- Email: [email protected]
Image-guided Therapy for Hepatic Neoplasm Ablation
refuses protocol but wants therapy ---;> single agent doxorubicin poor KJ'S, extensive tumor ---;> supportive care only
References 1. Venook AP. Treatment of Hepatocellular Carcinoma: Too many options? J Clin Oncol1994; 12:1323-1334. 2. Nagasue N, Kohno H, Chang Y, et al. Liver resection for hepatocellular carcinoma. Ann Surg 1993; 217: 375-384. 3. Venook AP, Ferrell LD, Roberts JP, et al. Liver transplantation for hepatocellular carcinoma: results with preoperative chemoembolization. Liver Trans Surg 1995; 1:242-248. 4. Shiina S, Tagawa K, Unuma T, et al. Percutaneous ethanol injection therapy for hepatocellular carcinoma. Cancer 1991; 68:1524-1530. 5. Venook AP, Stagg RJ, Lewis BJ, et al. Chemoembolization for hepatocellular carcinoma. ] Clin Onc 1990; 8:1108-1114. 6. Hepatocellulaire, Groupe d'Etude et de Treatment du Carcinome. A comparison of Lipiodol chemoembolization and conservative treatment for unresedable hepatocellular carcinoma. N Engl J Med 1995; 332:1256-1261. 7. Steele G], Bleday R, Mayer RJ, et al. A prospective evaluation of hepatic resection for colorectal carcinoma metastases to the liver: Gastrointestinal Tumor Study Group Protocol 6584. J Clin Oncol 1991; 9:1105-1112. 8. Hajarizadeh H, Ivancev K, Mueller CR, et al. Effective palliative treatment of metastatic carcinoid tumors with intra-arterial chemotherapy/chemoembolization combined with octreotide acetate. Am J Surg 1992; 163:479-483. 9. Stagg RJ, Venook AP, Chase JL, et al. Chemoembolization of primary and metastatic liver tumors. Reg Cancer Treat 1992; 2:53-57. 10. Venook AP, Eaton V, Chang J, et al. Chemoembolization for liver metastases from uveal melanoma. GI Cancer 1996; 1:269-273. 11. Venook AP, Warren RS. Regional chemotherapy approaches for primary and metastatic liver tumors. Surg Oncol Clin No Am 1996; 5:411-427. 8:20 am
Image-guided Therapy for Hepatic Neoplasm Ablation Steven 1. Dawson, MD IMAGE-GUIDED therapy of liver tumors has two distinct pathways: chemo-embolization using catheter based techniques, and direct percutaneous or transcutaneous ablation of malignant deposits. Chemo-embolization will be considered elsewhere in this syllabus and this pre-
sentation deals exclusively with percutaneous and transcutaneous methods of tumor ablation. Malignant deposits within the liver are a very common manifestation of systemic malignancy: breast, lung, neuro-endocrine malignancies as well as melanoma are all commonly seen as metastatic deposits within the liver. In addition, primary hepatocellular carcinoma is a significant global problem, with HCC as the most common malignancy affecting the liver worldwide. Several therapies exist for patients with malignant involvement of the liver. For primary hepatocellular carcinoma, surgical resection and direct tumor ablation are considered the most effective treatments. For metastatic disease, surgical resection is considered the gold standard, realizing that the presence of metastatic disease in the liver indicates hematogeneous spread of the primary tumor, and these patients are likely to have metastatic involvement of other organs, rendering treatment of hepatic metastases alone somewhat problematic. However, systemic chemotherapy for hepatic metastases using 5-FU has only about a 20% response rate and no evidence of prolonged survival (9). With hepatic metastasectomy, there is a 30%-35% five year survival in properly selected patients, albeit with a perioperative mortality of 20/0-10%. In comparison, untreated hepatic metastases from colorectal carcinoma, for example, has a 5-year survival of less than 1% and a median survival of approximately 9.6 months.
Understanding the Big Picture If we are to embark on treating tumors percutaneously, we have to understand the big picture. In HCC, we are treating what may be the only visible site of cancer lying within a diseased organ. By definition, metastatic disease is present systemically at the time of treatment. With HCC, we may be able to significantly alter the course of the disease by treating the tumor. With metastases, we are only palliating systemic disease with local treatment. As percutaneous treatments are developed for liver tumors, their outcome must be validated, in order for us to have equal standing with the surgical treatment of metastatic disease, which is, after all, also a local treatment for systemic disease. There is a fundamental difference between treating a primary HCC which is usually visible as a solitary lesion or a series of small satellite lesions on the background of a diseased liver (hepatitis, cirrhosis) and treating metastatic disease which is seen as multiple small deposits on the background of a presumably n011llalliver. This difference in presentation is fundamental to understanding the differences in approach to treatment. Because of the normal functional reserve of the remaining liver, surgery can be performed for metastatic disease if the lesions are clustered in a manner which allows resection with preservation of functional hepatic units, such as a right hepatectomy, right trisegmentectomy, left hepatectomy, and/or extended left hepatectomy. However, because of the underlying hepatic parenchymal disease, hepatomas
63
are less likely to be surgically resectable because the remaining liver will not have adequate functional reserve. Thus, hepatomas are particularly well suited for percutaneous/transcutaneous image-guided therapies.
