RFA and cryoablation expand treatment of hepatic tumors

Ablative techniques have greatly improved physicians' ability to definitively treat patients with primary and secondary hepatic tumors. These techniques include radiofrequency ablation (RFA) and cryoablation, as well as newer microwave and laser ablation methods. Ablation devices, used either alone or combined with hepatic resection, have made it feasible to treat patients with bilobar lesions and those who would not tolerate liver resection due to underlying comorbidities.

Patient selection for ablative techniques depends partially on whether the patient has primary or metastatic liver tumors. Liver resection remains the treatment of choice, when possible, for patients with isolated hepatic colorectal metastases. Most patients with metastatic disease are not amenable to resection, however, because of the number, size, or location of metastases, comorbidities, or limited hepatic reserve. Patients with limited hepatic metastatic disease who cannot, should not, or refuse to undergo resection are candidates for laparoscopic or percutaneous ablation techniques. In this population, patients with fewer than five tumors less than 3 cm in diameter tend to have better local control postablation, resulting in greater long-term survival. Preliminary five-year survival data for this population are just becoming available. One recent series reported three-year survival of 46% with a median survival of 33 months,¹ which approaches the survival rate following hepatic resection.²

Several other types of patients with metastatic colorectal tumors are increasingly being referred for tumor ablation. The first group comprises patients with treatable hepatic metastatic disease and limited extrahepatic disease. A second group of patients are those with hepatic tumors larger than 5 cm in size. Development of improved ablation technology and strategies, such as higher power generators, multiple probe devices, infusion of adjuvant materials and drugs, and protective techniques to limit collateral damage, will eliminate many of the barriers to treating these patients.

While prolonged survival is possible for patients with hepatic colorectal metastases adequately treated with ablation techniques, the utility of therapy for other types of metastatic tumors to the liver is unclear. For this reason, it is essential that patients are evaluated by multidisciplinary teams that may include a medical oncologist, hepatobiliary and/or transplant surgeon, radiologist, interventional radiologist, radiation oncologist, and anesthesiologist.

TREATMENT OPTIONS

Three definitive treatment options are available for patients with hepatocellular carcinoma (HCC): hepatic transplantation, hepatic resection, and ablation.

Transplantation is the favored modality for cirrhosis due to hepatitis, because it offers the ability to cure both the background disease and the accompanying tumor. However, a shortage of organs, a long waiting list, and age or medical comorbidities remove transplantation as an option for many patients.

Hepatic resection generally cures the targeted tumor, but it is associated with high morbidity and mortality in patients with Child's B and C cirrhosis, does not cure the underlying cirrhosis, and removes functioning liver along with tumor. Increasingly, patients who are not transplant candidates or who are on a potentially long waiting list for a transplant are being treated with percutaneous ablation. The technical success rate is very high, depending on tumor size, due to the encapsulated nature of HCC in cirrhotics, which selectively retains heat (RF, microwave, laser) or injected materials (ethanol, acetic acid, hot saline) and limits damage to the background liver. A survival advantage versus untreated HCC has been demonstrated for ablation at a rate similar to hepatic resection, but recurrence of tumor elsewhere in the liver is common (up to 85% at five years).³

The decision to perform percutaneous, open, or laparoscopic ablation is based on known advantages of each technique (Table 1). Although percutaneous interventions do not require a laparotomy incision, most procedures require general anesthesia. RFA causes severe pain during current application, but cryoablation is virtually painless after the probes have been introduced.

Another disadvantage of percutaneous approaches to liver tumors is the lack of a thorough evaluation of the abdominal contents to assess for extrahepatic disease and the lack of intraoperative ultrasound, which detects additional sites of hepatic disease in 40% to 55% of patients.^4-6 Although percutaneous ablation has historically been limited in its ability to safely treat lesions near other structures, the use prior to ablation of displacement techniques such as infusions of saline or dextrose in water or air, or physical barriers such as balloons, has made it possible to perform an increasing number of these procedures safely (Figure 1).

Finally, open and laparoscopic ablation performed by an appropriately trained laparoscopic surgeon enables utilization of other operative interventions, including hepatic or colon resection and hepatic artery chemotherapy pump placement. Unfortunately, laparoscopic ablation is technically difficult, due to the limited ability to image the liver in multiple planes, which severely limits accurate probe placement. Open ablation is therefore preferred for patients who can tolerate laparotomy.

CHOICE OF ABLATION TECHNIQUE

The choice of ablative technique depends on both the availability of the necessary equipment and the surgeon's or radiologist's familiarity with it. As many of the features of the various ablation modalities overlap, it is often unclear which is best for a given application. Although cryoablation was initially widely used for liver tumor ablation, RFA is currently the most commonly used modality in the U.S. European and Asian practitioners have extensive experience with microwave and laser ablation, but for various reasons these technologies have not been widely used worldwide.

RFA has been advocated as resulting in fewer complications and shorter procedure times, and it is ideally suited for percutaneous use because the intrinsic cautery effect decreases bleeding complications. It is, therefore, probably the favored modality for coagulopathic patients and patients with severe morbidities who cannot tolerate even minor complications.

Cryoablation can be performed with multiple applicators, allowing the operator to sculpt a cryolesion for maximum tumor coverage with minimum collateral damage. Until recently, cryoablation was associated with large-diameter applicators (3 to 8 mm), but small-gauge devices (down to 17 gauge) are now available for percutaneous use (Figure 2). Regardless of the approach to the patient-open, laparoscopic, or percutaneous-one of the main advantages of cryoablation over the heat-based ablation methods is the ability to visualize the developing iceball with ultrasound, CT, and MRI (Figure 3), and the excellent correlation between the location of the iceball and the zone of cell death.^7-9

Thermal ablation techniques cause tissue destruction by creating ionic agitation (in the case of RFA and microwave ablation) and heat, which results in tissue boiling and the creation of water vapor. If lethal temperatures above 60 degrees C are reached, protein denaturation, tissue coagulation, and vascular thrombosis will result in a zone of complete ablation. A zone of partial tissue destruction up to 8 mm in diameter can be seen surrounding the zone of coagulation (Figure 4).

Heat-based ablation modalities cause profound vascular thrombosis. As a result, bleeding is an unusual complication of RF ablation. In contrast, cryoablation has no intrinsic hemostatic properties and has rarely been associated with substantial hemorrhage during large-volume freezes performed at open laparotomy.¹⁰ With new technology resulting in smaller probe sizes (1.7 mm) for cryoablation, this is not a clinically significant problem, except when freezing results in cracking of the liver capsule during thawing.^11-13

OUTCOME

A recent large single-institution series evaluating periprocedural outcome after RFA found an overall morbidity of 10%, which was higher in patients treated with open RFA (13%) than in patients undergoing a percutaneous approach (8%).¹¹ In addition, patients with cirrhosis had a higher periprocedural complication rate.¹¹ In two other large studies, the overall morbidity rate for patients undergoing RFA was 7% to 9%, with a mortality rate of 0.3% to 0.5%.^12,13 Overall, it is clear that RFA is safe and well tolerated.

Cryoablation has been associated with a systemic complication termed cryoshock, which can result in disseminated intravascular coagulopathy and multisystem organ failure. The rapid destruction of cell membranes and the relative lack of protein denaturation associated with freezing (compared with thermal ablation) may be responsible for this systemic response.

The hypothesis is that intact cellular elements are more readily delivered into the bloodstream by freezing than with heat ablation, and this can result in thrombocytopenia, disseminated intravascular coagulation, and hepatic and renal failure in severe cases.¹⁴ Because it is now recognized that large-volume ablations involve an increased risk of cryoshock,¹⁵ the occurrence of this complication can probably be decreased by limiting the volume of tissue destroyed by freezing.

Comparing the relative effectiveness of tissue destruction by RFA and by cryoablation is problematic because of the lack of well-controlled studies. Most authors conclude that cryoablation has a slight advantage in the ability to cause cell death when tissue has been appropriately targeted in the laboratory,¹⁶ but controlled clinical studies have not been performed.

In order to thoroughly assess oncologic outcomes, it is important to evaluate overall and disease-free survival, including evaluation of local recurrence. Unfortunately, the limitations in the literature make it difficult to define overall and disease-free survival for specific tumor types because of the short follow-up, mixed histologies of tumors that are reported, and lack of assessment of disease-free survival.

Overall survival for colorectal and hepatocellular cancer after ablation is listed in Tables 2 and 3, respectively.

Dr. Weber is an associate professor in the department of surgery and Dr. Lee is an associate professor in the department of radiology at the University of Wisconsin in Madison.

References

1. Solbiati L. Radiofrequency ablation for liver colorectal metastases: is it possible to equal the 5-year survival rates of surgery? Radiological Society of North America Scientific Assembly and Annual Meeting, Chicago: 2004.

2. Fong Y, Fortner J, Sun RL, et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230:309-318.

3. Poon RT, Fan ST, Lo CM, et al. Intrahepatic recurrence after curative resection of hepatocellular carcinoma: long-term results of treatment and prognostic factors. Ann Surg 1999;229:216-222.

4. Elias D, Sideris L, Pocard M, et al. Incidence of unsuspected and treatable metastatic disease associated with operable colorectal liver metastases discovered only at laparotomy (and not treated when performing percutaneous radiofrequency ablation). Ann Surg Oncol 2005;12:298-302.

5. Wallace JR, Christians KK, Quiroz FA, et al. Ablation of liver metastasis: is preoperative imaging sufficiently accurate? J Gastrointest Surg 2001;5:98-107.

6. Cervone A, Sardi A, Conaway GL. Intraoperative ultrasound (IOUS) is essential in the management of metastatic colorectal liver lesions. Am Surg 2000;66:611-615.

7. Onik G, Gilbert J, Hoddick W, et al. Sonographic monitoring of hepatic cryosurgery in an experimental animal-model. AJR 1985;144:1043-1047.

8. Weber SM, Lee FT, Warner TF, et al. Hepatic cryoablation: US monitoring of extent of necrosis in normal pig liver. Radiology 1998;207:73-77.

9. Steed J, Saliken JC, Donnelly BJ, et al. Correlation between thermosensor temperature and transrectal ultrasonography during prostate cryoablation. Can Assoc Radiol J 1997;48: 186-190.

10. Seifert JK, Morris DL. World survey on the complications of hepatic and prostate cryotherapy. World J Surg 1999;23: 109-113.

11. Curley SA, Marra P, Beaty K, et al. Early and late complications after radiofrequency ablation of malignant liver tumors in 608 patients. Ann Surg 2004;239:450-458.

12. Livraghi T, Solbiati L, Meloni MF, et al. Treatment of focal liver tumors with percutaneous radio-frequency ablation: complications encountered in a multicenter study. Radiology 2003;226:441-451.

13. Mulier S, Mulier P, Ni Y, et al. Complications of radiofrequency coagulation of liver tumours. Br J Surg 2002;89: 1206-1222.

14. Washington K, Debelak JP, Gobbell C, et al. Hepatic cryoablation-induced acute lung injury: histopathologic findings. J Surg Res 2001;95:1-7.

15. Sarantou T, Bilchik A, Ramming KP. Complications of hepatic cryosurgery. Semin Surg Oncol 1998;14:156-162.

16. Collyer WC, Landman J, Olweny EO, et al. Comparison of renal ablation with cryotherapy, dry radiofrequency, and saline augmented radiofrequency in a porcine model. J Am Coll Surg 2001;193:505-513.

17. Berber E, Pelley R, Siperstein AE. Predictors of survival after radiofrequency thermal ablation of colorectal cancer metastases to the liver: a prospective study. J Clin Oncol 2005;23: 1358-1364.

18. Abdalla EK, Vauthey JN, Ellis LM, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 2004;239:818-825.

19. Yan DB, Clingan P, Morris DL. Hepatic cryotherapy and regional chemotherapy with or without resection for liver metastases from colorectal carcinoma-how many are too many? Cancer 2003;98:320-330.

20. Ruers TJ, Joosten J, Jager GJ, et al. Long-term results of treating hepatic colorectal metastases with cryosurgery. Br J Surg 2001;88:844-849.

21. Seifert JK, Morris DL. Prognostic factors after cryotherapy for hepatic metastases from colorectal cancer. Ann Surg 1998; 228:201-208.

22. Weaver ML, Atkinson D, Zemel R. Hepatic cryosurgery in treating colorectal metastases. Cancer 1995;76:210-214.

23. Lencioni R, Della PC, Bartolozzi C. Percutaneous image-guided radiofrequency ablation in the therapeutic management of hepatocellular carcinoma. Abdom Imaging 2005, e-pub.

24. Tateishi R, Shiina S, Teratani T, et al. Percutaneous radiofrequency ablation for hepatocellular carcinoma. An analysis of 1000 cases. Cancer 2005;103:1201-1209.

25. Lam CM, Ng KK, Poon RT, et al. Impact of radiofrequency ablation on the management of patients with hepatocellular carcinoma in a specialized centre. Br J Surg 2004;91: 334-338.

26. Curley SA, Izzo F, Ellis LM, et al. Radiofrequency ablation of hepatocellular cancer in 110 patients with cirrhosis. Ann Surg 2000;232:381-391.