Image-Guided Radiofrequency Ablation of Lung Neoplasm in 100 Consecutive Patients by a Thoracic Surgical Service

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1 Image-Guided Radiofrequency Ablation of Lung Neoplasm in 100 Consecutive Patients by a Thoracic Surgical Service Arjun Pennathur, MD, Ghulam Abbas, MD, William E. Gooding, MS, Matthew J. Schuchert, MD, Sebastien Gilbert, MD, Neil A. Christie, MD, Rodney J. Landreneau, MD, and James D. Luketich, MD Heart, Lung, and Esophageal Surgery Institute, University of Pittsburgh Medical Center, and The University of Pittsburgh Cancer Institute Biostatistics Facility, Pittsburgh, Pennsylvania Background. Surgical resection is the standard of care for patients with resectable non small cell lung cancer or selected patients with pulmonary metastases. However, for high-risk patients radiofrequency ablation (RFA) may offer an alternative option. The objective of this study was to evaluate computed tomography guided RFA for high-risk patients and report our initial experience in 100 consecutive patients by a thoracic surgical service. Methods. Medically inoperable patients were offered RFA. Thoracic surgeons evaluated and performed RFA under computed tomography guidance. Patients were followed in the thoracic surgery clinic. The primary end point evaluated was overall survival. Results. One hundred patients underwent imageguided RFA for lung neoplasm (40 men, 60 women; median age, 73.5 years; range, 26 to 95 years). Forty-six patients (46%) with primary lung neoplasm, 25 patients (25%) with recurrent cancer, and 29 patients (29%) with pulmonary metastases underwent RFA. The mean follow-up for alive patients was 17 months. The median overall survival for the entire group of patients was 23 months. The probabilities of 2-year overall survival for the entire group, primary lung cancer patients, recurrent cancer patients, and metastatic cancer patients were 49% (95% confidence interval, 37 to 60), 50% (95% confidence interval, 33 to 65), 55% (95% confidence interval, 25 to 77), and 41% (95% confidence interval, 19 to 62), respectively. Conclusions. Our experience indicates that imageguided RFA done by the thoracic surgeons is feasible and safe in high-risk patients with lung neoplasm with reasonable results in patients who are not fit for surgery. Thoracic surgeons can perform RFA safely, and should continue to investigate this new image-guided modality that may offer an alternative option in medically inoperable patients. (Ann Thorac Surg 2009;88:1601 8) 2009 by The Society of Thoracic Surgeons Surgical resection is the standard treatment in resectable disease and offers the best chance of cure, particularly in the earlier stages [1]. The standard treatment for early stage non small cell lung carcinoma (NSCLC) is a lobectomy [2]. However, a significant proportion of patients, particularly elderly patients with associated comorbidities, are not candidates for surgery, and these patients either receive no treatment or are treated with conventional external beam radiotherapy. In recent studies of patients with early stage NSCLC, who received no treatment, the median survival was 9 to 14 months [3, 4]. After treatment with external beam radiation for early stage NSCLC, 5-year survival rates are 10% to 30% [5 9]. Sibley and colleagues [6] reviewed the results of conventional radiotherapy for stage I NSCLC from Duke University in 156 patients and reported a Accepted for publication May 6, Presented at the Forty-fourth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28 30, Address correspondence to Dr Luketich, Department of Surgery, The Heart, Lung, and Esophageal Surgery Institute, University of Pittsburgh, Pittsburgh, PA 15213; luketichjd@upmc.edu. median survival of 18 months. Thus, the results of conventional radiation therapy have not been satisfactory, prompting investigators to study other modalities such as radiofrequency ablation (RFA) and stereotactic radiosurgery for treatment in this group of high-risk patients with lung cancer. Surgical resection is also beneficial for selected patients with pulmonary metastases. Patients who have a single metastasis, prolonged disease-free survival, complete control of the primary tumor, and no evidence of extrathoracic disease are good candidates for resection [10]. In medically inoperable or unresectable patients with pulmonary metastases, there are few effective options. These tumors are typically not sensitive to radiation or require a large field of radiation. Therefore, newer technologies, such as RFA, may also offer an alternative option in the management of medically inoperable or high-risk patients with lung neoplasm. Radiofrequency ablation is administered by means of a thermal energy delivery system that applies an alternating current supplied by a radiofrequency energy generator and delivered through a needle electrode. The nee by The Society of Thoracic Surgeons /09/$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 1602 