Conformational Cool-Tip Lung Radiofrequency Ablation

Primary non-small cell lung cancer (NSCLC) causes more deaths in the United States per year than the combined mortality of breast, colon, and prostate cancer.¹ For newly diagnosed patients, the 5-year overall survival rate is 15%. Due to frequent comorbidities including chronic obstructive pulmonary disease, coronary artery disease, or advanced age, as many as 20% of patients are not able to undergo definitive management with lobar resection.² Newer surgical techniques including video-assisted thoracoscopic sublobar or wedge resections reduce procedural morbidity but have not clearly improved progression-free survival.³

Treatment options for unresectable lung cancer patients are systemic chemotherapy, external beam or stereotactic body radiation, and image-guided tumor ablation.⁴ Radiation therapy can potentially induce radiation fibrosis or cause bronchial injury, which can further compromise respiratory function in patients who have decreased pulmonary reserve which can be typically found in patients with an extensive smoking history.⁵ Despite recent advancement in NSCLC genetics for identifying gene signatures for chemotherapy treatment,⁶ older patients who are less likely to be surgical candidates have a higher incidence of adverse events with chemotherapy treatment even though they receive less chemotherapy treatment than younger lung cancer patients.⁷ These patients also tend to be on multiple medications for other comorbidities that can decrease efficacy and increase toxicity of chemotherapy treatment.⁸

Radiofrequency ablation (RFA) is a well established, minimally invasive procedure for the treatment of hepatic and renal tumors, and its use for lung tumors was first reported in 2000 by Dupuy et al.⁹ The procedure is performed by percutaneously placing an RFA probe centrally within a lung tumor using computed tomography (CT) image guidance. The RFA probe is connected to a generator with a high-frequency alternating electric current. When energy is conducted through the probe tip, the current causes a concentric pattern of local ionic agitation, resulting in frictional heating and resultant localized and predictable necrosis of target tissue in a somewhat defined geometric pattern. Different configurations of RFA electrodes produce varying patterns and sizes of tissue ablation.

Previous research has shown that the incidence of local tumor recurrence of lung tumors post RFA is correlated with incomplete ablation margins achieved during treatment.¹⁰ To reduce this occurrence, optimal 3-dimensional positioning of RFA electrodes to assure complete lesion destruction is necessary. We herein report our retrospective experience using a conformational cool-tip radiofrequency ablation (CCT-RFA) technique to optimize ablation geometries and reduce local recurrence. In this technique, real-time orthogonal image reconstructions in 3 or more planes are generated during probe positioning, allowing a more precise determination of the pattern and extent of thermal tissue destruction.

Patients and Methods

This retrospective study was approved by the local Institutional Review Board. Forty-five consecutive primary lung cancer patients, 20 males and 25 females (mean age 76 years, range 56-93), were treated with CCT-RFA between January 2006 and October 2010. All patients were either not candidates for surgical resection because of age, underlying lung disease or other comorbidities, or they did not wish to undergo resection. Patient and lesion characteristics are shown in Table 1 (click image to enlarge).

Preablation Assessment

Before undergoing the procedure, a thorough history and physical exam was performed on all patients by the interventional radiologist who would perform the procedures. The most recent imaging studies were reviewed, often with the patient, for initial treatment planning. Preprocedural labs were reviewed to ensure that the patients had adequate kidney and coagulation function for the procedure. The risks and benefits of the ablation were explained to the patients and informed consent was obtained before each procedure.

Radiofrequency Ablation Technique

All RF ablations were performed percutaneously using CT guidance. A total of 53 ablation devices were used, and two types of ablation systems were employed: two ablations were performed with a multi-tined expandable electrode with a 2-cm, 3-cm, or 4-cm diameter array (LeVeen, Boston Scientific), and the remaining 51 were performed using one or multiple internally cooled electrodes with 2.5-cm, 3-cm, or 4-cm  noninsulated exposed active tips (Cool-tip, Covidien). 200-watt RFA generators were used in both systems.