Methods of Ablation Tumor ablation can be divided into injectable and thermal methods. Injectable agents include percutaneous ethanol injection (PEl), hot saline, and acetic acid. Future injectable agents will include percutaneously delivered depot drug sources which will release directly into the tumor over time. Thermal methods of ablation include those using heat (radiofrequency [RF], laser photocoagulation, microwave, and focused ultrasound), as well as cold thermal ablation (cryotherapy) (16). Technique of Ablation For the sake of clarity, two methods of ablation will be discussed in detail: PEl and RF ablation. By chOOSing these two means of ablation, a basic understanding of the differences between injectable agents and thermal agents can be understood. It is also likely that any interventional radiologist attempting percutaneous tumor ablation will have access to one of these two methods more frequently than to the other methods which have been mentioned. Percutaneous Ethanol Injection PEl is cheap, the materials are readily available, imaging guidance is straightforward, and the procedure is not exceptionally technically demanding. However, this procedure is also fraught with the risk of incomplete diffusion of alcohol within the tumor, leaving residual areas of untreated tumor to regrow. Alcohol ablation is probably the first tumor ablation procedure which the general interventionalist will attempt. Lesions which are amenable for alcohol ablation include primary hepatocellular carcinomas that are less than 5 cm in size, or three to four lesions which are less than approximately 3-4 cm in size. Ideally, there is a margin of liver surrounding the tumor that can be used to prevent reflux of alcohol into the peritoneal cavity when the needle is withdrawn. The easiest method of injecting alcohol is to monitor injection directly using ultrasound guidance, although CT may also be used, depending on personal preference. When using ultrasound guidance, injected alcohol appears as brightly echogenic material because of the microbubbles that are drawn into the syringe when the alcohol is aspirated from the bottle. Under CT gUidance, pure alcohol appears as a very dark low attenuation area. It is not necessary, and it is counterproductive, to add iodinated contrast to alcohol for CT guidance. Adding contrast only dilutes the alcohol and the easy visibility of injected alcohol makes any additional contrast unnecessary. The calculated volume of alcohol for a tumor is determined by using the formula for the corrected volume 64 of a sphere, assuming that the tumor grows spherically.
This formula is 4/3 ,pi (r + 0.5)3. After trying the measured volume for injection, we have fallen back to using approximately 15-20 mL for small tumors (2-3 cm), and 30 to 45 mL for larger tumors. These volumes are given each treatment session. Certainly, if ultrasound guidance shows that there is a large amount of leak, more volume may be needed, and if very good diffusion throughout the tumor is seen with smaller volumes, less alcohol can be used. Small tumors are treated three times during 3 weeks, one session per week. Larger tumors are treated for 4-5 sessions, again on a weekly basis. Follow-up evaluation is discussed below. We do not use alcohol for treatment of hepatic metastases, after an initial series of patients showed unfavorable responses, with residual untreated areas and peripheral regrowth. One possible explanation for the difference in success between hepatomas and metastatic deposits is that hepatomas are fairly soft tumor, encapsulated in about a third of patients, surrounded by a firm, cirrhotic liver. Thus, alcohol which is injected into the center of the soft tumor tends to stay in that location. Conversely, metastases are generally slightly firmer than the adjacent normal liver and alcohol which is injected runs easily from the liver to the surrounding parenchyma. When alcohol is injected, intravenous sedation is used and, of course, informed consent is obtained. Our informed consent includes the risks of incomplete treatment, reaction to injected medication, potential needle track seeding, and potential venous thrombosis. Although venous thrombosis is known in the literature, we have not experienced this, probably due to slow injection rates and relatively small volumes of injected alcohol. We do attempt to avoid direct intravasation of a bolus of alcohol to reduce the incidence of this complication. One reported complication of alcohol injection is tumor seeding along the tract.
