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J Thorac Cardiovasc Surg 2007;134:857-864
© 2007 The American Association for Thoracic Surgery
General Thoracic Surgery |
a Heart, Lung, and Esophageal Surgery Institute, Pittsburgh, Pa
b University of Pittsburgh Medical Center, and the University of Pittsburgh Cancer Institute Biostatistics Facility, Pittsburgh, Pa
c Boston Medical Center, Boston, Mass.
Read at the Thirty-second Annual Meeting of the Western Thoracic Surgical Association, Sun Valley, Idaho, June 21-24, 2006.
Received for publication June 27, 2006; revisions received April 1, 2007; accepted for publication April 11, 2007. * Address for reprints: James D. Luketich, MD, Sampson Family Endowed Professor of Surgery, The Heart, Lung, and Esophageal Surgery Institute, University of Pittsburgh Medical Center, 200 Lothrop St, C-800, Pittsburgh PA 15213. (Email: luketichjd{at}upmc.edu).
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Abstract |
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Methods: Patients with medically inoperable stage I non–small lung cancer were offered radiofrequency ablation. Thoracic surgeons evaluated and performed radiofrequency ablation under computed tomographic scanning guidance. Response was assessed by means of computed tomographic and positron emission tomographic scanning. Time to progression and survival were monitored every 3 months.
Results: Nineteen patients underwent radiofrequency ablation over a 3-year period. There were 8 men and 11 women with a median age of 78 years (range, 68-88 years). Radiofrequency ablation resulted in pneumothorax requiring a pigtail catheter in 12 (63%) patients. An initial complete response was observed in 2 (10.5%) patients, a partial response in 10 (53%) patients, and stable disease in 5 (26%) patients. Early progression occurred in 2 (10.5%) patients. During follow-up, local progression occurred in 8 (42%) nodules, and the median time to progression was 27 months. There were no procedure-related mortalities, and 6 deaths occurred during follow-up. The mean follow-up in the remaining patients was 29 months (range, 9-52 months). The probability of survival at 1 year was estimated to be 95% (95% confidence interval, 0.85-1.0). The median survival was not reached.
Conclusion: Our experience indicates that radiofrequency ablation is safe in high-risk patients with stage I non–small lung cancer, with reasonable results in patients who are not fit for surgical intervention.
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Introduction |
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Lung cancer is the most common cause of cancer-related mortality in the United States. Surgical resection is the standard treatment in resectable disease and offers the best chance of cure, particularly in the earlier stages.1-3 In an aging population, many patients with otherwise resectable lung cancer have other comorbidities, including pulmonary dysfunction, which might preclude them from surgical resection.4 In these patients conventional external beam radiotherapy is typically offered as treatment, with reported 5-year survival rates of 10% to 30%.5-8 Sibley and colleagues6 reviewed the results of radiotherapy for stage I non–small lung cancer (NSCLC) from Duke University in 156 patients and reported a 2- and 5-year survival of 39% and 13%, respectively. Recently, Qiao and associates8 reviewed 18 studies investigating the treatment of stage I NSCLC with radiotherapy and reported a mean 3-year and 5-year overall survival of 34% and 21%, respectively. Thus the results of conventional radiotherapy have not been satisfactory, prompting investigators to study other modalities of treatment, such as radiofrequency ablation (RFA), in this high-risk group of patients with lung cancer.
The use of interstitial hyperthermia to treat lung neoplasm was initially reported by Lilly and colleagues9 in 1983. RFA is a thermal ablative technique and is a relatively new modality of treatment, which might be applicable in high-risk patients with lung cancer. There have been several reports in the literature on the use of RFA for lung neoplasm, but many of these are case reports or series with a focus on immediate response, without rigorous longer-term follow-up for recurrence or survival.10-14 Furthermore, there are few reports with an emphasis on stage I NSCLC. We have previously described our experience with RFA in the treatment of both primary and metastatic lung neoplasms.15,16 The principal findings of our earlier report were that RFA was more effective for smaller (
5 cm) tumors, with better early survival and response to treatment. Additionally, in our previous report, we described a modification of the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (Table 1) that were used to assess treatment response and progression at the ablated sites. In this article we report our experience with the use of RFA in the treatment of stage I NSCLC in medically inoperable patients. This is part of an ongoing institutional review board-approved study that continues to accrue at the University of Pittsburgh.