All procedures were performed by board certified interventional radiologists. Device type, location of the tumor, and proximity to vascular, mediastinal and pleural structures were recorded in all cases. Initial treatment parameters, including ablation time, number and size of probes used, and position of the probes was noted. The probes were positioned with the aim of achieving a contoured zone of ablation that included the entire lesion to be treated and a “treatment margin” of approximately 0.5 cm to 1.0 cm of normal perilesional lung parenchyma. Once probes were positioned in the target tumor, axial data sets were transmitted to a third-party workstation (TeraRecon) allowing real-time multiplanar orthogonal reconstructions to assess probe positioning and measurements of the distance from the probe to the lesion margins. This information was utilized to confirm that probe placement would achieve appropriate margins in all dimensions. The dimensions and configuration of the anticipated burn was based upon the manufacturers specifications and were used to assess the expected extent of the ablation. If the orthogonal measurements suggested that the initial electrode positions would not achieve appropriate margins, then they were adjusted or additional probes were inserted (Figures 1 and 2; click images to enlarge). Following the 3-dimensional conformational assessment of probe placement and the anticipated optimized ablation geometry, ablation was performed. For the majority of treatments using the Cool-tip system, an initial “burn” (activation of the generator to initiate delivery of energy to the RFA probe) was performed for approximately 5 minutes longer than the manufacturers recommendations for solid organ ablation; the duration of the burn for the two patients treated with the LeVeen electrode was based upon automated feedback denoting high tissue impedance implying dessication of the treated tissue volume. Using integrated thermometry in the Cool-tip system, the initial ablation temperature goal was at least 60^oC at all probe tips. Immediately after the initial ablation, repeat CT imaging was performed to assess adequacy. Imaging findings used to determine that the ablation margin was adequate have been previously described¹¹ and included perilesional ground glass opacity, microbubbles adjacent to the treated tumor, and blurring of the tumor margins. The presence of complete circumferential perilesional ground glass opacities or other imaging endpoints immediately following the ablation was recorded as complete ablation and an initial technical success. When the tumor margins were only partially obscured or the other signs of having achieved adequate margins were not apparent, additional ablations were performed in an attempt to achieve a complete ablation. If necessary, electrodes were repositioned prior to additional burns and orthogonal real-time 3-dimensional imaging again performed to assure the best electrode placement.

Vital signs were monitored throughout the procedure. Patients received intraprocedural pain control with either a combination of local anesthetic and conscious sedation or with general anesthesia. Throughout the procedures and immediately upon their conclusion, repeat CTs were performed to both assess treatment success and to monitor for pneumothorax. Chest tubes were placed for significant pneumothoraces and these patients were monitored with repeat chest x-rays. Post procedure, all patients were initially monitored in the post anesthesia care unit and then remained in the hospital for at least 1 day following the procedure.

Follow-Up Assessment

After treatment, patients were scheduled for follow-up CT or positron emitted tomography CT (PET-CT) scans at 1, 3, 6, and 12 months and then annually. The largest diameter of the index lesion compared with initial postablation scans was used to measure and assess local tumor recurrence. Because the ablation margins included a small amount of normal tissue, the initial 1-month post-ablation CT was used as the baseline for measuring changes in lesion size on subsequent studies. PET-CT scans were also utilized as part of tumor restaging. Although PET activity after ablation has been described and may persist for several months,¹² a pattern of a central void of activity on the PET scan corresponding to the initial tumor diameter, along with smooth and homogeneous perilesional 18-fluorodeoxyglucose (18-FDG) uptake was considered as successful tumor ablation. Response Evaluation Criteria In Solid Tumors (RECIST) was used to document tumor response (www.recist.com).¹³ In addition, if available, PET scans and contrast-enhanced CT was used to assess tumor viability and perfusion post treatment. Local tumor progression was defined as areas of contrast enhancement or PET-positivity within the ablation zone, or in new regions outside the treatment area. Smooth, concentric areas of perilesional PET activity within the first 3 months of CCT-RFA was felt to correspond to postprocedure inflammatory changes and not tumor progression. Beyond 3 months, any areas of contrast enhancement or PET-positivity within or surrounding the ablation zone were felt to indicate local tumor progression (Figure 3). Studies were reviewed for new sites of disease as well.

Data Collection

Data for evaluation was obtained from medical records, treatment records, and procedural as well as postprocedure imaging. Additional data was obtained from our institution’s Cancer Data Coordinator and tumor registry. Patient records were reviewed for demographic data, baseline tumor characteristics, disease stage, treatment parameters, comorbidities, neoadjuvant/adjuvant treatments, and related complications. Days of known survival were calculated based on the last documented contact date with the patient from initial treatment date. The Social Security Death Index and medical records were used to report patient deaths.

Evaluated variables included cancer stage, primary lesion size, tumor contiguity with a pleural surface, lesion location adjacent to vascular structures >3 mm in diameter (juxtavascular), imaging findings of complete or partial perilesional ablation injury immediately after treatment, and whether or not adjuvant external beam radiation therapy was used. Principal measured outcomes were overall survival (OS), time to local tumor recurrence, and progression-free survival (PFS). PFS was defined as the occurrence of tumor recurrence, new metastatic disease, or mortality from any cause.