Radiofrequency RF treatment of liver tumors can be performed irrespective of the original pathology. Both metastases and hepatomas can be treated, making this a more attractive general purpose method for percutaneous ablation. At our institution, after several years of research using IRE approved protocols, we have settled on the use of a prototype 18 gauge water cooled needle which contains a 23-gauge RF transducer. This needle is inserted under imaging guidance, either alone or in an array, and radiofrequency energy is applied to the electrode tip. The presence of the 18-gauge needle around the 23-gauge electrode allows constant perfusion of the tip to keep it cool. This has the effect of enlarging the zone of treatment beyond that which is obtained with other thermal methods such as laser photocoagulation. Traditionally, there has been a biological barrier to diffusion of heat beyond approximately a 16-18 mm diameter using the laser photocoagulation. This barrier occurs because the
presence of flowing blood around the treatment area, cools the peripheral treatment zones to below cytotoxic temperatures. However, with cooled tip RF electrodes, the area around the tip of the electrode remains cool and the heat is diffused further into the tissue. When the energy is turned off, the tip re-warms and the energy diffuses back to the central portion, killing the cells adjacent to the needle itself. When RF ablation is performed, informed consent is obtained, as above and the patients are treated with conscious sedation, identical to the methods used for PEL Grounding pads are applied and the monopolar RF needle is inserted under direct imaging guidance, either ultrasound or CT. Our system uses a Radionics generator and the needle is constantly monitored for current, tissue impedance, and tip temperature. Energy is applied for approximately twelve minutes with a tip temperature between 20 and 28 degrees centigrade. With lower tip temperatures, larger lesions can be created. European experience has shown that larger lesions can also be created with increased power levels, but the Food and Drug Administration limits our power. At the time of this writing (August, 1997) the cooled tip electrode is not yet commercially available. Results PEl for Hepatoma Liviraghi's initial results with 3-year follow-up of patients treated by PEl for hepatocellular carcinoma less than 5 cm in diameter showed results that were equivalent to surgical resection, with lower perioperative morbidity and mortality. In subsequent work, a 5-year follow-up showed local recurrent disease in the area of previous treatment in 17% of patients and recurrence of disease elsewhere in the liver in over 70%. Before casting a critical eye on these results, it should be noted that these are comparable results to surgical resection and 5-year follow-up. As would be expected, patients with a better functional classification (child's class A) had better survival at 1, 3, and 5-year intervals than patients with poor function (Child's B and above).
Radiofrequency The greatest human experience in RF ablation has been obtained in Italy. Rossi and Solbiati have reported treatment of both hepatomas and metastases. Results with HCCs were comparable to PEl treatment. Interestingly, treatment with metastases for palliation of local disease was also favorable, with one series showing an absence of local tumor recurrence in small (less than 3 cm) metastases in two-thirds of treated patients. Fifty percent of the patients in this series had disease-free follow-up at 16 months. Follow-up In patients who have measurable tumor markers, frequent assessment of tumor markers should be performed and any elevation should prompt the search for
new areas of disease, not only in the liver, but also in the remainder of likely sites for metastatic disease, depending on the primary tumor type. In successfully treated lesions, imaging studies should show absence of growth and gradual reduction in size over 6 to 12 months. In our experience, the most sensitive test for recurrence of tumor has been liver Mill, with regrowth seen as areas of high T2 signal intensity either within the original treated area, surrounding the original treated area, or in new areas of the liver. Areas which show contrast enhancement on either CT or MR are considered residual or recurrent tumor and should be biopsied. Any biopsy proven residual tumor requires retreatment or assessment for possible chemo-embolization.
The Future As enthusiastic as I am about percutaneous methods of tumor ablation, at this time, I do not see them replacing surgical therapy or chemotherapy for chemosensitive tumors. However, there will always be patients for whom surgery is not an option either because of their underlying disease or their comorbid conditions, and for these patients, alternative methods of treatment are desirable. A large burden of proof rests upon those who perform percutaneous tumor ablation, to demonstrate efficacy and outcomes comparable to accepted surgical therapy. In my opinion, alcohol ablation was the first method of percutaneous treatment, and, in selected patients, it proved the validity of the concept. I anticipate that radiofrequency ablation and methods such as focused ultrasound will come to dominate the field because of the greater control over energy deposition afforded with RF, and because of the completely noninvasive nature of focused ultrasound. However, considerable practical difficulties remain. For instance, at this point in its development, focused ultrasound requires an exceedingly long time to treat clinically important sized lesions, and ultrasound is not feasible in areas where bone and air interfere with the ultrasound beam. Other methods such as the injection of hot saline, acetic acid, laser photocoagulation, and microwave therapy have received too litde critical review or, in the case of laser photocoagulation, have been proven to give treatment zones that are currently too small to be clinically useful. Cryotherapy deserves special mention, if only because it has a longer history than some of the other methods which have been discussed. At present, cryotherapy still requires an operative exposure and runs the risk of complications of incomplete treatment at the margins of the iceball, damage to the liver by probes which are in place for prolonged periods during the time of freezing, and the complication of "cryo shock." We have no experience with cryo ablation at MGH.
