Chapter 85B Cryoablation for liver tumors

Overview

Hepatic resection is the standard of care for the majority of resectable primary and metastatic liver tumors confined to the liver (Cha et al, 2002; Fong et al, 1999; Scheele et al, 1995; Wei et al, 2006; see Chapters 80 and 81A). In patients with impaired liver function or small hepatocellular tumors, ablation is sometimes employed as first-line treatment (Chen et al, 2006; Livraghi et al, 2008); however, most patients with malignant liver tumors are not amenable to potentially curative resection because of anatomic, functional, or prognostic factors (see Chapter 2). Even when the malignancy is considered unresectable, local control of primary and isolated metastatic hepatic malignancy may change the natural history of these diseases. Several prospective and retrospective analyses have shown liver failure to be a common cause of death in patients with unresected liver tumors (Couto et al, 2007; Nagorney & Gigot, 1996). Ablative techniques can be combined with surgical resections to decrease hepatic tumor load and possibly eliminate it. They also expand the treatment options for disease recurrence in patients whose liver remnant is not optimized or amenable to surgical resection. With ablation, it is possible to prolong survival and increase the disease-free interval in patients. Cryotherapy was one of the original ablative techniques, but it has increasingly been replaced by radiofrequency ablation (RFA) and more recently microwave ablation (MWA) because of high complication rates and high local recurrence rates, somewhat cumbersome technology, and higher complication rates with cryoablation, although its use continues to be described for treating close or positive margins after resection.

Patient Population

Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world with more than 1 million cases occurring each year worldwide (see Chapter 80; Nordenstedt et al, 2010). It is well known that HCC is the most common malignancy in Southeast Asia and in sub-Saharan Africa owing to endemic viral hepatitis, especially hepatitis B. Since the 1990s the incidence of HCC has increased significantly in the United States and other Western countries as hepatitis C rates have risen. In the United States, the mortality rate for HCC has improved over the past 2 decades, as screening programs have identified patients with tumors at earlier stages. Of patients presenting with HCC, only 15% to 25% are operable, and less than 10% are resectable with curative intent (Bolondi et al, 2001; Farmer et al, 1994); however, most patients with unresectable disease have tumor confined to the liver. At a regional referral center for liver cancer, curative treatments can be applied to 30% to 40% of patients (Bruix & Llovet, 2002). More than half of patients presenting with primary liver cancer are potential candidates for hepatic regional therapy, of which a significant number may be amenable to ablative techniques.

Metastatic Disease

The liver is one of the most common sites of metastatic spread, particularly from gastrointestinal malignancies (see Chapter 81A). Most malignancies that recur in the liver do so in combination with extrahepatic metastases, making resection or ablative regional therapies unsuitable management strategies. In contrast, recurrences from colorectal primary tumors are localized to the liver in approximately one third of patients, allowing use of potentially curative regional interventions. Only a small proportion of patients with metastases confined to the liver are operable, and an even smaller fraction are resectable, owing to technical and prognostic factors. By evaluating all patients with hepatic colorectal metastases at a single center, Scheele and colleagues (1995) found 21% of patients with synchronous disease and 51% of patients with metachronous disease to be potentially resectable.

Most patients with metastatic disease confined to the liver are not candidates for resection therapies but are potentially eligible for regional ablative treatments. Systemic and regional chemotherapy for metastatic colorectal cancer has improved dramatically, with median survivals of greater than 20 months now commonly reported (see Chapters 86 and 87). Additionally, response rates for systemic chemotherapy are generally greater than 50%, and combined with regional chemotherapy, they approach 90%. Survival at 5 years for patients after resection of colorectal liver metastases in modern series ranges from 46% to 58% (Karanjia et al, 2009; Pawlik et al, 2005). Resectional and ablative therapies now must be interpreted in the context of effective chemotherapy, opening the door for downstaging of unresectable tumors and adjuvant therapy for borderline resectable tumors.

General Indications for Nonresectional Therapy of Liver Tumors

Numerous patient- and tumor-related factors conspire to make liver tumors “inoperable” or “unresectable.” General and liver-related comorbidities are common contraindications to hepatic resection and are often independent of the extent of disease or proposed operation. Most patients with HCC have limited hepatic reserve secondary to cirrhosis or portal hypertension or both, which often precludes a safe liver resection (see Chapters 2 and 70A). Many technical factors make a hepatic malignancy unresectable. Insufficient future liver remnant, involvement of all three hepatic veins, and involvement of portal inflow to both lobes of the liver are examples of such technical issues. Many techniques to deal with technically unresectable tumors have been developed, such as portal vein embolization, parenchymal-sparing segmental resections, and two-stage operations (see Chapters 92, 93A, and 93B); nonetheless, most liver tumors are still unresectable.

