- Email: [email protected]
Radiofrequency Ablation of Liver Tumors
lization (for dominant lesions >3 cm in size). Acetic acid may also hold promise in the treatment of nonhepatic neoplasms. Swnmary Percutaneous chemical ablation is an established, effective technique which is easy to perform and requires no specialized equipment. Chemical ablation is well tolerated by patients and is associated with a low complication rate. No compelling outcomes data yet exist to favor other ablative techniques (RF, cryo) over chemical ablation in terms of survival or cost-effectiveness for small hepatocellular carcinoma. Acetic acid has additional advantages over ethanol of homogenous tumor diffusion and lower volumes required for celt kill, enabling treatment of liver metastases, alone or in combination with chemoembolization. Chemical ablation is likely to remain a useful tool in the interventional radiologist's armamentarium for regional cancer therapy.
References 1. Livraghi T, Goldberg SN, Lazzaroni S, et a1. USgUided percutaneous alcohol injection of small hepatic and abdominal tumors. Radiology 1986;161: 309-312. 2. Shiina S, Tagawa K, Unuma T et a1. Percutaneous ethanol injection therapy of hepatocellular carcinoma: analysis ofn patients. AJR 1990;155:1221-1226. 3. Livraghi T, Giorgio A, Marin G et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol ablation. Radiology 1995;197:101-108. 4. Lee MJ, Mueller PR, Dawson SL et al. Percutaneous ethanol injection for the treatment of hepatic tumors: indications, mechanism of action, technique and efficacy. AJR 1995;164:215-220. 5. Livraghi T, Bolondi L, Lazzaroni S et al. Percutaneous ethanol injection in the treatment of hepatocellular carcinoma in cirrhosis. Cancer 1992;69:925-929. 6. Bartolozzi C, Lencioni R, Caramella D et al. Treatment of large HCC: transcatheter arterial embolization combined with percutaneous ethanol injection versus repeated transcatheter arterial chemoembolization. Radiology 1995;97:812-818. 7. Castells A, Bruix J, Bru C, et al. Treatment of small hepatocellular carcinoma in cirrhotic patients: a cohort study comparing surgical resection and percutaneous ethanol injection. Hepatology 1993;18:1221-1226.
tors in 105 Western patients. Cancer 1995;76:17371746. 10. Taavitsainen M, Vehmas T, Kauppila R. Fatal liver necrosis follOWing percutaneous ethanol injection for hepatocellular carcinoma. Abdom Imag 1993;18: 357-359. 11. Goletti 0, De Negri F, Pucciarelli M et al. Subcutaneous seeding after percutaneous ethanol injection of liver metastasis. Radiology 1992;183:785-786. 12. Cedrone A, Rapaccini GL, Pompili M et al. Neoplastic seeding complicating percutaneous ethanol injection for treatment of hepatocellular carcinoma. Radiology 1992:183:787-788. 13. Zcrbey Ai, Mueller PR, Dawson SL, et al. Pleural seeding from hepatocellular carcinoma: a complication of percutaneous alcohol ablation. Radiology 1994;193:81-82. 14. Livraghi T, Goldberg SN, Lazzaroni S et al. Small hepatocellular carcinoma: treatment with radiofrequency ablation versus ethanol ablation. Radiology 1999;210:655-661. 15. Livraghi T, Vettod C, Lazzaroni S, et al. Liver metastases: results of percutaneous ethanol injection in 14 patients. Radiology 1991 ;179:709-712. 16. Amin Z, Bown SG, Lees WR. Local treatment of colorectal liver metastases: a comparison of interstitial laser photocoagulation (lLP) and percutaneous alcohol injection (PAl). Clin Radiol 1993;48:166-71. 17. Ohnishi K, Ohyama N, Ito S, Fujiwara K. Ultrasound guided intra tumor injection of acetic acid for the treatment of small hepatocellular carcinoma. Radiology 1994;193:747-752. 18. Ohnishi K, Yoshioka H, Ito S, Fujiwara K. Percutaneous randomized controlled trail comparing acetic acid injection and percutaneous ethanol injection for small hepatocellular carcinoma. Hepatology 1998; 27:67-72. 19. Ohnishi K, Yoshioka H, Ito S, Fujiwara K. Treatment of nodular hepatocellular carcinoma larger than 3 em with ultrasound-guided percutaneous acetic acid injection. Hepatology 1996;24:1379-1378. 20. Van Hoof M, Jorris JP, Horsmans Y, Geubel A. Acute renal failure requiring hemodialysis after high dose percutaneous acetic acid injection for hepatocellular carcinoma. Acta Gastroenterol Belg 1999;62:49-51.
4:15 p.m.