Statistical Analysis

The primary endpoints of this study were days to local tumor progression, disease-free days with no new disease or local tumor progression, and days to patient death. Summary statistics was performed using an Excel spreadsheet (Microsoft). Kaplan-Meier survival analysis and univariate analysis using the log-rank test were performed using PASW Statistics 18 (formerly called SPSS 19 Statistics Base). A P value of ≤.05 was considered statistically significant.

Results

Fifty-three CCT-RFA sessions were performed to treat 48 tumors in 45 patients. Forty-four lesions in 42 patients were available for follow-up. Five patients had repeat ablations due to suspected residual viable tumor after assessment on the initial follow-up CT or PET-CT. Fifty-one ablations used Cool-tip technology while the remaining 2 used LeVeen electrodes. For the Cool-tip cases, the minimum temperature and ablation time achieved was 60^oC and 12 minutes respectively.

The average length of stay following treatment was 2.5 days (range 1-20). Reasons for prolonged admission include continued close surveillance of fragile patients and chest tube removal.

Median survival for stages I, II, III, and IV were 30.2, 15.7, 10.2, and 25.1 months respectively (Table 2). By univariate analysis, favorable predictors of overall survival were stage I disease (P=.02). Predictors of improved progression free survival (PFS) were tumor diameter ≤3 cm (P=.009), with a trend towards benefit with the utilization of adjuvant external beam radiation (P=.068). Median time to recurrence was 11.5 months in patients not receiving adjuvant radiation compared with 26.1 months in patients receiving adjuvant radiation (P=.068) (Table 2).

Kaplan-Meier analysis for overall and progression free survival was calculated as illustrated in Tables 3, 4, and 5.

Complications

There were 3 periprocedural deaths: one myocardial infarction 4 days following RFA, one arrhythmia following electrolyte disturbance related to small bowel obstruction occurring 3 days after the RFA treatment, and one respiratory failure secondary to phrenic nerve palsy after RFA of a superior sulcus tumor. This last complication was considered directly attributable to the procedure and the patient expired on postprocedural day 12. Six patients had a pneumothorax requiring a chest tube, three patients developed pneumonia, and one patient had a hemothorax. All chest tubes were successfully removed.

Discussion

Therapeutic paradigms for inoperable lung cancer are difficult and associated with reduced overall mortality and PFS compared with surgical resection. Because the majority of patients with primary NSCLC are not surgical candidates, reported survival rates remain poor and have not substantially improved in the last decade.¹ Most patients with unresectable tumors have advanced age and comorbidities that can be further complicated by chemotherapy and radiation. However, concomitant chemoradiation was shown to improve survival of patients with locally advanced NSCLC compared to sequential chemoradiation,¹⁴ which has been attributed to improved locoregional control, suggesting that treatment options that specifically target local pulmonary disease may have benefit for improving outcomes.

Radiofrequency ablation has reported as a potentially effective locoregional treatment option, with reported Stage I 5-year OS and PFS ranging from 27% (OS) to 47% (PFS, less than 3 cm), respectively.⁷ However, an integral limitation of RFA is an inability to accurately assess in real-time the extent of ablation, in part due to a reliance on axial imaging to guide treatment.

Because many NSCLC lesions are nonspherical or have spiculated and infiltrative margins, imaging in one dimension may not allow for optimal RFA probe positioning, potentially increasing the hazard for local disease progression or recurrence.

Analogous to techniques used with conformal radiation therapy, the CCT-RFA technique utilizes multidimensional imaging during RFA using a third-party workstation to reconstruct coronal, sagittal, and parasagittal planes during the treatment session. This potentially allows a better assessment of probe positioning and anticipated ablation geometry, in essence providing better simulation of treatment outcomes with the goal of assuring complete tumor destruction as well as necrosis of a small portion of adjacent normal lung to prevent recurrence due to microscopic local spread of malignancy. This is particularly important for larger lesions and tumors with irregular geometry. Beland et al reported the higher incidence of local tumor recurrence in RFA lung cancer patients with larger tumors, which was attributed to difficulty in obtaining the target ablation margins of 8 mm to 10 mm surrounding index tumors.¹⁰ Furthermore, Lee et al also reported that smaller tumor size (less than 3 cm) was significant in RFA procedural success in achieving greater complete tumor necrosis as compared to larger tumors.¹⁵

Our local tumor recurrence rates compare favorably with previous analyses of lung cancer RFA results.^5,7,15 Similar to these series, lesion size was the single most important predictor of local recurrence. However, while overall median time to local recurrence was similar between our study and earlier data,⁷ there was a notable increase in our median survival for tumors larger than 3 cm. Simon et al reported that the time to local progression for tumors smaller than 3 cm was 45 months and for tumors larger than 3 cm the time to progression was 12 months.⁷ Our results showed a progression-free survival time of 16.7 months for tumors greater than 3 cm. This suggests that 3-dimensional conformational assessment of treatment parameters may be most beneficial in tumors 3 cm and larger.

