Lung cancer, with approximately 174,000 new cases per

Transcription

1 Radiofrequency Ablation of Lung Malignancies Christophe L. Nguyen, MD, Walter J. Scott, MD, and Melvyn Goldberg, MD Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania Radiofrequency ablation is a new technology that has been used successfully to treat hepatic tumors. Recently, an increasing number of reports have described the use of radiofrequency ablation for primary and metastatic lung tumors. Although such early experience appears promising, many questions regarding patient selection, radiofrequency ablation technique, effectiveness of ablation on lung tumors, radiographic follow-up, and survival remain unanswered. This article addresses these issues and provides the thoracic surgeon with a current review of the application of radiofrequency ablation to lung tumors. (Ann Thorac Surg 2006;82:365 71) 2006 by The Society of Thoracic Surgeons Lung cancer, with approximately 174,000 new cases per year, is the most common cause of cancer-related death in the United States and represents the second most common malignancy [1]. Surgical resection remains the gold standard of treatment for early-stage nonsmall-cell lung cancer (NSCLC) and is also beneficial in selected patients with limited pulmonary metastases from extrathoracic primary tumors [2]. However, many of the patients who present with primary and secondary lung tumors are poor surgical candidates because of limited pulmonary function or the presence of severe medical comorbidities. Accepted treatment alternatives to surgical resection in these patients include external beam radiation and chemotherapy, but long-term survival rates remain poor [3]. Furthermore, regional complications such as radiation pneumonitis, fibrosis, and esophagitis may limit treatment efficacy [4]. Other strategies such as stereotactic radiotherapy, brachytherapy, photodynamic therapy, bronchial artery infusion of chemotherapy, cryotherapy, and radiofrequency (RF) ablation (RFA) are being developed to assist in the local management of these tumors. Radiofrequency ablation has been used extensively in the treatment of unresectable liver tumors [5, 6], and is increasingly being used as therapy for other solid tumors [7]. Clinical experience with RFA for lung tumors has been limited, but is rapidly growing. However, general guidelines regarding the optimal ablative technique, patient selection, and radiographic follow-up are lacking. This article reviews the application of RFA for primary and metastatic lung tumors and focuses on RFA technique, patient selection, complications of RFA, and measurements of therapeutic responses. Material and Methods A review of the literature by search of the PubMed database, limited to studies published in English, was performed with the keywords RFA, lung, and tumors. Address correspondence to Dr Scott, Department of Surgical Oncology, Fox Chase Cancer Center, 333 Cottman Ave, Room C-308, Philadelphia, PA ; walter.scott@fccc.edu. Relevant animal and human clinical studies were examined. Single-patient case reports were excluded. Results Background Radiofrequency energy is produced by an alternating current that develops from a voltage gradient between the electrode that is placed within tumor tissue and the dispersive electrodes that are placed on the patient s skin. Frictional heating of the tissue ensues as ions within the tissue oscillate in an attempt to follow the change in the direction of the alternating current. As the temperature within the tissue increases, cells begin to die ( 45 C ) and a region of necrosis develops around the electrode [8]. Each RFA system consists of three components: an active electrode, a generator, and dispersive electrode pads. Three RFA systems are available and have been shown to be clinically useful in treating lung tumors (Table 1). The RadioTherapeutics (Boston Scientific, Boston, MA) and Radionics (Burlington, MA) RFA systems produce ablative energy while continuously monitoring the increase in tissue resistance, or impedance, which develops during tissue heating. Ablation is terminated when tissue impedance falls ( roll-off ), suggesting complete tissue necrosis. The RITA Medical Systems (Mountain View, California) generator is a temperature-based system capable of measuring target tissue temperature during ablation. Ablation ceases when temperature limits are reached ( 45 C). Animal