CLINICAL STUDY
Radiofrequency Ablation for Ground-Glass Opacity– Dominant Lung Adenocarcinoma Hiroshi Kodama, MD, Koichiro Yamakado, MD, PhD, Takaaki Hasegawa, MD, Motoshi Takao, MD, PhD, Osamu Taguchi, MD, PhD, Ichiro Fukai, MD, PhD, and Hajime Sakuma, MD, PhD
ABSTRACT Purpose: To evaluate retrospectively the clinical utility of lung radiofrequency (RF) ablation for the treatment of ground-glass opacity (GGO)–dominant lung adenocarcinoma. Materials and Methods: From August 2004 through May 2012, 33 consecutive patients (14 men and 19 women; mean age, 71.1 y; age range, 46–84 y) with 42 lung tumors having Z 50% GGO component received lung RF ablation. The mean maximum tumor diameter was 1.6 cm ⫾ 0.9 (range, 0.7–4.0 cm). Feasibility, safety, local tumor progression, and survival were evaluated. Results: For the 42 RF sessions, after RF electrodes were placed in each target tumor, planned ablation protocols were completed in all sessions (100%; 42 of 42). No deaths related to the RF procedure occurred. Major and minor complication rates were 4.8% and 23.8%, respectively. Local tumor progression developed in 6 tumors (14.3%; 6 of 42) during a mean follow-up of 42 months ⫾ 23 (range, 5–92 mo). Four of six tumors with local progression were controlled by repeated RF ablation. No evidence of disease was achieved in 31 of 33 patients (93.9%) at the end of the follow-up period. All but one patient (who died of brain hemorrhage) are alive today. Overall and cancer-specific survival rates were 100% and 100% at 1 year, 96.4% (95% confidence interval [CI], 77.5%–99.5%) and 100% at 3 years, and 96.4% (95% CI, 77.5%–99.5%) and 100% at 5 years, respectively. Conclusions: Lung RF ablation is a feasible, safe, and useful therapeutic option to control GGO-dominant lung adenocarcinoma.
ABBREVIATIONS CI = confidence interval, GGO = ground-glass opacity
Lung cancer is the leading cause of death among all cancers in many countries (1). Lobectomy is the “gold standard” treatment for early-stage non–small cell lung cancer rather than sublobar resection because of high local recurrence or poor prognosis (2–5). However, clinical behavior varies depending on the histologic type, and good prognosis is expected with a 5-year survival
From the Departments of Radiology (H.K., K.Y., T.H., H.S.), Thoracic Surgery (M.T.), Internal Medicine (O.T.), Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; and Department of Respiratory Surgery (I.F.), Suzuka Central General Hospital, Suzuka, Japan. Received July 30, 2013; final revision received and accepted November 27, 2013. Address correspondence to H.K.; E-mail: [email protected] None of the authors have identified a conflict of interest. & SIR, 2014 J Vasc Interv Radiol 2014; 25:333–339 http://dx.doi.org/10.1016/j.jvir.2013.11.035
rate of around 100% even after sublobar resection when a tumor has a wide area of ground-glass opacity (GGO) (6–8). Limited surgery could be an alternative to lobectomy to treat GGO-dominant lung adenocarcinoma. However, GGO-dominant lung adenocarcinomas manifest as multifocal with an incidence of 25%, making it difficult to design a surgical strategy (9). Radiofrequency (RF) ablation has been used for the treatment of lung cancer in nonsurgical candidates. Many studies have demonstrated the clinical usefulness of RF ablation in controlling not only non–small cell lung cancer but also lung metastases (10,11). RF ablation is less invasive than surgery and repeatable. It is applicable to multiple lung tumors (12). However, few studies have been undertaken to evaluate the clinical utility of RF ablation in treating GGO-dominant lung adenocarcinoma. We retrospectively evaluate the clinical utility of RF ablation for the treatment of GGOdominant lung adenocarcinoma.
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MATERIALS AND METHODS Study Design This retrospective study was approved by our institutional review board. The necessity of informed consent for inclusion in this study was waived. Informed consent to perform lung RF ablation was obtained from all patients.
