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1 Unità Operativa di Radiologia Interventistica, Istituto di Ricovero e
Cura a Carattere Scientifico (IRCCS) Oncologico, Via Amendola 209, Bari 70126,
Italy.
2 Dipartimento di Area Critica e Quartiere Operatorio, IRCCS Oncologico, Bari
70126, Italy.
3 Dipartimento di Oncologia, IRCCS Oncologico, Bari 70126, Italy.
4 Unità Operativa di Radiologia, IRCCS Oncologico, Bari 70126,
Italy.
5 Unità Operativa di Radioterapia, IRCCS Oncologico, Bari 70126,
Italy.
6 Unità Operativa di Oncologia, Ospedale Generale S. Giuseppe, Via
Paladini 40, 50053 Empoli (Firenze), Italy.
7 Direzione Scientifica, IRCCS Oncologico, Bari 70126, Italy.
Received September 18, 2003;
accepted after revision February 13, 2004.
Presented at 2003 meeting of the American Roentgen Ray Society, San Diego,
CA.
Abstract
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SUBJECTS AND METHODS. Between February 2002 and March 2003, 18 subjects with unresectable lung neoplasms, four of whom had primary neoplasms and 14 of whom had metastatic neoplasms, underwent lung radiofrequency ablation. The technique was performed percutaneously using a monopolar cooled-tip electrode needle under CT guidance with the patient under general anesthesia. Patients had no more than three nodules with a total diameter of 10 cm and no evidence of extrathoracic disease. A total of 40 nodules were treated in 24 therapeutic sessions. After treatment, patients underwent follow-up every 3 months by CT and nuclear MRI with gadolinium for a median time of 8 months (range, 2–14 months).
RESULTS. No evidence of local relapse was discovered in 94.4% of subjects. The treatment was safe and well tolerated. Complications encountered included massive pneumothorax, which occurred in one subject, requiring pleural drainage. Other complications were moderate pneumothorax (also requiring pleural drainage), cough, fever, slight dyspnea, and pain, but these complications were short in duration and successfully treated.
CONCLUSION. Radiofrequency thermal ablation is a promising technique in the treatment of patients with lung neoplasms and has been found to be both safe and technically feasible.
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The predominant mechanism of action of radiofrequency ablation is thermal injury. A high-frequency alternating current emitted from the exposed noninsulated portion of the electrode generates frictional heat, agitating ions in the tissue surrounding the tip of the needle. The heat causes coagulative necrosis, driving extracellular and intracellular water out of the tissue, thereby denaturing proteins [19–21]. These effects are achieved in a predictable manner at predictable temperatures and in a relatively predictable volume [22]. Histopathologic findings have been evaluated both in animal models [23] and in human specimens [24] and reveal well-defined areas of tumor necrosis. Lung tumors seem well suited to radiofrequency ablation because the surrounding air in adjacent normal lung parenchyma provides an insulating effect that seems to concentrate radiofrequency energy [25]. Moreover, CT allows accurate localization of the electrode needle, facilitating optimal treatment of the neoplasm. Other advantages of using radiofrequency ablation include the ability to administer treatment percutaneously as well as a short hospital stay for the patient, which tends to have a favorable impact on the patient's quality of life.
The aim of this study was to assess the safety and technical feasibility of lung radiofrequency ablation in patients with primary and secondary unresectable lung tumors. A secondary objective was to determine the efficacy of treatment.
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Between February 2002 and March 2003, 18 consecutive patients (11 men and seven women) were enrolled in this study, and a total of 40 lung neoplastic lesions were treated with percutaneous radiofrequency thermal ablation. The median age was 69 years (range, 26–80 years). Four subjects were treated for primary neoplasms, and 14 subjects were treated for metastatic lesions. Ten subjects had single nodules. Eight subjects had multiple nodules; however, one of these eight subjects was treated for a single nodule and the other nodules had previously received another form of treatment. The median number of treated lesions per patient was one (range, 1–7). The median nodule size was 3 cm, with a range of 0.6 to 11 cm. All subjects received prior systemic chemotherapy. In addition, three subjects were previously treated with surgical pulmonary resection. Four subjects underwent two radiofrequency ablation sessions, and one subject underwent three radiofrequency ablation sessions after having developed subsequent nodules.