Studies Early experience with RFA in animal models demonstrated its safety and efficacy in lung tissue. Goldberg and colleagues [22] developed a model of lung sarcoma tumors in 11 rabbits. Seven lesions were treated with RFA for 6 minutes at 90 C, and the remaining 4 untreated tumors served as controls. Histologic analysis of the treated tumors revealed that more than 95% of the tumor cells were necrotic, but that several specimens (43%) had viable tumor nests at the periphery of the tumor. Pneumothorax, which occurred in 29% of the treated animals, was the only procedure-related complication by The Society of Thoracic Surgeons /06/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 366 REVIEW NGUYEN ET AL Ann Thorac Surg RADIOFREQUENCY ABLATION OF LUNG TUMORS 2006;82: Table 1. Clinical Studies of Radiofrequency Ablation for Lung Tumors Author Year Electrode/Generator Approach Tumors Dupuy [9] 2000 Cool-tip/Radionics PC 3 Nishida [10] 2002 LeVeen/RadioTherapeutics PC 8 Herrera [11] 2003 LeVeen/RadioTherapeutics Open a /PC 33 Suh [12] 2003 Starburst XL/RITA Medical Systems PC 17 Cool-tip/Radionics PC 2 Gadaleta [13] 2004 Cool-tip/Radioincs PC 40 Belfiore [14] 2004 Cool-tip/Radionics PC 23 Starburst/RITA Medical Systems PC 10 Steinke [15] 2004 Starburst XL/RITA Medical Systems PC 52 Lee [16] 2004 Cool-tip/Radionics PC 32 Kang [17] 2004 LeVeen/RadioTherapeutics PC 120 Yasui [18] 2004 Cool-tip/Radionics PC 99 Akeboshi [19] 2004 Cool-tip/Radionics PC 54 Fernando [20] 2005 LeVeen/RadioTherapeutics Open a /PC 21 vansonnenberg [21] 2005 LeVeen/RadioTherapeutics PC 30 a Minithoracotomy. PC percutaneous computed tomography guided. Investigators at M.D. Anderson Cancer Center determined the effect of RF energy on lung tissue in a porcine model [23]. Using differing power settings and length of application times, they determined that the thermal lesions created in the porcine lung tissue were complete and entire, with no procedure-related complications. Animals surviving to 28 days after RFA were active and showed no evidence of detrimental effects of the RF-induced necrosis on respiratory capacity or function. In a more recent study, Miao and colleagues [24] reported their experience with RFA in 18 rabbits using the VX2 lung sarcoma model. Twelve rabbits underwent RFA of their lung tumors using a cooled-tip electrode for 60 seconds, and the remaining 6 rabbits received a sham operation. Therapeutic efficacy was evaluated by survival rate, magnetic resonance imaging (MRI), and postmortem histology. Tumor eradication was achieved in 9 of 12 rabbits undergoing RFA, and the 3-month survival rate of RFA-treated rabbits was significantly higher than that of control rabbits. One rabbit underwent incomplete tumor ablation, and 2 rabbits had local tumor relapse or lung metastasis or both. Procedure-related complications included a tension pneumothorax in 1 rabbit, and pyothorax in another. Radiofrequency Ablation Technique Most published studies have been performed by interventional radiologists and describe RFA through a percutaneous, computed tomography guided (PC) approach (Table 1). Although the majority of these patients received only local anesthesia and conscious sedation [14 16, 19], other authors have described PC RFA using epidural [18] or general [11, 13, 17] anesthesia. Herrera and coauthors [11] have reported the largest surgical experience with RFA in which all patients underwent general anesthesia and received ablation either through a PC approach or through a minithoracotomy. In the cases of PC RFA, the services of a CT technician were utilized, and the procedure was conducted in an operating room equipped with a CT scanner. There are no universally accepted technical guidelines or ablation protocols. Some authors have followed the RFA manufacturer s recommended ablation settings, whereas others have modified their technique according to experience. As a result, several ablation protocols have been reported with slight differences depending upon the author and type of electrode/generator used. The following is a description of these techniques according to the type of RFA system. The Radionics generator delivers energy through a Cooltip electrode (Tyco, Boulder, CO). This electrode, which is internally cooled during ablation, is available as a single or cluster needle point. The size of the ablative zone is determined by the length of exposed electrode tip (1 cm