Patients During August 2004 through May 2012, 33 consecutive patients with GGO-dominant primary lung cancer received curative lung RF ablation. Lung RF ablation was performed because of poor pulmonary function and difficulty in performing repeat surgery in 18 postoperative patients, comorbid cardiopulmonary diseases in 11 patients, and refusal of surgical intervention in 4 patients. Inclusion criteria to perform lung RF ablation at our institution were the following: tumor size of r 5 cm, tumors numbering five or fewer, not abutting large vessels or the lung hilum, no uncontrolled extrapulmonary metastasis, no abnormal coagulability, and Eastern Cooperative Oncology Group performance status of 0 or 1. A GGO-dominant tumor was defined as a tumor with a GGO component in Z 50% on computed tomography (CT) images (13). Patient demographic information is presented in Table 1. This study included 14 men and 19 women with a mean age of 71.1 ⫾ 10.4 years (range, 46– 84 y). Lung RF ablation was the initial treatment for lung tumors in 9 patients (27.3%; 9 of 33). RF ablation was performed after one or two GGO-dominant adenocarcinomas were resected (hybrid surgery) in 7 patients with multiple tumors (21.2%; 7 of 33). It was used for the treatment of recurrent or metachronous lung tumors 1.3–8.0 years after surgery (mean, 3.2 ⫾ 2.3 y) in 17 patients (51.5%; 17 of 33). No patients received concurrent therapy with lung RF ablation including chemotherapy or radiation therapy. Lung tumors were multiple at the time of lung RF ablation in 6 patients (13.2%; 6 of 33), 1 initially treated patient and 5 postoperative patients. In consideration of the complete history of the patients, two or more lung adenocarcinomas developed in 25 patients (75.8%; 25 of 33). There were 42 lung tumors with mean maximum tumor diameter of 1.6 cm ⫾ 0.9 (range, 0.7–4.0 cm) treated. Of tumors, 20 tumors had a GGO component alone (pure GGO), and 22 tumors had both GGO (4 50%) and solid components. The diagnosis of lung adenocarcinoma was made by percutaneous lung biopsy in 23 patients (69.7%; 23 of 33). In the other 10 patients who had undergone surgery for GGO-dominant adenocarcinoma before, diagnosis was made by serial followup CT findings that were compatible for GGO-dominant lung cancer. GGO was defined as hazy opacity that does not obscure associated pulmonary vessels on CT images with a lung window setting (window width, 1,700 HU;
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Table 1 . Patient Demographic Information at the Time of Radiofrequency Ablation Age (y) Mean ⫾ SD r 65 4 65 Gender Male Female Previous surgery No Yes Maximum tumor diameter (cm) Mean ⫾ SD r2 42 No. tumors
71.1 ⫾ 10.4 10 (30.3%) 23 (69.7%) 14 (42.4%) 19 (57.6%) 9 (27.3%) 24 (72.7%) 1.6 ⫾ 0.9 27 (81.8%) 6 (19.2%)
Mean ⫾ SD
1.3 ⫾ 0.5
Single Multiple
28 (84.8%) 5 (15.2%)
CT finding GGO with solid component Pure GGO
19 (57.6%) 14 (42.4%)
Histologic proof of adenocarcinoma Yes No Total
23 (69.7%) 10 (30.3%) 33
CT ¼ computed tomography; GGO ¼ ground-glass opacity; SD ¼ standard deviation.
window level, 700 HU). The percentage area of GGO was measured by two expert chest diagnostic radiologists (S.M. and K.Y., each with approximately 22 years of experience) at the maximal slice of the lesions. Among the 23 patients who underwent percutaneous lung biopsy, the tumor was diagnosed as bronchoalveolar carcinoma in 10 patients (43.5%; 10 of 23). Before lung RF ablation in all patients, routine physical examination; laboratory tests; pulmonary function tests; and imaging studies (chest radiograph; chest, abdominal, and pelvic CT scans; and brain magnetic resonance imaging with and without contrast enhancement) were performed.
Lung RF Ablation Lung RF ablation was performed by three interventional radiologists with approximately 22 years, 20 years, and 10 years of experience in oncologic interventional radiology under moderate sedation and local anesthesia on an inpatient basis. Fentanyl citrate (Fentanest; Daiichi Sankyo Co Ltd, Tokyo, Japan) was used for analgesia, and lidocaine (Xylocaine; Astellas Pharma Inc, Tokyo, Japan) was used for local anesthesia. Cefazolin (Cefamezine; Astellas Pharma Inc) were administered prophylactically before and for 2 days after RF ablation. Real-time CT fluoroscopy (Asteion; Toshiba Corp, Otawara, Japan) was used to place the internally cooled
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electrodes (Cool-tip RF ablation system; Covidien, Boulder, Colorado) in the tumor. The electrode was placed in the center of the tumor when the tumor was r 2 cm. The electrode was placed sequentially at two or three different sites in the tumor based on the tumor size and shape when the tumor was 4 2 cm. After the electrode was connected with the generator (Series CC-1; Covidien), RF energy was applied with 20 W power. The power output was increased continuously in increments of 10 W at 1-minute intervals until the generator stopped delivering RF energy three times attributable to a Z 20 Ω impedance increase of the ablated tissue from the baseline, or 12 minutes at each site of the tumor (Fig 1a–d).
Technical Success and Technique Effectiveness When RF electrodes were placed at the planned sites of each tumor and RF ablation was completed according
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to the planned protocol, the procedure was defined as technically successful (technical success) (14). Initial therapeutic response was evaluated by CT images acquired 2–5 days after RF ablation. Full coverage of treated tumors by ablative zone of GGO was regarded as constituting technique effectiveness (14). When the tumor was not covered completely with the ablative zone, repeat RF ablation was performed 1 week later.
Follow-up Follow-up was closed at the time of death or the last visit of the patient until November 2012. Patients were followed by three interventional radiologists, one thoracic surgeon (M.T.), and one respiratory internist (O.T.). Routine physical examination, laboratory tests, and measurement of carcinoembryonic antigen levels were conducted every month, along with chest, abdominal, and pelvic CT scans with and without contrast enhancement every 3–4 months.
Figure 1. A 61-year-old woman underwent left lung segmentectomy for minimally invasive adenocarcinoma. On follow-up CT scan, GGO-dominant lung adenocarcinoma measuring 7 mm (arrow) appeared at the upper right lobe (a). In consideration of poor cardiopulmonary function, lung RF ablation was performed (arrow) (b), and the tumor was covered by the ablative zone (arrowheads) (c). Follow-up CT scan at 5 years revealed that the tumor was well controlled (arrowhead) (d).