PENNATHUR ET AL Ann Thorac Surg RADIOFREQUENCY ABLATION FOR LUNG NEOPLASM 2009;88: dle electrode is introduced percutaneously under computed tomography (CT) guidance, and the tines are deployed within the tumor. This allows for maximal distribution of energy. The alternating current creates ionic agitation, generating heat that can reach 90 C. This leads to coagulative necrosis and tissue destruction in the area of the probe [11]. In this paper, we present our results with the use of image-guided RFA for the treatment of lung neoplasm in 100 consecutive patients by a thoracic surgical service. Our objective was to determine the outcomes of RFA in the treatment of lung neoplasm. Material and Methods We retrospectively evaluated our experience with imageguided RFA for the treatment of lung neoplasm in medically inoperable patients at the University of Pittsburgh from 2000 to Informed consent for treatment with RFA was obtained from all patients. The study was approved by the Institutional Review Board at the University of Pittsburgh. Selection of Patients Patients with primary lung neoplasm were routinely staged with chest CT scan, and most patients (39 of 46; 84.8%) also underwent a positron emission tomography scan. Patients with primary lung cancer with mediastinal lymph nodes greater than 1 cm in short-axis view or a positive positron emission tomography scan underwent mediastinoscopy. In patients with primary lung cancer, mediastinoscopy was performed in 9 patients and left video-assisted thoracoscopy was performed in 1 patient to biopsy hilar and aortopulmonary window nodes. The inclusion criteria for RFA in the treatment of patients for this study were (1) patients who were considered medically inoperable owing to (a) poor pulmonary function (predicted postoperative forced expiratory volume in 1 second less than 40% or predicted postoperative lung diffusing capacity for carbon monoxide less than 40%) [12] or (b) high cardiac risk, which includes severe coronary or valvular disease, and uncompensated congestive heart failure as described by the perioperative guidelines for risk assessment in noncardiac surgery by the American College of Cardiology/American Heart Association [13] or other comorbidities; (2) patients who had failure of previous therapies; or (3) patients who refused surgical resection. Exclusion criteria included central tumors (within 3 cm of the hilum). All patients were evaluated by a thoracic surgeon to determine inoperability and suitability for RFA. Treatment Protocol Technique A percutaneous CT-guided approach was used in all patients, and thoracic surgeons performed all procedures as described previously [14, 15]. The majority of patients (n 86) underwent the procedure under general anesthesia. The electrosurgical needle s deployment was staged according to the size of the tumor, and the manufacturer s suggested algorithm was followed. In one system (Boston Scientific, Natick, MA), an impedancebased algorithm was used, and with another system (RITA Medical Systems, Inc, Mountainview, CA) a temperature-based algorithm was used. With both these systems, the electrode was repositioned as many times as necessary to ablate the target tissue and a small rim of approximately 0.5 to 1 cm of nondiseased pulmonary tissue to ensure adequate tumor margins. Follow-Up of Patients and Assessment of Response Patients were followed in 4-month intervals with clinical examinations, CT scans, and, selectively, with positron emission tomography scans. A modified Response Evaluation Criteria in Solid Tumors (RECIST) criterion incorporating CT scan and positron emission tomography scan was used to assess initial response to treatment [15]. We evaluated initial response rate, time to local progression, and overall survival. Table 1. Patient Characteristics Characteristics Results Male/female 40:60 Age (y) Mean 72.8 Median 73.5 Range Histology Primary lung neoplasm 46 Squamous 18 Adenocarcinoma 10 NSCLC, not specified 17 Others 1 Recurrent lung neoplasm 25 Squamous 6 Adenocarcinoma 5 NSCLC, not specified 14 Metastatic 29 Colorectal cancer 13 Breast 2 Renal cell 3 Sarcoma 5 Cervical 2 Squamous cell tongue 1 Testicular 1 Pheochromocytoma 1 Esophageal 1 Reason for RFA a Poor PFTs 43 Increased cardiac risk 18 Failed previous therapy 34 Multiple comorbidities 29 Refused surgery 7 a Some patients had more than one reason for RFA. NSCLC non small cell lung cancer; test; RFA radiofrequency ablation. PFT pulmonary function

