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Editorial |
Department of Surgery, Hepatobiliary Unit, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL, United Kingdom
Correspondence: Address correspondence and reprint requests to: Ajith K. Siriwardena, MD, FRCS; E-mail: ajith.siriwardena{at}cmmc.nhs.uk.
Liver resection is generally accepted as the standard of care for patients with hepatic metastases from colorectal tumors in the absence of extrahepatic disease1 and for selected patients with primary hepatocellular carcinoma.2 However, in any given cohort of patients with hepatic tumors, most will be unsuitable for resection because of the extent of hepatic tumor burden, extrahepatic disease, or comorbidity. Treatment options in this setting include systemic modalities such as chemotherapy, regional interventions such as intra-arterial chemotherapy, and direct tumor ablation.
Direct ablative treatments include intratumoral ethanol, laser, cryotherapy, and, more recently, radiofrequency ablation.3 Until the advent of radiofrequency, direct intratumoral ethanol and cryotherapy were perhaps the most widely used ablative approaches.3 Ethanol can be injected percutaneously and does not rely on costly equipment for delivery, and treatments can be repeated. Cryotherapy uses liquid nitrogen at –196°C delivered through a closed triple-lumen probe and relies on cooling of liver tumors to at least –35°C.4 Tumor cell death occurs as a consequence of the formation of intracellular crystals during rapid freezing. Although widely used over the past decade, cryotherapy for liver tumors is not without problems.5,6 Freezing can lead to cracking or shearing of the liver parenchyma, and major hemorrhage results if these shearing injuries extend into major vessels. Late hemorrhage and intrahepatic abscesses related to biliary injury are also recognized complications. In addition to these local effects of cryotherapy, there are systemic side effects: the cytokine-mediated systemic illness associated with cryotherapy is characterized by fever, tachycardia, and tachypnea. This is known as the cryoshock syndrome and, in particular, can be associated with pleural effusion, diffuse lung injury, and acute renal tubular necrosis.
The role of cryotherapy has become increasingly challenged since the advent of radiofrequency thermal ablation. This technique involves the passage of alternating high-frequency current (typically 10 kHz) through tissue.7 The molecular agitation caused by high-frequency energy leads to an increase in temperature in the tissue through which the current passes without causing muscle contraction or pain. If the field is applied between two equal-sized electrodes, the current flow per unit area of the electrode (current density) is similar in both electrodes. However, if one electrode is smaller, then, because the same total amount of current still has to flow, the current density is much higher at the smaller electrode, with a correspondingly higher temperature. Commercial availability of cooled-tip multiprobe electrodes equipped with probe-tip thermal sensors now permits the creation of a precise hepatic parenchymal ablation.7 In an important study, Scudamore et al.8 performed radiofrequency ablation of resectable liver tumors in 10 patients (7 patients with colorectal liver metastases) and then undertook liver resection in 9 of these individuals within 6 weeks of the ablation. On histological examination of the resected specimen by using nicotinamide adenine dinucleotide (NADH; a histochemical technique for demonstration of tissue oxidative enzyme activity), ablated tissue was recognized in all nine cases. The zone of ablation identified by the loss of staining revealed that NADH oxidation was high in normal liver, low in metastatic tumors, and absent in ablated or naturally necrotic tissue. Eight (89%) of nine specimens demonstrated successful ablation, and no evidence of viable tumor was demonstrated by the NADH technique.
In addition to this evidence of tumor ablation, the side-effect profile of radiofrequency ablation seems less severe. Although intrahepatic abscess, biliary leak, and hemorrhage have been reported, there is no heat-related thermal analog of the cryoshock syndrome, and hepatic parenchymal cracking is also thought not to occur with this technique.7 Radiofrequency has two additional critical practical advantages over cryotherapy—it can be delivered percutaneously with patients under local anesthesia, and, with contemporary equipment, a 5-cm ablation can be delivered rapidly.