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Local tumor progression was defined as appearance of enlarging GGO or nodule on CT images around the ablated tumor. Local tumor progression was treated again by lung RF ablation when the recurrent tumor met the inclusion criteria for lung RF ablation. Tumor recurrence other than local tumor progression was defined as distant metastasis.
Complications Complications were assessed based on the number of ablation sessions and defined based on Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03; National Institutes of Health, National Cancer Institute). Any patient death within 30 days of image-guided tumor ablation was addressed (grade 5 adverse event). Grade 3 or 4 adverse events were defined as major complications, and grade 1 or 2 adverse events were defined as minor complications. The complication rate was calculated based on the RF session.
Assessment and Statistical Analysis Technical success, technique effectiveness, and local tumor progression rates were evaluated based on the tumor. Survival was calculated from the time of lung RF ablation. Cumulative overall and cancer-specific survival and local tumor progression curves were generated using the Kaplan-Meier method. Statistical analyses were performed using software (SPSS for Windows, version 15; SPSS Japan Inc, Tokyo, Japan).
RESULTS
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consisted of a pneumothorax requiring chest tube placement in all.
Tumor Recurrence During a mean follow-up of 42 months ⫾ 23 (range, 5– 92 mo), tumor recurrence was found in 10 patients (30.3%; 10 of 33); local tumor progression was found in 4 patients (12.1%; 4 of 33), both local tumor progression and distant metastasis were found in 2 patients (6.1%; 2 of 33), and distant metastasis was found in 4 patients (12.1%; 4 of 33) (Table 2). Six tumors (14.3%; 6 of 42) in 6 patients (18.2%; 6 of 33) showed local tumor progression 16–44 months after RF ablation (mean, 30 ⫾ 10 mo). All recurrent tumors appeared as GGO on CT images. The local tumor progression rates were 0% at 1 year, 15.1% (95% confidence interval [CI], 1.1%–29.0%) at 3 years, and 24.5% (95% CI, 7.0%– 42.0%) at 5 years (Fig 2). There was no significant difference in local tumor progression rates between the two patient groups with and without histologic proof. The rates were 0% and 0% at 1 year, 14.3% (95% CI, 4.8%–38.3%) and 14.3% (95% CI, 2.2%–66.4%) at 3 years, and 21.4% (95% CI, 2.2%–40.7%) and 28.6% Table 2 . Patterns of Tumor Recurrence No. Local tumor progression
4
Local tumor progression with lung metastasis Local tumor progression with brain metastasis
1 1
Lung metastasis
3
Bone metastasis with pleural dissemination Total
1 10
Feasibility and Safety For 42 tumors, 42 RF sessions were performed (1.0 RF sessions/tumor). RF electrodes were placed into planned sites, and ablation was completed with planned protocol in all tumors. The technical success rate was 100% (42 of 42). In some instances, it was difficult to evaluate whether ablative zones completely covered tumors because both tumors and ablative zones had GGO character (15). In such cases, technical effectiveness was evaluated by referencing the anatomic landmark such as vessels. Ablative zones covered 36 tumors (85.7%; 36 of 42) entirely after initial RF ablation. The other six tumors were also fully covered by ablative zones after the second RF ablation. The technique effectiveness rate was 100% (42 of 42). No deaths related to the RF ablation procedure occurred (grade 5 adverse event, 0%; 0 of 42). Major complications (grade 3 adverse event) occurred in two RF sessions (4.8%; 2 of 42): pneumothorax requiring pleurosclerosis in one session and pleural effusion requiring chest tube placement in the other session. Minor complications (grade 1 or 2 adverse events) were encountered in 10 of 42 (23.8%) RF sessions and
Figure 2. Cumulative initial and secondary local tumor progression rate. Local tumor progression developed in 6 of 42 tumors (14.3%). The primary local tumor progression rates were 0% at 1 year, 15.1% (95% CI, 1.1%–29.0%) at 3 years, and 24.5% (95% CI, 7.0%–42.0%) at 5 years. Four of the six tumors with local tumor progression were controlled by repeat RF ablation, and treated tumors were well controlled in 93.9% (31 of 33) of patients.
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(95% CI, 8.0%–73.4%) at 5 years (P ¼ .98). Repeat RF ablation was performed for 4 of 6 tumors with local progression (67.7%; 4 of 6) in 4 patients (67.7%; 4 of 6), although the other 2 patients declined further treatments. Four ablated tumors were controlled. At the end of follow-up, 40 of 42 treated tumors (95.2%; 40 of 42) had been controlled in 31 patients (93.9%; 31 of 33). Distant metastasis developed in the lung in 4 patients (12.1%; 4 of 33), in the brain in 1 patient (3.0%; 1 of 33), and in both the rib and the pleura in 1 patient (3.0%; 1 of 33). Lung metastases were treated by RF ablation in three patients and by resection in one patient. Stereotactic radiosurgery was performed for brain metastasis, and chemotherapy was administered for bone metastasis with pleural dissemination in each patient. At the end of the follow-up period, 28 patients (84.8%; 28 of 33) were alive with no evidence of disease (Fig 3).
