Percutaneous CT-Guided Radiofrequency Ablation as Supplemental Therapy After Systemic Chemotherapy for Selected Advanced Non Small Cell Lung Cancers

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1 Vascular and Interventional Radiology Original Research Li et al. Vascular and Interventional Radiology Original Research Xishan Li 1 Ming Zhao 1 Jianpeng Wang 2 Weijun Fan 1 Wang Li 1 Tao Pan 1 Peihong Wu 1 Li X, Zhao M, Wang J, et al. Keywords: chemotherapy, non small cell lung cancer, radiofrequency ablation, supplemental therapy DOI: /AJR Received December 18, 2012; accepted after revision March 8, This work was supported by the Sciences and Technology Committee of Guangdong Province (grant 2011B ). 1 Minimally Invasive Interventional Division and Medical Imaging Center, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, 651 Dongfeng Rd East, Guangzhou , P. R. China. Address correspondence to M. Zhao (zhaoming@sysucc.org.cn). 2 Minimally Invasive Interventional and Target Treatment Division and Cancer Center, The First People s Hospital of Foshan City, The Affiliated Foshan Hospital of Sun Yat-sen University, Chancheng District, Foshan, P. R. China. AJR 2013; 201: X/13/ American Roentgen Ray Society Percutaneous CT-Guided Radiofrequency Ablation as Supplemental Therapy After Systemic Chemotherapy for Selected Advanced Non Small Cell Lung Cancers OBJECTIVE. The purpose of this study is to evaluate the safety and efficacy of percutaneous CT-guided radiofrequency ablation (RFA) as a supplemental therapy after systemic chemotherapy for selected patients with advanced non small cell lung cancer (NSCLC). MATERIALS AND METHODS. We retrospectively reviewed the medical records of 220 patients with advanced NSCLC who were treated with platinum-doublet chemotherapy between January 2000 and January Among them, 49 patients underwent RFA as a supplemental therapy for tumors in partial response or stable diseases after first-line chemotherapy. The progression-free survival (PFS) was evaluated by Kaplan-Meier method. RESULTS. There were nine women and 40 men (median age, 60 years; range, years), including 28 patients with stage IIIb cancer and 21 with stage IV cancer. All 49 patients (partial response, 23 patients; stable disease, 26 patients) underwent 67 RFA sessions for 61 targeted tumors after systemic chemotherapy. There were no procedure-related deaths. Pneumothorax requiring chest tubes developed in eight sessions (11.9%). Thirty-one patients (63.3%) had complete response, 12 patients (24.5%) had partial response, six patients (12.2%) had stable disease, and no patients had progressive disease. The median follow-up period was 19 months (range, 6 34), and the median PFS was 16 weeks (95% CI, ). CONCLUSION. Percutaneous CT-guided RFA can be performed as a feasible minimally invasive supplemental therapy with satisfactory PFS after systemic chemotherapy for patients L ung cancer is the leading contributor to new cancer diagnoses and to cancer-related deaths worldwide [1]. Non small cell lung cancer (NSCLC) represents more than 85% of cases of lung cancer and accounts for most of the patients with comorbid disease or advanced stages at the time of initial diagnosis [2]. Four or six cycles of platinum-doublet chemotherapy are recommended as the first-line treatment for patients with advanced disease, resulting in response or stable disease rates of 70 80% and median overall survival (OS) of 8 12 months [3, 4], whereas most patients experience progressive disease within 2 4 months of the final chemotherapy cycle [5 7]. Efforts have focused on prolonging progression-free survival (PFS) by administering well-tolerated maintenance therapy in patients who attained tumor control after first-line chemotherapy [8, 9]. Several large randomized clinical trials have suggested that pemetrexed, erlotinib, and gefitinib used as maintenance agents can improve the PFS for selected pa- tients [6, 10 12]. However, histologic subtype or epidermal growth factor receptor (EGFR) immunohistochemistry mutation status and the adverse events related to the maintenance treatment make these agents most beneficial for special kinds of advanced NSCLC, and the disease, for the most part, still will have a dismal outcome. Radiofrequency ablation (RFA), a minimally invasive procedure, has been widely used as a viable alternative or complementary treatment option for patients with unresectable pulmonary malignancies [13 17]. The rates of complete in situ tumor necrosis achieved by RFA in lung tumors ranged from 38% to 97% (median, 90%), with a median PFS of 21 months [15]. The high local control rate, together with its characteristics of minimal invasiveness and repeatability, allow RFA to maximize coagulative necrosis of the targeted lesion and to minimize the damage to the surrounding normal pulmonary parenchyma. Furthermore, the efficacy of RFA is not affected by tumor histologic profile or 1362 AJR:201, December 2013

