Despite recent medical advances, the prognosis of metastatic

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1 BRIEF REPORT A Novel Strategy for Treatment of Metastatic Pulmonary Tumors: Radiofrequency Ablation in Conjunction with Surgery Yoshifumi Sano, MD,* Susumu Kanazawa, MD, Hidefumi Mimura, MD, Hideo Gobara, MD, Takao Hiraki, MD, Hiroyasu Fujiwara, MD, Masaomi Yamane, MD,* Shinichi Toyooka, MD,* Takahiro Oto, MD,* and Hiroshi Date, MD* Introduction: Local treatment that includes surgical resection of metastatic pulmonary tumors is controversial because of the biologic features and invasiveness of these tumors. We report our experience with a premeditated treatment involving combined computed tomography-guided radiofrequency ablation and surgical resection in three patients with metastatic pulmonary tumors. Methods: Three patients underwent radiofrequency ablation in conjunction with surgical resection. The first was a 67-year-old man with pulmonary metastases of bronchial adenoid cystic carcinoma. We performed partial resection of five tumors in the right lung and ablated a tumor in the left lung. The second was a 66-year-old man with pulmonary metastases of renal cell carcinoma. He underwent radiofrequency ablation for three tumors in the right upper and middle lobes, and right lower lobectomy for tumors in that lobe. The third was a 55-year-old man with pulmonary metastases of highgrade sarcoma of the right thigh. We performed partial resection of five tumors in the left lung and ablated a tumor in the right lung. Results: Two patients had metastatic lesions on both sides of the lung; we performed surgical resection on one side and radiofrequency ablation contralaterally to avoid bilateral thoracotomy. The third patient underwent surgical resection and radiofrequency ablation to avoid highly invasive right pneumonectomy. All patients survived for more than years after combination therapy. Conclusions: Premeditated treatment involving a combination of radiofrequency ablation and surgical resection can be a useful option in patients with metastatic pulmonary tumors, improving curability and avoiding highly invasive procedures. Key Words: Metastasis, Radiofrequency Ablation, Surgery, Metastasectomy. (J Thorac Oncol. 2008;3: ) Despite recent medical advances, the prognosis of metastatic pulmonary tumors is still poor, perhaps because of their biologic features. Most pulmonary metastases arise from the hematogenous spread of malignant cells, and the lung is considered to be the first filter for malignant cells in most primary cancers. In selected patients, local treatment that includes surgical resection of these tumors is considered a controversial but acceptable option. Especially in nonsurgical candidates, treatment options are limited to chemotherapy with or without radiation therapy. Nevertheless, no effective chemotherapy regimen has been proposed for most metastatic pulmonary tumors, and therefore we must find alternative modalities. Since the early 1990s, percutaneous radiofrequency ablation (RFA) has been one of the more successful options for the treatment of solid malignant tumors in various organs, especially the liver, because of its minimal invasiveness. 1 6 RFA of pulmonary tumors was first reported in and has become a promising treatment option for patients who are not surgical candidates. We have treated patients with metastatic pulmonary tumors using a premeditated treatment involving RFA in conjunction with surgical resection, as there is potential for local control with these two modalities. In this article, we propose a new treatment option for metastatic pulmonary tumors. From the Departments of *Cancer and Thoracic Surgery and Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. There were no conflicts of interest and no commercial funding was used for this research. Address for correspondence: Yoshifumi Sano, MD, Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Shikata-cho, Okayama , Japan. ysano@md.okayama-u.ac.jp Copyright 2008 by the International Association for the Study of Lung Cancer ISSN: /08/ PATIENTS AND METHODS Percutaneous RFA was performed in patients with intrathoracic malignancies between June 2001 and April 2006 in Okayama University Hospital. The RFA technique has been described previously The study was conducted with the approval of our institutional Human Studies Committee on June 12, 2001, and written informed consent was obtained from all patients. In brief, RFA is usually performed under local anesthesia and sedation with intravenous fentanyl or epidural anesthesia, if necessary. Patients are monitored by continuous Journal of Thoracic Oncology Volume 3, Number 3, March