Survival One patient died of brain hemorrhage 16 months after lung RF ablation (3.0%; 1 of 33). The 1-year, 3-year, and 5-year overall survival rates were 100%, 96.4% (95% CI, 77.5%–99.5%), and 96.4% (95% CI, 77.5%–99.5%) in all patients. Overall survival rates were 100% at 1 year, 95.2% (95% CI, 69.3%–99.3%) at 3 years, and 95.2% (95% CI,
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69.3%–99.3%) at 5 years in 23 patients with histologically proven adenocarcinoma. All 1-year, 3-year, and 5-year overall survival rates were 100% in the 10 patients without histologic proof of adenocarcinoma. No patient died of lung cancer progression. All 1-year, 3-year, and 5-year cancer-specific survival rates were 100% regardless of the histologic proof of adenocarcinoma.
DISCUSSION Results suggest that lung RF ablation is a safe and useful therapeutic option for the treatment of GGO-dominant primary lung cancer. A GGO lesion is a hazy opacity and less visible on CT fluoroscopic images compared with solid tumor. However, it was feasible to place the RF electrode at the planned site similar to CT fluoroscopic guided lung biopsy for GGO lesions (16). GGOdominant tumors contain more air, so there might be a concern about anticancer effects of RF ablation because of less electrical conductivity than solid tumors. However, all of the tumors were ablated completely according to the planned protocol, and the technique effectiveness rate achieved in this study (100%) was identical to rates achieved in solid lung tumors (75%–92%) (11,17,18). Incidence and types of complications seen in this study
Figure 3. Outcomes after treatment. After lung RF ablation, 10 patients (30.3%; 10 of 33) experienced tumor recurrence. Among them, recurrent tumor was well controlled by RF ablation or surgical treatment in 6 patients (60.0%; 6 of 10). Four patients (40.0%; 4 of 10) were alive with disease under treatment or declined any other treatment after treatment. One patient died of another disease. At the end of follow-up, 28 patients (84.8%; 28 of 33) were alive with no evidence of disease. BSC ¼ best supportive care; RFA ¼ radiofrequency ablation; SRS, stereotactic radiosurgery.
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were identical to those after RF ablation of solid lung tumors (19). Local tumor progression after lung RF ablation was found in 14.3% (6 of 42) of treated GGO-dominant tumors in this study. Although the frequency of local tumor progression was equal to that of solid tumors (15%–30%), time to local tumor progression appeared to be longer in GGO-dominant tumors (16–44 mo) than in solid tumors (12–14 mo) (12,20–22). The slow-growing nature of GGO-dominant adenocarcinoma seems to be attributable to this difference (23). The local tumor progression rate may be underestimated, given the fact that it is difficult to differentiate the ablation zone and the tumor margins. Careful long-term follow-up of ablated tumors is necessary. Good local tumor control is known to engender favorable outcomes in patients with lung cancers regardless of initially treated cancer or postoperative recurrent tumors (20–22). In addition to strong anticancer effects, repeatability appears to be one salient benefit of lung RF ablation. About 70% (67.7%; 4 of 6) of tumors with local progression were treated by RF ablation again, achieving no evidence of disease in 4 90% of patients at the end of the follow-up period of 4 3 years (42 mo ⫾ 23). This study revealed the same 5-year overall and cancer-specific survival rates (96.4% and 100%) as reported after sublobar resection (24,25). An advantage of surgical intervention is nodal sampling and dissection (26). Although systematic nodal dissection engenders longer survival in patients with non–small cell lung cancer (27,28), nodal metastasis develops rarely in patients with GGO-dominant adenocarcinomas. Suzuki et al (6) showed a lower incidence of nodal metastasis in patients with GGO-dominant adenocarcinomas compared with patients with adenocarcinomas containing less GGO component (o 50%) (0.1% vs 19.7%, P o .001). Nodal recurrence was not found in this study. Given less incidence of nodal metastasis and multifocal characteristics, patients with GGO-dominant lung adenocarcinoma might be good candidates for lung RF ablation. However, application of lung RF ablation does not exclude surgical intervention. The use of RF ablation might expand the indication for hybrid surgery. In this study, six patients received RF ablation after surgical intervention as hybrid surgery. However, distant metastasis occurred in 18% of the patients (6 of 33), including some patients (33%; 3 of 9) with pure GGO lung adenocarcinoma. Given that pure GGO lung adenocarcinoma seldom develops distant metastasis (29), new lesions might be metachronous lung cancers, although it is difficult to distinguish them. The higher incidence of distant recurrence might be attributed to the patient population in this study; at the time of RF ablation, 4 70% of patients eventually developed multiple tumors. Periodic follow-up examinations should be conducted, just as they are with dominant lung cancer.
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This study has some limitations. First, it is a retrospective study. Second, the study comprised a small number of patients. Third, we did not perform lung biopsy in all patients. Fourth, the follow-up duration might be short to address GGO-dominant lesions. Despite these limitations, these encouraging results suggest a useful framework for future prospective studies. In conclusion, lung RF ablation is a safe and effective treatment for patients with GGO-dominant lung cancer.
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20. Angeletti CA, Mussi A, Janni A, et al. Second primary lung cancer and relapse: treatment and follow-up. Eur J Cardiothorac Surg 1995; 9: 607–611. 21. De Ruysscher D, Wanders R, van Baardwijk A, et al. Radical treatment of non-small-cell lung cancer patients with synchronous oligometastases: long-term results of a prospective phase II trial (Nct01282450). J Thorac Oncol 2012; 7:1547–1555. 22. Pfannschmidt J, Dienemann H. Surgical treatment of oligometastatic non-small cell lung cancer. Lung Cancer 2010; 69:251–258. 23. Oda S, Awai K, Murao K, et al. Volume-doubling time of pulmonary nodules with ground glass opacity at multidetector CT: assessment with computer-aided three-dimensional volumetry. Acad Radiol 2011; 18: 63–69. 24. Arenberg D. Bronchioloalveolar lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007; 132:306S–313S.