to 3 cm). The 3 cm Cool-tip electrode is typically used to ablate tumors smaller than 4.0 cm in diameter, and the cluster electrode is used for tumors larger than 4.0 cm in diameter [16]. The Radionics generator allows for a maximum output of 120 W to 140 W, and loss of tissue impedance generally occurs after 12 minutes of ablation [9, 18]. Overlapping zones of ablation are used for larger tumors and are created by repositioning the electrode within the tumor [18]. After completion of RFA, a thermosensor located at the end of the electrode tip can be used to ensure adequate thermoablation ( 60 C). The Starburst XL electrode and RITA 1500 generator are manufacturered by RITA Medical Systems. The Starburst XL electrode has 9 tines and is available in electrode lengths of 10 cm and 15 cm [15]. The RITA 1500 generator provides a maximum output of 150 W and typically achieves final ablation zones of 3 cm, 4 cm, and 5 cm at 15, 20, and 27 minutes, respectively. Immediate ablation endpoints include reaching target temperatures of 90 C to 95 C, the creation of 1-cm tumor margins, and the development of

3 Ann Thorac Surg REVIEW NGUYEN ET AL 2006;82: RADIOFREQUENCY ABLATION OF LUNG TUMORS 367 Table 2. Patient and Tumor Characteristics Author Primary NSCLC a Lung Metastases a Mean Size of Treated Lesion (cm) Dupuy [9] Nishida [10] Herrera [11] Suh [12] Gadaleta [13] Belfiore [14] Steinke [15] 0 23 Lee [16] Kang [17] Yasui [18] Akeboshi [19] Fernando [20] vansonnenberg [21] a Indicates number of patients. NSCLC nonsmall-cell lung cancer. ground-glass attenuation (GGA) in the surrounding lung parenchyma as seen on CT imaging [12]. Boston Scientific manufactures the LeVeen electrode and RF 2000/3000 generator. The LeVeen electrode, which has 12 tines, is available in several diameters of 2 cm to 5 cm. The RadioTherapeutics generator outputs energy until roll-off occurs in the heated tissue (maximum output of 200 W) [10, 11, 17]. Tumors smaller than 3.5 cm are typically given full heating energy once, and tumors larger than 3.5 cm receive multiple, overlapping treatments. Patient Selection Clinical reports of the use of RFA to treat patients with primary and secondary lung tumors describe a heterogenous patient population (Table 2). These series included patients who refused surgical resection and patients who were considered poor surgical candidates because of insufficient pulmonary reserve, the presence of severe comorbidities, or tumor multifocality. For patients with compromised pulmonary reserve, the reports generally provide no detailed information regarding their pulmonary function (forced expiratory volume at 1 second, diffusion capacity of lung for carbon monoxide, and so forth) either before or after ablation. Furthermore, authors have treated single and multiple tumors of variable sizes. Belfiore and colleagues [14] have reported the largest experience of RFA for primary lung cancer. Thirty-three patients who either refused surgery or were deemed poor surgical candidates underwent PC RFA. Interestingly, 15 of the 33 patients were initially treated with either radiation or chemotherapy and presented for PC RFA with evidence of active disease. The authors excluded patients with coagulation disorders, those with distant metastases, and those with either chest wall invasion or massive invasion of the mediastinum. Eligible patients included those with localized, intrathoracic tumors regardless of stage or size. These included 21 cases of adenocarcinoma, 11 cases of squamous cell carcinoma, and 1 case of small cell carcinoma. Lee and associates [16] have also reported experience with PC RFA in treating 26 patients with primary lung tumors. Selected patients included those with a histologically proven NSCLC as verified by either percutaneous transthoracic needle biopsy or transbronchial lung biopsy. Clinical staging identified 10 patients with stage IA or IB disease, 1 patient with stage IIB, and 15 patients with either stage III or IV. Four of the patients with stage I lung cancer were not considered surgical candidates because of poor pulmonary function or major cardiac disease. The other 6 patients refused surgical resection. Studies reporting results of PC RFA for lung metastases have used similar inclusion criteria. Yasui and coworkers [18], who treated 96 tumors with PC RFA, also included patients deemed poor surgical candidates because of coexistent morbidities and