65
Summary Percutaneous and transcutaneous methods of tumor ablation will continue to be investigated and find clinical application, both because the diseases for which they are used are very common and also because patients who suffer these diseases are frequently not surgical candidates. Except in isolated cases (neuro-endocrine tumors), systemic chemotherapy offers little for hepatic metastatic disease. The simplest technique to use for those who wish to begin to study this method of treatment is percutaneous ethanol injection, but the most effective may turn out to be RF ablation. The future holds much potential for this particular image-guided therapy, but we must be cautious to backup our experimentation with documentation of outcomes.
Selected Bibliography 1. Dawson SL. Alcohol ablation of hepatic neoplasms, 19th Annual Scientific Meeting Preceedings, SCVIR, 1994. 2. Dawson SL, Ray CE, Geller Se. Hepatic chemoembolization and percutaneous ablation. Radiology-Diagnosis Imaging Intervention. Taveras ]M, Ferrucci ]T, eds. Lippincott-Raven, 1996. 3. Solbiati L, Goldberg SN, Ierace T, et al. Radiofrequency ablation of hepatic metastases using cool tipped electrodes: results in twenty-nine patients. In press. 4. Hoover He. Surgical resection of primary hepatomas and hepatic metastases. Semin Intervent Radiol 1993; 10:2.
12. Goldberg SN, Gazelle GS, Solbiati L, Rittman W], Mueller PRo Radiofrequency tissue ablation: increased lesion diameter with a perfusion electrode. Acad Radiology 1996; 3:636-644. 13. Solbiati L, Ierace T, Goldberg SN, Livraghi T, Rizzatto G, Mueller PR, Gazelle GS. Percutaneous US-guided RF tissue ablation of liver metastases: long-term follow up. Radiology 1997; 202:195-203. 14. Livraghi T, Goldberg SN, Lazzaroni S, Meloni F, Monti F, Solbiati L, Gazelle GS. Saline-enhanced radiofrequency tissue ablation in the treatment of liver metastases. Radiology 1997; 202:205-210. 15. Solbiati L, Goldberg SN, Ierace T, Livraghi T, Sironi S, Gazelle GS. Radiofrequency ablation of hepatic metastases with cooled-tip electrodes: results in 29 patient. Radiology 1997;(in press). 16. Goldberg SN, Livraghi T, Solbiati L, Gazelle GS. In situ ablation of focal hepatic neoplasms. In: Hepatobiliary and pancreatic radiology: imaging and intervention. Gazelle GS, Saini S, Mueller PR, eds. Thiema Medical Pur., New York, 1997. 17. Amin Z, Donald ]], Masteres A, Kant R, Steger AC, Bown SG, Lees WR. Hepatic metastases: interstitial laser photocoagulation with real-time US monitoring and dynamic TC evaluation of treatment. Radiology 1993; 187:339. 18. LeVeen RF, Fox RL, Schneider PD, Hinrichs SH. Large RF ablation lesions produced with a radially expanding monopolar array electrode: long-tenn porcine experiments.]VIR 1997; 8:1.
5. Gazelle GS, Boland G, Dawson SL, et al. Hepatic segmental anatomy and its relevance to the management of patients with hepatic malignancies. Semin Intervent Radiol 1993; 10:2.
8:45 am
6. Kane RA. Ultrasound guided hepatic cryosurgery for tumor ablation. Semin Intervent Radiol 1993; 10:2.
Imaging of Tumors After Interventional Therapy judith 1. Chezmar, MD
7. Dawson SL, Lee M], Mueller PR, eds. Non-surgical treatment of liver tumors. Semin Intervent Radiol 1993; 10:2. 8. Livraghi T, Giorgio A, Marin G, et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology 1995; 197:101-108. 9. Clouse ME, Lee RGL, Duszlak E], et al. Peripheral hepatic artery embolization for primary and secondary hepatic neoplasms. Radiology 1983; 147:407411. 10. Sironi S, Livraghi T, DelMaschio A. Small hepatocellular carcinomas treated with percutaneous ethanol injection: MR imaging findings. Radiology 1991; 180: 333-336.
66
tion of percutaneous alcohol ablation. Radiology 1994; 193:81.