Two subjects with non–small cell lung cancer were ineligible for the study because they refused surgery, and another two were ineligible because of comorbidity. Fourteen subjects with metastatic lung disease were considered ineligible for surgery: 11 refused surgery, and the other three were ineligible because of technical, anatomic, or functional contraindicating conditions. In total, 13 patients had potentially resectable neoplasms, but they refused to undergo surgery and five patients did not undergo surgery because of technical, anatomic, or functional contraindications.
The diagnostic workup before the treatment included CT scans of the brain, thorax, and abdomen; skeletal radiographs (including skull, vertebral column, pelvis, femur, and humerus); and anesthesiology examination. Lesions were subclassified by site. Paramediastinal lesions were those in contact with mediastinal structures (without infiltration) or those that were less than 1 cm from mediastinal structures, including fibrous pericardium, major vessels, cardiac pedicle, trachea, and bronchi. Central parenchymal lesions were those that were fully surrounded by pulmonary parenchyma (aerated) or those that were more than 1 cm from the mediastinal structures and visceral pleura. Lesions considered to be subpleural were those in direct contact with the pleura (without infiltration) or those that were less than 1 cm from the pleura.
Radiofrequency Ablation Technique
After CT scan centering, radiofrequency ablation was performed
percutaneously using a 17-gauge monopolar cooled electrode needle (Cooled-tip
RF system, Radionics), with lengths ranging between 10 and 15 cm, depending on
the depth of the lesion to be treated. The exposed part of the needle (i.e.,
the noninsulated portion) was between 1 and 3 cm. Selection of the exposed tip
length of the needle was based on the diameter of the lesion—that is,
the needle size was always greater than the area to be treated (e.g., a 7.0-mm
lesion would require a 1-cm needle). The wattage–current setting is
selected automatically by the system and is based on the amount of water in
any specific tissue (i.e., the amount of free ions present). The system
adjusts itself according to the level of resistance and impedance. A maximum
treatment time of 12 min has been found to ensure complete necrotic
coagulation of the tumor volume according to the corresponding diameter of the
exposed part of the needle. The system alternates between "on"
(active) and "off" (inactive) modes. Long periods (30–40
sec) of inactivity by the machine and short periods (5–7 sec) of
activity (i.e., with readings by the system of > 100 
) indicate that
the scheduled volume of the nodule has been ablated. Larger lesions (> 3
cm) are divided into sectors, and each sector is treated as if it were a 2-cm
lesion, with the exposed part of the needle being 3 cm. The sectors overlap to
ensure full ablation of the entire nodule. All lesions are treated in one
session in the manner described. Both multiple lesions and large lesions can
result during long treatment sessions however, and in both instances are
treated in a single session. Grounding pads (22 x 19 cm) were placed in
the lumbar or gluteal region, according to the position of the nodule to be
treated. Nodules close to the apex of the lung required pads to be placed in
the lumbar region, and nodules close to the base of the lung required pad
placement in the gluteal region.
A single insertion was used for lesions with a diameter less than or equal to 2.8 cm, and treatment sessions lasted 12 min. All subjects were treated under general anesthesia. Premedication was administered using fentanyl, midazolam, and atropine. Propophol and succinylcholine were used to induce anesthesia, while fentanyl, propophol 20%, and cisatracurium besylate were used to maintain anesthesia. All subjects were intubated with a double-lumen tube and monitored with mechanical ventilation using fraction of inspired O2 of 0.35–0.40. Continuous monitoring of heart rate, blood pressure (measured noninvasively with cuff), ECG, blood oxygen levels, blood carbon dioxide levels, saturated blood oxygen levels, and diuresis was performed during the procedure. A hemogasometric check was made before, during, and after treatment. Subjects were maintained in the prone position if the lesion was dorsal. If the lesion was anterior or lateral, the subject was maintained in the supine or lateral position, respectively.