How, then, do these two ablative modalities fare in direct comparison with each other? To maintain a balanced perspective, it should be acknowledged that information on the effect of both ablative treatments on long-term survival is limited. Further, assessment of the oncological efficacy of any ablative technique can be problematic. Criteria based on computed tomography may not adequately compensate for treatment-related swelling, and computed tomography cannot reliably exclude viable tumor in the ablation zone. Histological techniques such as NADH immunohistochemistry may be required to assess tumor biopsy samples for necrosis.8
Evidence from a porcine liver injury model comparing radiofrequency with cryotherapy demonstrated that the systemic inflammatory marker concentrations (tumor necrosis factor 
and interleukin 1ß) were significantly lower in the radiofrequency group, whereas indices of hematological, hepatic, and renal impairment were worse in animals undergoing cryotherapy.9 These benefits of radiofrequency seem to translate to clinical practice: Schell et al.10 showed that the plasma cytokine profile of a series of proinflammatory and anti-inflammatory cytokines was not altered by ablation of up to 35% of the hepatic parenchyma.
The available clinical evidence comparing radiofrequency with cryotherapy must also be appraised in the light of deficiencies in treatment randomization. Bismuth’s group11 reported the outcome in 33 patients undergoing percutaneous radiofrequency compared with 31 patients undergoing percutaneous cryotherapy. Patient treatment was allocated according to the "random availability of probes" rather than formal randomization.11 Their study showed a higher incidence of intrahepatic recurrence in patients treated with cryotherapy.
Bilchik et al.12 reported their experience in 308 patients with unresectable hepatic tumors who underwent either cryotherapy or radiofrequency ablation. Radiofrequency resulted in less blood loss, a lower incidence of thrombocytopenia, and a shorter hospital stay than cryotherapy alone. Median ablation times for lesions >3 cm were longer with radiofrequency, and the local recurrence rate was greater after radiofrequency than after cryotherapy. It should be noted that better thermal ablation areas can be achieved with contemporary probe design than with those used in Bilchik’s study and also that the design of this study compared patients undergoing radiofrequency ablation with a recent—but nevertheless historical—control group undergoing cryotherapy, hence leaving the study open to bias in terms of evolving imaging sophistication and patient selection.
In a prospective nonrandomized trial from the M. D. Anderson Cancer Center, Pearson et al.13 compared outcome in 54 patients (88 tumors) undergoing cryotherapy with outcome in 92 patients (138 tumors) undergoing radiofrequency. Treatment-related complications, including 1 postoperative death, occurred in 22 (41% procedure-related morbidity) of the 54 undergoing cryotherapy, compared with 3 (3% morbidity, with no deaths) after radiofrequency. At a median follow-up of 15 months, tumor recurrence had occurred in 3 (2%) patients treated with radiofrequency, compared with 12 (14%) patients treated with cryotherapy. The differences in procedure-related complications and recurrence were statistically significant. In addition, with minimal-access surgery increasingly being promulgated, a study examining laparoscopic in situ ablation reported outcome in a small cohort of 38 patients treated with cryotherapy alone (n = 9), combined cryotherapy and radiofrequency (n =8), or radiofrequency alone (n = 15). At a mean follow-up of 26 months, survival was increased after in situ ablation compared with controls, but local recurrence was present in 12 of 44 lesions treated with cryotherapy, compared with 20 of 102 treated with radiofrequency.14
When this evidence is synthesized to reach a balanced conclusion regarding the current status of hepatic ablative therapies, it becomes apparent that there is a dearth of adequately powered and well-constructed randomized trial evidence in favor of either cryotherapy or radiofrequency. The available evidence suggests that the biophysical interface seems less traumatic with radiofrequency than with cryotherapy, although neither treatment is devoid of complications. In addition, radiofrequency seems to have fewer adverse systemic effects. The ability to avoid laparotomy has led to radiofrequency’s increasingly being delivered nonoperatively. The treatment is thus more widely available, and this, together with aggressive commercial promotion and rapidly evolving probe technology (compared with relatively static cryoprobe evolution), has led to the current dominant position of radiofrequency. The position of equipoise regarding cryotherapy has probably been passed by the advent of large-scale trials, such as the current European trial of chemotherapy and local ablation versus chemotherapy alone (CLOCC), which compare radiofrequency ablation, as the proposed new standard, with systemic chemotherapy.
In conclusion, the weight of practical and scientific evidence in favor of radiofrequency, together with the incorporation of this treatment in current ongoing trials, renders this modality the current preferred choice when compared with cryotherapy. In turn, with this prevailing evidence, it becomes difficult to justify new trials of cryotherapy. The era of cryotherapy for ablation of nonresectable liver tumors seems to be drawing to a close.
Received for publication October 15, 2004. Accepted for publication December 2, 2004.
REFERENCES
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