11. Zerebey AL, Mueller, PR, Dawson SL, et aI. Pleural seeding from hepatocellular carcinoma: complica-
Session objectives: As a result ofattending this session, the attendee will be able to: (1) Realize the risk of recurrence of hepatocellular carcinoma after percutaneous alcohol ablation. (2) Interpret CT, MR and color Doppler US features of successful tumor ablation. (3) Identify imaging features of residual tumor after treatment on CT or MR. (4) Identify an appropriate imaging protocol for follow-up of treated patients. PERCUTANEOUS alcohol ablation for hepatocellular carcinoma, chemoembolization, and more recently, radiofrequency ablation are among the nonsurgical therapies available for treatment of malignant hepatic tumors. While good long-term survival statistics have been reported in patients treated with these methods, tumor recurrence in the liver is high. This is particularly welldocumented for therapies directed at hepatocellular carcinoma in the cirrhotic liver, where large series have reported high long-term survival in patients after alcohol ablation for hepatocellular carcinoma 0,2), but with
References 1. Venook AP. Treatment of Hepatocellular Carcinoma: Too many options? J Clin Oncol1994; 12:1323-1334. 2. Nagasue N, Kohno H, Chang Y, et al. Liver resection for hepatocellular carcinoma. Ann Surg 1993; 217: 375-384. 3. Venook AP, Ferrell LD, Roberts JP, et al. Liver transplantation for hepatocellular carcinoma: results with preoperative chemoembolization. Liver Trans Surg 1995; 1:242-248. 4. Shiina S, Tagawa K, Unuma T, et al. Percutaneous ethanol injection therapy for hepatocellular carcinoma. Cancer 1991; 68:1524-1530. 5. Venook AP, Stagg RJ, Lewis BJ, et al. Chemoembolization for hepatocellular carcinoma. ] Clin Onc 1990; 8:1108-1114. 6. Hepatocellulaire, Groupe d'Etude et de Treatment du Carcinome. A comparison of Lipiodol chemoembolization and conservative treatment for unresedable hepatocellular carcinoma. N Engl J Med 1995; 332:1256-1261. 7. Steele G], Bleday R, Mayer RJ, et al. A prospective evaluation of hepatic resection for colorectal carcinoma metastases to the liver: Gastrointestinal Tumor Study Group Protocol 6584. J Clin Oncol 1991; 9:1105-1112. 8. Hajarizadeh H, Ivancev K, Mueller CR, et al. Effective palliative treatment of metastatic carcinoid tumors with intra-arterial chemotherapy/chemoembolization combined with octreotide acetate. Am J Surg 1992; 163:479-483. 9. Stagg RJ, Venook AP, Chase JL, et al. Chemoembolization of primary and metastatic liver tumors. Reg Cancer Treat 1992; 2:53-57. 10. Venook AP, Eaton V, Chang J, et al. Chemoembolization for liver metastases from uveal melanoma. GI Cancer 1996; 1:269-273. 11. Venook AP, Warren RS. Regional chemotherapy approaches for primary and metastatic liver tumors. Surg Oncol Clin No Am 1996; 5:411-427. 8:20 am
Image-guided Therapy for Hepatic Neoplasm Ablation Steven 1. Dawson, MD IMAGE-GUIDED therapy of liver tumors has two distinct pathways: chemo-embolization using catheter based techniques, and direct percutaneous or transcutaneous ablation of malignant deposits. Chemo-embolization will be considered elsewhere in this syllabus and this pre-
sentation deals exclusively with percutaneous and transcutaneous methods of tumor ablation. Malignant deposits within the liver are a very common manifestation of systemic malignancy: breast, lung, neuro-endocrine malignancies as well as melanoma are all commonly seen as metastatic deposits within the liver. In addition, primary hepatocellular carcinoma is a significant global problem, with HCC as the most common malignancy affecting the liver worldwide. Several therapies exist for patients with malignant involvement of the liver. For primary hepatocellular carcinoma, surgical resection and direct tumor ablation are considered the most effective treatments. For metastatic disease, surgical resection is considered the gold standard, realizing that the presence of metastatic disease in the liver indicates hematogeneous spread of the primary tumor, and these patients are likely to have metastatic involvement of other organs, rendering treatment of hepatic metastases alone somewhat problematic. However, systemic chemotherapy for hepatic metastases using 5-FU has only about a 20% response rate and no evidence of prolonged survival (9). With hepatic metastasectomy, there is a 30%-35% five year survival in properly selected patients, albeit with a perioperative mortality of 20/0-10%. In comparison, untreated hepatic metastases from colorectal carcinoma, for example, has a 5-year survival of less than 1% and a median survival of approximately 9.6 months.
Understanding the Big Picture If we are to embark on treating tumors percutaneously, we have to understand the big picture. In HCC, we are treating what may be the only visible site of cancer lying within a diseased organ. By definition, metastatic disease is present systemically at the time of treatment. With HCC, we may be able to significantly alter the course of the disease by treating the tumor. With metastases, we are only palliating systemic disease with local treatment. As percutaneous treatments are developed for liver tumors, their outcome must be validated, in order for us to have equal standing with the surgical treatment of metastatic disease, which is, after all, also a local treatment for systemic disease. There is a fundamental difference between treating a primary HCC which is usually visible as a solitary lesion or a series of small satellite lesions on the background of a diseased liver (hepatitis, cirrhosis) and treating metastatic disease which is seen as multiple small deposits on the background of a presumably n011llalliver. This difference in presentation is fundamental to understanding the differences in approach to treatment. Because of the normal functional reserve of the remaining liver, surgery can be performed for metastatic disease if the lesions are clustered in a manner which allows resection with preservation of functional hepatic units, such as a right hepatectomy, right trisegmentectomy, left hepatectomy, and/or extended left hepatectomy. However, because of the underlying hepatic parenchymal disease, hepatomas
63
are less likely to be surgically resectable because the remaining liver will not have adequate functional reserve. Thus, hepatomas are particularly well suited for percutaneous/transcutaneous image-guided therapies.