patients refusing surgery. Although they included similar groups of patients in their study of RFA for colorectal metastases, King and colleagues [25] described more comprehensive exclusion criteria; PC RFA was not performed for patients with more than 10 lesions, lesion diameter greater than 3.5 cm, prothrombin time greater than 1.5 seconds, platelet count less than /L, emphysematous bullae, central lesions, history of previous surgery or radiotherapy to the affected lung, expected survival less than 3 months, age less than 18 or greater than 85 years, and significantly compromised lung function. Complications of RFA Most series of PC RFA suggest that it can be performed safely as an outpatient procedure. However, intraprocedural and delayed complications have been reported. Despite the use of analgesics and sedatives, Lee and coauthors [16] reported aborting RFA in 17% of patients with central tumors because of intractable coughing. All of these cases occurred when RF energies higher than 100 W were applied. Although, the development of a pneumothorax is common during ablation (Table 3), the majority can be treated conservatively. Pneumothorax occurs more frequently after RFA of central tumors than in patients with peripheral tumors [16]. According to one report, the presence of emphysema, size of electrode, and number of electrode passes into the tumor do not appear to increase the risk of pneumothorax [16]. Aspiration or drainage should be reserved for large pneumothoraces or for symptomatic patients. Fever and chest pain are also common during the first week after RFA [15]. Other less common postprocedural complications included subcutaneous emphysema (11%) [16], hemoptysis (3% to 5%) [11, 16], pleural effusion (7% to 50%) [11, 12, 14, 16], lung abscess (22%) [19], and pneumonia (4% to 66%). [10, 11, 15, 16] The majority of these complications were treated expectantly, or responded to antibiotic therapy. Gadaleta and colleagues [13] reported the use of parenteral antibiotics before PC-RFA and for 6 days thereafter, with no cases of lung abscess. It is not clear whether all patients undergoing RFA should receive such an antibiotic course. Reports of death after RFA are rare, with a reported range of 0% to 5.5% [11, 14, 16, 18, 19]. Herrera and coauthors [11]

4 368 REVIEW NGUYEN ET AL Ann Thorac Surg RADIOFREQUENCY ABLATION OF LUNG TUMORS 2006;82: Table 3. Frequency of Pneumothorax After Radiofrequency Ablation Author Immediate (%) Delayed (%) Required Treatment (%) a Dupuy [9] Nishida [10] Herrera [11] 54 b Suh [12] Gadaleta [13] Belfiore [14] Steinke [15] Lee [16] Yasui [18] Akeboshi [19] Fernando [20] vansonnenberg [21] a Denotes percent of radiographically evident pneumothoraces requiring either aspiration or drainage. b Percutaneous computed tomography guided radiofrequency ablation group only. described a death from massive hemoptysis 21 days after open RFA of a central tumor. Death secondary to the development of acute respiratory distress syndrome after PC RFA has also been reported [14, 20]. Radiographic and Histologic Responses After RFA Noncontrast CT imaging of the tumor immediately after RFA has yielded a consistent radiographic response [16, 18]. The ablative zone appears as an area of low density (as measured in Hounsfield units [HU]), and tumor tissue is enveloped in GGA (Fig 1). Contrast-enhanced CT imaging of the tumor in the immediate post-rfa setting demonstrates an ablation zone with a nonenhancing central area, decreased density, intralesional bubbles, and enveloped ground-glass opacity [14]. Lee and coauthors [16] used patterns of contrast enhancement to determine the extent of tumor necrosis. Three overlapping regions of CT imaging that included 60% or more of the cross-sectional area of the tumor were obtained before and after contrast enhancement. The HU measurements were performed on these images, and mean values were recorded. Any region that enhanced more than 10 HU after contrast administration was considered to represent viable unablated tumor. The authors defined complete tumor necrosis as the presence of a nonenhancing area with a diameter equal to or greater than that of the initial tumor. Frequent CT scanning within the 2-month period after RFA has demonstrated that the zone of nonenhancement will increase 50% to 100% of the size of the original tumor [18]. This zone, which contains ablated tumor, hemorrhage, and consolidated