3 Ann Thorac Surg PENNATHUR ET AL 2009;88: RADIOFREQUENCY ABLATION FOR LUNG NEOPLASM 1603 Table 2. Reason for Radiofrequency Ablation and Comorbidities Stratified by Group a Variable Primary Lung Cancer Recurrent Lung Cancer Metastatic Lung Cancer Poor lung function Increased cardiac risk Failed other therapies Multiple comorbidities Refused surgery Charlson comorbidity index Mean Median a Some patients had more than one reason for the use of radiofrequency ablation. Fig 1. Kaplan-Meier analysis of overall survival of patients with primary lung cancer (all stages). The time shown on the x axis is in months from radiofrequency ablation (RFA). The dotted lines are 95% confidence bands for the probability of overall survival. The number of patients at risk at the start of each 6-month interval is included above the x axis. Fig 2. Kaplan-Meier analysis of overall survival of patients with recurrent lung cancer. The time shown on the x axis is in months from radiofrequency ablation (RFA). The dotted lines are 95% confidence bands for the probability of overall survival. The number of patients at risk at the start of each 6-month interval is included above the x axis. Data Collection and Statistical Analysis Information on patient demographics, tumor characteristics, treatment, and comorbidities (Charlson comorbidity index) was collected. The Charlson comorbidity index [16] was originally described to assess the impact of comorbidity on survival in hospitalized patients. In this index, a total of 19 conditions, found to significantly influence survival, are assessed, and a weighted score is given based on the relative risk. Specific end points studied were complications, clinical response rates, time to progression, and overall survival. All analyses were performed from the time of the first RFA session. The pretreatment CT scan was used as a baseline for evaluation of response and disease progression. Local disease progression of the treated nodule was assessed in accordance with the modified RECIST criteria in comparison with baseline diameter. Time to progression was calculated from the treatment date. Kaplan- Meier plots were constructed using Greenwood confidence limits. Log rank test was used to determine differences between groups. Association between categorical variables was tested with Fisher s exact test or the 2 test. Results Patient Characteristics One hundred patients underwent image-guided RFA during a 7-year period. There were 40 men and 60 women with a median age of 73.5 years (range, 26 to 95 years). There were 46 patients (46%) with primary lung neoplasm (all stages), 25 patients (25%) with recurrent lung cancer, and 29 patients (29%) with metastatic disease. Patient characteristics are summarized in Table 1.A total of 109 lesions were treated with RFA in these 100 patients. In 92 patients, a single lesion was treated. In 8 patients, two to three lesions were treated in a single session. These patients had significant comorbidities as indicated by a mean Charlson comorbidity index score of 7.5 (median, 7; range, 2 to 13; Table 2). The most common reason for RFA was poor pulmonary function tests precluding resection (Tables 1, 2). The median forced expiratory volume in 1 second in these patients was 0.81 L (44% of predicted), and the median predicted diffusing capacity of the lung for carbon monoxide was 35%. The reasons for RFA and comorbidity index stratified by group are shown in Table 2. Periprocedure Course The median hospital stay was 2 days (range, 1 to 33 days). The most common complication was pneumothorax requiring a pigtail catheter in 59 patients (59%). Prolonged air leak ( 5 days) occurred in 7 patients (7%). Other complications included bleeding in 1 patient requiring bronchoscopy; myocardial infarction, cerebrovascular ac-

4 1604 PENNATHUR ET AL Ann Thorac Surg RADIOFREQUENCY ABLATION FOR LUNG NEOPLASM 2009;88: cident, deep vein thrombosis, and respiratory failure in 1 patient; pleural effusions requiring drainage in 3 patients; and arrhythmias in 6 patients. There was 1 death within 30 days of the procedure, which occurred as an outpatient after the patient was discharged (death occurred 2 weeks after the procedure). Response to Treatment Initial response was determined by the modified RECIST criteria [14]. The response could not be evaluated in 9 patients. In the remaining patients, an initial complete response was observed in 21% of patients, and a partial response was observed in 41%. Stable disease was noted in 20% and progressive disease occurred in 18% of patients. Time to Progression During follow-up, local progression of the treated lesion occurred in 35 patients (35%) and the median time to local progression was 15 months (95% confidence interval [CI], 8 to 27 months). Overall progression (all sites) occurred in 60 patients, and the median time to overall progression was 7 months (95% CI, 6 to 11 months). The median times to overall progression by type of neoplasm were primary lung neoplasm (all stages), 7 months (95% CI, 6 to 15 months); recurrent neoplasm, 7 months (95% CI, 6 to 16 months); and metastatic lung neoplasm, 8 months (95% CI, 4 to 17 months). Survival The median overall survival for the entire group of patients was 23 months (95% CI, 18 to 37 months). The mean follow-up was 17 months (median, 12 months). The median overall survival for patients with primary lung neoplasm (all stages) was 27 months (95% CI, 18 to 47 months) (Fig 1). Median overall survival was 33 months (95% CI, 11 to 