Methods of Ablation Tumor ablation can be divided into injectable and thermal methods. Injectable agents include percutaneous ethanol injection (PEl), hot saline, and acetic acid. Future injectable agents will include percutaneously delivered depot drug sources which will release directly into the tumor over time. Thermal methods of ablation include those using heat (radiofrequency [RF], laser photocoagulation, microwave, and focused ultrasound), as well as cold thermal ablation (cryotherapy) (16). Technique of Ablation For the sake of clarity, two methods of ablation will be discussed in detail: PEl and RF ablation. By chOOSing these two means of ablation, a basic understanding of the differences between injectable agents and thermal agents can be understood. It is also likely that any interventional radiologist attempting percutaneous tumor ablation will have access to one of these two methods more frequently than to the other methods which have been mentioned. Percutaneous Ethanol Injection PEl is cheap, the materials are readily available, imaging guidance is straightforward, and the procedure is not exceptionally technically demanding. However, this procedure is also fraught with the risk of incomplete diffusion of alcohol within the tumor, leaving residual areas of untreated tumor to regrow. Alcohol ablation is probably the first tumor ablation procedure which the general interventionalist will attempt. Lesions which are amenable for alcohol ablation include primary hepatocellular carcinomas that are less than 5 cm in size, or three to four lesions which are less than approximately 3-4 cm in size. Ideally, there is a margin of liver surrounding the tumor that can be used to prevent reflux of alcohol into the peritoneal cavity when the needle is withdrawn. The easiest method of injecting alcohol is to monitor injection directly using ultrasound guidance, although CT may also be used, depending on personal preference. When using ultrasound guidance, injected alcohol appears as brightly echogenic material because of the microbubbles that are drawn into the syringe when the alcohol is aspirated from the bottle. Under CT gUidance, pure alcohol appears as a very dark low attenuation area. It is not necessary, and it is counterproductive, to add iodinated contrast to alcohol for CT guidance. Adding contrast only dilutes the alcohol and the easy visibility of injected alcohol makes any additional contrast unnecessary. The calculated volume of alcohol for a tumor is determined by using the formula for the corrected volume 64 of a sphere, assuming that the tumor grows spherically.
This formula is 4/3 ,pi (r + 0.5)3. After trying the measured volume for injection, we have fallen back to using approximately 15-20 mL for small tumors (2-3 cm), and 30 to 45 mL for larger tumors. These volumes are given each treatment session. Certainly, if ultrasound guidance shows that there is a large amount of leak, more volume may be needed, and if very good diffusion throughout the tumor is seen with smaller volumes, less alcohol can be used. Small tumors are treated three times during 3 weeks, one session per week. Larger tumors are treated for 4-5 sessions, again on a weekly basis. Follow-up evaluation is discussed below. We do not use alcohol for treatment of hepatic metastases, after an initial series of patients showed unfavorable responses, with residual untreated areas and peripheral regrowth. One possible explanation for the difference in success between hepatomas and metastatic deposits is that hepatomas are fairly soft tumor, encapsulated in about a third of patients, surrounded by a firm, cirrhotic liver. Thus, alcohol which is injected into the center of the soft tumor tends to stay in that location. Conversely, metastases are generally slightly firmer than the adjacent normal liver and alcohol which is injected runs easily from the liver to the surrounding parenchyma. When alcohol is injected, intravenous sedation is used and, of course, informed consent is obtained. Our informed consent includes the risks of incomplete treatment, reaction to injected medication, potential needle track seeding, and potential venous thrombosis. Although venous thrombosis is known in the literature, we have not experienced this, probably due to slow injection rates and relatively small volumes of injected alcohol. We do attempt to avoid direct intravasation of a bolus of alcohol to reduce the incidence of this complication. One reported complication of alcohol injection is tumor seeding along the tract.