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Radiofrequency Ablation for Ground-Glass Opacity– Dominant Lung Adenocarcinoma Hiroshi Kodama, MD, Koichiro Yamakado, MD, PhD, Takaaki Hasegawa, MD, Motoshi Takao, MD, PhD, Osamu Taguchi, MD, PhD, Ichiro Fukai, MD, PhD, and Hajime Sakuma, MD, PhD
ABSTRACT Purpose: To evaluate retrospectively the clinical utility of lung radiofrequency (RF) ablation for the treatment of ground-glass opacity (GGO)–dominant lung adenocarcinoma. Materials and Methods: From August 2004 through May 2012, 33 consecutive patients (14 men and 19 women; mean age, 71.1 y; age range, 46–84 y) with 42 lung tumors having Z 50% GGO component received lung RF ablation. The mean maximum tumor diameter was 1.6 cm ⫾ 0.9 (range, 0.7–4.0 cm). Feasibility, safety, local tumor progression, and survival were evaluated. Results: For the 42 RF sessions, after RF electrodes were placed in each target tumor, planned ablation protocols were completed in all sessions (100%; 42 of 42). No deaths related to the RF procedure occurred. Major and minor complication rates were 4.8% and 23.8%, respectively. Local tumor progression developed in 6 tumors (14.3%; 6 of 42) during a mean follow-up of 42 months ⫾ 23 (range, 5–92 mo). Four of six tumors with local progression were controlled by repeated RF ablation. No evidence of disease was achieved in 31 of 33 patients (93.9%) at the end of the follow-up period. All but one patient (who died of brain hemorrhage) are alive today. Overall and cancer-specific survival rates were 100% and 100% at 1 year, 96.4% (95% confidence interval [CI], 77.5%–99.5%) and 100% at 3 years, and 96.4% (95% CI, 77.5%–99.5%) and 100% at 5 years, respectively. Conclusions: Lung RF ablation is a feasible, safe, and useful therapeutic option to control GGO-dominant lung adenocarcinoma.
ABBREVIATIONS CI = confidence interval, GGO = ground-glass opacity
Lung cancer is the leading cause of death among all cancers in many countries (1). Lobectomy is the “gold standard” treatment for early-stage non–small cell lung cancer rather than sublobar resection because of high local recurrence or poor prognosis (2–5). However, clinical behavior varies depending on the histologic type, and good prognosis is expected with a 5-year survival
From the Departments of Radiology (H.K., K.Y., T.H., H.S.), Thoracic Surgery (M.T.), Internal Medicine (O.T.), Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; and Department of Respiratory Surgery (I.F.), Suzuka Central General Hospital, Suzuka, Japan. Received July 30, 2013; final revision received and accepted November 27, 2013. Address correspondence to H.K.; E-mail: [email protected] None of the authors have identified a conflict of interest. & SIR, 2014 J Vasc Interv Radiol 2014; 25:333–339 http://dx.doi.org/10.1016/j.jvir.2013.11.035
rate of around 100% even after sublobar resection when a tumor has a wide area of ground-glass opacity (GGO) (6–8). Limited surgery could be an alternative to lobectomy to treat GGO-dominant lung adenocarcinoma. However, GGO-dominant lung adenocarcinomas manifest as multifocal with an incidence of 25%, making it difficult to design a surgical strategy (9). Radiofrequency (RF) ablation has been used for the treatment of lung cancer in nonsurgical candidates. Many studies have demonstrated the clinical usefulness of RF ablation in controlling not only non–small cell lung cancer but also lung metastases (10,11). RF ablation is less invasive than surgery and repeatable. It is applicable to multiple lung tumors (12). However, few studies have been undertaken to evaluate the clinical utility of RF ablation in treating GGO-dominant lung adenocarcinoma. We retrospectively evaluate the clinical utility of RF ablation for the treatment of GGOdominant lung adenocarcinoma.
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RF Ablation for GGO-Dominant Lung Adenocarcinoma
MATERIALS AND METHODS Study Design This retrospective study was approved by our institutional review board. The necessity of informed consent for inclusion in this study was waived. Informed consent to perform lung RF ablation was obtained from all patients.