2 Sano et al. Journal of Thoracic Oncology Volume 3, Number 3, March 2008 pulse oximetry, electrocardiography, and blood pressure measurement. The placement of the radiofrequency electrode is confirmed by computed tomographic fluoroscopy. We usually use two types of electrodes coupled to a radiofrequency generator and a perfusion pump (Cool-tip RF system, 17-gauge internally cooled electrodes; Radionics/ValleyLab, Boulder, CO) or a LeVeen Needle Electrode (17-gauge multitined expandable electrodes with an RF 3000 generator; RadioTherapeutics Corp., Sunnyvale, CA, distributed by Boston Scientific, Natick, MA). The electric current was grounded by applying four grounding pads to the opposite chest wall. A total of 229 patients underwent 389 RFA sessions applied for 637 lesions. Of these 229 patients, 188 (82.1%) who received RFA had metastatic pulmonary lesions, whereas 41 (17.9%) had primary lung carcinomas. All patients were nonsurgical candidates because they were at high risk for surgery, or had refused surgery, or because of the extent of their disease. The hospital observation period after RFA was 24 hours for most patients without any complications. Three patients underwent RFA in conjunction with surgical resection in this series. The first patient, 67-year-old man, was diagnosed with bronchial adenoid cystic carcinoma and underwent sleeve resection of the bronchus in A metastatic tumor in the right lung was revealed on follow-up chest computed tomography (CT) in 1999, for which partial resection of the lung with adjuvant chemotherapy was performed. Approximately 1 year later, there was a new lesion in the left lung, and he underwent partial resection by video-assisted thoracic surgery. In 2003, six metastatic lung tumors on both sides were revealed on follow-up CT (five tumors on the right side and one on the left) (Figure 1A E1). Bone scintigraphy and magnetic resonance imaging of the brain revealed no other metastatic lesions. The patient was not considered a candidate for surgical resection in both lungs because of the extent of the disease and poor respiratory function because of his history of multiple pulmonary resections. Surgical resection of the five tumors in the right lung followed by percutaneous RFA for the tumor in the left lung was considered the best option for local tumor eradication. We performed partial resection of the five tumors in the right lung on August 15, 2003 and ablated the tumor in the left lung (left S8, mm) on September 9, 2003 (Figure 1E 2). Ablation was done three times using a Cool-tip electrode (total time 34 minutes, maximum power 117 W) under local anesthesia. The second patient, a 66-year-old man, was diagnosed with renal cell carcinoma after presenting with hematuria in August 1995; he underwent left nephrectomy in September His medical history included diabetes mellitus, hypertension, and arrhythmia. A chest radiograph taken during a check-up in September 2002 revealed a nodule in the right lung, which was biopsied and found to be a metastatic lesion from the renal cell carcinoma. He then received immunotherapy with interferon. In September 2004, a follow-up CT revealed metastatic tumors in the right lung (Figure 2A D). We considered it imperative for him to avoid right pneumonectomy, because of his comorbid conditions. Percutaneous RFA for three tumors in the right upper and middle lobes FIGURE 1. A 67-year-old man with pulmonary metastases from bronchial adenoid cystic carcinoma. A, B, C, D, E-1, CT scans of the chest show metastatic tumors in both lungs. E-2, CT scan obtained during radiofrequency ablation shows the position of the electrode in the tumor. 284 Copyright 2008 by the International Association for the Study of Lung Cancer

3 Journal of Thoracic Oncology Volume 3, Number 3, March 2008 Treatment of Metastatic Pulmonary Tumors The third patient was a 55-year-old man with a history of high-grade sarcoma of the right thigh that was treated with wide resection in August He received chemotherapy (ICE-T with interferon) and radiotherapy after the surgical procedure. In January 2006, a follow-up CT revealed six metastatic lung tumors (five on the left side and one on the right) (Figure 3), with no evidence of metastases in other organs. He also had a medical history of Von Recklinghausen disease (neurofibromatosis-1). We considered combined therapy with surgical resection and RFA because of the low invasiveness of this procedure. Thus, we performed partial resection of the five tumors in the left lung on February 6, 2006 and ablated a tumor in the right lung (S6, 5 5 mm) on February 22, 2006 (Figure 3A E-1). The ablation was done three times using a LeVeen electrode (total time 19 minutes, maximum power 25 W) under local anesthesia (Figure 3E-2). FIGURE 2. A 66-year-old man with pulmonary metastases from renal cell carcinoma. A C, CT scans of the chest obtained during radiofrequency ablation show the position of the electrode in three tumors in the right upper and middle lobes (right S1, S4, and S5). D, CT scan of the chest shows metastatic tumors in the right lower lobe. (right S1, S4, and S5) followed by surgical resection of tumors in the right lower lobe was thought to be the best option for local tumor eradication. In October 2004, we performed RFA for the three tumors in the right upper and middle lobes (Figure 2A C); in November 2004 we performed right lower lobectomy as complete resection, because the tumors extended to the right hilum (Figure 2D). The ablations were performed under local anesthesia as follows: for the S1 tumor (20 17 mm), Cool-tip electrode, total time 14 minutes, maximum power 60 W; for the S4 tumor (9 9 mm), LeVeen electrode, total time 9 minutes, maximum power 60 W; for the S5 tumor (24 18 mm), LeVeen