45 months) for recurrent lung neoplasm Fig 3. Kaplan-Meier analysis of overall survival of patients with metastatic lung cancer. The time shown on the x axis is in months from radiofrequency ablation (RFA). The dotted lines are 95% confidence bands for the probability of overall survival. The number of patients at risk at the start of each 6-month interval is included above the x axis. (Fig 2), and 18 months (95% CI, 7 months to not reached) for metastatic disease (Fig 3). The estimated 2-year overall survival for the entire group was 49% (95% CI, 37 to 60). The estimated 2-year overall survival for patients with primary lung neoplasm (all stages) was 50% (95% CI, 33 to 65). Estimated 2-year overall survival for patients with recurrent lung neoplasm was 55% (95% CI, 25 to 77), and estimated 2-year overall survival for patients with metastatic disease was 41% (95% CI, 19 to 62). Comment Surgical resection is the preferred treatment for patients with early stage lung cancer [1, 2], and surgical treatment is also beneficial in selected patients with metastatic and recurrent lung cancer [10, 17]. Unfortunately, patients who are medically inoperable but otherwise resectable have few effective options. In patients with stage I NSCLC, who receive no treatment or who refuse treatment, a recent study showed that the estimated 5-year survival was 6% and the median survival was 9 months [3]. In another study of 129 patients with early stage NSCLC, patients who did not receive any treatment had a median survival of 14 months, significantly lower than patients who were treated with surgery (46 months) or radiotherapy (19.9 months). In addition, the cause of death for patients who were not treated was related to cancer in 53% of patients, suggesting that treatment is beneficial in nonsurgical patients [4]. In the current study the estimated median survival of 27 months after treatment with RFA compares favorably to either no treatment or standard external beam radiation. In this high-risk patient population with lung cancer, newer modalities, such as RFA or stereotactic radiosurgery, may be applicable [15, 18]. This study indicates that image-guided RFA performed by the thoracic surgeons is feasible and safe in high-risk patients with lung neoplasm with reasonable results in patients who are not fit for surgery. The assessment of response after RFA is difficult because, unlike surgical resection, there is a lesion or scar, which remains after therapy. The reported response rates vary considerably in the literature, with differing criteria being applied to assess response. We have adopted strict criteria and have used a modified RECIST criterion to evaluate response in these patients after RFA. However, this criterion has to be validated [15]. Patients with recurrent lung cancer after surgical resection comprise a difficult group of patients. Importantly, treatment of recurrent disease is associated with a survival benefit. Sugimura and associates [17] from the Mayo clinic reported the results in 390 patients who experienced recurrent cancer after complete surgical resection. The median postrecurrence survival in their study was 8.1 months, with estimated 1- and 2-year overall survivals of 37% and 17%, respectively. Surgical treatment for recurrences limited to the lung was performed in a very selected group of patients, and when the treatment included surgery, median survival was 32.8

5 Ann Thorac Surg PENNATHUR ET AL 2009;88: RADIOFREQUENCY ABLATION FOR LUNG NEOPLASM 1605 months. Median survival was only 13.4 months for nonsurgical treatment and 8.4 months for no treatment. In our study, RFA for the treatment of recurrent lung cancer resulted in a median survival of 33 months. These results appear reasonable, and in nonoperative candidates, RFA may provide an alternative option. Metastatic Lung Cancer The International Registry for Lung Metastases reported the results in 5,206 patients, who were treated with surgical resection for pulmonary metastases [10]. The estimated 5-year survival after complete resection was 36%, and the median survival was 35 months. Recurrences occurred in 53% of patients, and the median time to recurrence was 10 months. When the metastases were resectable and when all factors were favorable the median survival was 61 months; when they were unresectable, the median survival was 14 months with an estimated 5-year overall survival of 5%. In the current study, the pulmonary metastases group was heterogeneous. The median survival in this diverse group of patients was 18 months, and the overall 2-year survival was 41%. Other investigators have also reported the results of RFA in the treatment of metastatic lung tumors [19 23]. Yan and colleagues [19, 20] reported the results of RFA for the treatment of pulmonary metastases in 55 patients with primary colorectal neoplasms. The median survival in these patients was 33 months and the estimated 2-year survival was 64%. Although these results do not appear to be equivalent