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Radiofrequency Ablation for Extrahepatic Disease
starch microspheres in cancer chemotherapy. J Nucl Med 1983;24:871-875. 77. Leung WT, Lau WY, Ho SK, et aJ. Measuring lung shunting in hepatocellular carcinoma with intrahepatic-arterial technetium-99m macroaggregated albumi~. J Nucl Med 1994;35:70-7378. Nakamura H, Tanaka M, Oi H. HepatiC embolization from the common hepatic artery using balloon occlusion technique. Am J Radiol 1985;145:115-116. 79. Russell JL Jr, Carden JL, Herron HL. Dosimetry calculations for yttrium-90 used in the treatment of liver cancer. EndocurietherapylHyperthermia Oncology 1988;4: 171-186. 80. Synder WS, Ford MR, Warner GG, Watson SB. 'S' absorbed dose per unit cumulated activity for selected radionuclides and organs. NM/MIRD Pamphlet No 11. New York: Society of Nuclear Medicine, 1975-1976. 81. Dancey JE. Treatment of nonresectable hepatocellular carcinoma with intrahepatic 90Y-microspheres. J Nucl Med 2000;41:1673-1681.
10:40 a.m. Radiofrequency Ablation for Extrahepatic Disease Patrick E. Sewell, MD University Radiology Associates jackson, Mississippi Learning objectives: upon completion of this presentation, the attendee should be able to: 1) Describe the application of radiofrequency ablation technology to pulmonary nodules; 2) List potential complications and strategies for dealing with complications arising from percutaneous computed tomography-gUided radtofrequency ablation ofpulmonary tumors; 3) Explain treatment goals regarding primary and secondary pulmonary tumors treated with radiojrequency ablation. Lung cancer is the most frequent cause of cancer deaths in males and females. It accounts for 35% of all cancer deaths in males and 21% of all cancer deaths in females. It is the most common malignancy of men in the world. The majority of these cancers are non-small cell lung cancers. ApproXimately 40% of lung cancers are associated with cigarette smoking and approximately 85% of lung cancer deaths are attributed to cigarette smoking. The mean age at diagnosis is 60 years (range, 40-80 y). Because of the advanced mean age at diagnosis, coexisting pathology from cigarette smoking, and because between 10% and 50% of the peripheral tumors are asymptomatic, only approximately 15% of patients diagnosed with bronchogenic carcinoma are considered surgical candidates. An additionally disturbing statistic is the fact that 10%-32% of patient~ surviving resection of a lung cancer primary will develop a second lung primary during their lifetime. With regard to multiple primary lung cancers,
approximately one third of these are synchronous and approximately two thirds are metachronous. Most would agree that currently the best therapy for non-small cell lung cancer primaries is surgical resection, because a 5-year survival rate of 66% can be achieved with stage I and 46% with stage II tumors. Five-year survival rates for stage III and IV are substantially less than adequate and unfortunately, a significant number of patients diagnosed with primary pulmonary malignancies are classified as stage III or stage IV at diagnosis. Secondary pulmonary malignancies occur in 30% of all malignancies. Approximately 900Al of patients with secondary pulmonary malignancies are over 50 years of age. The risklbenefit ratio of surgical resection of secondary pulmonalY malignancies suggests that surgical resection of secondary pulmonary malignancies is not indicated in the majority of patients with that disease process. With the development of minimally invasive imageguided ablative technologies such as radiofrequency ablation, we now have the ability to apply this technology to primary and secondary malignancies of the lung. This holds the potential for treating a large number of patients with primary lung malignancies who do not qualify for traditional surgical resection because of medical comorbidity, as well as for treating secondary pulmonary malignances to address focal, well-defined clinical problems thought to be caused by that secondary pulmonary malignancy.
Equipment In the United States, there are three licensed radiofrequency systems. While personal communication has demonstrated that all three systems have been used for pulmonary malignancy radiofrequency ablation, my experience is limited to the RadioTherapeutics system (Sunnyvale, CA). A superficial examination of the three systems will demonstrate some obvious differences. Each;of the three companies' radiofrequency generators has different power limits. There are significant differences in the probe technology between the three systems. While no one system is superior in all aspects to another system, each system has strengths unique to that design. Because the technology is ever-changing, differences today are transient. Understanding thermal ablation in terms of heat generation and heat diffusion, with emphasis on the physiology of a particular tumor's location, is the most important aspect of optimally performing radiofrequency ablation. Many factors determine the volume of tissue ablated as well as the time required to ablate that volume of tissue. Some of these factors are under our control and can be modified to facilitate the ablation process. These factors are starting power, power increase rate, and maximum power. Devascularizing procedures such as embolization or alcohol sclerosis can be used to turn a heterogeneous thermal environment into a homogeneous one just before radiofrequency ablation. Factors P123
that are not subject to modification are the physiological response CO the thermaJ ablation process such as bronchial dilation, capillary dUation, and redirection or shunt· ing of blood flow. Because in vivo physiology is dramatically dynamic, in vitro studies, which have provided power settings and treatment times, are merely guidelines and should be treated as such. Interaction with the ablation process frequently dictates deviation from the protocol with regard to power settings, starting power, and power increase rate. Contraindications Contra indications are relative and are similar to biopsy criteria. Patients with coagulation system disorders are obviously at increased risk for hemorrhage. Theoretically, patients with pacemakers or pacemaker wires could develop intraoperative complications from radiofrequency energy absorption by those wires or interference with pacemaker function.