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Materials and Methods |
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Informed consent was obtained from all patients, and the study was approved by the Institutional Review Board at the University of Pittsburgh.
Selection of Patients
Patients with NSCLC were routinely staged with chest computed tomographic (CT) scanning, and most patients also underwent a positron emission tomographic (PET) scan. Patients with mediastinal lymph nodes greater than 1 cm in the short axis, a positive PET scan result, or both underwent mediastinoscopy. Mediastinoscopy was performed in 2 patients, and left-sided video-assisted thoracoscopic surgery was performed in 1 patient for biopsy of hilar and aortopulmonary window nodes. The inclusion criteria for RFA in the treatment of patients with stage I NSCLC for this study were as follows: (1) patients who were considered medically inoperable because of poor pulmonary function, high cardiac risk, and/or other comorbidities and (2) presence of a target tumor of 4 cm or smaller. In addition, patients who refused an operation were offered RFA if the tumor was peripheral and less than 4 cm. Exclusion criteria included central tumors. 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 as described previously, all procedures were performed by thoracic surgeons.15,16 The RFA equipment consists of a generator, active electrode, and dispersive pads. Electrosurgical dispersive pads (Dispersive Electrodes, RITA Medical Systems, Inc, Moutainview, Calif, or Valleylab Polyhesive, Valleylab, Boulder, Colo) were applied to the patient’s thighs and plugged into the return electrode socket on the front panel of the radiofrequency generator.
RFA was performed by using 2 different radiofrequency generators and needle electrodes. The radiofrequency generator was set up in accordance with the generator’s instructions for use. One system comprised of a radiofrequency generator (RF3000; Boston Scientific Corp, Boston, Mass) and needle electrodes (LeVeen Needle Electrode; RadioTherapeutics Corporation, Sunnyvale, Calif). Under CT guidance, a finder needle (22-gauge long spinal needle) was used to determine the trajectory and placement of the active RFA probe. The LeVeen needle electrode (Boston Scientific Corp), which opens up as an array, was selected according to the diameter of the target lesion and placed into the target lesion. A 2-phase impedance-based algorithm was used according to the protocol suggested by the manufacturer. Briefly, the initial power applied was at the lowest setting and then increased in 5- to 10-W increments until system impedance increased to more than 400 
. A second application of radiofrequency energy (a second phase) was provided at this same location (after waiting approximately 30 seconds) until system impedance increases to more than 400 for a second time.
The second system was comprised of a radiofrequency generator, the RITA Starburst XL Electrosurgical Device (RITA Medical Systems, Inc). Based on the size of the target tumor, the multitined expandable array (Starburst XL Electrosurgical Device, RITA Medical Systems, Inc) was deployed. Temperature was monitored from 5 electrodes, which are equipped with thermocouples. The radiofrequency generator was set to a target temperature of 90°C, and the initial power was applied at between 35 and 50 W. The electrosurgical needle’s deployment was staged according to the size of the tumor being treated, and the manufacturer-suggested algorithm was followed.
With both of these systems, if necessary, the electrode was repositioned as many times as necessary to encompass the target tissue and a small rim with approximately 0.5 to 1 cm of nondiseased pulmonary tissue to ensure an adequate tumor margin.
Postprocedure follow-up of patients and assessment of response
Patients were followed up in 3-month intervals with clinical examinations, CT scans, and selectively with PET scans. Modified RECIST criteria were used to assess initial response to treatment at 3 to 5 months (Table 1).13,14 Patients were evaluated for initial response rate, time to local progression, and overall survival.
Data Collection and Statistical Analysis
The objective of the study was to determine the outcomes of RFA in the treatment of stage I NSCLC. Information on patient demographics, tumor characteristics, treatment, and comorbidities (Charlson Comorbidity Index [CCI]) were collected.17 Specific end points studied were complications, clinical response rates, time to local progression, and overall survival. 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. The time to progression was calculated from the treatment date. Kaplan–Meier plots were constructed by using Greenwood confidence limits. The log–rank test was used to determine differences between groups. Association between categoric variables was tested with the Fisher exact test or the 
2 test.