to complete surgical resection when possible, RFA may offer an alternative in a select group of high-risk patients who are unable to undergo surgical therapy. It is important to emphasize that the patients in our study had significant associated comorbidities with a median Charlson comorbidity index score of 7. This index has been validated in a cohort of surgically resected patients with NSCLC in a study of 205 patients [24]. The score was divided into four grades of increasing severity of the Charlson comorbidity index with greater than 5 representing the highest grade of comorbidities. For every increase in grade of Charlson comorbidity index, there was an increase in the risk of adverse outcome after surgery. It is very important that a qualified thoracic surgeon evaluate the patient for assessment of resection and determination of medical inoperability, because of these complicating comorbidities,. For example, in patients with upper lobe predominant emphysema and coexisting neoplasm, surgical resection may be feasible even if the pulmonary function tests appear borderline. Choong and colleagues [25] reported a series of 21 clinical stage I NSCLC with a mean forced expiratory volume in 1 second of 0.7 L (29% of predicted) who underwent surgical resection with upper lobe predominant emphysema. In patients with pathologic stage I, overall survival was estimated to be 79% at 3 years. One of the unique aspects of this series of 100 consecutive patients is that all the procedures were performed under CT guidance by thoracic surgeons. Another large series from the United States was reported by Simon and colleagues [23], who evaluated the results in 153 patients. Their procedure-related mortality was 2.6%, and the 30-day mortality was 3.9%. The mortality of 1% in our current series compares favorably with this report. The most common complication of RFA was a pneumothorax, which was effectively treated with a pigtail catheter in most patients. Although serious complications were rare in our series, this group of patients had significant comorbidities with a high comorbidity index. It is, therefore, very critical that the procedure be performed by a team that follows these patients closely and also manages complications effectively. It is also important to follow these patients long term, similar to the follow-up for lung cancer patients after surgical resection. Thoracic surgeons are, therefore, ideally positioned not only to perform RFA but also provide perioperative care and longterm follow-up for patients receiving RFA. Decreasing Local Progression The incidence of local progression was significant in this study (35%) as well as in studies by other investigators [21, 26]. There are several factors that may influence local recurrence or progression of disease. The important technical issues include the degree of ablation, whether complete ablation is achieved, and the adequacy of the margins of ablation around the tumor. Our data on margins and sublobar resection demonstrated that when the margins were less than 1 cm, the rate of local recurrence was 14% whereas local recurrence was 7% when the margins were greater than 1 cm [27]. In general, we strive to attain a 0.5- to 1.0-cm margin around the tumor. In addition, in our current protocol, we limit RFA to lesions less than 5 cm and limit RFA to three or fewer lesions in a single session. Experimental studies have also demonstrated increases in the area of ablation by increasing conductivity with saline infusion [28]. Hiraki and colleagues [21], in an interesting study, evaluated the risk factors for local progression after RFA in a series of 128 patients with lung tumors. This series included primarily patients with metastatic lung neoplasm. The median follow-up was 12 months; local progression was seen in 94 of 342 lesions (27%). Larger tumor size and the use of an internally cooled electrode were independent risk factors for local progression. Thus, in the future, further advances in technology or adjuvant therapy may be useful in decreasing progression after RFA and, perhaps, in improving survival. Limitations The current study also has the limitations that are common to retrospective studies, such as selection bias. The patients who were treated in this study comprise a very heterogeneous group, which encompasses not only primary lung neoplasm, but also recurrent lung cancer and metastatic disease. Further, many patients had failed other therapies, and these treated tumors may represent a more aggressive tumor biology. In addition, the use of other therapies in the patients treated with RFA confounds the analysis of efficacy of treatment with RFA. We also need longer follow-up to fully evaluate survival end