Cryotherapy has been used to treat many primary and metastatic liver tumors; however, extensive experience exists only for hepatic metastases from colorectal and neuroendocrine primary tumors and for primary liver cancer. Ablation should be considered a second-line alternative to liver resection in patients with resectable disease, except in patients with small HCCs, where the choice between resection and ablation is controversial; however, in the situations enumerated previously, in which resection is not possible or safe, ablation can provide a relatively effective alternative therapy with less morbidity than open hepatic resection. The most pronounced benefits of ablation in these situations are that it can be done laparoscopically, percutaneously, or with a small laparotomy; it can also preserve maximal parenchyma and minimize the overall surgical insult to the patient.

The choice of ablative device is surgeon dependent, and no absolute indications and contraindications apply to cryoablation specifically. Ablation often is employed in combination with resection to treat contralateral tumors in a small remnant.

Pathophysiology of Cryoablation

The methods by which subzero temperatures destroy tumors are not tissue specific, and both normal and neoplastic tissues are sensitive to extreme cold. Cryotherapy causes cell death by a variety of physical and chemical mechanisms that depend on the rate of cooling, absolute depth of hypothermia, rate of thawing, number of freeze-thaw cycles used, and delayed effects of ischemia after thawing. When a cryoprobe is inserted into the liver, three overlapping zones of injury develop within the ice ball. Rapid tissue freezing occurs closest to the cryoprobe, and the rate of freezing decreases in proportion to the distance from the probe, creating zones of intermediate and slow cooling. Similarly, a gradient of temperature develops in the ice ball, decreasing 3° C/mm to 10° C/mm from −170° C near the probe to just below 0° C at the periphery of the cryolesion. The dynamics of the freezing process cause different mechanisms of injury in these three idealized zones (Gage & Baust, 1998; Mascarenhas & Ravikumar, 1998).

Cooling Rate

The rate at which tissue cools affects the proportion of cells killed by a single freeze cycle. Maximal cell death is achieved at slow and rapid cooling rates, although from different mechanisms, whereas greatest cell survival is seen with intermediate cooling rates. Cellular dehydration causes lethal injury at slow cooling rates, whereas rapidly cooled cells are destroyed by the mechanical action of ice crystallization and expansion.

Depth of Hypothermia

Independent of the cooling rate, extensive tissue injury occurs at temperatures below −20° C, and temperatures below −40° C are lethal for almost all tumor cells. The mechanism of cell injury at these temperatures is the formation of intracellular ice. At higher temperatures, the rate of cooling influences the rate of ice formation and the mechanism of cell death; however, when the temperature is below −40° C, almost all of the water within the cell is frozen, ensuring complete tissue ablation. For cryotherapy to be reliable, all targeted tissue must reach these levels of hypothermia to achieve reproducible and certain cell death, the theoretic goal of cryotherapy. This level of hypothermia is not consistently reached at the periphery of the ice ball, where temperatures may be 0° C.

The sensitivity of different tissues to hypothermia varies considerably. Most normal hepatocytes die at −15° C to −20° C, whereas at −10° C most hepatocytes survive. Bile ducts, connective tissue, and vascular structures tolerate slightly lower temperatures than hepatocytes. In contrast, liver tumors tend to require deeper hypothermia to −40° C for complete and reliable cell death. As a general rule, the −40° C isotherm is located approximately three quarters of the distance from the probe to the edge of the ice ball as seen at intraoperative sonography. To reach this level of hypothermia and obtain reliable ablation at the tumor margin, the ice ball is extended 1 cm beyond the peripheral edge of the tumor.

Thawing Process

Further damage to tissue occurs during the thawing process and varies according to the rate of the thaw. Rapid thawing of frozen tissue tends to increase cell survival, whereas slow thawing is more destructive than either rapid or slow cooling. In slowly thawed tissue, the extracellular ice melts before the intracellular ice, briefly making the extracellular fluid relatively hypoosmolar compared with the intracellular fluid. Free water flows down this osmotic gradient into the cells, causing them to swell and ultimately burst. Simultaneously, the ice within the cell undergoes recrystallization, especially in the temperature range of −20° C to −25° C. Recrystallization is a process by which ice crystals reform, coalesce, and enlarge, mechanically disrupting the cellular membranes. The effects of thawing are potentiated by allowing the entire lesion to reach ambient temperature slowly and passively.