Technique Pre-procedure lab consists of PT/PTT, CBC, and chemistries. EKG and preoperative chest x·ray are also obtained. The procedure is done with conscious sedation, MAC (managed anesthesia care), or general anesthesia depending on the patient's preference, the size and location of the lesion, the need for precise respiratory control, and the anticipated length of the procedure. Some solitary lesions are small enough and peripherally located so that they can be treated on an outpatient basis with conscious sedation. Other lesions can be so large that prolonged treatment times are required and general anesthesia is used for patient and doctor COmfOlt. The procedure is performed similarly to that of a computed tomography-guided biopsy of a pulmonary nodule; however, the times are deployed so that the targeted tissue is within the sphere of influence of the array. It is best to closely match the array diameter to the lesion diameter. Slight oversizing by a few millimeters is better than undersizing. One should minimize the application of thermal energy to the surrounding normal lung because a pronounced injury response can occur thus prolonging the treatment session. Overlapping of ablation zones is optimal. This increases tumor kill and minimizes the chance of any tumor remaining viable. Lesions are divided into three subtypes based on location: 1) purely parenchymal tumors <3.5 em and surrounded entirely by air-filled lung, (2) tumors <3.5 em with <25% tumor/pleura interface, and (3) rumors greater than 3.5 em or tumors having >25% mass/pleura interface. Power is supplied according to the lung algorithm untU impedence is maximized and power correspondingly drops. The tines are then retracted and the array is re-deployed at a second location, if needed, depending on the anatomy. Once all targeted tissue has been treated, the tines are retracted and the needle is removed. Scanning through
P124
the chest is performed to assess for pneumothorax or other complications. These are addressed using s[andard interventional radiology image-guided techniques. Pneumothorax is c1assifie~ as a minor complication. It is expected in approximately 25% of the cases, as in the case with needle biopsy. Factors that increase the incidence of pneumothorax are bullous disease, multiple needle placements, and multiple array deployments. Pe~ ripherally or pleural-based nodules in which the tines can puncture the pleura at multiple locations also increases the incidence of pneumothorax. In the setting of a solitary pulmonary nodule surrounded by air~filled parenchyma, the incidence of pneumothorax is approximately 5%. In the setting of multiple metastatic nodules located diffusely throughout the lung and requiring multiple needle placements and multiple punctures, [he incidence of pneumothorax can rise as high as 5QOIo. Another factor that also plays a role in pneumothorax development is the number of pleural surfaces crossed by the needle as it traverses the lung to reach the targeted tissue. Pneumothoraces are treated with 8, 10, or 12 French APD catheters. They.are placed to 10-20 em water seal through an atrium device. They are evacuated with low or medium wall suction through the atrium. Chest tubes are routinely removed approximately 24 hours post-procedure if the test clamping demonstrates no recurrence of the pneumothorax. Administration of thermal energy in the body raises the core body temperature during the process. Because of the risk of hyperthermia, patients are placed on a cooling blanket, which circulates refrigerated water through a closed system. In the lung, heating result'> in an injury response around the rumor visualized as opacified pulmonary parenchyma. With prolonged heating, at 48-72 hours after radiofrequency ablation, a sympathetic pleural effusion becomes evident. It is most easily removed using a 5 French angiocatheter or centesis needle placed under ultrasound guidance. Frequently, between 200 and 400 cc of fluid are removed. The benefit is fe-expansion of the atelectatic or compressed lower lobe. 1 think [his is important to prevent the development of post-radiofrequency ablation pneumonia. Compression of [he lower lobe, along with impaired or incomplete inspiration from the recent anesthesia and from post-procedure pain, are factors that increase the risk of pneumonia. Additionally, patients are frequently immunosuppressed as a resul[ .of recent or previous chemotherapy, thus they are at increased risk for perioperative pneumonia. Some lesions are so simple that they are treated on an outpatient basis; however, some patient,> have a multipositioned tumor burden requiring several hours of treatment and multiple probe positions. This dictates increased post-procedure pain, prolonged post-procedure monitoring, and translates into an average of 2.5 inpatient hospital days. Routine postoperative orders consist of a 7-day course of prophylactic antibiotics (500 mg Levaquin
My Ever-evolving Lung Tumor Radlofrequency Ablation Power Algorithm
Purely Parenchymal Tumor Less Than 4 cm in Diameter Array Size (cm) 2 3 35 4.0
Less than 25% of Tumor Surface in Contract with Pleura
Start Power (w)
Power Inc. Rate (w/min)
Start Power (w)
5 10 20 30
5 W every 1-3 min 10 10
10 20 30 40
10
orally each morning, 450 mg Clindamycin orally every 8 hours). Oxygen is titrated to maintain a blood oxygen saturation of >90% and monitored with a bedside pulseox. DVT prophylaxis is established with the use of a sequential inflation/compression device during the procedure and is discontinued on ambulation. Patients are placed on morphine, Demerol, or Dilaudid PCA for pain management. They are converted to oral oxycodone or hydrocodone once their use of the PCA diminishes. Post-procedure hospital course is characterized by a generalized myalgia and low-grade temperature (up to 101.5°F). This flu-like illness is synonymous with tumor lyses syndrome, and we have termed it "tumor destruction syndrome." Of note is that this syndrome is seen when tumOr is ablated by any thermal technique, including interstitial laser or cryotherapy. The syndrome begins the morning after the procedure and can last up to 2 weeks. It is more pronounced in young people or people with well-functioning inunune systems. Symptomatic relief is achieved with antipyretics such as ibuprofen. I routinely see elevated temperature up to lO1.5°F with no source of infection. \Vhen temperature rises above 101.5°F, I worry about an existing infectious process and investigate accordingly and treat empirically if no source can be identified. Other pOst-procedure-related symptoms are a cough productive of brov.