Patients During August 2004 through May 2012, 33 consecutive patients with GGO-dominant primary lung cancer received curative lung RF ablation. Lung RF ablation was performed because of poor pulmonary function and difficulty in performing repeat surgery in 18 postoperative patients, comorbid cardiopulmonary diseases in 11 patients, and refusal of surgical intervention in 4 patients. Inclusion criteria to perform lung RF ablation at our institution were the following: tumor size of r 5 cm, tumors numbering five or fewer, not abutting large vessels or the lung hilum, no uncontrolled extrapulmonary metastasis, no abnormal coagulability, and Eastern Cooperative Oncology Group performance status of 0 or 1. A GGO-dominant tumor was defined as a tumor with a GGO component in Z 50% on computed tomography (CT) images (13). Patient demographic information is presented in Table 1. This study included 14 men and 19 women with a mean age of 71.1 ⫾ 10.4 years (range, 46– 84 y). Lung RF ablation was the initial treatment for lung tumors in 9 patients (27.3%; 9 of 33). RF ablation was performed after one or two GGO-dominant adenocarcinomas were resected (hybrid surgery) in 7 patients with multiple tumors (21.2%; 7 of 33). It was used for the treatment of recurrent or metachronous lung tumors 1.3–8.0 years after surgery (mean, 3.2 ⫾ 2.3 y) in 17 patients (51.5%; 17 of 33). No patients received concurrent therapy with lung RF ablation including chemotherapy or radiation therapy. Lung tumors were multiple at the time of lung RF ablation in 6 patients (13.2%; 6 of 33), 1 initially treated patient and 5 postoperative patients. In consideration of the complete history of the patients, two or more lung adenocarcinomas developed in 25 patients (75.8%; 25 of 33). There were 42 lung tumors with mean maximum tumor diameter of 1.6 cm ⫾ 0.9 (range, 0.7–4.0 cm) treated. Of tumors, 20 tumors had a GGO component alone (pure GGO), and 22 tumors had both GGO (4 50%) and solid components. The diagnosis of lung adenocarcinoma was made by percutaneous lung biopsy in 23 patients (69.7%; 23 of 33). In the other 10 patients who had undergone surgery for GGO-dominant adenocarcinoma before, diagnosis was made by serial followup CT findings that were compatible for GGO-dominant lung cancer. GGO was defined as hazy opacity that does not obscure associated pulmonary vessels on CT images with a lung window setting (window width, 1,700 HU;
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Table 1 . Patient Demographic Information at the Time of Radiofrequency Ablation Age (y) Mean ⫾ SD r 65 4 65 Gender Male Female Previous surgery No Yes Maximum tumor diameter (cm) Mean ⫾ SD r2 42 No. tumors
71.1 ⫾ 10.4 10 (30.3%) 23 (69.7%) 14 (42.4%) 19 (57.6%) 9 (27.3%) 24 (72.7%) 1.6 ⫾ 0.9 27 (81.8%) 6 (19.2%)
Mean ⫾ SD
1.3 ⫾ 0.5
Single Multiple
28 (84.8%) 5 (15.2%)
CT finding GGO with solid component Pure GGO
19 (57.6%) 14 (42.4%)
Histologic proof of adenocarcinoma Yes No Total
23 (69.7%) 10 (30.3%) 33
CT ¼ computed tomography; GGO ¼ ground-glass opacity; SD ¼ standard deviation.
window level, 700 HU). The percentage area of GGO was measured by two expert chest diagnostic radiologists (S.M. and K.Y., each with approximately 22 years of experience) at the maximal slice of the lesions. Among the 23 patients who underwent percutaneous lung biopsy, the tumor was diagnosed as bronchoalveolar carcinoma in 10 patients (43.5%; 10 of 23). Before lung RF ablation in all patients, routine physical examination; laboratory tests; pulmonary function tests; and imaging studies (chest radiograph; chest, abdominal, and pelvic CT scans; and brain magnetic resonance imaging with and without contrast enhancement) were performed.
Lung RF Ablation Lung RF ablation was performed by three interventional radiologists with approximately 22 years, 20 years, and 10 years of experience in oncologic interventional radiology under moderate sedation and local anesthesia on an inpatient basis. Fentanyl citrate (Fentanest; Daiichi Sankyo Co Ltd, Tokyo, Japan) was used for analgesia, and lidocaine (Xylocaine; Astellas Pharma Inc, Tokyo, Japan) was used for local anesthesia. Cefazolin (Cefamezine; Astellas Pharma Inc) were administered prophylactically before and for 2 days after RF ablation. Real-time CT fluoroscopy (Asteion; Toshiba Corp, Otawara, Japan) was used to place the internally cooled
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electrodes (Cool-tip RF ablation system; Covidien, Boulder, Colorado) in the tumor. The electrode was placed in the center of the tumor when the tumor was r 2 cm. The electrode was placed sequentially at two or three different sites in the tumor based on the tumor size and shape when the tumor was 4 2 cm. After the electrode was connected with the generator (Series CC-1; Covidien), RF energy was applied with 20 W power. The power output was increased continuously in increments of 10 W at 1-minute intervals until the generator stopped delivering RF energy three times attributable to a Z 20 Ω impedance increase of the ablated tissue from the baseline, or 12 minutes at each site of the tumor (Fig 1a–d).
Technical Success and Technique Effectiveness When RF electrodes were placed at the planned sites of each tumor and RF ablation was completed according
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to the planned protocol, the procedure was defined as technically successful (technical success) (14). Initial therapeutic response was evaluated by CT images acquired 2–5 days after RF ablation. Full coverage of treated tumors by ablative zone of GGO was regarded as constituting technique effectiveness (14). When the tumor was not covered completely with the ablative zone, repeat RF ablation was performed 1 week later.
Follow-up Follow-up was closed at the time of death or the last visit of the patient until November 2012. Patients were followed by three interventional radiologists, one thoracic surgeon (M.T.), and one respiratory internist (O.T.). Routine physical examination, laboratory tests, and measurement of carcinoembryonic antigen levels were conducted every month, along with chest, abdominal, and pelvic CT scans with and without contrast enhancement every 3–4 months.