6 1606 PENNATHUR ET AL Ann Thorac Surg RADIOFREQUENCY ABLATION FOR LUNG NEOPLASM 2009;88: points. In addition, further prospective studies are required to definitively compare RFA with conventional external beam radiation treatment or other emerging technologies, such as stereotactic radiosurgery. Conclusions In summary, this study is a report on the use of CTguided radiofrequency ablation for the treatment of lung neoplasm in 100 consecutive patients by thoracic surgeons. There are several factors that should be investigated further including optimal patient selection and measures to improve local control of the tumor. Surgery remains the best treatment for resectable lung cancer; however, emerging technologies, such as RFA or stereotactic radiosurgery, may have a role in patients who are medically inoperable. Further prospective studies are necessary to define the role of RFA in the treatment of lung neoplasm. Image-guided RFA performed by the thoracic surgeons is feasible and safe in high-risk patients with lung neoplasm, with reasonable results in patients who are not fit for surgery. Thoracic surgeons can perform RFA safely, and should continue to investigate this new image-guided modality, which may offer an alternative option to medically inoperable patients. Thoracic surgeons should continue to evaluate new technologies and add these to their armamentarium in the treatment of lung neoplasm. This research was funded in part by the National Institutes of Health Specialized Program of Research Excellence in Lung Cancer (P50 CA090440), and in part by research grants from RITA Medical/Angiodynamics to the University of Pittsburgh. References 1. Ginsberg RJ, Martini N. Non small cell lung cancer/surgical management. In: Pearson FG, Cooper JD, Deslauriers J, Ginsberg RJ, Hiebert CA, Patterson GA, Urschel HC Jr, eds. Thoracic surgery, 2nd ed. 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7 Ann Thorac Surg PENNATHUR ET AL 2009;88: RADIOFREQUENCY ABLATION FOR LUNG NEOPLASM 1607 DISCUSSION DR HIRAN C. FERNANDO (Boston, MA): Arjun, that was a very nice presentation. I have a question about the pulmonary metastasis group. I know at the beginning when I was in Pittsburgh, we were treating the worst of the worst, such as patients who had already undergone prior resection of pulmonary metastases, as well as some large tumors that we know now are not suitable for ablation. It seems from your data that there is not that much difference in survival between the metastasis group and the primary lung cancer patients, yet other studies are now starting to show that the pulmonary metastasis group does better because presumably they are treating a younger patient group, and a lot of those patients are being treated primarily with RFA from the outset. I m just curious if you looked at the characteristics of the metastases group further, such as what was the mean size of the metastases, and whether they had any other previous interventions such as surgery. DR PENNATHUR: Thank you, Dr Fernando, for those comments. Yes, we did look into the metastatic group, and about 2 or 3 months ago we presented our experience primarily focusing on the metastatic group treated with CT-guided RFA and RFA used as an adjunct to surgical resection at the Southern Thoracic Surgical Association. This current series includes only the CTguided ablations, but, as you know, the way we handle some of the metastatic group patients is to sometimes use it also as an adjuvant to surgery when we do open resection and with several lesions in order to preserve lung parenchyma. In this particular series, broken down on the metastasis patients, we had a median survival of about 18 months. The 2-year probability of overall survival was 41%. It does represent, however, several categories. Colon cancer was the predominant category in this particular group of patients and represented almost a third of the patients. Again, more than one third of the patients have had prior therapy for their metastatic cancer, and in several of them we did RFA (radiofrequency ablation) in order to prevent the morbidity of a redo thoracotomy. As you pointed out 2 days ago in the symposium, this group of patients even if you do an open thoracotomy, palpate all the lesions, and resect them approximately 60% of them seem to recur, and it appears that this group of patients may be ideally suitable for RFA. Thank you for your comments. mortality directly related to the procedure of 3%, and I m not sure whether that prompted the FDA warning, because that was one of the articles quoted in the FDA warning. In terms of the discussion with our patients, we get a complete informed consent from all patients. We also have an approved IRB (institutional review board) protocol for performing CTguided RFA in our institution, and informed consent is obtained from all patients. Similarly, we also have a protocol for stereotactic radiosurgery, which is IRB-approved at our institution. Now, regarding the RTOG trial for operable patients, I do not know the details of that, but as far as I can see with the data from the United States, I don t see the data mature for us to go ahead with stereotactic radiosurgery in operable patients. I think we have got significant evidence of long-term