
improvement in the technique. Cryobiology 16(1):50-55, 1979.
31. Bischof J, Christov K, Rubinsky B: A morphological study of
cooling rate response in normal and neoplastic human liver tissue:
cryosurgical implications. Cryobiology 30(5):482-492, 1993.
32. Ravikumar TS, Steele G, Jr, Kane R, et al: Experimental and
clinical observations on hepatic cryosurgery for colorectal
metastases. Cancer Res 51(23;pt 1):6323-6327, 1991.
33. Dilley AV, Dy DY, Warlters A, et al: Laboratory and animal model
evaluation of the Cryotech LCS 2000 in hepatic cryotherapy.
Cryobiology 30(1):74-85, 1993.
34. Onik G, Rubinsky B, Zemel R, et al: Ultrasound-guided hepatic
cryosurgery in the treatment of metastatic colon carcimona:
Preliminary results. Cancer 67(4):901-907, 1991.
35. Morris DL, Horton MD, Dilley AV, et al: Treatment of hepatic
metastases by cryotherapy and regional cytotoxic perfusion. Gut
36. Zhou X, Tang Z, Yu Y: Ablative approach for primary liver cancer,
in Cady B, Ravikumar T (eds): Surgical Oncology Clinics of North
America, vol. 5, pp 379-390. Philadelphia, WB Saunders, 1996.
37. Ravikumar TS, Kane R, Cady B, et al: A 5-year study of
cryosurgery in the treatment of liver tumors. Arch Surg
126(12):1520-1523;1523-1524 (discussion), 1991.
38. Wren SM, Coburn MM, Tan M, et al: Is cryosurgical ablation
appropriate for treating hepatocellular cancer? Arch Surg
132(6):599-603;603-604 (discussion), 1997.
39. Crews KA, Kuhn JA, McCarty TM, et al: Cryosurgical ablation of
hepatic tumors. Am J Surg 174(6):614-618, 1997.
40. Ravikumar TS, Steele G Jr, Kane R, et al: Experimental and
clinical observations on hepatic cryosurgery for colorectal
metastases. Cancer Res 51(23;pt 1):6323-6237, 1991.
41. Weaver ML, Atkinson D, Zemel R: Hepatic cryosurgery in the
treatment of unresectable metastases. Surg Oncol 4(5):231-236, 1995.
42. Koushafar H, Pham L, Lee C, et al: Chemical adjuvant cryosurgery
with antifreeze proteins. J Surg Oncol 66:114-121, 1997.
43. Cady B, Monson DO, Swinton NW: Survival of patients after colonic
resection for carcinoma with simultaneous liver metastases. Surg
Gynecol Obstet 131(4):697-700, 1970.
44. Wagner JS, Adson MA, Van Heerden JA, et al: The natural history
of hepatic metastases from colorectal cancer: A comparison with
resective treatment. Ann Surg 199(5):502-508, 1984.
45. Bengmark S, Hafström L: The natural history of primary and
secondary malignant tumors of the liver: The prognosis for patients
with hepatic metastases from colonic and rectal carcinoma by
laparotomy. Cancer 23(1):198-202, 1969.
46. Wood CB, Gillis CR, Blumgart LH: A retrospective study of the
natural history of patients with liver metastases from colorectal
cancer. Clin Oncol 2(3):285-288, 1976.
47. Bengtsson G, Carlsson G, Hafström L, et al: Natural history
of patients with untreated liver metastases from colorectal cancer.
Am J Surg 141(5):586-589, 1981.
48. Nagasue N, Kohno H, Chang YC, et al: Liver resection for
hepatocellular carcinoma: Results of 229 consecutive patients during
11 years. Ann Surg 217(4):375-384, 1993.
49. Tsuzuki T, Sugioka A, Ueda M, et al: Hepatic resection for
hepatocellular carcinoma. Surgery 107(5):511-520, 1990.
50. Nagao T, Inoue S, Goto S, et al: Hepatic resection for
hepatocellular carcinoma: Clinical features and long-term prognosis.
Ann Surg 205(1):33-40, 1987.
51. Adson MA, van Heerden JA, Adson MH, et al: Resection of hepatic
metastases from colorectal cancer. Arch Surg 119(6):647-651, 1984.
52. Fong Y, Cohen AM, Fortner JG, et al: Liver resection for
colorectal metastases. J Clin Oncol 15(3):938-946, 1997.
53. Rosen CB, Nagorney DM, Taswell HF, et al: Perioperative blood
transfusion and determinants of survival after liver resection for
metastatic colorectal carcinoma. Ann Surg 216(4):493-504;504-505
54. Scheele J, Stangl R, Altendorf-Hofmann A, et al: Indicators of
prognosis after hepatic resection for colorectal secondaries. Surgery
55. Shafir M, Shapiro R, Sung M, et al: Cryoablation of unresectable
malignant liver tumors. Am J Surg 171(1):27-31, 1996.
56. Korpan NN: Hepatic cryosurgery for liver metastases: Long-term
follow-up. Ann Surg 225(2):193-201, 1997.
57. Adam R, Akpinar E, Johann M, et al: Place of cryosurgery in the
treatment of malignant liver tumors. Ann Surg 225(1):39-48;48-50
58. Yeh KA, Fortunato L, Hoffman JP, et al: Cryosurgical ablation of
hepatic metastases from colorectal carcinomas. Am Surg 63(1):63-68, 1997.
59. Bilchik A, Sarantou T, Foshag LN, et al: Cryosurgical palliation
of metastatic neuroendocrine tumors resistent to conventional
therapy. Surgery 122:1040-1047, 1997.