Lung ablation shows promising results in safety and efficacy

Lung carcinoma remains the leading cause of cancer death in the U.S. Over the past decade, lung cancer death rates have more than quadrupled, from 5.4 to 29.4 per 100,000.¹ The American Cancer Society estimates that in 2005 the number of lung cancer deaths will rise to 163,510-90,490 men and 73,020 women-accounting for 28% of all cancer-related deaths. The number of newly diagnosed lung cancers will rise to 172,570, or 93,010 new cases in men and 79,560 in women.2 Nearly 60% of those diagnosed with lung cancer die within one year of their diagnosis and nearly 75% within two years.²

Despite recent advances in therapy, the relative five-year survival rate for all stages of lung cancer has improved only slightly to 15%.² For early-stage lung carcinoma, surgical resection confers the best survival option, with five-year survival rates approaching 80% for stage I disease and 40% for stage II disease.³

Only about 15% of patients diagnosed with lung carcinoma each year are surgical candidates.⁴ Most patients present with advanced or widespread disease at the time of diagnosis and, therefore, are not considered candidates for surgery. Some patients have technically resectable disease but cannot undergo surgery because of comorbid cardiopulmonary disease. This population represents a suitable target for novel, minimally invasive lung-sparing therapies providing local control.

The last decade has seen the emergence of minimally invasive therapies using thermal energy sources: radiofrequency, cryoablation, focused ultrasound, laser, and microwave. Radiofrequency ablation (RFA) is the best developed, secondary to the advent of bipolar and multi-electrode and internal tip-cooling RF electrodes as well as advances in CT technology.

RF ablation is a controlled electrosurgical technique that implements high-frequency alternating current to generate localized electromagnetic fields, heating targeted tissues to desiccation or thermal coagulation. Naturally, cells of targeted tissue die when exposed to high thermal doses. For a variety of reasons, including less efficient heat dissipation, the cells of neoplastic tissues are more sensitive to heat effects than are cells of healthy tissues.⁵ Thus, RF-induced hyperthermia exploits this difference in heat sensitivity by creating localized temperature increases in neoplastic tissues to greater than 57 degrees C to 60 degrees C, while restricting temperatures in healthy tissues to normal ranges.⁶ Several authors have advocated that lung tumors are well suited to RFA because of the so-called oven effect, whereby the air (high resistance) surrounding an intraparenchymal tumor (low resistance) affords an insulating effect and traps heat within the targeted tumor.⁷

Well established in the treatment of various cardiac and neurologic dysfunctions, RFA has faced a major barrier to further application: the small lesion size created by earlier generation devices and delivery methods. The advent of bipolar and multi-electrode and tip-cooled RF electrodes, enabling the creation of larger areas of controlled and reproducible necrosis in animal and human models in vitro and in vivo,⁸ has expanded potential clinical applications to include tumor therapy, notably in the treatment of primary and secondary brain and hepatic malignancies.^9,10

PATIENT SELECTION

No solid or strict criteria currently exist regarding patient appropriateness for undergoing RFA. For primary lung carcinoma, much of the current literature focuses on the unresectable or high-risk group.^11-19 These patients have early-stage lung carcinomas that could qualify for surgical resection but are medically inoperable because of comorbid cardiopulmonary disease, particularly severe chronic obstructive pulmonary disease, or inability to withstand lung loss. Other relevant populations have limited local recurrence following primary treatment, have refused surgical intervention, seek palliation such as pain control, or desire cytoreduction to render more feasible complementary therapy such as radiation using a smaller field.

In any scenario for stage I lung cancer, all imaging-CT, PET, and/or PET/CT-should demonstrate localized disease without hilar or mediastinal nodal and extrathoracic involvement. Even under the best-case scenario, disease is likely to be understaged by imaging alone.²⁰

Solid or strict criteria are also lacking for tumor characteristics favorable for RFA, although trends are beginning to emerge. "Ideal" lesion features include solitary status. But multiple lesions are considered if they are fewer than five in number, completely intraparenchymal, smaller than 5 cm (more appropriately 3 cm), confined within a single ablation zone, spherical versus irregular, and noncontiguous with the hila and its large airways and pulmonary arteries and veins, or the mediastinum or vital structures within such as the trachea, esophagus, heart, aorta, and great arteries.

Akeboshi et al achieved lower rates of complete necrosis in those targeted lesions greater than 3 cm,¹⁵ and Lee et al found that lower rates of control correlated with decreased mean survival rates: 8.7 months versus 19.7 months for the complete necrosis group.¹⁴ As with hepatic tumor ablation, tumors close to large arteries and veins are often incompletely ablated, owing to the heat-sink effect.^21,22 Tumors close to the hilum likely already have regional nodal involvement.