(n mucus and/or pieces of necrotic tumor. This can last from 1 to several weeks. Follow-up imaging consists of a computed tomography scan of the chest with and without contrast at approximately 1 month post-procedure. Measurements of the ablated tumor and the surrounding lung are then obtained and represent the new baseline measurements for that lesion. Immediately post-radiofrequency ablation, the treated lesi~:m and the surrounding lung are represented as an enlarged opacity when compared with the immediate pre-radiofrequency ablation measurements. These measurements should decrease over the course of time as demonstrated on follow-up computed tomography examinations. An increase in size or enhancement of an area in the treated region is consistent with residual or recurrent tumor. Treatment of 32 primary lung tumors and approximately 153 patients with metastasis (as few as 1 but as
Power Inc. Rate (w/min)
5 10 10 10
Greater than 25% of Tumor Surface in Contact with Pleura or Hilar Tumor Start Power (w)
Power Inc. Rate (w/min)
20 30 40 50
10 10 10 10
many as 13 per hemithorax) to the lung demonstrated a single incidence of pulmonary abscess. Intravenous antibiotics as well as a 10 French APD with active wall suction for 10 days yielded resolution of that abscess. A second patient developed life-threatening right hemithorax parenchymal hemorrhage approximately 90 minutes into the ablation. That procedure was performed in a patient with bilateral synchronous upper lobe primary lung cancers and a history of failed wedge resection, failed chemotherapy, and failed radiation therapy. He had significant coronary artery and carotid disease necessitating chronic administration of Plavix. Because of this significant arteriosclerotic disease, it was thought that the risk of catastrophic bleeding complications from racliofrequency ablation was less than that of the thrombotic event and thus, Plavix was not discontinued before the procedure. This was thought to be the contributing factor to his parenchymal hemorrhage. He survived and recovered from the parenchymal hemorrhage; however, he subsequently died 6 weeks later from a myocardial infarction unrelated to the procedure. Follow-up of patients treated to date (mean, 15 months) has demonstrated residual or recurrent tumor in only a small percentage (approximately 2%) of cases (primary and metastatic) in which the pulmonary tumors were thought to have been adequately treated. Frequently, treatment failures can be retrospectively attributed to large heat sinks, large tumors, or large tumor/ pleural interface. Discussion
Currently, primary pulmonary malignancies are treated in those patients who cannot undergo t.raditional surgical resection. This is most frequently the result of coexisting pulmonary morbidity. My experience demonstrates that patients who are too fragile to endure a wedge resection or lobectomy can frequently undergo percutaneous computed tomography-guided radiofrequency ablation of that pulmonary malignancy. I have successfully treated patients with an FEY1 as low as 24% predicted. Further treatment with chemotherapy or radiation is indicated, if applicable, to that patient'S tumor cell type. This can be done before or after the radiofrequency ablation process. P125
Secondary or metastatic foci in the lung can be treated as well; however, the treatment goals are significantly different. In the setting of metastatic disease, obviously one cannot cure the patient with this regional or focal treatment Thus, treatment goals are focused to address a clearly defined clinical problem. This frequently consists of pleural-based pain. Other rationale for treating metastatic foci is to eradicate the entire macroscopic tumor visible on cross-sectional imaging snJdies in a patient with Umited pulmonary metastatic disease. Essentially, the seledion criteria and the goals of treatment are the same as with those patients who you would consider surgical resection. The rationale is to treat the visible pulmonary tumor while preserving as much functional lung with an acceptable level of morbidity/mortality as compared with thoracotomy. Treatment failures are expected as a result of the spectrum of disease distribution and lesion size. The heat sink effect is probably the most significant physiological factor, which can impact trealment of a targeted lesion. In theory. survival of a single tumor cell can result in a recurrent tumor on follow-up imaging studies. Because we can only image the tumor macroscopically and tumor visualized on computed tomography examination represents millions of tumor cells, residual tumor in the treaunent site is not unexpected on occasion. Current experience suggests that this occurs approximatelY'20/0 of the time. Implications for treating primary lung tumors with radiofrequency ablation are obvious as this would result in a ZOA> failure rate to eradicate the primary tumor and would leave the patient at risk for metastatic tumor. For that reason, wide surgical excision holds a bener chance of cure and thus will remain the first therapeutic choice. A 2% treatment failure rate in the serring of metastatic lesion radiofrequency ablation is of little or no consequence because these lesions can be easily retreated, and the patient's disease status is already classified as metastatic. The treatment window time constraints present when treating primary tumors are nOl present with metastatic tumor. The ability Lo achieve local tumor control without the morbidity and mortality associated with thoracotomy makes radiofrequency ablation a better therapeutiC choice over surgical resection in some patients.
Suggested Reading 1. Manual of Clinical Oncology, 7th ed. New York: Wiley-Liss.