normal lung parenchyma, will typically return to the original tumor size by 3 months. As of yet, there are no standard criteria for measuring the therapeutic response after RFA. Some authors have relied exclusively on serial noncontrast CT imaging as the modality of choice for after tumor responses, whereas others have incorporated contrast CT imaging, HU densitometry measurements, and positron emission tomography (Table 4). Furthermore, different time schedules for imaging have been proposed. As a result, interpretation of published ablation rates is difficult. Response rates as reported based on the various imaging methods have ranged from 38% to 100% [10, 11, 13, 15 17, 19, 20]. The success of RFA, as defined by imaging criteria, appears to correlate with the pretreatment size of the tumor (Table 5), irrespective of tumor pathology or the size of the ablative field [19]. Radiofrequency ablation treated tumors less than 5 cm in size demonstrated more evidence of complete necrosis on imaging studies than larger tumors. In the clinical series reviewed here, histologic confirmation of complete tumor necrosis was uncommon, with only a few authors performing biopsy in the post-rfa setting [11, 14, 18]. Belfiore and colleagues [14] conducted CTguided percutaneous biopsy in 19 of 33 patients (57%) at the 6-month follow-up interval to assess histopathologic change. Complete coagulation necrosis (Fig 2) was noted in 7 patients (36%), and a mixed pattern of solid and necrotic tissue was reported in the remaining cases (63%). Of the cases demonstrating complete necrosis, 5 originated from tumors less than 3 cm in diameter. Yasui and coauthors [18] obtained biopsies of ablation zones at the 2-month follow-up interval. Necrosis or fibrosis without viable tumor cells, or both, was evident in 20 of 33 ablation zones (60.1%). Residual tumor cells were noted in the remaining 13 specimens (39.9%), with 5 samples demonstrating ghost cells. The presence of viable cells would suggest an unacceptably high local recurrence rate. Based on these results, the effectiveness of RFA in providing local control would certainly be inferior to the use of sublobar resection alone [26]. Survival Data The influence of RFA on patient survival is difficult to interpret because most studies report on a small number of Fig 1. Immediate post radiofrequency ablation noncontrast computed tomography image demonstrating ground-glass attenuation in the ablative zone (arrows). (Reprinted from Lee JM, et al, Radiology; 2004;230: [16], with permission.)

5 Ann Thorac Surg REVIEW NGUYEN ET AL 2006;82: RADIOFREQUENCY ABLATION OF LUNG TUMORS 369 Table 4. Modalities Used to Determine Therapeutic Response After Radiofrequency Ablation Author CT PET Percutaneous Biopsy Dupuy [9] 3 months Nishida [10] 9, 21 months 9 months Herrera [11] 1, q 3 months / d Suh [12] 1, 3, 6, 12 months a Gadaleta [13] 2 days, q 3 months b Belfiore [14] 1 week; 1, 6, 12 months c 6, 12 months Steinke [15] 1 week, 1 month, q 3 months Lee [16] 1, 3, q 6 months a Kang [17] 1 2 weeks 1 2 weeks Yasui [18] 1 week 2 months, q 2 6 months 2 9 months Akeboshi [19] 1 week; 1, 3, q 3 months a 1 week; 1, 3, q 3 months Fernando [20] 4 6 weeks, q 3 months / d vansonnenberg [21] 2 months b, c / d a Computed tomography (CT) with contrast enhancement and densitometry measurements. b Selective use of contrast-enhanced magnetic resonance imaging. c Computed tomography with contrast enhancement only. d Used selectively for equivocal findings on CT imaging. PET position emission tomography; q every. patients with short follow-up (less than 1 year). Furthermore, most of the published experience with RFA has been in patients with metastases who often have progression of their extrathoracic disease. Therefore, RFA studies of primary lung cancer deserve detailed analysis as they provide more accurate data for determining local recurrence and survival rates (Table 6). In their series of 33 patients who underwent PC RFA for primary lung cancer, Belfiore and coauthors [14] did not report the time of mean follow-up or mean survival. At 1 year after ablation, 18 patients were alive, 8 patients had died, and 7 patients were lost to follow-up. Of the patients who were alive, only 10 were available to undergo CT imaging for surveillance. Stable disease was present in 6 patients, and further reduction in the size of the ablative zone was noted in the remaining 4 