2 gene mutation status [15]. Several studies have described the synergistic effect of combination chemotherapy and RFA in treating NSCLC, and the efficacy is better than that for either treatment therapy alone [18]. All these advantages make RFA a feasible therapeutic option after systemic chemotherapy to eliminate residual tumors, to decrease the risk of chemoresistant tumor recurrence, and, ultimately, to improve PFS. RFA can be introduced as a supplemental therapy, which plays a role like that of maintenance therapy with cytotoxic or molecular-targeted agents. Some advances have been made in the RFA technique, and, because it is minimally invasive, it has been widely used clinically; however, few studies using this technique as a supplemental therapy for advanced NSCLC have been published. In this article, we retrospectively analyze our experiences with CTguided RFA for patients whose disease had not progressed after four or six cycles of chemotherapy and we evaluate the role of RFA as a supplemental therapy in treating patients Materials and Methods Patients This study was approved by the institutional review board. Written informed consent was obtained from all patients before treatment. Forty-nine patients with advanced NSCLC (nine women and 40 men; median age, 60 years; age range, years) were analyzed between January 2000 and January A total of 61 targeted tumors (mean longest diameter, 29 mm; range, mm) were treated in 67 CT-guided RFA sessions after four or six cycles of first-line chemotherapy. Patients with measurable lung tumors (with partial response or stable disease) were introduced to RFA by a multidisciplinary team comprising surgical oncologists, medical oncologists, radiation oncologists, anesthetist, and interventional oncologists. Specific inclusion criteria consisted of histologically or cytologically confirmed NSCLC, selected advanced (stage IIIb and IV) diseases, distant lung metastases controlled without progression, Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, completion of four or six cycles of platinum-doublet chemotherapy with tumors in partial response or stable diseases, the presence of at least one measurable tumor lesion, and choice of RFA as a supplemental therapy made by the patient and a multidisciplinary tumor board according to a risk-benefit analysis in patients. The exclusion criteria were maximum tumor diameter greater than 5.0 cm; more than three lesions; lesions located immediately adjacent (distance, 1.0 cm) to the pulmonary hilum, major bronchi, or major pulmonary vessels; and bleeding disorders not responding to medical treatment. The details of patient and tumor characteristics are presented in Table 1. Treatment Schedule Chemotherapy regimens Chemotherapy regimens were all platinum-doublet regimens that included cisplatin (75 80 mg/m 2 IV on day 1) plus vinorelbine (Navelbine; mg/m 2 IV on days 1 and 8) for a 3-week cycle (n = 12); cisplatin (75 mg/m 2 IV on day 1) plus gemcitabine (1250 mg/m 2 IV on days 1 and 8) for a 3-week cycle (n = 9); cisplatin (75 mg/m 2 IV on day 1) plus docetaxel (75 mg/m 2 IV on day 1) for a 3-week cycle (n = 10); and cisplatin (75 mg/m 2 IV on day 1) plus pemetrexed (500 mg/ m 2 IV on day 1) for a 3-week cycle for nonsquamous NSCLC (n = 18). Systemic chemotherapy was administered until disease progression or the patient developed intolerance to the treatment. The efficacy of systemic chemotherapy was assessed at every two cycles by revised Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) [19]. Patients with partial response or stable disease were introduced to RFA after multidisciplinary consultation. RFA procedure All the patients fasted for 12 hours. The RFA procedure was performed in a hospital CT room by two experienced interventional oncologists, an anesthetist, a technician, and a nurse. All the procedures were performed under a combination of local anesthesia and IV conscious sedation Complete Response Intense follow-up Advanced NSCLC Four or six cycles of chemotherapy Partial Response CT-guided RFA with ECG, blood pressure, and saturation of blood oxygen monitoring during the whole procedure. RFA was administered using two different radiofrequency systems and needle electrodes: a monopolar electrode system (Cool-Tip, Valleylab) under an impedance-control algorithm with an internally cooled electrode (17 gauge, 1.5-mm diameter, and a 3.0-cm exposed metallic active portion) and a multitined deployable electrode system (RITA Starburst XL, RITA Medical Systems) under a temperature-controlled algorithm with an umbrella-shaped electrode (16 gauge, 1.7-mm diameter, and an effective