Although our 1-year survival for Stage I patients is similar to other reported studies,^7,15 we believe the decrease in survival at 2 years compared to Simon et al is due to our patients larger tumor size and increased age. In the series by Simon et al, the average patient age was 68.5 years (and included patients treated for colorectal metastases), compared to an average age in our series of 76 years. Advanced age could greatly decrease the survival statistics as older patients are more sensitive to treatment and have more progressed comorbidities. The 5-year survival rate for lung cancer decreases as age increases and is 11.3% for patients 75 and older.¹⁶ The cause of death was not obtained in this study and it is possible that comorbidities in our older population of patients could have contributed to the cause of death rather than the treated lung cancer. Furthermore, most of our patients presented for CCT-RFA after other treatments and potentially represent a subset of patients that are preselected with more resistant tumors.

Our Stage IV patients showed increased median survival (25.1 months) compared to Stage II (15.7 months) and Stage III (10.2 months). Although the reason for this is uncertain, it is possible that the patients with Stage IV tumors represented a cohort with more indolent tumor pathogenicity. In this patient population, CCT-RFA could help prevent the lung tumor from impairing a patient’s pulmonary status through local tumor spreading. Further investigation of CCT-RFA impact on overall survival in Stage IV patients is warranted.

Although our conformational assessment of tumor geometry allowed ablation margins to be calculated, several factors could allow foci of tumor at the lesion margins not to reach target temperatures during ablation and therefore remain viable. Juxtavascular positioning of index tumors has been described as a risk factor for local recurrence as a result of convective heat loss (also called “heat sink” effect) preventing satisfactory achievement of cytotoxic ablation temperatures at the perivascular portion of the lesion. Other potential causes of incomplete ablation include suboptimal probe positioning due to limitations in the available cutaneous access sites (e.g. interference by overlapping ribs), or thermal degradation resulting from areas of collateral air drift within the lung. We have previously described improved outcomes following lung RFA in patients receiving adjuvant external beam radiation,¹⁷ and this trend was again noted in this larger series of patients. Perilesional inflammation following lung RFA has been well described and is evident on post treatment PET-CT scans for several months after treatment.¹² Conceivably, this inflammatory response increases oxygen tension adjacent to the region of ablation, enhancing the response of any remaining viable tumor to external beam radiation.

There were several limitations to our study. Although post-treatment imaging was scheduled immediately after treatment, the adherence to follow-up and the availability of early imaging was not uniform. This may have limited the opportunity to retreat these patients if there was early recurrence that could have been detected; often these decisions were made by the referring oncologist without further consultation with the interventional radiologist. Our patients did not routinely have biopsies post CCT-RFA so a cytologic assessment of treatment adequacy is unavailable. Finally, the retrospective nature of this study resulted in variation in the imaging methods used in follow-up; consequently, not all patients had PET-CT examinations to guide treatment planning.

In summary, we believe our results show that real-time conformal treatment planning during lung RFA may improve results for patients with unresectable primary lung cancer patients. The CCT-RFA method is most beneficial for larger tumors (>3 cm diameter) and those with asymmetrical geometry by allowing a more calculated ablation to occur compared to previous pulmonary RFA methods. Adjuvant radiation can have a synergistic effect to assure complete local eradication of malignancy. Based on the relative safety of the procedure, we feel that CCT-RFA should have a greater role in the discussion of treatment options for the unresectable lung cancer patient and that results will be more substantial if pulmonologists and oncologists refer these patients earlier for CCT-RFA. Further studies comparing the effectiveness of CCT-RFA with chemoradiation, stereotactic body radiation therapy, or sublobar resections should be considered.

Editor’s note: This article underwent peer review by one or more members of the Interventional Oncology 360 editorial board.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no disclosures related to the content of this manuscript.

Suggested citation: Weinstein J, Rundback JH, Anaokar J, Herman K. Conformational cool-tip lung radio frequency ablation. Intervent Oncol 360. 2013;1(1):E1-E14.

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