Radiofrequency RF treatment of liver tumors can be performed irrespective of the original pathology. Both metastases and hepatomas can be treated, making this a more attractive general purpose method for percutaneous ablation. At our institution, after several years of research using IRE approved protocols, we have settled on the use of a prototype 18 gauge water cooled needle which contains a 23-gauge RF transducer. This needle is inserted under imaging guidance, either alone or in an array, and radiofrequency energy is applied to the electrode tip. The presence of the 18-gauge needle around the 23-gauge electrode allows constant perfusion of the tip to keep it cool. This has the effect of enlarging the zone of treatment beyond that which is obtained with other thermal methods such as laser photocoagulation. Traditionally, there has been a biological barrier to diffusion of heat beyond approximately a 16-18 mm diameter using the laser photocoagulation. This barrier occurs because the
presence of flowing blood around the treatment area, cools the peripheral treatment zones to below cytotoxic temperatures. However, with cooled tip RF electrodes, the area around the tip of the electrode remains cool and the heat is diffused further into the tissue. When the energy is turned off, the tip re-warms and the energy diffuses back to the central portion, killing the cells adjacent to the needle itself. When RF ablation is performed, informed consent is obtained, as above and the patients are treated with conscious sedation, identical to the methods used for PEL Grounding pads are applied and the monopolar RF needle is inserted under direct imaging guidance, either ultrasound or CT. Our system uses a Radionics generator and the needle is constantly monitored for current, tissue impedance, and tip temperature. Energy is applied for approximately twelve minutes with a tip temperature between 20 and 28 degrees centigrade. With lower tip temperatures, larger lesions can be created. European experience has shown that larger lesions can also be created with increased power levels, but the Food and Drug Administration limits our power. At the time of this writing (August, 1997) the cooled tip electrode is not yet commercially available. Results PEl for Hepatoma Liviraghi's initial results with 3-year follow-up of patients treated by PEl for hepatocellular carcinoma less than 5 cm in diameter showed results that were equivalent to surgical resection, with lower perioperative morbidity and mortality. In subsequent work, a 5-year follow-up showed local recurrent disease in the area of previous treatment in 17% of patients and recurrence of disease elsewhere in the liver in over 70%. Before casting a critical eye on these results, it should be noted that these are comparable results to surgical resection and 5-year follow-up. As would be expected, patients with a better functional classification (child's class A) had better survival at 1, 3, and 5-year intervals than patients with poor function (Child's B and above).
Radiofrequency The greatest human experience in RF ablation has been obtained in Italy. Rossi and Solbiati have reported treatment of both hepatomas and metastases. Results with HCCs were comparable to PEl treatment. Interestingly, treatment with metastases for palliation of local disease was also favorable, with one series showing an absence of local tumor recurrence in small (less than 3 cm) metastases in two-thirds of treated patients. Fifty percent of the patients in this series had disease-free follow-up at 16 months. Follow-up In patients who have measurable tumor markers, frequent assessment of tumor markers should be performed and any elevation should prompt the search for
new areas of disease, not only in the liver, but also in the remainder of likely sites for metastatic disease, depending on the primary tumor type. In successfully treated lesions, imaging studies should show absence of growth and gradual reduction in size over 6 to 12 months. In our experience, the most sensitive test for recurrence of tumor has been liver Mill, with regrowth seen as areas of high T2 signal intensity either within the original treated area, surrounding the original treated area, or in new areas of the liver. Areas which show contrast enhancement on either CT or MR are considered residual or recurrent tumor and should be biopsied. Any biopsy proven residual tumor requires retreatment or assessment for possible chemo-embolization.
The Future As enthusiastic as I am about percutaneous methods of tumor ablation, at this time, I do not see them replacing surgical therapy or chemotherapy for chemosensitive tumors. However, there will always be patients for whom surgery is not an option either because of their underlying disease or their comorbid conditions, and for these patients, alternative methods of treatment are desirable. A large burden of proof rests upon those who perform percutaneous tumor ablation, to demonstrate efficacy and outcomes comparable to accepted surgical therapy. In my opinion, alcohol ablation was the first method of percutaneous treatment, and, in selected patients, it proved the validity of the concept. I anticipate that radiofrequency ablation and methods such as focused ultrasound will come to dominate the field because of the greater control over energy deposition afforded with RF, and because of the completely noninvasive nature of focused ultrasound. However, considerable practical difficulties remain. For instance, at this point in its development, focused ultrasound requires an exceedingly long time to treat clinically important sized lesions, and ultrasound is not feasible in areas where bone and air interfere with the ultrasound beam. Other methods such as the injection of hot saline, acetic acid, laser photocoagulation, and microwave therapy have received too litde critical review or, in the case of laser photocoagulation, have been proven to give treatment zones that are currently too small to be clinically useful. Cryotherapy deserves special mention, if only because it has a longer history than some of the other methods which have been discussed. At present, cryotherapy still requires an operative exposure and runs the risk of complications of incomplete treatment at the margins of the iceball, damage to the liver by probes which are in place for prolonged periods during the time of freezing, and the complication of "cryo shock." We have no experience with cryo ablation at MGH.
65
Summary Percutaneous and transcutaneous methods of tumor ablation will continue to be investigated and find clinical application, both because the diseases for which they are used are very common and also because patients who suffer these diseases are frequently not surgical candidates. Except in isolated cases (neuro-endocrine tumors), systemic chemotherapy offers little for hepatic metastatic disease. The simplest technique to use for those who wish to begin to study this method of treatment is percutaneous ethanol injection, but the most effective may turn out to be RF ablation. The future holds much potential for this particular image-guided therapy, but we must be cautious to backup our experimentation with documentation of outcomes.