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lung cancers of the superior sulcus. ] Thocac Cardiovase Surg 2000;119,1147-11S3. 4. Buccheri G, Ferrigno D. Prognostic value of stage grouping and TNM descriptors in lung cancer. Chest 2000;11 n 247-12SS. 5. Rusch VW. Surgical treatment of patients with N2 disease. Semin Radiol Oncol 1996;6,76-8S. 6. Sugaar S, LeVeen HH. A histopathological study on the effects of radiofrequency thermotherapy on malignant tumors of the lung. Cancer 1979;43,767-783. 7. Dupuy DE, Zagoria R), Akerley W, Mayo-Smith WW, Kavanagh PV, Safran H. Percutaneous radiofrequency ablation of malignancies in the lung. A]R Am) Roentgenol 2000;17457-S9. 8. Goldberg SN, Gazelle GS, Compton SS, Mcloud TC. Radiofrequency tissue ablation in the rabbit lung: efficacy and complications. Acad RadioI199S,2,776-
784. 9. Putnam )B, Thomsen SL, Siegenthaler M. Thernpeutic implications of heat-induced lung injury. In: Ryan TP ed. Matching the Energy Source to the Clinical Need. Bellingham, WA, SPJE Optical Engineering Press, 2000,139-160. I
10. Sewell PE, Vance RB, Wang YD. Assessing radiofrequency ablation of non-small cell lung cancer with positron emission tomography (pEn. Radiology 2000,217(suppIU34. 11. Connor S, Dyer], Guest P. Image-guided automated needle biopsy of 106 thoracic lesions: a retrospective review of diagnostic accuracy and complication rates. Eur Radiol 2000,10A90-494. 12. Charig M), Phillips AJ. a-guided cutting needle biopsy of lung lesions--safety and efficacy of an ou(patient service. Clin Radiol 2000;SS,964-969. 13. Hanninen EL, Vogi T), Ricke ), Felix R. a-guided percutaneous core biopsies of pulmonary lesions. Acta Radiol 2001;42,ISJ-1SS. 14. Stephan F, et al. Pulmonary complications following lung resection: a comprehensive analysis of incidence and possible risk factors. Chest 2000;118: 126}-1270. 15. Asaph JW. et al. Surgery for second lung cancers. Chest 2000;118,1621-162S. 16. Smythe WR, et al. Surgical resection of non-small cell carcinoma after treaunent for small cell carcinoma. Ann Thorne Surg 2001;7L962-966.
2. jassemJ, SkokowskiJ, Dziadziuszko R, et al. Results of surgical treatment of non-small cell lung cancer: validation of the new postoperative pathologic TNM classification. ) Thorne Cardiovasc Surg 2000,119, 1141-1146.
17. Ferguson MK, Durkin A. Lung cancer resection in the elderly: prediCtors of resource utilization and long-tenn outcomes. Poster presentation at annual meeting of the American Society of Clinical Oncologists (ASCO), May 200l.
3. Rusch VW, Parekh KR, Leon L, et al. Factors determining outcome after surgical resection of T3 and '1'4
18. Abecasis N, CoJtez F, Bettencourt A, Costa CS, Or· valho F, De Almeida JMM. Surgical treatment of lung
metastases: prognostic factors for long-term survival.
1 Surg Oncol 1999;72:193-198. 19. A1pard SK, Durate AG, Bidani A, Zwischenberger lB. Pathogenesis and management of respiratory insufficiency following pulmonary resect·ion. Semin Surg OncoI2000;18:183--196. 20. Kudu CA, Williams EA, Evans lW, Pastorino U, Goldstraw P. Acute lung injury and acute respiratory distress syndrome after pulmonary resection. Ann Thorac Surg 2000;69:376-380. 11:00 a.m. "A" is for Angiogenesis Michael S. O'Reilly, MD University of Texas MD Anderson Cancer Center Houston, Texas
Overview of Angiogenesis Angiogenesis, the growth of new blood vessels, is critical for a number of physiological and pathophysiological processes, and several lines of direct evidence now confirm that tumor growth is dependent on angiogenesis (1). The field of angiogenesis research has grown rapidly (2), and several angiogenesis inhibitors are now in clinical trials for the treatment of cancer (3). The process of angiogenesis is regulated by a number of stimulators and inhibitors, and it is the net balance of these factors that determine whether angiogenesis can occur. Antiangiogenic therapy offers a number of potential benefits, including lack of drug resistance for some agents, synergistic interaction with other modaJities, lack of significant toxicity as compared with conventional agents, and a potent antitumor effect. However, no angiogenesis inhibitor has been approved for clinical use. Furthermore, the optimal strategies for the use, monitoring, and validation of antiangiogenic agents in the clinic remains unclear. Early clinical trial results with the angiogenesis inhibitor thalidomide (4), for example, suggest that many antiangiogenic agents will induce stabilization of disease, and not regression, in patients with advanced disease. Before these agents can be integrated into clinical practice, a better understanding of their mechanism of action and regulation is required.