patients. Three patients died from progressive, extrathoracic tumor growth. The other 5 known deaths were caused by hepatic failure (3) and heart failure (2). Lee and coauthors [16] calculated mean survival according to two groups of treated patients. A definitive therapy group consisted of 10 patients with clinical stage I NSCLC who did not undergo surgical resection because of comorbid medical contraindications or refusal. A second, palliative therapy group consisted of 20 patients with locally advanced tumors who had failed various chemotherapy and radiation therapy regimens. With a mean follow-up of 12.5 months (range, 1 to 24), the mean survival of the patients in the definitive therapy group was significantly better than that of the palliative group ( months versus months, p 0.01). In the definitive therapy group, 8 of 10 patients (80%) were alive after ablation (mean, months). Two patients died of respiratory failure related to exacerbation of chronic obstructive pulmonary disease. In the palliative therapy group, 4 of 20 patients (20%) were alive, with a mean follow-up of 16.3 months 5.8. Of those patients who died, 5 (31%) died of causes related to tumor growth in lung such as obstructive Table 5. Tumor Size and Therapeutic Response Author Size (cm) Response Rate (%) a p Value Herrera [11] (8/12) (2/6) Lee [16] (6/6) (6/26) Akeboshi [19] 3 69 (25/36) (7/18) a Complete necrosis as determined radiographically. Fig 2. Histopathology from a percutaneous biopsy (6-month followup) demonstrating complete coagulation necrosis. Reprinted with permission from the American Journal of Roentgenology [14].

6 370 REVIEW NGUYEN ET AL Ann Thorac Surg RADIOFREQUENCY ABLATION OF LUNG TUMORS 2006;82: Table 6. Outcome Data for Radiofrequency Ablation Treated Patients With Primary Lung Cancer Author Mean Follow-Up Progression (%) Mean Survival Mortality (%) a Belfiore [14] 3/18 (16.7) b 3/26 (11.5) b Lee [16] 12.5 months 21.2 months c 0/10 (0) c Fernando [20] 14 months 6/18 (33.3) b 20.1 months b 1/18 (5.6) b a Radiofrequency ablation related mortality. b Patients with stages I IV nonsmall-cell lung cancer. c Patients with stage I nonsmall-cell lung cancer. pneumonia, hemoptysis, and acute respiratory distress syndrome. More significantly, the authors also correlated survival with extent of tumor necrosis after ablation. The mean survival of patients with RFA-induced complete necrosis as determined by imaging criteria was 19.7 months 2.0, compared with 8.7 months 1.8 (p 0.01) for patients with partial necrosis. In their series of PC RFA for primary lung cancer, Fernando and colleagues [20] reported a median follow-up of 14 months (range, 3 to 25) during which 15 patients (83.3%) were alive. One perioperative death was reported, that of a patient who underwent open RFA of a right upper lobe lesion in conjunction with a right lower lobectomy. This patient had a pulmonary embolus, pneumonia, and subsequently multisystem organ failure. Two other deaths were reported at 1 and 4 months after RFA, but were related to underlying patient comorbidities. Local progression occurred in 6 patients (33%). Salvage therapy included chemotherapy and radiation in 2 patients, repeat RFA in 1 patient, chemotherapy and completion pneumonectomy in 1 patient, lobectomy in 1 patient, and wedge resection in 1 patient. Mean and median progression-free intervals were 16.8 and 18 months, respectively. For patients with clinical stage I cancers (9), the mean progression-free interval was 17.6 months. Comment Early clinical experiences with RFA suggest that it could serve as a potential addition (or alternative) to surgery and radiation therapy for the local treatment of primary and secondary malignant lung tumors. Several electrode/ generator systems are available, and each has been shown to produce tissue ablation in the lung (Table 1). Radiofrequency ablation can be performed through either an open (surgical) approach or a percutaneous, CT-guided approach. Major complications are rare, with postprocedural fever, pain, and pneumothorax being most commonly reported. Despite the growing use of RFA for the treatment of lung tumors, however, many questions need to be answered before this technique can be offered to patients as an alternative to current therapies. The RFA protocols reported to date achieve, based on various imaging criteria, complete ablation of the tumor in 38% to 100% of cases after the initial