Figure 1. A 61-year-old woman underwent left lung segmentectomy for minimally invasive adenocarcinoma. On follow-up CT scan, GGO-dominant lung adenocarcinoma measuring 7 mm (arrow) appeared at the upper right lobe (a). In consideration of poor cardiopulmonary function, lung RF ablation was performed (arrow) (b), and the tumor was covered by the ablative zone (arrowheads) (c). Follow-up CT scan at 5 years revealed that the tumor was well controlled (arrowhead) (d).
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Local tumor progression was defined as appearance of enlarging GGO or nodule on CT images around the ablated tumor. Local tumor progression was treated again by lung RF ablation when the recurrent tumor met the inclusion criteria for lung RF ablation. Tumor recurrence other than local tumor progression was defined as distant metastasis.
Complications Complications were assessed based on the number of ablation sessions and defined based on Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03; National Institutes of Health, National Cancer Institute). Any patient death within 30 days of image-guided tumor ablation was addressed (grade 5 adverse event). Grade 3 or 4 adverse events were defined as major complications, and grade 1 or 2 adverse events were defined as minor complications. The complication rate was calculated based on the RF session.
Assessment and Statistical Analysis Technical success, technique effectiveness, and local tumor progression rates were evaluated based on the tumor. Survival was calculated from the time of lung RF ablation. Cumulative overall and cancer-specific survival and local tumor progression curves were generated using the Kaplan-Meier method. Statistical analyses were performed using software (SPSS for Windows, version 15; SPSS Japan Inc, Tokyo, Japan).
RESULTS
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consisted of a pneumothorax requiring chest tube placement in all.
Tumor Recurrence During a mean follow-up of 42 months ⫾ 23 (range, 5– 92 mo), tumor recurrence was found in 10 patients (30.3%; 10 of 33); local tumor progression was found in 4 patients (12.1%; 4 of 33), both local tumor progression and distant metastasis were found in 2 patients (6.1%; 2 of 33), and distant metastasis was found in 4 patients (12.1%; 4 of 33) (Table 2). Six tumors (14.3%; 6 of 42) in 6 patients (18.2%; 6 of 33) showed local tumor progression 16–44 months after RF ablation (mean, 30 ⫾ 10 mo). All recurrent tumors appeared as GGO on CT images. The local tumor progression rates were 0% at 1 year, 15.1% (95% confidence interval [CI], 1.1%–29.0%) at 3 years, and 24.5% (95% CI, 7.0%– 42.0%) at 5 years (Fig 2). There was no significant difference in local tumor progression rates between the two patient groups with and without histologic proof. The rates were 0% and 0% at 1 year, 14.3% (95% CI, 4.8%–38.3%) and 14.3% (95% CI, 2.2%–66.4%) at 3 years, and 21.4% (95% CI, 2.2%–40.7%) and 28.6% Table 2 . Patterns of Tumor Recurrence No. Local tumor progression
4
Local tumor progression with lung metastasis Local tumor progression with brain metastasis
1 1
Lung metastasis
3
Bone metastasis with pleural dissemination Total
1 10
Feasibility and Safety For 42 tumors, 42 RF sessions were performed (1.0 RF sessions/tumor). RF electrodes were placed into planned sites, and ablation was completed with planned protocol in all tumors. The technical success rate was 100% (42 of 42). In some instances, it was difficult to evaluate whether ablative zones completely covered tumors because both tumors and ablative zones had GGO character (15). In such cases, technical effectiveness was evaluated by referencing the anatomic landmark such as vessels. Ablative zones covered 36 tumors (85.7%; 36 of 42) entirely after initial RF ablation. The other six tumors were also fully covered by ablative zones after the second RF ablation. The technique effectiveness rate was 100% (42 of 42). No deaths related to the RF ablation procedure occurred (grade 5 adverse event, 0%; 0 of 42). Major complications (grade 3 adverse event) occurred in two RF sessions (4.8%; 2 of 42): pneumothorax requiring pleurosclerosis in one session and pleural effusion requiring chest tube placement in the other session. Minor complications (grade 1 or 2 adverse events) were encountered in 10 of 42 (23.8%) RF sessions and
Figure 2. Cumulative initial and secondary local tumor progression rate. Local tumor progression developed in 6 of 42 tumors (14.3%). The primary local tumor progression rates were 0% at 1 year, 15.1% (95% CI, 1.1%–29.0%) at 3 years, and 24.5% (95% CI, 7.0%–42.0%) at 5 years. Four of the six tumors with local tumor progression were controlled by repeat RF ablation, and treated tumors were well controlled in 93.9% (31 of 33) of patients.
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(95% CI, 8.0%–73.4%) at 5 years (P ¼ .98). Repeat RF ablation was performed for 4 of 6 tumors with local progression (67.7%; 4 of 6) in 4 patients (67.7%; 4 of 6), although the other 2 patients declined further treatments. Four ablated tumors were controlled. At the end of follow-up, 40 of 42 treated tumors (95.2%; 40 of 42) had been controlled in 31 patients (93.9%; 31 of 33). Distant metastasis developed in the lung in 4 patients (12.1%; 4 of 33), in the brain in 1 patient (3.0%; 1 of 33), and in both the rib and the pleura in 1 patient (3.0%; 1 of 33). Lung metastases were treated by RF ablation in three patients and by resection in one patient. Stereotactic radiosurgery was performed for brain metastasis, and chemotherapy was administered for bone metastasis with pleural dissemination in each patient. At the end of the follow-up period, 28 patients (84.8%; 28 of 33) were alive with no evidence of disease (Fig 3).