Angiostatin and the Potential Limitations of Antiangiogenic Therapy In some patients with cancer, the surgical removal of a primaly tumor can result in the rapid growth of metastases. Our prior work (5) demonstrated that the mobilization of angiogenesis inhibitors, such as angiostatin, by enzymes produced by or in response to a primary tumor can mediate the inhibition of metastatic tumor growth. More recently (6), we demonstrated that curative radiotherapy to primary tumors known to make angiogenesis inhibitors can be followed by the rapid growth of pre-
viously dormant metastases. However, systemic therapy with angiostatin prevented the growth of the metastases after the radiation therapy of the primary tumor. These studies suggest that there may be a population of patients that would require the addition of antiangiogenic therapy during and/or after radiation therapy and/or surgery to prevent the expansion of distant metastases. Angiostatin is an internal fragment of plasminogen and is a potent and specific inhibitor of angiogenesis and tumor growth. The discovery of angiostatin provides evidence that the clotting and fibrinolytic pathways are directly involved in the regulation of angiogenesis. In vivo, systemic therapy with angiostatin induces a virtual complete blockade of angiogenesis and potendy inhibits tumor growth. To date, all tumors tested in vivo have been potently inhibited, and no evidence of resistance to therapy has been demonstrated even after prolonged administration. Prolonged therapy with high doses of angiostatin and other angiogenesis inhibitors (7) leads to regression of established tumors and can induce tumor dormancy. The tumor dormancy is defined by a high rate of tumor cell proliferation balanced by apoptosis and a virtual complete blockade of angiogenesis. Although studies with angiostatin have shown that it is able to regress a wide variety of tumors without resistance to therapy or toxicity (8), potential limits of the Use of antiangiogenic therapy alone have also been revealed. Human and murine tumors in mice treated with angiostatin continued to grow after the initiation of antiangiogenic therapy. In many cases, tumors progressed by 200o/o-40()
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10:40 a.m. Radiofrequency Ablation for Extrahepatic Disease Patrick E. Sewell, MD University Radiology Associates jackson, Mississippi Learning objectives: upon completion of this presentation, the attendee should be able to: 1) Describe the application of radiofrequency ablation technology to pulmonary nodules; 2) List potential complications and strategies for dealing with complications arising from percutaneous computed tomography-gUided radtofrequency ablation ofpulmonary tumors; 3) Explain treatment goals regarding primary and secondary pulmonary tumors treated with radiojrequency ablation. Lung cancer is the most frequent cause of cancer deaths in males and females. It accounts for 35% of all cancer deaths in males and 21% of all cancer deaths in females. It is the most common malignancy of men in the world. The majority of these cancers are non-small cell lung cancers. ApproXimately 40% of lung cancers are associated with cigarette smoking and approximately 85% of lung cancer deaths are attributed to cigarette smoking. The mean age at diagnosis is 60 years (range, 40-80 y). Because of the advanced mean age at diagnosis, coexisting pathology from cigarette smoking, and because between 10% and 50% of the peripheral tumors are asymptomatic, only approximately 15% of patients diagnosed with bronchogenic carcinoma are considered surgical candidates. An additionally disturbing statistic is the fact that 10%-32% of patient~ surviving resection of a lung cancer primary will develop a second lung primary during their lifetime. With regard to multiple primary lung cancers,
approximately one third of these are synchronous and approximately two thirds are metachronous. Most would agree that currently the best therapy for non-small cell lung cancer primaries is surgical resection, because a 5-year survival rate of 66% can be achieved with stage I and 46% with stage II tumors. Five-year survival rates for stage III and IV are substantially less than adequate and unfortunately, a significant number of patients diagnosed with primary pulmonary malignancies are classified as stage III or stage IV at diagnosis. Secondary pulmonary malignancies occur in 30% of all malignancies. Approximately 900Al of patients with secondary pulmonary malignancies are over 50 years of age. The risklbenefit ratio of surgical resection of secondary pulmonalY malignancies suggests that surgical resection of secondary pulmonary malignancies is not indicated in the majority of patients with that disease process. With the development of minimally invasive imageguided ablative technologies such as radiofrequency ablation, we now have the ability to apply this technology to primary and secondary malignancies of the lung. This holds the potential for treating a large number of patients with primary lung malignancies who do not qualify for traditional surgical resection because of medical comorbidity, as well as for treating secondary pulmonary malignances to address focal, well-defined clinical problems thought to be caused by that secondary pulmonary malignancy.
Equipment In the United States, there are three licensed radiofrequency systems. While personal communication has demonstrated that all three systems have been used for pulmonary malignancy radiofrequency ablation, my experience is limited to the RadioTherapeutics system (Sunnyvale, CA). A superficial examination of the three systems will demonstrate some obvious differences. Each;of the three companies' radiofrequency generators has different power limits. There are significant differences in the probe technology between the three systems. While no one system is superior in all aspects to another system, each system has strengths unique to that design. Because the technology is ever-changing, differences today are transient. Understanding thermal ablation in terms of heat generation and heat diffusion, with emphasis on the physiology of a particular tumor's location, is the most important aspect of optimally performing radiofrequency ablation. Many factors determine the volume of tissue ablated as well as the time required to ablate that volume of tissue. Some of these factors are under our control and can be modified to facilitate the ablation process. These factors are starting power, power increase rate, and maximum power. Devascularizing procedures such as embolization or alcohol sclerosis can be used to turn a heterogeneous thermal environment into a homogeneous one just before radiofrequency ablation. Factors P123
that are not subject to modification are the physiological response CO the thermaJ ablation process such as bronchial dilation, capillary dUation, and redirection or shunt· ing of blood flow. Because in vivo physiology is dramatically dynamic, in vitro studies, which have provided power settings and treatment times, are merely guidelines and should be treated as such. Interaction with the ablation process frequently dictates deviation from the protocol with regard to power settings, starting power, and power increase rate. Contraindications Contra indications are relative and are similar to biopsy criteria. Patients with coagulation system disorders are obviously at increased risk for hemorrhage. Theoretically, patients with pacemakers or pacemaker wires could develop intraoperative complications from radiofrequency energy absorption by those wires or interference with pacemaker function.