electrode, total time 33 minutes, maximum power 90 W. RESULTS No pneumothoraces were seen in two of the patients after RFA, whereas the third patient developed a small pneumothorax that did not require treatment. No other complications or side effects (e.g., pleural effusion, pleurisy, relevant bleeding, high fever, and severe pain requiring medication) occurred during or after RFA in any of the three patients. There were also no complications or side effects after surgery and all of the patients returned to their normal daily activities. The first patient remained asymptomatic on clinical examination approximately 9 months after the RFA; however, contrast-enhanced CT revealed a right hilar lymph nodal swelling and regrowth with partial enhancement of the ablated tumor. Therefore, repeat RFA was performed in this region. Since the repeat RFA, he has been receiving chemotherapy (cisplatin S-1), and is alive with right hilar lymph node and pulmonary metastases approximately 4 years after the combination therapy, with no evidence of viability of the ablated tumor by contrast-enhanced CT scan. In the second patient, follow-up CT 3 months after the RFA showed three new metastatic tumors on both sides of the lungs, with no signs of progression of the ablated tumors. He underwent repeat RFA for these three tumors. CT done 5 months after the second RFA revealed some pleural dissemination in the right pleural cavity. He underwent embolization of the inferior phrenic arteries, and is alive with tumors approximately 1 year and 8 months after the combination therapy. The third patient is alive and well without any signs of recurrence or metastases detected by follow-up CT scans approximately 1 year and 6 months after the combination therapy. DISCUSSION In most patients with metastatic pulmonary disease, malignant cells are considered to disseminate in the bloodstream. In these circumstances, removing the tumors by local treatment such as surgical resection is usually not beneficial. Systemic therapies, such as chemotherapy, should be the treatment of first choice, but these are not usually effective in curing patients or prolonging their survival. For years, inves- Copyright 2008 by the International Association for the Study of Lung Cancer 285

4 Sano et al. Journal of Thoracic Oncology Volume 3, Number 3, March 2008 FIGURE 3. A 55-year-old man with pulmonary metastases of high-grade sarcoma of the right thigh. A, B, C, D, E-1, CT scans of the chest show metastatic tumors in both lungs. E-2, CT scan obtained during radiofrequency ablation shows the position of the electrode in the tumor. tigators have reported that surgical resection (metastasectomy) is a significant therapeutic option for metastatic pulmonary tumors, to improve long-term survival In 1965, Thomford et al. 15 originally reported the criteria for selecting patients for surgical resection of metastatic tumors in the lungs as follows 1 : the patient must be a good risk for surgical intervention 2 ; the primary malignancy is controlled 3 ; there is no evidence of metastatic disease elsewhere in the body; and 4 roentgenologic evidence of pulmonary metastasis is limited to one lung. These criteria have been accepted by many surgeons for years, though the indications have been expanded because of surgical and technological advances. For example, resection of multiple lesions or bilateral lesions remains controversial; however, it is acceptable to many surgeons. In this series, we encountered three patients who underwent combined therapy with surgical resection and RFA. Two cases had metastatic lesions in both lungs; we performed surgical resection on one side and RFA on the contralateral side to avoid highly invasive bilateral thoracotomy. We also came across a patient who underwent surgical resection of a string of tumors and RFA for a solitary tumor to avoid highly invasive right pneumonectomy. All of these patients survived more than 1 year after the combination therapy; however, two are alive with tumors. It appears to be important that the patients selected should be suitable for this therapeutic option. The most important factor to consider regarding local treatment for metastatic pulmonary tumors is whether curative local control is possible. It is believed that the strongest predictor of survival is completeness of resection, and that the greater the number of metastatic lesions, the lower the probability of complete resection. The Internal Registry of Lung Metastases, which was established in 1991 to assess the long-term results of pulmonary metastasectomy, has accrued 5206 cases. 16 The results confirm that metastasectomy is a potentially curative treatment that can be administered safely with low mortality. Consideration of resectability, disease-free interval, and the number of metastases enabled us to design a simple system of classification valid for different tumor types. It has been reported that surgical resection of pulmonary metastases from colorectal carcinoma, 17 renal cell carcinoma, 18 osteosarcoma, 19 soft tissue sarcoma, 11 hepatocellular carcinoma, 12 and breast carcinoma 20 can be beneficial even in patients with multiple pulmonary lesions. Use of surgical resection in patients with bilateral pulmonary metastases is also controversial because of the invasiveness of bilateral thoracotomy. Several studies have reported that patients with pulmonary metastasis limited to one lung have a better prognosis than those with both lungs affected 21 ; however, some studies have found no difference in 286 Copyright 2008 by the International Association for the Study of Lung Cancer