8. Kotoh K, Sakai H, Sakamoto S et al. The effect of percutaneous ethanol injection on small solitary hepatocellular carcinoma is comparable to d,at of hepatectomy. Am J Gastroenterol 1994;89:194-198.
Radiofrequency Ablation of Liver Tumors Gerald D. Dodd III, MD University of Texas Health Science Center San AntoniO, Texas
9. Lencioni R, Bartolozzi C, Caramella D et al. Treatment of small hepatocellular carcinoma with percutaneous ethanol injection: analysis of prognostiC fac-
Learning objectives: as a I"esult of attending the categorical course tbe attendee will be able to: 1) Explain tbe tbeory bebind RF ablation; 2) Identify appropriate can-
P209
didates for RF ablation of liver tumors; 3) List the advantages and disadvantages of RF ablation of liver tumors; 4) F'.XjJlain the risks associated with RF ablation of liver tumors Conventional chemotherapy and/or radiation therapy arc ineffective for the treatment of prbnary or secondary malignant hepatic tumors. Surgical resection is considered the only potentiaJly curative therapy for these tumors. However, because of advanced disease, unfavorable location, or impaired clinical condition, only a minority of patients are eligible for surgical resection. In addition, the results of surgical resection are poor; only 30% of patients remain tumor-free at 5 years. These poor results have led to the development of multiple minimally invasive forms of therapy. These therapies include intraarterial chcmoembolization, injection of ethanol, and interstitial laser, microwave, or radiofrequency (RF) ablation. Of these techniques, RF thermal ablation is one of the newest and most promising. RF Mechanism RF thermal ablation is a misnomer. The thermal injury created by this device is produced by alternating electric current not by the emitted radiofrequency waves. Special needle electrodes and ground pads act as conductors for the alternating current. The current agitates the ions in the tissue adjacent to the needle electrodes, thus creating frictional heal. The heat starts in a glove~like configuration around the electrodes then expands by conduction to form a thermal sphere. Temperatures in excess of 50°C produce coagulative necrosis. If temperatures around the electrodes are maintain.ed between 95-100°C for twelve minutes, a 3--4 cm spherical thermal injury will be created. Patients We re<;ruit patients for RF thermal ablation of hepatic tumors using the following selection criteria: 1. Four or fewer, smaller than 5 cm, primary or secondary malignant hepatic tumors 2. Not a candidate for liver resection 3. No evidence of extrahepatic tumor 4. Life expectancy >6 months. Patients less than 18 years old, altered mental status, existing pregnancy, extrahepatic tumor, active infection, uncorrectable coagulopathy, or Childs C cirrhosis are excluded.
Preprocedural Evaluation Within a month before the procedure, all patients have the follOWing laboratory. tests: Chern 20, serum ammonia, GGT, PT/PTI, CEA (in patients with metastatic tumors) or APP (in patients with hepatocellular carcinoma) and a hepatitis screen. Additionally, the following imaging studies are performed: cr of the chest (to exclude lung metastases), biphasic contrast enhanced cr of the liver (as a baseline for post procedure follow up), targeted sonogram of the
P210
liver (to plan rhe approach and assess feaSibility of the percutaneous performance of the procedure), and a bone scan Cif there is history of bone pain and/or the serum alkaline phosphatase is disproportionately elevated). On the clay before the procedure, the slibjects undergo an EKG and blood typing and screening in preparation for possible emergent surgery.
Equipment We use a lSO-200-watt alternating electric current generator that operates at 460-480 kHz. The unit has a temperature display, a timer, a wattage display, an impedance gauge, and a display for the lOtal energy emitted. The ground pads (n = 2-4) are large adhesive dispersive electrodes. They are placed on the skin over the low back muscles and/or thigh. The alternating current flows back and forth between the needle electrode and the ground pads. The electrodes are 14-17-gauge needles that are insulated except for distal tip. Cooled tip electrodes are straight 17 gauge needles with two internal channels through which chilled water is circulated. Multiarray electrodes have a plunger in the needle hub that advances 7-10 cUlved prongs from the tip. When deployed, the prongs and the needle resemble an open umbrella or Christmas tree. The diameter of the extended eleClrodes ranges from 2.5-4 cm. AU of the prongs and distal needle tip are active electrodes. Two of the devices have thermocouples in the tips of the electrodes that can be llsed lO measure local tissue temperaUne. Procedure Patients are treated on an outpatient basis. Each procedure takes between 1-3 hours depending on how many ablations are performed. After the procedure patients are observed for 4-6 hours, then released. All of the procedures are performed using sonographic gUidance and conscious sedation. Local anesthetic is injected at the puncture site and a small skin nick is made. The electrode is placed through the skin nick and advanced until the tip is positioned in the desired pan ion of a tumor. If a multi-array probe is used the plunger in [he hub of the needle is advanced causing the curved electrodes to be deployed in the rumor. The power is initiated and gradually increased until the mean temperature reaches 105°C. The tissue temperature is kept at lOsoC for 12-25 minutes. After each ablation the needle is repositioned as necessary to heat the entire tumor. The number of punctures of the liver capsule is kept to a minimum. "me needle tract is cauterized just below the liver capsule prior to removing the needle electrode. Treatment Strategies The goal in RF thermal ablation is to kill the target tumor as well as a 5-10 mm circumferential cuff of adjacent nonnal hepatiC parenchyma. We have developed three strategies that allow us to treat most tumors. Each strat-
egy is based on the 3 cm spherical thermal injury that is created by a single ablation. Tumors <2 cm are easily encompassed by a single ablation. Tumors between 2-3 cm are treated with 6 overlapping ablations. Four ablations are performed in the x-y plane and 2 are performed along z-axis. All ablations are positioned to touch at the center of the tumor. If placed correctly, the ablations create an inner spherical injury that measures approximately 3.75 cm in diameter. Tumors larger than 3 cm are treated by creating "thermal cylinders" that are systematically overlapped to cover the entire tumor. Each cylinder is created by overlapping ablations along a single needle tract from the deepest to the most superficial pOltions of a tumor. Each ablation is overlapped by 50%.