ablation area of 4.0 cm at full expansion). The type of device and electrode used was dependent on commercial availability and on the size of the target tumor. The electrode was carefully introduced into the optimal locations at a predetermined angle in a stepwise manner under CT guidance. The power settings and exposure times were selected according to the standard recommendations provided by the manufacturers of the equipment used and according to the experience of previous tumor RFA procedures [20, 21]. The process was targeted to achieve an overlapping ablative margin that would theoretically include the tumor and cm of surrounding tissue to eradicate microscopic foci of disease. In each treatment, tract ablation to prevent possible tumor seeding or tract bleeding was performed before the electrode was withdrawn. After ablation, an additional CT scan was performed for postprocedure surveillance, which showed no evidence of complications. A multidisciplinary tumor board Evaluated by RECIST 1.1 Stable Disease Four weeks later evaluated by modified RECIST Progressive Disease Complete Response Partial Response Stable Disease Progressive Disease Surveillance Additional RFA Second-line chemotherapy, molecularly targeted agent, or palliative treatment Fig. 1 Flowchart showing treatment algorithm used for patients with advanced non small cell lung cancer (NSCLC) in present study. RECIST = Response Evaluation Criteria in Solid Tumors, RFA = radiofrequency ablation. AJR:201, December

3 Li et al. TABLE 1: Univariate Analysis by Log-Rank Test for Prognostic Clinicopathologic and Procedure-Related Factors for Progression-Free Survival (PFS) Characteristic No. (%) of Patients Median PFS (Weeks) p Sex Male 40 (81.6) 16 Female 9 (18.4) 20 Age (y) (63.3) 17 > (36.7) 16 Smoking history < Never-smoker 22 (44.9) 21 Smoker 27 (55.1) 14 ECOG performance status < (14.3) (79.6) (6.1) 12 Histologic subtype Squamous cell carcinoma 20 (40.8) 16 Adenocarcinoma 26 (53.1) 17 Others 3 (6.1) 14 Stage IIIb 28 (57.1) 21 IV 21 (42.9) 14 Response to previous chemotherapy Partial response 23 (46.9) 16 Stable disease 26 (53.1) 17 Measurable tumor at first RFA Distribution Unilateral 31 (63.3) 20 Bilateral 18 (36.7) 14 Location Central 6 (12.2) 14 Peripheral 43 (87.8) 17 Maximum diameter (cm) (61.2) (38.8) 14 Number of tumors < (85.7) 17 > 1 7 (14.3) 14 Response to initial RFA < Complete response 31 (63.3) 21 Partial response 12 (24.5) 14 Stable disease 6 (12.2) 12 Progressive disease 0 0 Note ECOG = Eastern Cooperative Oncology Group, RFA = radiofrequency ablation. Assessment and Follow-Up The follow-up evaluations were performed at 1, 3, 6, 9, and 12 months after ablation and at 6-month intervals thereafter with radiologic and clinical examinations. The follow-up radiologic examinations were mainly contrast-enhanced three-phase CT scans. Additional examinations, such as PET/ CT scans, were performed to further evaluate the results if the CT scan and tumor marker analyses were insufficient for diagnosis, such as in the case of a local suspicious relapse or possible extrapulmonary metastasis. The target tumor s response to RFA was evaluated by use of the modified RECIST, as described elsewhere [17, 22, 23]. Additional RFA was performed for patients with a partial response or stable disease response to RFA. During the whole study, patients with a complete response after treatment were intensely followed up. For patients with progressive disease after the last RFA session, second-line chemotherapy with a molecular-targeted agent or palliative treatments were performed according to the recommendation of a multidisciplinary evaluation on the basis of a risk-benefit analysis in patients (more details are shown in Fig. 1). Statistical Analysis Follow-up was calculated from the date of last RFA session to the date of the last follow-up. PFS was defined as the time from the day of the last RFA session to the time of recurrence or detection of a newly metastatic lesion, or death for any reason (recorded according to the first event). OS was calculated from the first day of diagnosis to either the day of death from any cause or the last follow-up. The PFS and OS were estimated with the Kaplan-Meier method. Univariate analysis (log-rank) was performed to determine the prognostic factors for PFS. Multivariate analysis was performed on all factors with p less than 0.10 by using the Cox proportional hazards regression model. Because of the heterogeneity of the follow-up treatments after the progression of the disease, the prognostic factors associated with OS were not analyzed in this study. All analyses were performed using SPSS software (version 16.0, SPSS). A p value of 0.05 or less was considered statistically significant. Results Complications No death was related to the RFA procedure. The major complication was symptomatic pneumothorax requiring chest tube placement, which occurred in eight of 67 (11.9%) RFA sessions. Minor complications (19.4% [13/67]), including self-limited minor pneumothorax, slight cough, a low-grade fever ( 38.5 C), and local pain at the puncture site, were well tolerated and easily controlled AJR:201, December 2013