5 Journal of Thoracic Oncology Volume 3, Number 3, March 2008 Treatment of Metastatic Pulmonary Tumors survival among patients with unilateral or bilateral metastases. 11,13,17,22 These findings suggest that percutaneous RFA may play a useful role in selected patients with pulmonary metastases, especially because it avoids the need for bilateral thoracotomy. In patients with larger pulmonary tumors, RFA did not seem to be effective. In fact, 70% of patients with lesions of 3 cm succumbed to their disease within the first 14 months. 23 We previously reported that greater tumor size was an independent risk factor for local progression of ablated tumors. 9 In contrast, with RFA the size of pulmonary metastases is usually not prognostic for survival after surgical resection. Therefore, the risk of failure of lung RFA needs to be considered in patients with large pulmonary lesions. In addition, some lesions were adjacent to large vessels or bronchi, which produce a heat sink effect by decreasing thermal energy. 24,25 This phenomenon seems to protect these vessels or bronchi from heat injury, and at the same time prevents perivascular or peribronchiolar tissue necrosis. When considering strategies for local control of metastatic pulmonary tumors, we need to know their advantages and disadvantages. The advantages and disadvantages of surgical resection and RFA are summarized in Table 1. RFA and stereotactic radiotherapy have been accepted as alternative therapeutic tools for treating unresectable pulmonary malignancies. Moreover, stereotactic radiotherapy is a novel modality that not only overcomes certain limitations imposed by standard radiation therapy but also permits delivery of higher radiation doses to the target lung tumor. The incidence of complications and success rates does not differ greatly in patients treated with percutaneous RFA or stereotactic radiotherapy for unresectable pulmonary malignancies 26 ; however, no consensus exists for the preferential use of either of the therapeutic modalities. As both modalities have advantages as well as disadvantages, their comparison should be evaluated by means of randomized controlled studies. Another combined local therapy using two different modalities that included RFA was reported recently. Dupuy and colleagues demonstrated a potential benefit of percutaneous RFA followed by radiotherapy in patients with inoperable stage I or II non-small cell lung cancer. 27,28 They suggested that the combination therapy might improve the likelihood of local control. We also consider this combination therapy to be useful in increasing the local control rate in large pulmonary lesions. TABLE 1. Comparison Between Features of Radiofrequency Ablation and Surgical Resection Radiofrequency Ablation Resection Local control Inferior Superior Invasiveness Low High Repeated procedure Easy Difficult Therapeutic range Small Large Number of treatable tumors Limited Unlimited Tumor location Mid-peripheral Hilar-peripheral Lymph node dissection Impossible Possible CONCLUSIONS If the advantages and disadvantages of RFA and surgical resection are understood, combination therapy with these modalities can become a useful option in selected patients with metastatic pulmonary tumors, improving curability and avoiding highly invasive procedures. REFERENCES 1. Brown DB. Concepts, considerations, and concerns on the cutting edge of radiofrequency ablation. J Vasc Interv Radiol 2005;16: Gillams AR. The use of radiofrequency in cancer. Br J Cancer 2005; 92: Sutherland LM, Williams JA, Padbury RT, et al. Radiofrequency ablation of liver tumors: a systematic review. 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6 Sano et al. Journal of Thoracic Oncology Volume 3, Number 3, March 2008 pulmonary metastases from colorectal carcinoma: prognostic determinants for survival. Ann Surg Oncol 2006;13: Lu DS, Raman SS, Vodopich DJ, et al. Effect of vessel size on creation of hepatic radiofrequency lesions in pigs: assessment of the heat sink effect. AJR Am J Roentgenol 2002;178: Steinke K, Haghighi KS, Wulf S, et al. Effect of vessel diameter on the creation of ovine lung radiofrequency lesions in vivo: preliminary results. J Surg Res 2005;124: Timmerman RD, Kavanagh BD, Cho LC, et al. Stereotactic body radiation therapy in multiple organ sites. J Clin Oncol 2007;10:25: Dupuy DE, DiPetrillo T, Gandhi S, et al. Radiofrequency ablation followed by conventional radiotherapy for medically inoperable stage I non-small cell lung cancer. Chest 2006;129: Grieco CA, Simon CJ, Mayo-Smith WW, et al. Percutaneous imageguided thermal ablation and radiation therapy: outcomes of combined treatment for 41 patients with inoperable stage I/II non-small-cell lung cancer. J Vasc Interv Radiol 2006;17: Copyright 2008 by the International Association for the Study of Lung Cancer