Technique Pre-procedure lab consists of PT/PTT, CBC, and chemistries. EKG and preoperative chest x·ray are also obtained. The procedure is done with conscious sedation, MAC (managed anesthesia care), or general anesthesia depending on the patient's preference, the size and location of the lesion, the need for precise respiratory control, and the anticipated length of the procedure. Some solitary lesions are small enough and peripherally located so that they can be treated on an outpatient basis with conscious sedation. Other lesions can be so large that prolonged treatment times are required and general anesthesia is used for patient and doctor COmfOlt. The procedure is performed similarly to that of a computed tomography-guided biopsy of a pulmonary nodule; however, the times are deployed so that the targeted tissue is within the sphere of influence of the array. It is best to closely match the array diameter to the lesion diameter. Slight oversizing by a few millimeters is better than undersizing. One should minimize the application of thermal energy to the surrounding normal lung because a pronounced injury response can occur thus prolonging the treatment session. Overlapping of ablation zones is optimal. This increases tumor kill and minimizes the chance of any tumor remaining viable. Lesions are divided into three subtypes based on location: 1) purely parenchymal tumors <3.5 em and surrounded entirely by air-filled lung, (2) tumors <3.5 em with <25% tumor/pleura interface, and (3) rumors greater than 3.5 em or tumors having >25% mass/pleura interface. Power is supplied according to the lung algorithm untU impedence is maximized and power correspondingly drops. The tines are then retracted and the array is re-deployed at a second location, if needed, depending on the anatomy. Once all targeted tissue has been treated, the tines are retracted and the needle is removed. Scanning through
P124
the chest is performed to assess for pneumothorax or other complications. These are addressed using s[andard interventional radiology image-guided techniques. Pneumothorax is c1assifie~ as a minor complication. It is expected in approximately 25% of the cases, as in the case with needle biopsy. Factors that increase the incidence of pneumothorax are bullous disease, multiple needle placements, and multiple array deployments. Pe~ ripherally or pleural-based nodules in which the tines can puncture the pleura at multiple locations also increases the incidence of pneumothorax. In the setting of a solitary pulmonary nodule surrounded by air~filled parenchyma, the incidence of pneumothorax is approximately 5%. In the setting of multiple metastatic nodules located diffusely throughout the lung and requiring multiple needle placements and multiple punctures, [he incidence of pneumothorax can rise as high as 5QOIo. Another factor that also plays a role in pneumothorax development is the number of pleural surfaces crossed by the needle as it traverses the lung to reach the targeted tissue. Pneumothoraces are treated with 8, 10, or 12 French APD catheters. They.are placed to 10-20 em water seal through an atrium device. They are evacuated with low or medium wall suction through the atrium. Chest tubes are routinely removed approximately 24 hours post-procedure if the test clamping demonstrates no recurrence of the pneumothorax. Administration of thermal energy in the body raises the core body temperature during the process. Because of the risk of hyperthermia, patients are placed on a cooling blanket, which circulates refrigerated water through a closed system. In the lung, heating result'> in an injury response around the rumor visualized as opacified pulmonary parenchyma. With prolonged heating, at 48-72 hours after radiofrequency ablation, a sympathetic pleural effusion becomes evident. It is most easily removed using a 5 French angiocatheter or centesis needle placed under ultrasound guidance. Frequently, between 200 and 400 cc of fluid are removed. The benefit is fe-expansion of the atelectatic or compressed lower lobe. 1 think [his is important to prevent the development of post-radiofrequency ablation pneumonia. Compression of [he lower lobe, along with impaired or incomplete inspiration from the recent anesthesia and from post-procedure pain, are factors that increase the risk of pneumonia. Additionally, patients are frequently immunosuppressed as a resul[ .of recent or previous chemotherapy, thus they are at increased risk for perioperative pneumonia. Some lesions are so simple that they are treated on an outpatient basis; however, some patient,> have a multipositioned tumor burden requiring several hours of treatment and multiple probe positions. This dictates increased post-procedure pain, prolonged post-procedure monitoring, and translates into an average of 2.5 inpatient hospital days. Routine postoperative orders consist of a 7-day course of prophylactic antibiotics (500 mg Levaquin
My Ever-evolving Lung Tumor Radlofrequency Ablation Power Algorithm
Purely Parenchymal Tumor Less Than 4 cm in Diameter Array Size (cm) 2 3 35 4.0
Less than 25% of Tumor Surface in Contract with Pleura
Start Power (w)
Power Inc. Rate (w/min)
Start Power (w)
5 10 20 30
5 W every 1-3 min 10 10
10 20 30 40
10
orally each morning, 450 mg Clindamycin orally every 8 hours). Oxygen is titrated to maintain a blood oxygen saturation of >90% and monitored with a bedside pulseox. DVT prophylaxis is established with the use of a sequential inflation/compression device during the procedure and is discontinued on ambulation. Patients are placed on morphine, Demerol, or Dilaudid PCA for pain management. They are converted to oral oxycodone or hydrocodone once their use of the PCA diminishes. Post-procedure hospital course is characterized by a generalized myalgia and low-grade temperature (up to 101.5°F). This flu-like illness is synonymous with tumor lyses syndrome, and we have termed it "tumor destruction syndrome." Of note is that this syndrome is seen when tumOr is ablated by any thermal technique, including interstitial laser or cryotherapy. The syndrome begins the morning after the procedure and can last up to 2 weeks. It is more pronounced in young people or people with well-functioning inunune systems. Symptomatic relief is achieved with antipyretics such as ibuprofen. I routinely see elevated temperature up to lO1.5°F with no source of infection. \Vhen temperature rises above 101.5°F, I worry about an existing infectious process and investigate accordingly and treat empirically if no source can be identified. Other pOst-procedure-related symptoms are a cough productive of brov.(n mucus and/or pieces of necrotic tumor. This can last from 1 to several weeks. Follow-up imaging consists of a computed tomography scan of the chest with and without contrast at approximately 1 month post-procedure. Measurements of the ablated tumor and the surrounding lung are then obtained and represent the new baseline measurements for that lesion. Immediately post-radiofrequency ablation, the treated lesi~:m and the surrounding lung are represented as an enlarged opacity when compared with the immediate pre-radiofrequency ablation measurements. These measurements should decrease over the course of time as demonstrated on follow-up computed tomography examinations. An increase in size or enhancement of an area in the treated region is consistent with residual or recurrent tumor. Treatment of 32 primary lung tumors and approximately 153 patients with metastasis (as few as 1 but as