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Results |
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There were no procedure-related mortalities. There were 6 deaths during follow-up; 3 were cancer related, and 2 were not cancer related. One patient had distant recurrence, and the exact cause of death was not determined. The mean follow-up in the remaining patients was 29 months (median, 28 months; range, 9–52 months). The probability of overall survival at 1 year and 2 years were estimated to be 95% (95% confidence interval, 85%-100%) and 68% (95% confidence interval 49%–96%), respectively. The median survival was not reached (Figure 1).
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Discussion |
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In the medically inoperable patients with lung cancer, there are few effective options. Some of these patients with other associated comorbidities refuse treatment or receive no treatment with poor results. McGarry and coworkers18 reviewed the outcomes in 49 patients who received no treatment in early-stage disease, and the median survival was 14 months. Progressive cancer was the cause of death in 53% of patients. Conventional radiotherapy, as described earlier, is offered to many of these patients, and the results again are not encouraging.5-8 Therefore in this high-risk patient population with lung cancer, newer modalities, such as RFA or SRS, might be applicable.19-21 Timmerman and associates20 reported the results in 37 patients with stage I NSCLC treated with SRS. The disease-free and overall survivals at a median follow-up of 15 months were 50% and 64%, respectively. We have presented our early results in patients with stage I NSCLC treated with SRS with a 91% one-year overall survival at a median follow-up of 15 months.21 Further prospective studies are required to define the role of RFA and SRS in the treatment of lung neoplasms.
The issue of determination of medical operability or inoperability is critically important and should be assessed by a thoracic surgeon. One factor alone, such as poor pulmonary function test results, might not make a patient inoperable. With the potential benefits of lung volume reduction surgery, selected patients with upper lobe–predominant emphysema who have a coexistent lung cancer in the upper lobe may be candidates for lung resection, even when the pulmonary function test results are marginal. Choong and colleagues22 reported a series of 21 patients with clinical stage I NSCLC with a mean FEV1 of 0.7 (29% of predicted value) who underwent surgical resection. Lobectomy alone was performed in 9 patients, and in the remaining patients lobectomy or sublobar resection was supplemented with lung volume reduction surgery. In patients with pathologic stage I disease, the overall survival was 100%, 79%, and 68% at 1, 3, and 5 years, respectively. Therefore the assessment of medical operability requires a comprehensive evaluation of not only pulmonary function but also other factors and comorbidities in the patient by a qualified thoracic surgeon.
We have previously reported the results of RFA in the treatment of both primary and metastatic lung cancer in inoperable high-risk patients.15,16 There have been very few reports of patients with stage I NSCLC who have been treated with RFA. Lee and associates11 reported their experience in 10 patients with stage I NSCLC. Of these 10 patients, only 4 were considered high-risk patients in whom surgical intervention was contraindicated, and the remainder refused surgical intervention. Mean survival in these 10 patients was reported to be 21 months, and 80% were alive at a mean follow-up of 14.8 months. Lencioni and coworkers23 presented their preliminary results in 14 patients with stage I disease. Kaplan–Meier analysis showed an overall 1-year survival of 81% at a mean follow-up of 9 months. Recently, Dupuy and colleagues24 reported their experience with RFA followed by external beam radiation in the treatment of stage I NSCLC. At a mean follow-up of 26 months, 14 (58%) patients had died, and the estimated overall survival was 83% and 50% at 1 and 2 years, respectively. Our results of 95% overall survival in 1 year compare favorably with the results of these studies.
These results during intermediate-term follow-up are encouraging, and the results appear to be equivalent or superior to the reported results with conventional radiation therapy.5-8 However, longer follow-up for this cohort is required, and full evaluation of survival end points will require greater maturity of time-to-event data. In addition, further prospective studies are required in high-risk patients to definitively compare RFA with conventional external beam radiation treatment or other emerging technologies, such as SRS.