Survival One patient died of brain hemorrhage 16 months after lung RF ablation (3.0%; 1 of 33). The 1-year, 3-year, and 5-year overall survival rates were 100%, 96.4% (95% CI, 77.5%–99.5%), and 96.4% (95% CI, 77.5%–99.5%) in all patients. Overall survival rates were 100% at 1 year, 95.2% (95% CI, 69.3%–99.3%) at 3 years, and 95.2% (95% CI,
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69.3%–99.3%) at 5 years in 23 patients with histologically proven adenocarcinoma. All 1-year, 3-year, and 5-year overall survival rates were 100% in the 10 patients without histologic proof of adenocarcinoma. No patient died of lung cancer progression. All 1-year, 3-year, and 5-year cancer-specific survival rates were 100% regardless of the histologic proof of adenocarcinoma.
DISCUSSION Results suggest that lung RF ablation is a safe and useful therapeutic option for the treatment of GGO-dominant primary lung cancer. A GGO lesion is a hazy opacity and less visible on CT fluoroscopic images compared with solid tumor. However, it was feasible to place the RF electrode at the planned site similar to CT fluoroscopic guided lung biopsy for GGO lesions (16). GGOdominant tumors contain more air, so there might be a concern about anticancer effects of RF ablation because of less electrical conductivity than solid tumors. However, all of the tumors were ablated completely according to the planned protocol, and the technique effectiveness rate achieved in this study (100%) was identical to rates achieved in solid lung tumors (75%–92%) (11,17,18). Incidence and types of complications seen in this study
Figure 3. Outcomes after treatment. After lung RF ablation, 10 patients (30.3%; 10 of 33) experienced tumor recurrence. Among them, recurrent tumor was well controlled by RF ablation or surgical treatment in 6 patients (60.0%; 6 of 10). Four patients (40.0%; 4 of 10) were alive with disease under treatment or declined any other treatment after treatment. One patient died of another disease. At the end of follow-up, 28 patients (84.8%; 28 of 33) were alive with no evidence of disease. BSC ¼ best supportive care; RFA ¼ radiofrequency ablation; SRS, stereotactic radiosurgery.
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were identical to those after RF ablation of solid lung tumors (19). Local tumor progression after lung RF ablation was found in 14.3% (6 of 42) of treated GGO-dominant tumors in this study. Although the frequency of local tumor progression was equal to that of solid tumors (15%–30%), time to local tumor progression appeared to be longer in GGO-dominant tumors (16–44 mo) than in solid tumors (12–14 mo) (12,20–22). The slow-growing nature of GGO-dominant adenocarcinoma seems to be attributable to this difference (23). The local tumor progression rate may be underestimated, given the fact that it is difficult to differentiate the ablation zone and the tumor margins. Careful long-term follow-up of ablated tumors is necessary. Good local tumor control is known to engender favorable outcomes in patients with lung cancers regardless of initially treated cancer or postoperative recurrent tumors (20–22). In addition to strong anticancer effects, repeatability appears to be one salient benefit of lung RF ablation. About 70% (67.7%; 4 of 6) of tumors with local progression were treated by RF ablation again, achieving no evidence of disease in 4 90% of patients at the end of the follow-up period of 4 3 years (42 mo ⫾ 23). This study revealed the same 5-year overall and cancer-specific survival rates (96.4% and 100%) as reported after sublobar resection (24,25). An advantage of surgical intervention is nodal sampling and dissection (26). Although systematic nodal dissection engenders longer survival in patients with non–small cell lung cancer (27,28), nodal metastasis develops rarely in patients with GGO-dominant adenocarcinomas. Suzuki et al (6) showed a lower incidence of nodal metastasis in patients with GGO-dominant adenocarcinomas compared with patients with adenocarcinomas containing less GGO component (o 50%) (0.1% vs 19.7%, P o .001). Nodal recurrence was not found in this study. Given less incidence of nodal metastasis and multifocal characteristics, patients with GGO-dominant lung adenocarcinoma might be good candidates for lung RF ablation. However, application of lung RF ablation does not exclude surgical intervention. The use of RF ablation might expand the indication for hybrid surgery. In this study, six patients received RF ablation after surgical intervention as hybrid surgery. However, distant metastasis occurred in 18% of the patients (6 of 33), including some patients (33%; 3 of 9) with pure GGO lung adenocarcinoma. Given that pure GGO lung adenocarcinoma seldom develops distant metastasis (29), new lesions might be metachronous lung cancers, although it is difficult to distinguish them. The higher incidence of distant recurrence might be attributed to the patient population in this study; at the time of RF ablation, 4 70% of patients eventually developed multiple tumors. Periodic follow-up examinations should be conducted, just as they are with dominant lung cancer.
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This study has some limitations. First, it is a retrospective study. Second, the study comprised a small number of patients. Third, we did not perform lung biopsy in all patients. Fourth, the follow-up duration might be short to address GGO-dominant lesions. Despite these limitations, these encouraging results suggest a useful framework for future prospective studies. In conclusion, lung RF ablation is a safe and effective treatment for patients with GGO-dominant lung cancer.
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