Power Inc. Rate (w/min)
5 10 10 10
Greater than 25% of Tumor Surface in Contact with Pleura or Hilar Tumor Start Power (w)
Power Inc. Rate (w/min)
20 30 40 50
10 10 10 10
many as 13 per hemithorax) to the lung demonstrated a single incidence of pulmonary abscess. Intravenous antibiotics as well as a 10 French APD with active wall suction for 10 days yielded resolution of that abscess. A second patient developed life-threatening right hemithorax parenchymal hemorrhage approximately 90 minutes into the ablation. That procedure was performed in a patient with bilateral synchronous upper lobe primary lung cancers and a history of failed wedge resection, failed chemotherapy, and failed radiation therapy. He had significant coronary artery and carotid disease necessitating chronic administration of Plavix. Because of this significant arteriosclerotic disease, it was thought that the risk of catastrophic bleeding complications from racliofrequency ablation was less than that of the thrombotic event and thus, Plavix was not discontinued before the procedure. This was thought to be the contributing factor to his parenchymal hemorrhage. He survived and recovered from the parenchymal hemorrhage; however, he subsequently died 6 weeks later from a myocardial infarction unrelated to the procedure. Follow-up of patients treated to date (mean, 15 months) has demonstrated residual or recurrent tumor in only a small percentage (approximately 2%) of cases (primary and metastatic) in which the pulmonary tumors were thought to have been adequately treated. Frequently, treatment failures can be retrospectively attributed to large heat sinks, large tumors, or large tumor/ pleural interface. Discussion
Currently, primary pulmonary malignancies are treated in those patients who cannot undergo t.raditional surgical resection. This is most frequently the result of coexisting pulmonary morbidity. My experience demonstrates that patients who are too fragile to endure a wedge resection or lobectomy can frequently undergo percutaneous computed tomography-guided radiofrequency ablation of that pulmonary malignancy. I have successfully treated patients with an FEY1 as low as 24% predicted. Further treatment with chemotherapy or radiation is indicated, if applicable, to that patient'S tumor cell type. This can be done before or after the radiofrequency ablation process. P125
Secondary or metastatic foci in the lung can be treated as well; however, the treatment goals are significantly different. In the setting of metastatic disease, obviously one cannot cure the patient with this regional or focal treatment Thus, treatment goals are focused to address a clearly defined clinical problem. This frequently consists of pleural-based pain. Other rationale for treating metastatic foci is to eradicate the entire macroscopic tumor visible on cross-sectional imaging snJdies in a patient with Umited pulmonary metastatic disease. Essentially, the seledion criteria and the goals of treatment are the same as with those patients who you would consider surgical resection. The rationale is to treat the visible pulmonary tumor while preserving as much functional lung with an acceptable level of morbidity/mortality as compared with thoracotomy. Treatment failures are expected as a result of the spectrum of disease distribution and lesion size. The heat sink effect is probably the most significant physiological factor, which can impact trealment of a targeted lesion. In theory. survival of a single tumor cell can result in a recurrent tumor on follow-up imaging studies. Because we can only image the tumor macroscopically and tumor visualized on computed tomography examination represents millions of tumor cells, residual tumor in the treaunent site is not unexpected on occasion. Current experience suggests that this occurs approximatelY'20/0 of the time. Implications for treating primary lung tumors with radiofrequency ablation are obvious as this would result in a ZOA> failure rate to eradicate the primary tumor and would leave the patient at risk for metastatic tumor. For that reason, wide surgical excision holds a bener chance of cure and thus will remain the first therapeutic choice. A 2% treatment failure rate in the serring of metastatic lesion radiofrequency ablation is of little or no consequence because these lesions can be easily retreated, and the patient's disease status is already classified as metastatic. The treatment window time constraints present when treating primary tumors are nOl present with metastatic tumor. The ability Lo achieve local tumor control without the morbidity and mortality associated with thoracotomy makes radiofrequency ablation a better therapeutiC choice over surgical resection in some patients.
Suggested Reading 1. Manual of Clinical Oncology, 7th ed. New York: Wiley-Liss.
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lung cancers of the superior sulcus. ] Thocac Cardiovase Surg 2000;119,1147-11S3. 4. Buccheri G, Ferrigno D. Prognostic value of stage grouping and TNM descriptors in lung cancer. Chest 2000;11 n 247-12SS. 5. Rusch VW. Surgical treatment of patients with N2 disease. Semin Radiol Oncol 1996;6,76-8S. 6. Sugaar S, LeVeen HH. A histopathological study on the effects of radiofrequency thermotherapy on malignant tumors of the lung. Cancer 1979;43,767-783. 7. Dupuy DE, Zagoria R), Akerley W, Mayo-Smith WW, Kavanagh PV, Safran H. Percutaneous radiofrequency ablation of malignancies in the lung. A]R Am) Roentgenol 2000;17457-S9. 8. Goldberg SN, Gazelle GS, Compton SS, Mcloud TC. Radiofrequency tissue ablation in the rabbit lung: efficacy and complications. Acad RadioI199S,2,776-
784. 9. Putnam )B, Thomsen SL, Siegenthaler M. Thernpeutic implications of heat-induced lung injury. In: Ryan TP ed. Matching the Energy Source to the Clinical Need. Bellingham, WA, SPJE Optical Engineering Press, 2000,139-160. I
10. Sewell PE, Vance RB, Wang YD. Assessing radiofrequency ablation of non-small cell lung cancer with positron emission tomography (pEn. Radiology 2000,217(suppIU34. 11. Connor S, Dyer], Guest P. Image-guided automated needle biopsy of 106 thoracic lesions: a retrospective review of diagnostic accuracy and complication rates. Eur Radiol 2000,10A90-494. 12. Charig M), Phillips AJ. a-guided cutting needle biopsy of lung lesions--safety and efficacy of an ou(patient service. Clin Radiol 2000;SS,964-969. 13. Hanninen EL, Vogi T), Ricke ), Felix R. a-guided percutaneous core biopsies of pulmonary lesions. Acta Radiol 2001;42,ISJ-1SS. 14. Stephan F, et al. Pulmonary complications following lung resection: a comprehensive analysis of incidence and possible risk factors. Chest 2000;118: 126}-1270. 15. Asaph JW. et al. Surgery for second lung cancers. Chest 2000;118,1621-162S. 16. Smythe WR, et al. Surgical resection of non-small cell carcinoma after treaunent for small cell carcinoma. Ann Thorne Surg 2001;7L962-966.