TECHNIQUE AND DELIVERY

RFA has mostly been performed as an outpatient procedure, usually under conscious sedation. Operators have at times favored deep conscious sedation and even general anesthesia, however,¹⁹ particularly in patients with targeted lesions on the pleura and/or chest wall, and especially in those seeking palliation for pain. As with most interventional procedures, intravenous access is established and blood pressure, heart rate and rhythm, and oxygen saturation are continuously monitored. Because all delivered electrical current must be grounded, RF devices require application of two or four grounding pads to the chest wall or thighs, and proper contact of the electrode gel sometimes necessitates the shaving of body hair. Some authors have advocated prophylactic antibiotics, particularly in the ablation of masses greater than 5 cm, due to the ensuing large volume of necrosis.¹⁵ All intended tumors targeted for RFA should have histopathologic confirmation.

Conventional CT with incremental scanning or CT fluoroscopy is used to localize the target tumor. Following standard sterile preparation and draping, 1% lidocaine hydrochloride is administered as local anesthesia intradermally and into the deeper subcutaneous and muscular tissue tract. At this juncture, at least two approaches have been used. Some authors favor placement of a localization needle, such as a 20- or 22-gauge Chiba or spinal needle, with subsequent placement of the RF electrode via tandem needle technique, and others favor direct placement of the RF electrode. The former approach is more practical under conventional scanning.¹³

Operators should situate the chosen electrode so as to ensure at least 1-cm margins around the entire target lesion,²³ with multiple and overlapping ablations if needed (Figure 1). Ideally, for tumors measuring between 3 to 5 cm in diameter, six overlapping ablations should be performed, four in the axial plane and two along the z-axis, with all ablations coinciding at the tumor's center.²⁴ CT documentation is critical, using at least 5-mm collimation or thinner images through target lesion and electrode and tine positions,²⁵ of electrode placement and, where appropriate, tine deployment with each ablation.

Lencioni et al have demonstrated that multiplanar reformations can greatly aid and document accurate tine placement.²⁶ Depending on the device selected, end points for each ablation are variable, since each system operates on different principles. Each manufacturer provides general algorithms and guidelines, but modification of these guidelines is allowable as the operator gains experience and familiarity with the device(s). The operator determines ablation completion, dependent on adequate margins of coverage, patient condition, and CT imaging end points, which include documentation of electrode position, tine deployment to establish adequate margins, and the presence of ground-glass parenchymal change adjacent to areas of ablation and surrounding the targeted tumor in its entirety with 0.5 to 1-cm margins.^14,27

Immediate postprocedural care involves noninvasive monitoring, pain control, and assessment of potential complications through physician and nurse assessment and postprocedural chest radiographs. Generally, an expiratory chest radiograph should be obtained within the first two hours of the procedure, with a second one obtained between three and four hours after the procedure. Following assessment of the second chest radiograph and examination, the patient may be discharged. Depending on the patient's clinical course and assessment, the operator will determine whether limited or overnight admission for observation is required.

Both reported complications and complication rates related to RF lung ablation have been variable, but overall rates of morbidity and mortality are extremely low.²⁸ Complications are related to electrode placement and the delivery of RF energy. These include prolonged pain following ablation,¹³ hemoptysis and pulmonary hemorrhage,²⁹ pneumonia and abscess,¹⁵ pleural effusion,²⁸ pneumothorax requiring observation and/or evacuation,²⁸ bronchopleural fistula, cerebral air embolism,^30,31 acute respiratory distress syndrome (ARDS) and death,^12,14,29 inability to retract electrode tines,³² and electrode tract³³ and pleural²³ tumor seeding.

Specific complications related to the delivery of RF energy include dispersive electrode or grounding pad skin burns and interference with co- and/or preexisting medical devices. Lung ablation patients also exhibit a postablation syndrome similar to that described in patients post-hepatic tumor ablation,³⁴ consisting of low-grade fevers and malaise, with productive cough with brown or rust-colored expectorant and dyspnea, particularly in the severe lung disease population.

Complications have been reported in up to 76% of patients, most of them minor postablation-type symptoms, pneumothoraces, and pleural effusions. Pneumothorax rates have ranged from 4.2% to 53.8%, and those requiring evacuation with pleural catheter or thoracostomy tube from 7.2% to 25%. The occurrencemof pleural effusions has been reported as 3.7% to 52.4%. Other complications have been sporadically reported with incidence rates at 10% or less.

At least three deaths have been reported, the first due to lethal pulmonary hemorrhage in a patient on a commonly used antiplatelet drug, clopidogrel,²⁹ the second related to ARDS four days following the RF procedure,¹⁴ and the third as result of hemoptysis 19 days following RFA of a central tumor.¹²

IMAGING FOLLOW-UP

Reliable imaging is essential for RF ablation to become widely used in the treatment of lung tumors, not only for following tumor regression and postablation coagulation involution but to discern incompletely ablated or recurrent tumor within the ablation zone. Unfortunately, ablation zone size and morphology at conventional CT may not always be useful indices of ablation efficacy. For postablation follow-up, the larger reported patient series have used contrast-enhanced CT, including CT contrast nodule densitometry, PET and PET/CT, and MR. Contrast-enhanced CT has been the most widely used and studied.