A CT scan with contrast medium was obtained 48 hr before treatment to evaluate baseline enhancement of the tumor. Immediately before treatment, a thoracic CT scan without contrast medium was obtained with a collimation of 5 mm to select the optimal percutaneous access of the needle. A CT scan without contrast medium was also obtained every 3 min during treatment. Obtaining CT scans was considered necessary to detect possible acute complications, such as massive pneumothorax and hemorrhage, in a timely manner. Because a CT scan is not a real-time technology, we believe the 3-min intervals to be sufficient to detect and manage complications. CT scans also allowed monitoring of structural changes induced by treatment. In addition, because making small corrections in the position of the needle during this procedure is often necessary as a result of the morphology and volume of the lesion, CT provides the ability to monitor even the smallest repositioning of the needle.
Immediately after the removal of the endotracheal tube, an additional unenhanced CT scan was obtained of all subjects while in the supine position. Chest radiographs to detect and monitor pneumothorax and other complications were obtained 2 hr after treatment and daily until discharge of the subject from the hospital. All subjects received antibiotic prophylaxis with parenteral cephalosporin immediately before the procedure and for 6 days thereafter.
Assessment of Treatment Efficacy
All subjects underwent CT with contrast medium 48 hr after treatment,
followed by CT 30 days later. In addition, eight (44.4%) of 18 subjects were
also administered gadolinium for MRI. CT and MRI were performed on average
every 3 months after treatment.
The efficacy of treatment was assessed according to the presence or absence of enhancement. The presence of cavitation may be used as an additional marker of treatment efficacy.
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Impedance values ranged between 75 and 140 ; values in the range of
100–140 were found in five cases in which the electrode needle
was partially outside the lesion and inside the aerated parenchyma. The
internal temperature, close to the electrode needle, ranged between 45°C
and 75°C. Temperatures not greater than 58°C were sometimes recorded
during successive insertions of the electrode needle into large lesions, which
are treated in partially overlapping sectors to allow complete ablation of the
full volume of the tumor. Nevertheless, in all cases the temperature was never
less than 45°C. The power generated during the procedure was between 85
and 140 W. Values between 85 and 90 W were observed in six instances while
treating nodules smaller than 3 cm, during which times the electrode needle
was partially outside the lesion. These instances seemed to be inversely
correlated to impedance.
Subjects
The median hospitalization time after treatment was 6 days (range,
3–13 days), whereas median follow-up time was 8 months (range,
2–14 months). Relapsed disease in the treated area was observed in one
case (5.6%) and was seen in six subjects (33.3%) at distant sites. Seventeen
(94.4%) of 18 patients are alive, 12 of them without evidence of disease.
The side effects for 24 sessions of treatment are summarized in Table 1. Moderate-grade fever (< 38.5°C), requiring antipyretic medication, occurred during 11 sessions of treatment and usually resolved within a few days. Cough with rust-colored spitting occurred in seven sessions, lasting 48–72 hr. In nine sessions, patients complained of slight thoracic pain and were treated with nonsteroidal antiinflammatory medication. Minimal pleural asymptomatic effusion occurred in seven sessions; it resolved spontaneously. Slight and transient dyspnea was observed in three sessions.
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Pneumothorax requiring pleural drainage occurred in three sessions, involving more than 30% of the ventilated volume of the treated lung in one case and more than 10% but less than 30% in the other two cases. After the first insertion of the electrode needle, (Cooled-tip RF system), two subjects—those with monolateral pneumothorax involving ventilation volumes of greater than 10% but less than 30%—required pleural drainage. The chest tube was removed without further complication after 5 and 7 days, respectively, when the pneumothorax was corrected. In the third patient with a reduction of ventilation volume greater than 30%, pneumothorax was observed 48 hr after the procedure. The subject became symptomatic with mild subcutaneous interstitial emphysema 72 hr later and required pleural drainage for 10 days. Two months later, this subject exhibited disease progression with extensive pleural infiltration that was not previously visible on CT, leading to an unfavorable outcome, accompanied by cachexia and diminished respiratory function. No other complications, such as hemorrhages, bronchopulmonary fistulas, arteriovenous fistulas, or lung abscesses were observed, nor were there any treatment-related deaths, and no subjects suffered neurologic sequelae after the radiofrequency ablation procedure.
Radiologic Imaging
Figure 1A shows a primary
lung carcinoma before radiofrequency thermal ablation.
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Between the first 3 and 12 min of treatment, the appearance of the lesions on CT was as follows: wrinkling of the edges; partial emptying, likely due to vaporization of tissue; and unchanged diameter (Fig. 1B). Multiple concentric rings with varying densitometric characteristics appeared in the pulmonary parenchyma around the lesion immediately after treatment. These concentric rings resembled a cockade, which is a particular sort of bow made from ribbon, historically worn on berets (Figs. 1C and 1D). We have thus coined the term "cockade phenomenon." In all cases, the cockade phenomenon was most evident 48–72 hr after treatment.
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Additional effects of treatment included a clear sectorial hyperemia surrounding the lesion, conical with the apex at the hilus. This effect lasted 24–72 hr (Fig. 1E). Pleural effusion reached a maximum level between 24 and 48 hr after radiofrequency ablation and resolved itself in a few days.
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CT scans obtained before radiofrequency ablation revealed a typical contrast-enhanced image of a malignant neoplasm (Fig. 2A). Immediately after radiofrequency ablation, CT scans showed the following peculiar aspects: persistent cockade phenomenon, clearly visible (Fig. 2B); persistent coneshaped sectorial hyperemia; and moderate pleural effusion.
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CT scans obtained after 30 days and all successive CT scans revealed progressively less and less definition, fading over time, of the lesion, and ultimately a core of hyperdense scar tissue surrounded by a thin hyperdense ring with a distance from the nucleus that was inversely correlated to the size of the nodule. The treated nodules appeared enlarged, most likely because of central necrosis and cavitation surrounded by reparative fibrosis, without contrast enhancement (Figs. 2C and 2D).
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Only one subject, who was affected by non–small cell lung cancer with a maximum diameter of 7 cm, showed contrast enhancement in a small peripheral area 2 months after radiofrequency ablation. A fine-needle aspiration biopsy was performed under CT guidance that revealed tumoral relapse.
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Surgery is considered to be the standard treatment for patients with localized primary lung cancer and metastatic resectable lesions, although only a small percentage of patients are candidates for surgery because of comorbidity, poor cardiorespiratory reserve, and technical contraindications. Therefore, the use of a minimally invasive procedure such as radiofrequency ablation is attractive, especially when considering the generally poor outcome of these patients when being treated with systemic chemotherapy and radiotherapy.
In this study, the 18 treated subjects showed a strong willingness to receive radiofrequency ablation therapy. Pneumothorax requiring pleural drainage occurred in only three sessions (12.5%) and was effectively treated in each case, along with the other side effects of treatment. This procedure, performed with a monopolar electrode needle under CT guidance and the patient under general anesthesia, was found to be safe and technically feasible. This assessment takes into account the potential risk for cerebrovascular accident due to microbubble passage into the pulmonary veins [27].
General anesthesia was deemed necessary for both medical and radiologic reasons. With regard to medical considerations, general anesthesia provides the ability to control airway passages in the event of a massive pneumothorax or serious intraparenchymal hemorrhage. It also provides the ability to improve the ventilation–perfusion rate in the event of serious concomitant bronchopulmonary insufficiency and due to physiologic changes during treatment secondary to the lateral positioning of the subject. The use of general anesthesia also ensures the complete immobilization of the subject, which contributes to making the technique as minimally invasive as possible because abrupt, unintentional movements of the body or respiratory movements can be avoided. Moreover, intubation with a doublelumen tube allows the management of a possible massive and monolateral pneumothorax while allowing ventilation of the other lung. This capability is especially useful in patients with severe obstructive chronic bronchial disease and even more so in cases of massive hemorrhage [16, 18, 26, 28].
Radiologic motives for using general anesthesia include the assurance of a correspondence between the thoracic CT scans and each superficial section of the nodule being treated being obtained as a result of the patient's immobility and avoiding the need to obtain repeated CT scans in the event that the patient had moved in some way or in cases in which there are multiple or large lesions. In addition, performing radiofrequency ablation on a small nodule (e.g., 1 cm) in the lower portion of the lung would be impossible to center with the patient breathing normally. The use of a double-lumen tube makes it possible to block ventilation of the lung being treated using just enough O2 to keep it inflated by continuous positive airway pressure (5–10 cm H2O) while ventilating the other lung, thereby allowing accurate centering of the needle.