2. jassemJ, SkokowskiJ, Dziadziuszko R, et al. Results of surgical treatment of non-small cell lung cancer: validation of the new postoperative pathologic TNM classification. ) Thorne Cardiovasc Surg 2000,119, 1141-1146.
17. Ferguson MK, Durkin A. Lung cancer resection in the elderly: prediCtors of resource utilization and long-tenn outcomes. Poster presentation at annual meeting of the American Society of Clinical Oncologists (ASCO), May 200l.
3. Rusch VW, Parekh KR, Leon L, et al. Factors determining outcome after surgical resection of T3 and '1'4
18. Abecasis N, CoJtez F, Bettencourt A, Costa CS, Or· valho F, De Almeida JMM. Surgical treatment of lung
metastases: prognostic factors for long-term survival.
1 Surg Oncol 1999;72:193-198. 19. A1pard SK, Durate AG, Bidani A, Zwischenberger lB. Pathogenesis and management of respiratory insufficiency following pulmonary resect·ion. Semin Surg OncoI2000;18:183--196. 20. Kudu CA, Williams EA, Evans lW, Pastorino U, Goldstraw P. Acute lung injury and acute respiratory distress syndrome after pulmonary resection. Ann Thorac Surg 2000;69:376-380. 11:00 a.m. "A" is for Angiogenesis Michael S. O'Reilly, MD University of Texas MD Anderson Cancer Center Houston, Texas
Overview of Angiogenesis Angiogenesis, the growth of new blood vessels, is critical for a number of physiological and pathophysiological processes, and several lines of direct evidence now confirm that tumor growth is dependent on angiogenesis (1). The field of angiogenesis research has grown rapidly (2), and several angiogenesis inhibitors are now in clinical trials for the treatment of cancer (3). The process of angiogenesis is regulated by a number of stimulators and inhibitors, and it is the net balance of these factors that determine whether angiogenesis can occur. Antiangiogenic therapy offers a number of potential benefits, including lack of drug resistance for some agents, synergistic interaction with other modaJities, lack of significant toxicity as compared with conventional agents, and a potent antitumor effect. However, no angiogenesis inhibitor has been approved for clinical use. Furthermore, the optimal strategies for the use, monitoring, and validation of antiangiogenic agents in the clinic remains unclear. Early clinical trial results with the angiogenesis inhibitor thalidomide (4), for example, suggest that many antiangiogenic agents will induce stabilization of disease, and not regression, in patients with advanced disease. Before these agents can be integrated into clinical practice, a better understanding of their mechanism of action and regulation is required.
Angiostatin and the Potential Limitations of Antiangiogenic Therapy In some patients with cancer, the surgical removal of a primaly tumor can result in the rapid growth of metastases. Our prior work (5) demonstrated that the mobilization of angiogenesis inhibitors, such as angiostatin, by enzymes produced by or in response to a primary tumor can mediate the inhibition of metastatic tumor growth. More recently (6), we demonstrated that curative radiotherapy to primary tumors known to make angiogenesis inhibitors can be followed by the rapid growth of pre-
viously dormant metastases. However, systemic therapy with angiostatin prevented the growth of the metastases after the radiation therapy of the primary tumor. These studies suggest that there may be a population of patients that would require the addition of antiangiogenic therapy during and/or after radiation therapy and/or surgery to prevent the expansion of distant metastases. Angiostatin is an internal fragment of plasminogen and is a potent and specific inhibitor of angiogenesis and tumor growth. The discovery of angiostatin provides evidence that the clotting and fibrinolytic pathways are directly involved in the regulation of angiogenesis. In vivo, systemic therapy with angiostatin induces a virtual complete blockade of angiogenesis and potendy inhibits tumor growth. To date, all tumors tested in vivo have been potently inhibited, and no evidence of resistance to therapy has been demonstrated even after prolonged administration. Prolonged therapy with high doses of angiostatin and other angiogenesis inhibitors (7) leads to regression of established tumors and can induce tumor dormancy. The tumor dormancy is defined by a high rate of tumor cell proliferation balanced by apoptosis and a virtual complete blockade of angiogenesis. Although studies with angiostatin have shown that it is able to regress a wide variety of tumors without resistance to therapy or toxicity (8), potential limits of the Use of antiangiogenic therapy alone have also been revealed. Human and murine tumors in mice treated with angiostatin continued to grow after the initiation of antiangiogenic therapy. In many cases, tumors progressed by 200o/o-40()
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