Selected Bibliography 1. Dawson SL. Alcohol ablation of hepatic neoplasms, 19th Annual Scientific Meeting Preceedings, SCVIR, 1994. 2. Dawson SL, Ray CE, Geller Se. Hepatic chemoembolization and percutaneous ablation. Radiology-Diagnosis Imaging Intervention. Taveras ]M, Ferrucci ]T, eds. Lippincott-Raven, 1996. 3. Solbiati L, Goldberg SN, Ierace T, et al. Radiofrequency ablation of hepatic metastases using cool tipped electrodes: results in twenty-nine patients. In press. 4. Hoover He. Surgical resection of primary hepatomas and hepatic metastases. Semin Intervent Radiol 1993; 10:2.
12. Goldberg SN, Gazelle GS, Solbiati L, Rittman W], Mueller PRo Radiofrequency tissue ablation: increased lesion diameter with a perfusion electrode. Acad Radiology 1996; 3:636-644. 13. Solbiati L, Ierace T, Goldberg SN, Livraghi T, Rizzatto G, Mueller PR, Gazelle GS. Percutaneous US-guided RF tissue ablation of liver metastases: long-term follow up. Radiology 1997; 202:195-203. 14. Livraghi T, Goldberg SN, Lazzaroni S, Meloni F, Monti F, Solbiati L, Gazelle GS. Saline-enhanced radiofrequency tissue ablation in the treatment of liver metastases. Radiology 1997; 202:205-210. 15. Solbiati L, Goldberg SN, Ierace T, Livraghi T, Sironi S, Gazelle GS. Radiofrequency ablation of hepatic metastases with cooled-tip electrodes: results in 29 patient. Radiology 1997;(in press). 16. Goldberg SN, Livraghi T, Solbiati L, Gazelle GS. In situ ablation of focal hepatic neoplasms. In: Hepatobiliary and pancreatic radiology: imaging and intervention. Gazelle GS, Saini S, Mueller PR, eds. Thiema Medical Pur., New York, 1997. 17. Amin Z, Donald ]], Masteres A, Kant R, Steger AC, Bown SG, Lees WR. Hepatic metastases: interstitial laser photocoagulation with real-time US monitoring and dynamic TC evaluation of treatment. Radiology 1993; 187:339. 18. LeVeen RF, Fox RL, Schneider PD, Hinrichs SH. Large RF ablation lesions produced with a radially expanding monopolar array electrode: long-tenn porcine experiments.]VIR 1997; 8:1.
5. Gazelle GS, Boland G, Dawson SL, et al. Hepatic segmental anatomy and its relevance to the management of patients with hepatic malignancies. Semin Intervent Radiol 1993; 10:2.
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6. Kane RA. Ultrasound guided hepatic cryosurgery for tumor ablation. Semin Intervent Radiol 1993; 10:2.
Imaging of Tumors After Interventional Therapy judith 1. Chezmar, MD
7. Dawson SL, Lee M], Mueller PR, eds. Non-surgical treatment of liver tumors. Semin Intervent Radiol 1993; 10:2. 8. Livraghi T, Giorgio A, Marin G, et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology 1995; 197:101-108. 9. Clouse ME, Lee RGL, Duszlak E], et al. Peripheral hepatic artery embolization for primary and secondary hepatic neoplasms. Radiology 1983; 147:407411. 10. Sironi S, Livraghi T, DelMaschio A. Small hepatocellular carcinomas treated with percutaneous ethanol injection: MR imaging findings. Radiology 1991; 180: 333-336.
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tion of percutaneous alcohol ablation. Radiology 1994; 193:81.
11. Zerebey AL, Mueller, PR, Dawson SL, et aI. Pleural seeding from hepatocellular carcinoma: complica-
Session objectives: As a result ofattending this session, the attendee will be able to: (1) Realize the risk of recurrence of hepatocellular carcinoma after percutaneous alcohol ablation. (2) Interpret CT, MR and color Doppler US features of successful tumor ablation. (3) Identify imaging features of residual tumor after treatment on CT or MR. (4) Identify an appropriate imaging protocol for follow-up of treated patients. PERCUTANEOUS alcohol ablation for hepatocellular carcinoma, chemoembolization, and more recently, radiofrequency ablation are among the nonsurgical therapies available for treatment of malignant hepatic tumors. While good long-term survival statistics have been reported in patients treated with these methods, tumor recurrence in the liver is high. This is particularly welldocumented for therapies directed at hepatocellular carcinoma in the cirrhotic liver, where large series have reported high long-term survival in patients after alcohol ablation for hepatocellular carcinoma 0,2), but with