4 Local Efficacy Patients successfully underwent 67 RFA sessions after systemic chemotherapy. Thirty-six sessions were performed with a multitined deployable electrode system, and 31 were performed with a monopolar electrode system. At 1-month follow-up after initial RFA, 31 patients (63.3%) had a complete response, 12 patents (24.5%) had a partial response, six patients (12.2%) had stable disease, and no patients had progressive disease. For patients with partial response and stable disease, RFA was repeated. Survival During the median follow-up period after the last lung RFA session of 19 months (range, 6 34 months), 41 (83.7%) patients died and eight (16.3%) patients were still alive. The causes of death were intrapulmonary progression (n = 21), adrenal metastasis (n = 2), bone metastasis (n = 5), brain metastasis (n = 4), multiple systemic (more than two organs) metastases (n = 6), respiratory failure (n = 1), and pneumonia (n = 2). For all intention-totreat patients, the median PFS and OS were 16 weeks (95% CI, ) and 14 months (95% CI, 13 15), respectively. Factors associated with PFS identified through univariate analysis are shown in Table 1. From the multivariate analysis, ECOG performance status (hazard ratio, 2.545; 95% CI, ; p = 0.030) and response to treatment (hazard ratio, 7.244; 95% CI, ; p < ) were independent predictors for PFS (details are shown in Table 2 and Fig. 2). TABLE 2: Cox Regression Multivariate Analysis (Method = Enter) of Prognostic Factors for Progression-Free Survival (PFS) Discussion The current standard first-line therapy for advanced NSCLC is four or six cycles of platinum-based chemotherapy [4]. Although 70 80% of patients who undergo chemotherapy receive clinical benefits in terms of response or stable disease, the PFS and OS profile remains poor. For decades, the standard of care was a watch-and-wait approach after initial therapy, and then patients with NSCLC with a good performance status were offered second-line treatment at progression of disease. To date, accumulated evidence has shown that maintenance therapy with either a continuous or a switch strategy is a beneficial treatment with improved PFS ( months) [6, 11, 12, 24]. However, evidence from the SATURN study [11] shows that erlotinib has a better PFS for patients with an activating EGFR mutation status, and the PARAMOUNT study [6] emphasizes that pemetrexed is more approved for use in the nonsquamous subset on the basis of its efficacy and PFS, which might limit the benefit of maintenance therapy for selected patients RFA has been accepted as a therapeutic option, with safety, feasibility, and anticancer efficacy, for patients with NSCLC who are not candidates for curative surgical resection [13 16]. In previous studies [18], improved local disease control and increased survival rate were observed when combined chemotherapy and RFA were used for treating NSCLC. Lee et al. [18] reported that the median survival times for patients with NSCLC (stage III to IV) treated with chemotherapy and RFA, chemotherapy alone, and RFA alone were 42, 29, and 13.6 months, respectively, which indicated that RFA followed by conventional chemotherapy is feasible as a sequential therapy PFS Rate (%) Factors p < Time (wk) ECOG performance status censored censored censored A for patients However, there are no reports about RFA playing a role as a maintenance therapy after systemic chemotherapy in patients with advanced NSCLC. In our study, the survival benefit was preceded by delaying tumor progression, with PFS of 16 weeks, which is consistent with the reported maintenance therapeutic agents of months. These promising results indicate that the therapeutic efficacy of RFA is a feasible therapeutic option as a supplemental therapy after systemic chemotherapy in advanced NSCLC. In the analysis of factors associated with PFS and OS, ECOG performance status and response to RFA were correlated with PFS outcome. Patients with ECOG performance status 0 and complete response to RFA may benefit from RFA during the supplemental therapy period. There were no variables that PFS Rate (%) p < Time (wk) Response Complete Response Partial Response Stable Disease CR-censored PR-censored SD-censored Fig. 2 Univariate analysis (log-rank) was performed to determine prognostic factors for progression-free survival (PFS). A, Log-rank analysis of PFS stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (p < ). B, Log-rank analysis of PFS stratified according to response to radiofrequency ablation (p < ). PFS HR 95% CI p Never-smoker vs smoker ECOG performance status, 0 vs 1 vs Stage, IIIb vs IV Distribution, unilateral vs bilateral Maximum diameter, 3 vs 3~5 cm Number, 1 vs > Response to initial RFA, CR vs PR vs SD vs PD < B AJR:201, December