results with surgery, and we just don t have that kind of result with stereotactic radiosurgery, and this is an area we are very interested in studying and evaluating the results. So our feeling is that this can be offered more to medically inoperable patients and also patients who refuse surgery. I think stereotactic radiosurgery can be offered as a Phase II trial, in those who refuse surgery, but I do not know the details of the RTOG trial. I think that it may be a Phase II trial for patients who refuse. I m not sure. With regard to RFA or stereotactic radiosurgery, these approaches can be complimentary, however, we do not have long term results of treatment from either modality in the United States and this is an area we are actively investigating. DR FRANK D. DETTERBECK (New Haven, CT): I enjoyed your presentation very much. I enjoyed your presentation yesterday very much on stereotactic radiosurgery as well. I m going to focus just on the primary lung cancer patients. It seems that in both of your presentations, the 5-year survival was actually relatively low compared to what we re used to with surgery, which would argue that perhaps this RTOG trial is a little bit premature. My question is this. With your experience with various modalities, if your uncle came to you and had very poor pulmonary function and was not a candidate for a lobectomy, what would you recommend, RFA, stereotactic radiosurgery, a sublobar resection, or, for that matter, are you sure that these modalities are actually better than the old standard of external beam radiotherapy? DR TODD L. DEMMY (Buffalo, NY): In light of the recent FDA (US Food and Drug Administration) warning regarding use of this technology and deaths and now the expanding use of stereotactic radiosurgery (in fact, there is now a Phase II RTOG (Radiation Therapy Oncology Group) protocol using stereotactic radiosurgery in resectable cases), how do we justify using RFA? How do you present using RFA for these types of patients who can t have resection? What are the things you discuss with the patient to justify its use over the stereotactic radiosurgery? Thank you. DR PENNATHUR: Thank you, Dr Demmy, for your comments. We have received the notification from the FDA, and also ACOSOG (American College of Surgeons Oncology Group) has given it to all the ACOSOG participating surgeons because we do have an ongoing RFA trial with ACOSOG. I m not sure what the data for the FDA is. Doctor Dupuy presented a series of 153 patients, out of which he had a reported procedure-related DR PENNATHUR: Thank you for your comments, Dr Detterbeck. I think my primary preference would be a sublobar resection if that s feasible, because I think the results of sublobar resection are, again, superior to the results of medically inoperable patients treated with RFA or stereotactic radiosurgery. Now, in terms of patient selection between radiofrequency ablation and stereotactic radiosurgery, we offer radiofrequency ablation for only peripheral tumors, not for central tumors. For central tumors we offer them stereotactic radiosurgery but at a reduced dose. We now are administering them 12 times 4, as I indicated yesterday. For the peripheral tumors, I think one can really choose between both those regimens, and many times it can be used in a complementary fashion. For example, if you decide to go to the RFA route, we would perform the RFA and at the same time place fiducials, so that if there is progression, which occurs in a fair amount of patients, we can then treat the patient with a different modality, such as stereotactic radiosurgery. So I think

8 1608 PENNATHUR ET AL Ann Thorac Surg RADIOFREQUENCY ABLATION FOR LUNG NEOPLASM 2009;88: that these two modalities can actually work in a complementary fashion. Thank you for your question and comments. DR JOE B. PUTNAM (Nashville, TN): I have a few questions and Dr Rocco has a question as well. Dr Pennathur, thank you so much for this nice presentation on radiofrequency ablation, Abstract No. 50, as well as your discussion of stereotactic radiosurgery in Abstract No. 17. What were the time periods involved and did they overlap? DR PENNATHUR: Yes, they did overlap. The time period for the radiofrequency ablation was over a 7-year period and the time period for the stereotactic radiosurgery was over a 4-year period. So we did have more patients per year in the time on the stereotactic group. DR PUTNAM: What was your selection criteria for your patients for this technique given the significant overlap between these two local-control modalities as well as the option for standard pulmonary resection surgery, other than location within the lung? DR PENNATHUR: We have two protocols, one for RFA and one for stereotactic radiosurgery, and one of the primary distinguishing features, of course, is the location of the tumor. I think beyond that, in terms of criteria for medical operability, they are quite similar, and similarly, patients who refuse surgery, we look at the