Most subjects were completely autonomous within 12 hr of treatment. The median hospitalization time was influenced by factors such as the experimental nature of the study as well as continued monitoring and observation of subjects after treatment in the absence of complications and in three cases in which three subjects required pleural drainage secondary to development of pneumothorax. With respect to our discussion of the cockade phenomenon in the Results section of this article, our description correlates well with the results reported by Miao et al. [29] in an article highlighting typical MR images of lung neoplasms in rabbits treated with radiofrequency ablation. The authors believe that the cockade phenomenon could reflect similar histopathologic changes (Figs. 3A and 3B) with concentric layers of varying thicknesses, which they attribute to thermal gradients between the tumoral nodule and the surrounding parenchyma. Radiofrequency ablation of a tumor results in an area at the periphery of the ablated tumor that is in contact with necrotized healthy tissue, thereby creating an area that reduces the risk of local recurrence of the disease. This area is referred to as the "safety zone." The thickness of the safety zone is inversely correlated to the diameter of the tumor. Small lesions have a more extensive peripheral safety zone because of a higher thermal gradient. In large lesions, heat loss occurs easily because the greater the distance from the center of the nodule, the greater the occurrence of heat loss, resulting in a smaller peripheral safety zone. Generally, scar tissue forms at the periphery of the nodule where microhemorrhages and hyperemic rings are found and surrounds the necrotic area to form widespread air pockets in nodules smaller than 2 cm. In these smaller lesions, the formation of these empty spaces often resulted in the fragmentation of the nodule and the fragments migrating toward the periphery and attaching themselves to the scar-tissue fibers (Fig. 2E).
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In this study, only one patient with a diagnosis of primary non–small cell lung cancer, with a diameter of 7 cm, presented with relapsed disease visible on CT and MRI at the periphery of the treated lesion (Fig. 4A). Three months after the first treatment, the subject underwent a second radiofrequency ablation treatment to completely eradicate the lung neoplasm. Five months after the second procedure, the subject is alive with no evidence of disease shown on MRI with gadolinium (Fig. 4B). Despite the short followup, these data suggest that radiofrequency ablation is an efficient treatment for lung neoplasms with a low percentage of local relapse (1/40 [2.5%] treated nodules). Four subjects with relapse at pulmonary sites distant from the initially treated lesions were referred for an additional therapeutic session.
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Notwithstanding the theoretic considerations regarding the capability of the cooledtip electrode needle to encompass the entire tumoral lesion and safety margin, we deem radiofrequency ablation useful in treating nodules larger than 3.5 cm in diameter with adjunctive radiotherapy, when possible, to reduce the risk of recurrent disease at the peripheral areas of ablated neoplasms.
As previously described in the treatment of liver neoplasms [30], histopathologic findings seem well correlated to radiologic imaging [29]. Therefore, CT and MRI could be useful in making it easier to assess the efficacy of treatment [29–32].
In this study, four (22.2%) of 18 patients had paramediastinal lesions close to the hilus, pericardium, proximal bronchi, and major vessels without infiltration of these structures. Nevertheless, the treatment was performed without technical problems or complications, thus confirming its feasibility in such cases.
We wish to emphasize the safety of lung radiofrequency ablation. It is a conservative, minimally invasive treatment that can be administered multiple times; it could be effective especially in patients not eligible for surgery or with slow-growing lesions. In addition, the promising results obtained in treating small lesions warrant investigation of this technique in patients with resectable lung neoplasms. In conclusion, lung radiofrequency ablation has been found to be an interesting technique that could play a role in a multidisciplinary approach to primary and secondary lung tumors. We strongly suggest that further investigation with larger and randomized studies is performed to assess the optimal combination of radiofrequency ablation with other antitumoral treatments and to better identify patients who could benefit from this therapeutic option.
Acknowledgments
We thank Giuseppe Laricchia, Vito Cilifrese, Teresa Lionetti, and Vincenzo
Colaluce for their technical expertise in the realization of this study. We
also thank Michael Kolk for his help in the preparation of this
manuscript.
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