5 Li et al. could predict for OS. Hence, it appears that RFA may be useful in decreasing the rate of tumor recurrence and progression and then improving the PFS outcomes, but as a monotherapy, it may not be sufficient to achieve satisfactory OS. This finding reiterates the importance of combining RFA with systemic therapies to improve survival in patients with advanced NSCLC. RFA may have several theoretic advantages as a supplemental therapy after systemic chemotherapy in patients First, RFA induced coagulation necrosis and cell death destruction of the centrally located hypoxic tumor, which is typically less responsive to chemotherapy. Second, as shown in our study, the cytoreduction induced by RFA eradicates the viable tumor cells without damage to the surrounding nontumoral lung parenchyma and without the toxicity caused by cytotoxic or molecular-targeted agents used in maintenance therapy. Third, RFA can enhance the therapeutic effectiveness of second-line chemotherapy for patients with tumor progression. Studies have shown that tumor volume was associated with local control and OS of patients treated with chemotherapy [25]. RFA can induce in situ thermal injury of the bulky tumor mass with coagulation necrosis, which can produce a chemotherapy-sensitizing effect in the second-line chemotherapy courses. Several studies have proven the synergistic effect of the combination of RFA and chemotherapy [18, 26 28]. In addition, the efficacy of RFA in NSCLC is irrespective of EGFR mutation status or histologic subtype [15], which has much broader applications. Finally, RFA can eradicate in situ the residual tumor after systemic chemotherapy with satisfactory PFS, which, in the biopsychosocial medical model, is easier for patients to accept. Percutaneous CT-guided RFA is a safe procedure. The most commonly reported complication after RFA was pneumothorax, which was mainly encountered in elderly patients with chronic obstructive pulmonary disease, with an incidence of about % [15, 29]. Most cases of pneumothorax were selflimiting, and only % (median, 11%) of cases required chest drain insertion. Symptomatic pneumothorax can be easily handled with closed pleural cavity drainage for less than 24 hours (range, 1 3 days). Less common complications, including chest pain and postoperative fever, are tolerable and easily resolved. In the current study, procedure-related complications were infrequent; the most frequent major complication was pneumothorax in ablating lung lesions larger than 3.0 cm, and the incidence was similar to those reported in previous studies [15, 29]. Other reported procedure-related complications, such as pneumonia, hemorrhage, and tumor seeding along the needle tract, were not observed in this study. On the basis of our preliminary results, we consider RFA a safe and well-tolerated procedure in the treatment of NSCLC as a supplemental therapy after systemic chemotherapy. Patients who have contraindications to cytotoxic or molecular-targeted maintenance therapy, or who are unable to tolerate the adverse events, or who are unwilling to receive these treatments could be recommended to undergo the RFA procedure. Our study has some potential limitations. First, this is a retrospective study with a small sample size, which limits the value of the findings, although the preliminary results show that RFA as a supplemental therapy is a safe therapeutic option with promising long-term PFS for advanced NSCLC. Because RFA has rarely been reported as a supplemental therapy after four or six cycles of first-line chemotherapy for advanced NSCLC clinically, we think that those promising outcomes will add to the evidence-based medicine in this field and contribute to the conduct of prospective studies with larger samples to further validate the efficacy. Second, limited by our strict matching criteria, we could not do matched-pair analysis for RFA and conventional cytotoxic or moleculartargeted agents. However, RFA would appear from our experience to be a promising alternative to conventional maintenance therapeutic agents for selected patients with advanced NSCLC. Third, we used two commercially available RFA systems, and all treatments were performed according to the manufacturer s recommended protocol. As a retrospective study, it was hard to collect completely related data and to analyze the differing efficacies between the two systems. 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