Evaluation of Treatment Outcome Follow-up blood work and abdominal CT scans are scheduled at 2 hours, 1 month, and every 3 months thereafter for 2 years. The success of an ablation is judged by the appearance of the treated nunor on the follow-up CT scans. Based on CT results, we have found that treated patients fall into one of three categories: completely ablated (no visible enhancing tumor), incompletely ablated (residual enhancing tumor), or completely ablated with recurrence (new enhancing tumor in the margin of the treated nlmor or elsewhere in the liver). Current Results Multiple clinical series have been published on percutaneous RF ablation of hepatic metastases and HCC. Their results appear promising with complete local kill rates for metastases and HCC of 40% and 70%, respectively. Curley et ai, who used an open surgical approach and a 3-minute Pringle maneuver for the majority of their patients have reported the best results. They reported a local recurrence rate of only 1.8% for both metastases and HCC. To date, we have treated approximately 130 patients using a percutaneous approach. Our results have improved with experience and refinements in eqUipment. However, to date we have been unable to achieve the same success as Curley et al.
new tumor. It has far fewer complications than chemoembolization. Lastly, it has twO major advantages over percutaneous ethanol ablation: it can be used to treat primary and secondary malignant hepatic tumors, and it requires fewer sessions to treat hepatocellular carcinoma. However, creating an adequate tumor-free margin around tumors can be difficult; failure to do so results in incomplete ablations and tumor recurrence. The local failure rate is controlled by two factors: high volume blood flow from the portal venous system cools the heating process and thus limits the size of an ablation, and exact needle placement is almost impossible. The use of a Pringle maneuver or other technique to diminish hepatiC blood flow during an ablation may yield larger more effective ablations. Likewise, adoption of effective geometriC ablation strategies may diminish the number of incomplete ablations.
Conclusion Based on current publications and our own experience RF thermal ablation is a quick, relatively safe, and highly effective technique for debulking primary and secondary malignant hepatic tumors. Additionally, it holds great promise as a technique for local tumor eradication.
Suggested Readings 1. Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer 1993;54:594-606. 2. Baron RL, Oliver JH 1Il, Dodd GD 1Il, Nalesnik MN, Holbert BL, Carr B. Hepatocellular carcinoma: evaluation with biphasic, contrast-enhanced, helical CT. Radiology 1996;99:505-511. 3. Kawasaki S, Makuuchi M. Miyagawa S, et al. Results of hepatic resection for hepatocellular carcinoma. World J Surg 1995;19:31-34. 4. Livraghi T, Giorgio A, Marin A., et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long term results of percutaneous ethanol injection. Radiology 1995;197:101-108. 5. Shiina S, Tagawa K, Unuma T, et al. Percutaneous ethanol injection therapy of hepatocellular carcinoma: analysis of77 patients. AJR 1990;155:1221-1226.
Complications Worldwide, thousands of patients have been treated by RF ablation. Overall, the complication rate has been very low ( <5%). The most common complications are bleeding, tumor seeding, ground pad burns, thermal burns of adjacent viscera, and delayed infection of ablated tissue. A handful of deaths have been attributed to RF ablations; the causes have been bleeding or infection.
6. Solbiati L, Goldberg SN, Ierace T, et al. Hepatic metastases: percutaneous radiofrequency ablation with cooled-tip electrodes. Radiology 1997;205:367-373.