Repeated Freeze-Thaw Cycles

Repeated freeze-thaw cycles in animal models have been shown to move the margin of reliable complete cell kill outward by producing larger ice balls more rapidly (Poppendiek, 1967). This movement is due to increased thermoconductivity of the previously frozen liver. Tissue near the cryoprobe is ablated adequately with one freeze-thaw cycle, because low enough temperatures are achieved to ensure complete cellular destruction. The added benefit of multiple cycles occurs in the periphery of the tumor, where the depth of hypothermia is unpredictable, and the cell kill is unreliable. Early histologic signs of cellular damage in lesions undergoing multiple freeze-thaw cycles are more dramatic, confirming the added benefit of such cycles.

Microvascular Effects

In addition to the acute physicochemical and structural damage to the cell and its environment, the lethal effects of cryoablation are potentiated by disruption of vascular structures, which causes delayed hypoxia and necrosis (Rubinsky et al, 1990). The vascular effects are acute and chronic. Freezing at slow cooling rates causes the radius of the sinusoids to increase by a factor of 2, which is equivalent to increasing the volume in the intravascular space by a factor of 4. The expansion of the vascular space tears the endothelium, exposing and disrupting the underlying basement membrane. Platelet thrombi develop, and permeability increases, leading to swelling and microcirculatory failure. The tissues supplied by these damaged vessels become ischemic and necrotic. This mechanism of injury is more important in the intermediate and slow cooling zones, where direct cellular injury by intracellular ice formation or dehydration is not reliable. For maximal benefit, cryosurgery should be performed so that there is rapid freeze, slow thaw, and repeated freeze-thaw cycles; however, experimental evidence has shown that high-flow venules at the periphery of an ice ball are crucial in shutting down the microcirculation of the tumor, and repeated cycles do not seem to improve this effect (Richter et al, 2005). It also has been shown in experimental models that the serine protease inhibitor aprotinin decreases platelet trapping and improves tissue destruction in cryolesions (Kollmar et al, 2004). The effects of cryosurgery on tissues are a result of direct cellular damage secondary to physicochemical effects and indirect cell damage secondary to loss of cellular integrity and destruction of vascular channels.

Morphologic and Histologic Changes After Cryotherapy

Immediately after thawing, the area of liver treated with cryoablative techniques appears dark red, swollen, and usually well demarcated. Histologic examination reveals congestion of the hepatic sinusoids associated with hemorrhage, decreased levels of cellular glycogen, and an absolute reduction in the number of mitochondria. With time, the lesion takes on a light gray color and slowly resorbs over the ensuing weeks. Microscopically, this period correlates with polymorphonuclear cell and macrophage infiltration of the tissue. The cryolesion is progressively replaced with fibrous tissue, usually with a persistent area of necrosis and fibrosis, but occasionally the lesion is completely resorbed.

Immunologic Effects of Cryoablation

In early studies of cryotherapy, anecdotal reports of regression of untreated tumor sites suggested a generalized, tumor-specific immunologic response to the cryoablated lesion (Faraci et al, 1975). These effects have not been substantiated in animal or human models, although it is unlikely that an antitumor immune response enhances the effect of cryotherapy.

Operative Technique

Hepatic cryotherapy can be performed via a variety of approaches, including percutaneous, laparoscopic, and open methods, but the open approach allows the most flexibility and accuracy. Cryotherapy at laparotomy also is less anatomically limiting than minimally invasive approaches and permits treatment of lesions in areas difficult to access by other methods. The difficulty with the open approach is the morbidity that accompanies a major abdominal incision; however, minimally invasive cryotherapy techniques have been developed and are increasingly popular. The technology of laparoscopic instrumentation and percutaneous localization continues to improve for all types of ablation, and the role of these techniques continues to increase.

Preoperative Preparation

The extent, location, and proximity of the liver tumor to the hepatic vascular and biliary structures should be defined by careful review of preoperative imaging studies. Patients with more than 40% of the liver replaced with tumor are not candidates for cryoablative techniques, because it is difficult to ablate this volume of tumor, and the perioperative morbidity is prohibitive. In general, the same preoperative preparations are required before cryosurgery as for liver resection, because a small percentage of patients may be converted to resection owing to unexpected resectability or intraoperative complications.

Two devastating complications associated with hepatic cryotherapy are the cryoshock syndrome, a complex of coagulopathy and renal and pulmonary failure, and intraoperative hypothermia (Seifert & Morris 1998); preoperative hydration is important to decrease the incidence of renal dysfunction (Bagia et al, 1998). Hypothermia is another significant complication that can be alleviated using heated fluid and airway circuits and a Bair Hugger (Arizant Healthcare, Eden Prairie, MN) warming system (Onik et al, 1993). Blood and blood products should be made available for the infrequent cases of intraoperative bleeding.

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Cryoablation for liver tumors