This group of patients had significant associated comorbidities, with a mean Charlson score of 5.5 and a median CCI of 4. The CCI was originally described to assess the effect of comorbidity on survival in 559 hospitalized patients. Nineteen conditions were found to significantly influence survival in the study population, and a weighted score was given based on the relative risk.17 This score has been validated in surgically resected patients with NSCLC in a study of 205 patients.25 The score was divided into 4 grades of increasing severity of the CCI index, with greater than 5 representing the highest grade of comorbidities. Multivariate analysis showed that a CCI 3 to 4 was the only predictive factor of increased risk of major complications (odds ratio, 9.8; 95% confidence interval, 2.1-45.9), and for every increase in grade, the relative risk of an adverse outcome showed an increase. In the current study patients who underwent RFA were elderly (median age, 78 years), had significant comorbidities (mean CCI, 5.5), and represent a high-risk population.
The assessment of response after RFA is difficult because, unlike surgical resection, there is a lesion or scar that remains after therapy. There is considerable variation in how response is defined and evaluated. Chest CT scans, changes in contrast enhancement, and PET scans have all been used. Thus the reported response rate in the literature varies considerably. We have adopted strict criteria and have used modified RECIST criteria to evaluate response in these patients after RFA. We have combined not only the size of the lesion but also the changes in the density of the lesion along with metabolic activity based on PET scans to determine the response rate. The proposed modified RECIST criteria have limitations and have to be validated in a larger group of patients. Ultimately, however, disease progression and survival will be the measures by which the efficacy of RFA will have to be evaluated.
There are several factors that influence local recurrence or progression of disease. The important technical issues include (1) the degree of ablation and whether complete ablation is achieved and (2) the adequacy of margins of ablation obtained around the tumor. Completeness of ablation has also been evaluated in a few ablate-and-resect studies examining the extent of ablation after RFA. Review of these studies shows that effective 100% ablation varies from 38% to 67%. Yang and coworkers26 presented the results of a multicenter ablate-and-resect study in 13 patients. The median tumor kill was 70%, and 7 (55%) patients had 100% ablation. These investigators also demonstrated a learning curve that exists in achieving 100% ablation. Nguyen and associates27 did a prospective ablate-and-resect study after open thoracotomy in patients with stage I or II NSCLC. RFA of the tumor was performed after a standard thoracotomy, and subsequently, a lobectomy was performed. Tumor cell viability was determined by means of routine histology, as well as supravital dye staining. Three (38%) of 8 patients had complete ablation of tumors. In another study by Ambrogi and colleagues,28 a total of 9 patients underwent RFA either by means of the CT-guided approach or by means of open thoracotomy followed by resection.28 Complete ablation was noted in 6 (67%) of 9 patients. However, supravital dye was not used to determine cell viability. The margins of ablation were a mean of 8 mm in completely ablated lesions and less than 5 mm in patients who had an incomplete ablation.
The adequacy of margins of ablation obtained around the tumor might be an important factor in local progression of disease. Our data with regard to wedge resections suggest a significant increase in the local recurrence rates (14.6% vs 7.5%) when the margins were less than 1 cm versus more than 1 cm.29 In general, we strive to attain a 0.5- to 1-cm margin around the tumor. Despite these margins, local progression (as determined by imaging studies) occurred in 42% of patients, and the median time to progression was 27 months. However, despite this incidence of progression, the results in terms of overall survival appear reasonable at intermediate-term follow-up. It is possible that the early detection of recurrence by means of close follow-up and the prompt treatment of recurrence might have contributed to the results of overall survival, but the limited number of patients did not allow us to derive definitive conclusions. In the future, further advances in technology or adjuvant therapy might be useful in decreasing this progression rate and perhaps in improving survival.
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Conclusions |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
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; however, RFA might have a role in patients who are medically inoperable. Prospective studies are necessary to address these issues and to define the role of RFA in the treatment of lung neoplasms. Thoracic surgeons should continue to evaluate new technology and add these techniques to their armamentarium in the treatment of lung neoplasms. In conclusion, RFA appears safe in high-risk patients with stage I NSCLC, with reasonable results in patients who are not fit for surgical intervention. | Earn CME credits at http://cme.ctsnetjournals.org
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Footnotes |
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* James Luketich reports grant support from RITA Medical, and Hiran Fernando reports lecture fees from Boston Scientific. 
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