Parameters vary from one series to the next in collimation and timing of image acquisition, rate and volume of administered intravenous contrast, and imaging characteristics suggestive of efficacy. Most authors advocate a pretreatment scan followed by postablation scans at varying time intervals, usually every three to six months beginning around one month and continuing through 12 months. Some authors have scanned postablation patients as early as one day and one week postprocedure.

Immediately following ablation, nonenhanced CT usually shows slightly increased attenuation along the electrode tract and decreased attenuation of the treated tumor, with enveloping ground-glass attenuation. Lee et al considers the thickness and pattern of ground-glass on initial imaging at one day useful in predicting treatment success. All eight tumors in which the ground-glass completely surrounded the treated tumor and extended more than 5 mm beyond the original tumor margins avoided local recurrence at a mean 22.2 months follow-up.¹⁴

During and shortly after ablation, the opacification associated with ablation has been described as light bulb-shaped, surrounding both the electrode and tumor.³⁵ Gadaleta et al coined the colorful term "cockade phenomenon" to describe the multiple concentric rings with varying densitometric characteristics that appear in the parenchyma surrounding the lesion after 48 to 72 hours, because of their resemblance to a bow historically worn on berets.¹⁷ This group also described clear sectorial hyperemia surrounding the lesion, or conical consolidation with its apex at the hilus lasting 24 to 72 hours.¹⁷

Despite varying CT appearances, ablation zones will be largest immediately or approximately one week following ablation and will subsequently decrease over time (Figure 2). Treating metastatic colon carcinoma to the lung, Steinke et al demonstrated that at one week almost 100% of treated lesions were larger than baseline, at one month 95%, three months 76%, and six months 47%.³⁵ Jin et al showed similar decreases over time in the ablation zone, which decreased more than 40% after one year of follow-up.²⁷ Continued enlargement, particularly beyond six months, was consistent with partial ablation (Figure 3). Cavitation within the ablation zone seems to be a frequent and uneventful occurrence that may or may not resolve over the course of follow-up.²³

Features of the ablation zone on enhanced CT have also been described. Lee et al defined tumor necrosis as complete when the nonenhancing area at the treatment site had a diameter greater than or equal to that of the initially viable tumor, with no residual portion of the lesion enhancing more than 10 HU after contrast administration.¹⁴ Following RFA of completely and even incompletely ablated tumor, a thin rim, usually less than 5 mm in thickness, can be seen along the circumference of the ablation zone. This benign peri-ablational enhancement,³⁴ lasting up to six months, represents a benign physiologic response to thermal injury, initially from reactive hyperemia and subsequently from fibrosis and giant cell reaction.

Irregular peripheral enhancement, referring to scattered, nodular, or eccentric patterns of contrast enhancement within or immediately around the ablation zone, is best seen on delayed imaging during the venous phase ( > 180 seconds post-contrast injection) and represents residual or recurrent tumor (Figure 4).³⁴ Irrespective of enhancement pattern, mean contrast uptake substantially decreases within the first one to two months postablation. In most instances, the appearance of abnormal enhancement first occurs at approximately three months and indicates the presence of recurrent disease.¹³

CLINICAL RESULTS

Even though RFA has been used to treat lung tumors in more than 500 patients worldwide, further results are required to define its role for pulmonary malignancies. Since clinical RF applications in three patients were first reported by Dupuy et al,³⁶ the number of published reports has continued to grow. Larger prospective series of treated patients include some with longer than one-year follow-up. Most of these more current studies^15-19,37 report diverse patient populations, however, often mixing primary and secondary lung tumors. Even studies limited to primary lung cancer report heterogeneous patient populations, some of them receiving either prior and/or adjuvant chemotherapy and ranging from stage IA to limited recurrent disease. Most studies are underpowered in terms of consistency and number of diseased individuals. Despite these drawbacks, safety and technical feasibility profiles, the latter approaching 100%, have been established.

Lee et al¹⁴ includes 32 tumors in 30 patients, four with five lung metastases, achieving complete necrosis in 12 of 32 lesions based on imaging parameters. Statistically significant complete necrosis rates were achieved in six of six (100%) treated tumors smaller than 3 cm versus six of 26 (38%) in tumors larger than 3 cm. Additionally, 18 of 32 (60%) patients died within the 21-month follow-up period, with a mean of 6.9 months.

Akeboshi et al¹⁵ treated 54 nodules in 31 patients, 13 with primary lung carcinomas. Twenty-five of 36 (69%) treated tumors 3 cm and smaller demonstrated complete necrosis as assessed by imaging versus seven of 18 (39%) tumors greater than 3 cm. Of the 22 incompletely treated tumors, 13 were retreated, five with complete necrosis. No significant statistical difference was found in the one-year survival rate between patients with complete tumor necrosis and those with residual tumor.

Dr. Suh is an associate professor and director of thoracic interventional services in radiological sciences, Dr. Reckamp is an assistant professor and a member of the thoracic oncology program in the Jonsson Comprehensive Cancer Center, Dr. Zeidler is an assistant professor in the internal medicine division of pulmonary and critical care, and Dr. Cameron is an associate professor and surgical director of thoracic oncology, all at the David Geffen School of Medicine at the University of California, Los Angeles.

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