images and we discuss with the patient what the options might be. So other than the location, I think the criteria for medical operability are quite similar. Other criteria which are used and considered by patients, include exposure to radiation, and women who are in the child-bearing age group. DR PUTNAM: In our current American College of Surgeons Oncology Group trial Z4033 evaluating radiofrequency ablation for local control and survival, we require an ACOSOG thoracic surgeon evaluate the patient for lobectomy or wedge resection prior to consideration for RFA. Did your selection criteria include evaluation by medical oncology and radiation oncology prior to treatment by either the radiofrequency ablation or the stereotactic radiosurgery? DR PENNATHUR: With the stereotactic radiosurgery protocol, evaluation by the thoracic surgeon is mandatory and so is evaluation by the radiation oncologists. Now, we have a multidisciplinary clinic wherein we discuss patients with medical oncology and several patients are presented also in tumor board, but it is not a part of the requirement in terms of enrolling in the protocol. We discuss all these cases with our oncologists, radiation oncologists before deciding on proceeding. DR PUTNAM: Thank you. You had 30% to 40% of patients with recurrent lung cancer. Were these patients evaluated by medical oncology before RFA? DR PENNATHUR: Yes. I think they were all seen also by medical oncology before subjecting them to RFA. It is important to point out that patients with recurrent lung cancer do represent a very complicated group of patients. About 3 years ago the Mayo Clinic presented a really nice series on recurrent lung cancers wherein they presented the results of about 390 patients with recurrent lung cancer after complete surgical resection, and surprisingly, and quite disappointingly, the median survival on these patients was just about 8 months, and patients who got surgically resected, a very select group, had a much improved survival, but if you don t treat them at all, their survival was the worst. I remember it was something like 8 months. So in this group of recurrent lung cancer patients where RFA formed a part of the treatment, their 2-year estimated survival was about 55%, which compares favorably to what has been reported in the literature, but certainly is not equal to surgical resection if that is feasible. DR PUTNAM: I want to commend the authors for a prospective protocol which was in place and that these patients were enrolled onto these therapies following informed consent for these specific types of local-control therapy. I believe this reflects a careful balance of the options available, and provides a basis for a subsequent appropriate evaluation of these localcontrol modalities for the stage and location of disease, particularly in high-risk patients. DR GAETANO ROCCO (Naples, Italy): Just expanding on the functional profile, how many of these medically inoperable patients were inoperable due to poor pulmonary function? You showed that your median FEV 1 (forced expiratory volume in 1 second) was 0.8. Many of us would think that most of these patients could in fact be operable from the standpoint of the pulmonary function tests. How many times did you use the V o 2 max, maximum oxygen consumption determination? And, lastly, what is the quality of life after radiofrequency ablation in your group of patients? DR PENNATHUR: Thank you, Dr Rocco. Those are all extremely relevant points. Yes, there are patients who have an FEV 1 of 0.8 who are in fact surgical candidates, at least for a wedge resection, and I think some people with upper lobe predominant emphysema, for example, and have a small focus of cancer in the upper lobe can benefit by lobectomy, and that was shown very nicely by a presentation in the Society about 4 or 5 years ago by the Washington University group. So there are some patients with poor PFTs (pulmonary function tests) that we do operate on, and that s why I think it is critical that these patients are evaluated by a thoracic surgeon before they are being declared as inoperable. The second question regarding the quality of life, in our prospective protocol, we are evaluating the quality of life, with validated questionnaires. We have not analyzed the data in terms of the quality of life yet, but that data is being prospectively collected as part of the prospective protocol. Thank you for your questions and comments. DR PUTNAM: I do want to emphasize the need for a multidisciplinary evaluation prior to the initiation of treatment in these patients. This discussion provides our patients with additional information and perspective on treatment options. As thoracic surgeons we must engage our medical oncologists, radiation oncologists, pulmonary medicine physicians, and others in an integrated approach to these very complex patients with local and locoregional disease. DR PENNATHUR: I would like to thank the Society for the opportunity to present this paper.