Discussion RF thermal ablation has many potential advantages over existing therapies. It is far more effective for debulking tumors than is radiation therapy or systemic chemotherapy. Unlike surgical resection or ClyosurgelY, it is minimally invasive and can be repeated as necessary to treat
8. Rossi S, Di Stasi M, Buscarini E, et a1. Percutaneous RF interstitial thermal ablation in the treatment of hepatic cancer. AJR 1996; 167:759 -768.
7. Rossi S, Di Stasi M, Buscarini E, et al. Percutaneous RF interstitial thermal ablation in the treatment of small hepatocellular carcinoma. Cancer J Sci Am 1995;1:7381.
9. Curley SA, Izzo F, Delrio P, et al. Radiofrequency
P211
ablation of unresectable primary and metastatic hepatic malignancies. Ann Surg 1999;230:1-8.
, Intervenlional Oncology: Research to Practice [Part III
Sunday, March 4, 2001 5:00 p.m.-6:30 p.m. Moderators: Ketmeth C. Wright, PhD Ma((hew S. Johnson, MD
Objectives: Upon completion of this course, the attendee should be able to: 1. Discuss currently performed and promising new oncologic imaging techniques. 2. Describe available percutaneous image-guided therapies for hepatic malignancies. 3. Explain the current status of oncologic gene therapy and immunotherapy. 4. Recognize the vascular applications of localized drug delivery using nanotechnology and other systems. 5,00 p.m.
Tumor Biology: Implications for Management Kamran Ahrar, MD M.D. Anderson Cancer Center Houston, Texas Learning objectives: upon completion of this presenta-
tion, the attc-~dee should be able to: 1) E'\plain why cancer is considered a genetic disease; 2) Listfactors that influence the behavior of a cell mass; 3) Define oncogene, tumor suppressor gene, and apoptosis; 4) List strategies for molecular therapy of cancer. Molecular Biology in Cancer Medicine In the lasL lwo decades, basic science research has produced remarkable advances in our understanding of cancer biology and cancer genetics. It is now widely accepted that cancer in its various forms is a genetic disease (1). Human DNA undergoes continuous damage, repair, and resynlhesis. In normal cells, a homeostatic equilibrium is established by means of various complex regulatory pathways in which most DNA dam~ age is repaired without error. During carcinogenesis, this equilibrium is disrupted, resulting in the accumulation of multiple mutations (2). Multiple genetic alterations accu~ mulaLe in a stepwise manner during tumor progression resulLing in a group of cells Wilh a survival advantage over others (Fig 1). This unregulated growth is the end product of several interrelated influences, most importantly, the control of proliferalion, the balance between cell survival and programmed cell death, the communication with neighboring cells and the extracellular ma-
P212
trix, and the induction of tumor neovascularization (Fig 2).
Cells normally proceed through a regulated program of cell growth and differentiation, followed by programmed cell death or apoptosis (3). Proliferation, differentiation, and cell death are subject to internal and external regulatory signals that are lost or altered during carcinogenesis. Either an increased rate of proliferation or a decreased ldte of cell death could lead to cancer. Understanding the cell cycle and its regulatory signals is important to our understanding of how the extracellular environment can influence cell function, how a cancer cell can manipulate its environment, and what determines the overall behavior of a mass of cells. For a cell to divide, it must replicate its DNA and distribute that DNA equally to the daughter cells. The DNA synthesis (5) and mitosis (M) are separated by gaps (G I and G2) during which RNA and proteins are made (Fig 3). These events constitute the cell cycle and are mostly regulated by oncogenes and tumor suppressor genes (5). Oncogenes are altered forms of normal cellular genes called proto-oncogenes that are involved in pathways regulating cell growth and differentiation. Tumor suppressor genes act to inhibit cell growth in normal cells. Dominant mutations in oncogenes and recessive mutations in tumor suppressor genes contribute to deregulated cell growth (3). Both normal and mutant genes may have profound effects on the rate of cell proliferation and cell death. Many cells in vivo are in a quiescent state (GO). Progression from GO into the cell cycle requires adhesion to the extracellular matrix, the continued presence of growth factors, and the influence of special molecules called cyclins and cyelin-dependent kinases. Some or all of these requiremenls may be overcome by oncogenes (Fig 3) (3), At a critical point in G], known as the restriction point, a cell decides between continued proliferation Or withdrawal from the cycle. Deregulation of this transition- is critical to malignant transformaLion, and is thought to be an obligatory step for tumorigenesis (3), Deregulation of the cell cyele may be achieved by several different mechanisms including activation of oncogenes, overexpression of growth factors and/or their receptors, or inactivation of tumor suppressor genes. Checkpoints prior to Sand M phases serve to arreSL the cell cyele in the presence of DNA damage so that DNA may be repaired prior to undergOing replication Or mitosis. This is mediated by tumor suppressor gene, p53 (6). Inactivation of p53, commonly encountered in human cancers (7), disables these regulatory checkpoints, allowing damaged DNA to undergo replicaLion and mi~ tosis (8). Under normal circumstances, cells with unrepairable DNA are programmed for cell death and undergo apoptosis (6). The apoptotic program is complex and is often deregulated in tumorigenesis (9,10). During carcinogenesis, disordered regulation of genes
References 1. Livraghi T, Goldberg SN, Lazzaroni S, et a1. USgUided percutaneous alcohol injection of small hepatic and abdominal tumors. Radiology 1986;161: 309-312. 2. Shiina S, Tagawa K, Unuma T et a1. Percutaneous ethanol injection therapy of hepatocellular carcinoma: analysis ofn patients. AJR 1990;155:1221-1226. 3. Livraghi T, Giorgio A, Marin G et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol ablation. Radiology 1995;197:101-108. 4. Lee MJ, Mueller PR, Dawson SL et al. Percutaneous ethanol injection for the treatment of hepatic tumors: indications, mechanism of action, technique and efficacy. AJR 1995;164:215-220. 5. Livraghi T, Bolondi L, Lazzaroni S et al. Percutaneous ethanol injection in the treatment of hepatocellular carcinoma in cirrhosis. Cancer 1992;69:925-929. 6. Bartolozzi C, Lencioni R, Caramella D et al. Treatment of large HCC: transcatheter arterial embolization combined with percutaneous ethanol injection versus repeated transcatheter arterial chemoembolization. Radiology 1995;97:812-818. 7. Castells A, Bruix J, Bru C, et al. Treatment of small hepatocellular carcinoma in cirrhotic patients: a cohort study comparing surgical resection and percutaneous ethanol injection. Hepatology 1993;18:1221-1226.
tors in 105 Western patients. Cancer 1995;76:17371746. 10. Taavitsainen M, Vehmas T, Kauppila R. Fatal liver necrosis follOWing percutaneous ethanol injection for hepatocellular carcinoma. Abdom Imag 1993;18: 357-359. 11. Goletti 0, De Negri F, Pucciarelli M et al. Subcutaneous seeding after percutaneous ethanol injection of liver metastasis. Radiology 1992;183:785-786. 12. Cedrone A, Rapaccini GL, Pompili M et al. Neoplastic seeding complicating percutaneous ethanol injection for treatment of hepatocellular carcinoma. Radiology 1992:183:787-788. 13. Zcrbey Ai, Mueller PR, Dawson SL, et al. Pleural seeding from hepatocellular carcinoma: a complication of percutaneous alcohol ablation. Radiology 1994;193:81-82. 14. Livraghi T, Goldberg SN, Lazzaroni S et al. Small hepatocellular carcinoma: treatment with radiofrequency ablation versus ethanol ablation. Radiology 1999;210:655-661. 15. Livraghi T, Vettod C, Lazzaroni S, et al. Liver metastases: results of percutaneous ethanol injection in 14 patients. Radiology 1991 ;179:709-712. 16. Amin Z, Bown SG, Lees WR. Local treatment of colorectal liver metastases: a comparison of interstitial laser photocoagulation (lLP) and percutaneous alcohol injection (PAl). Clin Radiol 1993;48:166-71. 17. Ohnishi K, Ohyama N, Ito S, Fujiwara K. Ultrasound guided intra tumor injection of acetic acid for the treatment of small hepatocellular carcinoma. Radiology 1994;193:747-752. 18. Ohnishi K, Yoshioka H, Ito S, Fujiwara K. Percutaneous randomized controlled trail comparing acetic acid injection and percutaneous ethanol injection for small hepatocellular carcinoma. Hepatology 1998; 27:67-72. 19. Ohnishi K, Yoshioka H, Ito S, Fujiwara K. Treatment of nodular hepatocellular carcinoma larger than 3 em with ultrasound-guided percutaneous acetic acid injection. Hepatology 1996;24:1379-1378. 20. Van Hoof M, Jorris JP, Horsmans Y, Geubel A. Acute renal failure requiring hemodialysis after high dose percutaneous acetic acid injection for hepatocellular carcinoma. Acta Gastroenterol Belg 1999;62:49-51.
4:15 p.m.
8. Kotoh K, Sakai H, Sakamoto S et al. The effect of percutaneous ethanol injection on small solitary hepatocellular carcinoma is comparable to d,at of hepatectomy. Am J Gastroenterol 1994;89:194-198.
Radiofrequency Ablation of Liver Tumors Gerald D. Dodd III, MD University of Texas Health Science Center San AntoniO, Texas
9. Lencioni R, Bartolozzi C, Caramella D et al. Treatment of small hepatocellular carcinoma with percutaneous ethanol injection: analysis of prognostiC fac-
Learning objectives: as a I"esult of attending the categorical course tbe attendee will be able to: 1) Explain tbe tbeory bebind RF ablation; 2) Identify appropriate can-
P209
didates for RF ablation of liver tumors; 3) List the advantages and disadvantages of RF ablation of liver tumors; 4) F'.XjJlain the risks associated with RF ablation of liver tumors Conventional chemotherapy and/or radiation therapy arc ineffective for the treatment of prbnary or secondary malignant hepatic tumors. Surgical resection is considered the only potentiaJly curative therapy for these tumors. However, because of advanced disease, unfavorable location, or impaired clinical condition, only a minority of patients are eligible for surgical resection. In addition, the results of surgical resection are poor; only 30% of patients remain tumor-free at 5 years. These poor results have led to the development of multiple minimally invasive forms of therapy. These therapies include intraarterial chcmoembolization, injection of ethanol, and interstitial laser, microwave, or radiofrequency (RF) ablation. Of these techniques, RF thermal ablation is one of the newest and most promising. RF Mechanism RF thermal ablation is a misnomer. The thermal injury created by this device is produced by alternating electric current not by the emitted radiofrequency waves. Special needle electrodes and ground pads act as conductors for the alternating current. The current agitates the ions in the tissue adjacent to the needle electrodes, thus creating frictional heal. The heat starts in a glove~like configuration around the electrodes then expands by conduction to form a thermal sphere. Temperatures in excess of 50°C produce coagulative necrosis. If temperatures around the electrodes are maintain.ed between 95-100°C for twelve minutes, a 3--4 cm spherical thermal injury will be created. Patients We re<;ruit patients for RF thermal ablation of hepatic tumors using the following selection criteria: 1. Four or fewer, smaller than 5 cm, primary or secondary malignant hepatic tumors 2. Not a candidate for liver resection 3. No evidence of extrahepatic tumor 4. Life expectancy >6 months. Patients less than 18 years old, altered mental status, existing pregnancy, extrahepatic tumor, active infection, uncorrectable coagulopathy, or Childs C cirrhosis are excluded.
Preprocedural Evaluation Within a month before the procedure, all patients have the follOWing laboratory. tests: Chern 20, serum ammonia, GGT, PT/PTI, CEA (in patients with metastatic tumors) or APP (in patients with hepatocellular carcinoma) and a hepatitis screen. Additionally, the following imaging studies are performed: cr of the chest (to exclude lung metastases), biphasic contrast enhanced cr of the liver (as a baseline for post procedure follow up), targeted sonogram of the
P210
liver (to plan rhe approach and assess feaSibility of the percutaneous performance of the procedure), and a bone scan Cif there is history of bone pain and/or the serum alkaline phosphatase is disproportionately elevated). On the clay before the procedure, the slibjects undergo an EKG and blood typing and screening in preparation for possible emergent surgery.
Equipment We use a lSO-200-watt alternating electric current generator that operates at 460-480 kHz. The unit has a temperature display, a timer, a wattage display, an impedance gauge, and a display for the lOtal energy emitted. The ground pads (n = 2-4) are large adhesive dispersive electrodes. They are placed on the skin over the low back muscles and/or thigh. The alternating current flows back and forth between the needle electrode and the ground pads. The electrodes are 14-17-gauge needles that are insulated except for distal tip. Cooled tip electrodes are straight 17 gauge needles with two internal channels through which chilled water is circulated. Multiarray electrodes have a plunger in the needle hub that advances 7-10 cUlved prongs from the tip. When deployed, the prongs and the needle resemble an open umbrella or Christmas tree. The diameter of the extended eleClrodes ranges from 2.5-4 cm. AU of the prongs and distal needle tip are active electrodes. Two of the devices have thermocouples in the tips of the electrodes that can be llsed lO measure local tissue temperaUne. Procedure Patients are treated on an outpatient basis. Each procedure takes between 1-3 hours depending on how many ablations are performed. After the procedure patients are observed for 4-6 hours, then released. All of the procedures are performed using sonographic gUidance and conscious sedation. Local anesthetic is injected at the puncture site and a small skin nick is made. The electrode is placed through the skin nick and advanced until the tip is positioned in the desired pan ion of a tumor. If a multi-array probe is used the plunger in [he hub of the needle is advanced causing the curved electrodes to be deployed in the rumor. The power is initiated and gradually increased until the mean temperature reaches 105°C. The tissue temperature is kept at lOsoC for 12-25 minutes. After each ablation the needle is repositioned as necessary to heat the entire tumor. The number of punctures of the liver capsule is kept to a minimum. "me needle tract is cauterized just below the liver capsule prior to removing the needle electrode. Treatment Strategies The goal in RF thermal ablation is to kill the target tumor as well as a 5-10 mm circumferential cuff of adjacent nonnal hepatiC parenchyma. We have developed three strategies that allow us to treat most tumors. Each strat-
egy is based on the 3 cm spherical thermal injury that is created by a single ablation. Tumors <2 cm are easily encompassed by a single ablation. Tumors between 2-3 cm are treated with 6 overlapping ablations. Four ablations are performed in the x-y plane and 2 are performed along z-axis. All ablations are positioned to touch at the center of the tumor. If placed correctly, the ablations create an inner spherical injury that measures approximately 3.75 cm in diameter. Tumors larger than 3 cm are treated by creating "thermal cylinders" that are systematically overlapped to cover the entire tumor. Each cylinder is created by overlapping ablations along a single needle tract from the deepest to the most superficial pOltions of a tumor. Each ablation is overlapped by 50%.
Evaluation of Treatment Outcome Follow-up blood work and abdominal CT scans are scheduled at 2 hours, 1 month, and every 3 months thereafter for 2 years. The success of an ablation is judged by the appearance of the treated nunor on the follow-up CT scans. Based on CT results, we have found that treated patients fall into one of three categories: completely ablated (no visible enhancing tumor), incompletely ablated (residual enhancing tumor), or completely ablated with recurrence (new enhancing tumor in the margin of the treated nlmor or elsewhere in the liver). Current Results Multiple clinical series have been published on percutaneous RF ablation of hepatic metastases and HCC. Their results appear promising with complete local kill rates for metastases and HCC of 40% and 70%, respectively. Curley et ai, who used an open surgical approach and a 3-minute Pringle maneuver for the majority of their patients have reported the best results. They reported a local recurrence rate of only 1.8% for both metastases and HCC. To date, we have treated approximately 130 patients using a percutaneous approach. Our results have improved with experience and refinements in eqUipment. However, to date we have been unable to achieve the same success as Curley et al.
new tumor. It has far fewer complications than chemoembolization. Lastly, it has twO major advantages over percutaneous ethanol ablation: it can be used to treat primary and secondary malignant hepatic tumors, and it requires fewer sessions to treat hepatocellular carcinoma. However, creating an adequate tumor-free margin around tumors can be difficult; failure to do so results in incomplete ablations and tumor recurrence. The local failure rate is controlled by two factors: high volume blood flow from the portal venous system cools the heating process and thus limits the size of an ablation, and exact needle placement is almost impossible. The use of a Pringle maneuver or other technique to diminish hepatiC blood flow during an ablation may yield larger more effective ablations. Likewise, adoption of effective geometriC ablation strategies may diminish the number of incomplete ablations.
Conclusion Based on current publications and our own experience RF thermal ablation is a quick, relatively safe, and highly effective technique for debulking primary and secondary malignant hepatic tumors. Additionally, it holds great promise as a technique for local tumor eradication.
Suggested Readings 1. Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer 1993;54:594-606. 2. Baron RL, Oliver JH 1Il, Dodd GD 1Il, Nalesnik MN, Holbert BL, Carr B. Hepatocellular carcinoma: evaluation with biphasic, contrast-enhanced, helical CT. Radiology 1996;99:505-511. 3. Kawasaki S, Makuuchi M. Miyagawa S, et al. Results of hepatic resection for hepatocellular carcinoma. World J Surg 1995;19:31-34. 4. Livraghi T, Giorgio A, Marin A., et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long term results of percutaneous ethanol injection. Radiology 1995;197:101-108. 5. Shiina S, Tagawa K, Unuma T, et al. Percutaneous ethanol injection therapy of hepatocellular carcinoma: analysis of77 patients. AJR 1990;155:1221-1226.
Complications Worldwide, thousands of patients have been treated by RF ablation. Overall, the complication rate has been very low ( <5%). The most common complications are bleeding, tumor seeding, ground pad burns, thermal burns of adjacent viscera, and delayed infection of ablated tissue. A handful of deaths have been attributed to RF ablations; the causes have been bleeding or infection.
6. Solbiati L, Goldberg SN, Ierace T, et al. Hepatic metastases: percutaneous radiofrequency ablation with cooled-tip electrodes. Radiology 1997;205:367-373.
Discussion RF thermal ablation has many potential advantages over existing therapies. It is far more effective for debulking tumors than is radiation therapy or systemic chemotherapy. Unlike surgical resection or ClyosurgelY, it is minimally invasive and can be repeated as necessary to treat
8. Rossi S, Di Stasi M, Buscarini E, et a1. Percutaneous RF interstitial thermal ablation in the treatment of hepatic cancer. AJR 1996; 167:759 -768.
7. Rossi S, Di Stasi M, Buscarini E, et al. Percutaneous RF interstitial thermal ablation in the treatment of small hepatocellular carcinoma. Cancer J Sci Am 1995;1:7381.
9. Curley SA, Izzo F, Delrio P, et al. Radiofrequency
P211
ablation of unresectable primary and metastatic hepatic malignancies. Ann Surg 1999;230:1-8.
, Intervenlional Oncology: Research to Practice [Part III
Sunday, March 4, 2001 5:00 p.m.-6:30 p.m. Moderators: Ketmeth C. Wright, PhD Ma((hew S. Johnson, MD
Objectives: Upon completion of this course, the attendee should be able to: 1. Discuss currently performed and promising new oncologic imaging techniques. 2. Describe available percutaneous image-guided therapies for hepatic malignancies. 3. Explain the current status of oncologic gene therapy and immunotherapy. 4. Recognize the vascular applications of localized drug delivery using nanotechnology and other systems. 5,00 p.m.
Tumor Biology: Implications for Management Kamran Ahrar, MD M.D. Anderson Cancer Center Houston, Texas Learning objectives: upon completion of this presenta-
tion, the attc-~dee should be able to: 1) E'\plain why cancer is considered a genetic disease; 2) Listfactors that influence the behavior of a cell mass; 3) Define oncogene, tumor suppressor gene, and apoptosis; 4) List strategies for molecular therapy of cancer. Molecular Biology in Cancer Medicine In the lasL lwo decades, basic science research has produced remarkable advances in our understanding of cancer biology and cancer genetics. It is now widely accepted that cancer in its various forms is a genetic disease (1). Human DNA undergoes continuous damage, repair, and resynlhesis. In normal cells, a homeostatic equilibrium is established by means of various complex regulatory pathways in which most DNA dam~ age is repaired without error. During carcinogenesis, this equilibrium is disrupted, resulting in the accumulation of multiple mutations (2). Multiple genetic alterations accu~ mulaLe in a stepwise manner during tumor progression resulLing in a group of cells Wilh a survival advantage over others (Fig 1). This unregulated growth is the end product of several interrelated influences, most importantly, the control of proliferalion, the balance between cell survival and programmed cell death, the communication with neighboring cells and the extracellular ma-
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trix, and the induction of tumor neovascularization (Fig 2).
Cells normally proceed through a regulated program of cell growth and differentiation, followed by programmed cell death or apoptosis (3). Proliferation, differentiation, and cell death are subject to internal and external regulatory signals that are lost or altered during carcinogenesis. Either an increased rate of proliferation or a decreased ldte of cell death could lead to cancer. Understanding the cell cycle and its regulatory signals is important to our understanding of how the extracellular environment can influence cell function, how a cancer cell can manipulate its environment, and what determines the overall behavior of a mass of cells. For a cell to divide, it must replicate its DNA and distribute that DNA equally to the daughter cells. The DNA synthesis (5) and mitosis (M) are separated by gaps (G I and G2) during which RNA and proteins are made (Fig 3). These events constitute the cell cycle and are mostly regulated by oncogenes and tumor suppressor genes (5). Oncogenes are altered forms of normal cellular genes called proto-oncogenes that are involved in pathways regulating cell growth and differentiation. Tumor suppressor genes act to inhibit cell growth in normal cells. Dominant mutations in oncogenes and recessive mutations in tumor suppressor genes contribute to deregulated cell growth (3). Both normal and mutant genes may have profound effects on the rate of cell proliferation and cell death. Many cells in vivo are in a quiescent state (GO). Progression from GO into the cell cycle requires adhesion to the extracellular matrix, the continued presence of growth factors, and the influence of special molecules called cyclins and cyelin-dependent kinases. Some or all of these requiremenls may be overcome by oncogenes (Fig 3) (3), At a critical point in G], known as the restriction point, a cell decides between continued proliferation Or withdrawal from the cycle. Deregulation of this transition- is critical to malignant transformaLion, and is thought to be an obligatory step for tumorigenesis (3), Deregulation of the cell cyele may be achieved by several different mechanisms including activation of oncogenes, overexpression of growth factors and/or their receptors, or inactivation of tumor suppressor genes. Checkpoints prior to Sand M phases serve to arreSL the cell cyele in the presence of DNA damage so that DNA may be repaired prior to undergOing replication Or mitosis. This is mediated by tumor suppressor gene, p53 (6). Inactivation of p53, commonly encountered in human cancers (7), disables these regulatory checkpoints, allowing damaged DNA to undergo replicaLion and mi~ tosis (8). Under normal circumstances, cells with unrepairable DNA are programmed for cell death and undergo apoptosis (6). The apoptotic program is complex and is often deregulated in tumorigenesis (9,10). During carcinogenesis, disordered regulation of genes