treatment. Higher ablation rates have generally been reported for smaller ( 3 cm) tumors (Table 5), but histologic confirmation of the effect of RFA has been rare. Therefore, long-term effectiveness of RFA is uncertain. Fernando and colleagues [20] have provided the longest patient follow-up of 14 months after PC RFA and demonstrated a radiographic local progression rate of nearly 40%. Based on data from only two studies, CT-guided biopsies performed 2 to 6 months after RFA in selected patients demonstrated complete necrosis of the RFA-treated area in only 36% to 60% of tumors [14, 18]. How can the variable rate of RFA-induced complete tumor ablation observed in these studies translate into a meaningful rate of cure or even local tumor control for patients? Current studies, with their heterogeneous patient populations, short-term follow-up, and variable methods of determining treatment response do not provide clinicians with the answers to that question. Nonetheless, the potential for RFA to treat small tumors with curative intent, to improve local control of larger tumors, and to be used in addition to current treatments such as radiation therapy warrants further study. The American College of Surgeons Oncology Group is developing a pilot study of RFA (Z4033) for the treatment of localized lung cancers in patients who are determined by surgeons not to be candidates for resection on the basis of medical comorbidities. Trials such as this are important to determine the appropriate criteria for patient selection and the best methods for follow-up, as well as to document the success rate of RFA and to carefully assess complication rates. Based on our review of the literature, we believe RFA treatment of lung tumors should not currently be considered standard therapy, even for patients who are not candidates for resection, and that it should be performed only as part of a clinical research trial or protocol. Studies correlating tumor size with RFA effectiveness (as determined radiographically [Table 5]) suggest that peripheral T1 tumors represent the best targets for PC RFA. Because RFA is a local treatment, patients with primary NSCLC who have evidence of N1, N2, or metastatic disease will not benefit from such therapy and should not receive RFA of their primary tumor. Potential RFA candidates should be staged with CT, positron emission tomography, and even mediastinoscopy depending on the severity of comorbidities. Similarly, subsequent trials of PC RFA for metastatic disease to the lung should also be restricted to peripheral tumors ( 5 cm), and must carefully document concurrent or antecedent systemic therapies to afford accurate monitoring of effectiveness and local progression. Future studies must characterize the effectiveness of RFA as a local control modality and move beyond the issue of feasibility. Such trials must include standardized ablation protocols and establish post-rfa surveillance programs. Toward the development of these trials, we recommend the following: (1) contrast CT imaging every 3 months after an initial scan at 1 month after RFA; (2) that local recurrence be

7 Ann Thorac Surg REVIEW NGUYEN ET AL 2006;82: RADIOFREQUENCY ABLATION OF LUNG TUMORS 371 defined not only as reappearance or persistence of disease within the treated lobe, but also include disease progression in N1 and N2 lymph nodes; (3) histopathologic confirmation of unablated tumor or possible local recurrence; and (4) reporting of disease-free interval and disease-free survival. Finally, in every series that we reviewed but one, interventional radiologists performed the RFA procedure. We cannot emphasize enough how important it is for surgeons to participate in the development of this and other emerging technologies. While the indications for RFA and other image-guided therapies for lung cancer may currently be limited to patients who are medically inoperable, the experiences of vascular and cardiac surgeons suggest that indications for the use of emerging technologies expand over time [27]. Thoracic surgeons are and should remain the experts in the treatment of patients with early-stage lung cancer. We should not yield this position to anyone even if it requires that we learn to use image-guided techniques. Our thoracic surgery professional societies should be active and not reactive, formulating policies that will enable us to incorporate RFA and other emerging technologies into our practices for the safety and well-being of our patients. References 1. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, CA Cancer J Clin 2004;54: Pastorino U, Buyse M, Friedel G, et al. Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases. The International Registry of Lung Metastases. J Thorac Cardiovasc Surg 1997;113: Sibley GS, Jamieson TA, Marks LB, Anscher MS, Prosnitz LR. Radiotherapy alone for medically inoperable stage I non-small-cell lung cancer: the Duke experience. Int J Radiat Oncol Biol Phys 1998;40: Morita K, Fuwa N, Suzuki Y, et al. Radical radiotherapy for medically inoperable non-small cell lung cancer in clinical stage I: a retrospective analysis of 149 patients. Radiother Oncol 1997;42: Curley SA, Izzo F, Delrio P, et al. Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies: results in 123 patients. Ann Surg 1999;230: Bilchik AJ, Wood TF, Allegra DP. Radiofrequency ablation of unresectable hepatic malignancies: lessons learned. Oncologist 2001;6: Mirza AN, Fornage BD, Sneige N, et al. Radiofrequency of solid tumors. Cancer J 2001;7: Goldberg SN, Gazelle G, Compton C, McLoud TC. Radiofrequency tissue ablation in the rabbit lung: efficacy and complications. Acad Radiol 1995;2: DePuy D, Zagorias R, Akerley W, et al. Percutaneous computed-tomographic ablation of malignancies in the lung. AJR Am J Roentgenol 2000;174: Nishida T, Inoue K, Kawata Y, et al. Percutaneous radiofrequency ablation of lung neoplasms: a minimally invasive strategy for inoperable patients. J Am Coll Surg 2002; 195: Herrera LJ, Fernando HC, Perry Y, et al. Radiofrequency ablation of pulmonary malignant tumors in nonsurgical candidates. J Thorac Cardiovasc Surg 2003;125: Suh RD, Wallace AB, Sheehan RE, Heinze SB, Goldin JG. Unresectable pulmonary malignancies: CT-guided percutaneous radiofrequency ablation-preliminary results. Radiology 2003;229: Gadaleta C, Mattioli V, Colucci G, et al. Radiofrequency ablation of 40 lung neoplasms: preliminary results. AJR Am J Roentgenol 2004;183: Belfiore G, Moggio G, Tedeschi E, et al. CT-guided radiofrequency ablation: a potential complementary therapy for patients with unresectable primary lung cancer a preliminary report of 33 patients. AJR Am J Roentgenol 2004;183: Steinke K, Glenn D, King J, et al. Percutaneous imagingguided radiofrequency ablation in patients with colorectal pulmonary metastases: 1-year follow-up. Ann Surg Oncol 2004;11: Lee JM, Jin GY, Goldberg SH, et al. Percutaneous radiofrequency ablation for inoperable non-small cell lung cancer and metastases: preliminary report. Radiology 2004;230: Kang S, Luo R, Liao W, et al. Single group study to evaluate the feasibility and complications of radiofrequency ablation and usefulness of post treatment positron emission tomography in lung tumours. World J Surg Oncol 2004;2: Yasui K, Kanazawa S, Sano Y, et al. Thoracic tumors treated with CT-guided radiofrequency ablation: initial experience. Radiology 2004;231: Akeboshi M, Yamakado K, Natatsuka A, et al. Percutaneous radiofrequency ablation of lung neoplasms: initial therapeutic response. J Vasc Interv Radiol 2004;15: Fernando HC, De Hoyos A, Landreneau RJ, et al. Radiofrequency ablation for the treatment of non-small cell lung cancer in marginal surgical candidates. J Thorac Cardiovasc Surg 2005;129: vansonnenberg E, Shankar S, Morrison PR, et al. Radiofrequency ablation of thoracic lesions: part 2, initial clinical experience-technical and multidisciplinary considerations in 30 patients. AJR Am J Roentgenol 2005;184: Goldberg SN, Gazelle GS, Compton CC, Mueller PR, McLoud TC. Radio-frequency tissue ablation of VX2 tumor nodules in the rabbit lung. Acad Radiol 1996;3: Putnam JB, Thomsen SL, Siegenthaler M. Therapeutic implications of heat-induced lung injury. In: Ryan, ed. TP Matching the energy source to the clinical need. Bellingham, WA: SPIE Optical Engineering Press, 2000: Miao Yi, Yicheng N, Bosmans H, et al. Radiofrequency ablation for eradication of pulmonary tumor in rabbits. J Surg Res 2001;99: King J, Glenn D, Clark W, et al. Percutaneous radiofrequency ablation of pulmonary metastases in patients with colorectal cancer. Br J Surg 2004;91: Martini N, Bains MS, Burt ME, et al. Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 1995;109: Lang PO, Schwarze ML, Alexander GC. New technologies meeting old professional boundaries: the emergence of carotid artery stenting. J Am Coll Surg 2005;200: