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Image-guided ablation of lung tumors

Image-guided ablation of lung tumors
Literature review current through: Jan 2024.
This topic last updated: Nov 06, 2023.

INTRODUCTION — In the United States, lung cancer occurred in over 230,000 patients and caused over 130,000 deaths [1]. Worldwide, lung cancer occurred in approximately 2.2 million patients in 2020 and caused an estimated 1.8 million deaths [2]. The lung is also a common site for metastatic disease. Common primary tumors metastasizing to the lungs include colorectal cancer, breast cancer, renal cancer, melanoma, sarcomas, and head and neck cancer.

Surgery is the standard treatment option for most patients with resectable lung cancer and for the unusual patient with oligometastatic lung metastases. However, surgery is not appropriate in many cases because of the presence of disseminated disease or because the patient's age or comorbidity precludes a surgical approach. In these settings, palliation of pulmonary symptoms may be beneficial.

The options for patients in this situation include palliative surgical procedures, different types of radiation therapy, and image-guided techniques. Systemic chemotherapy may be too toxic for this group of patients, and many may have already failed this treatment option. Over the past two decades, many image-guided techniques have been applied to the treatment of lung neoplasms. All of these techniques rely on thermal or electrical methods to directly destroy tumor cells in situ [3]. These image-guided procedures are almost exclusively performed under computed tomography (CT) guidance. There are many factors that affect the utilization and patient outcomes when these techniques are to be considered, including tumor biology, tumor location and extent, and the patient's overall health.

Among image-guided techniques, radiofrequency ablation is used more commonly than microwave ablation, laser ablation, cryoablation, and irreversible electroporation. These techniques are discussed below, including clinical data where available. However, there are no trials comparing these image-guided techniques.

The roles of limited surgical techniques and stereotactic body radiation therapy are discussed separately. (See "Management of stage I and stage II non-small cell lung cancer", section on 'Limited (sublobar) resection, in select groups' and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques" and "Stereotactic body radiation therapy for lung tumors".)

RADIOFREQUENCY ABLATION — Radiofrequency (RF) ablation (RFA) is the most widely used ablative technique for the treatment of lung malignancies. The term radiofrequency applies to all electromagnetic energy sources with frequencies less than 30 MHz; however, most clinically available devices function in the 375 to 500 kHz range.

For RFA, the electrode is placed into the tumor using imaging guidance. The electrode is coupled to an RF generator and is grounded by means of a grounding pad or pads applied to the thighs. The radiofrequency generator produces a voltage between the active electrode (applicator) and the reference electrode (grounding pad), establishing electric field lines that oscillate with the alternating current. This oscillating electric field causes electron collisions with the adjacent molecules closest to the applicator, inducing frictional heating [4]. Tissue heating to temperatures greater than 60°C leads to immediate cell death; for any given RFA procedure, the application of energy from the applicator is maximized to create a zone of tissue necrosis that encompasses the tumor and a margin of normal parenchyma [5]. The volume of ablation achieved is based on the energy balance between heat conduction of the local radiofrequency energy applied and heat convection from the circulating blood and extracellular fluid.

There are multiple RFA systems commercially available [6-8]. Two of the systems use a deployable radiofrequency array electrode with 4 to 16 small wires (tines) deployed through a 14- to 17-gauge needle [6,7]. The site of deployment of the electrode may vary depending upon the design of the electrode. The third system utilizes a single or triple "cluster" (three single electrodes spaced 5 mm apart) perfusion electrode; the tip is positioned in the deepest part of the tumor.

The safety, local control rates, and survival rates have been published in single nonrandomized institutional series and an industry-funded multicenter trial [9-14]. To date, no properly powered trials have compared one RFA system with another, RFA with other image-guided ablative techniques, or RFA with stereotactic body radiation therapy [15].

Key results from various studies include the following:

The feasibility of RFA in patients with either primary non-small cell lung cancer (NSCLC) or pulmonary metastases has been established in multiple institution case series [9,13,16-18]. As an example, the use of RFA in a patient with NSCLC and the resolution of the tumor over time are shown in the images (image 1 and image 2 and image 3 and image 4 and image 5). Analyses from single-institution studies suggested that better results are achieved in patients with smaller lesions (ie, ≤3 cm) [9].

The efficacy of RFA was prospectively evaluated in a study that included 106 patients with 183 lung tumors from seven centers in the United States, Europe, and Australia [11]. The study population included 33 patients with primary NSCLC and 73 patients with lung metastases (73 percent from a colorectal primary). All lesions were less than 3.5 cm in diameter. Overall survival at one and two years was 70 and 48 percent, respectively. Complete response (eg, complete thermal ablation of the target lesion) of at least one year's duration was observed in 75 of 85 assessable patients (eg, patients had follow-up contrast-enhanced computed tomography [CT]) (88 percent), and there was no difference between those with NSCLC and those with pulmonary metastases. In those with primary NSCLC, the two-year cancer-specific survival was 92 percent.

The efficacy of RFA in lung metastases was evaluated in a series of 566 patients with 1037 lung metastases [18]. The most common primary sites were colon or rectum, kidney, and soft tissue sarcoma (52, 18, and 9 percent of patients, respectively). At a median follow-up, the one-, three-, and five-year survival rates were 92, 68, and 52 percent, respectively. These highly positive results can be explained by a mean tumor diameter of 15 mm, and 90 percent of patients had three or fewer tumors.

In a series of 59 stage I NSCLC patients, the complete response rate was 59 percent [13]. Median overall survival and cancer-specific survival were 33 and 41 months, respectively. Cancer-specific survival rates at one, three, and five years were 89, 59, and 40 percent, respectively.

The overall frequency of complications varies among different series. As an example, in one series of 153 consecutive patients with either primary or metastatic lesions, a pneumothorax was observed in 28 percent of sessions, with 10 percent requiring chest tube insertion [9]. A session is defined as the entire procedure performed in one sitting. In another series of 129 RFA sessions in 100 patients, the incidence of pneumothorax was 32 percent; other complications included chest drain insertion, chest pain, pleural effusions, and hemoptysis (20, 18, 12, and 7 percent, respectively).

The largest assessment of serious complications comes from a retrospective single-institution series of 420 patients with 1403 lung tumors who underwent 1000 RFA sessions [14]. There were four deaths related to the RFA procedure, one from hemothorax and three from interstitial pneumonia (0.4 percent). The major complication rate was 9.8 percent, the most frequent of which were thermal pleurisy, pneumonia, lung abscess, bleeding requiring transfusion, and pneumothorax requiring pleural sclerosis.

A National Cancer Institute (NCI)-funded multicenter trial (ACOSOG Z4033, now the Alliance Cooperative group) evaluated the safety and efficacy of RFA alone in patients deemed medically inoperable by a board-certified thoracic surgeon. The overall survival rate was 86.3 percent at one year and 69.8 percent at two years. The local tumor recurrence-free rate was 68.9 percent at one year and 59.8 percent at two years and was worse for tumors >2 cm. There were no grade 4 or grade 5 attributable events. There was no significant change in the forced expiratory volume at one second (FEV1) or diffusing capacity of the lungs for carbon monoxide (DLCO). Tumors sized less than 2 cm and patients with performance status of 0 or 1 were associated with statistically significant improved survival of 83 percent and 78 percent, respectively, at two years [19].

An analysis of 12 years of Surveillance, Epidemiology, and End Results data compared clinical outcomes between thermal ablation and stereotactic radiation based on lung cancer histology and showed no differences in survival for the more common NSCLC histology, but did show improved survival in the thermal ablation group for NSCLC with neuroendocrine histology [20].

Fatal hemoptysis is rare (less than 1 percent) and has been associated with pulmonary artery pseudoaneurysm formation [21] and inadvertent cessation of clopidogrel [22].

Although a meta-analysis of studies of stereotactic body radiation therapy (SBRT, 31 studies) and RFA (13 studies) suggested worsened local tumor control with RFA (42 versus 86 percent at five years), there was no difference in overall survival [23]. Given the absence of randomized trials, with available data suggesting equivalent survival between RFA and SBRT, the choice between these modalities should be made in a multidisciplinary setting, taking into account the expertise of the treating institution as well as patient and provider preferences.

A subsequent analysis of the survival rates of stage I NSCLC treated with thermal ablation versus SBRT from the National Cancer Database established by the American College of Surgeons and the American Cancer Society demonstrated equivalent five-year survival rates [24].

Establishing the role of RFA compared with other image-guided techniques, SBRT, or surgical sublobar resection will ultimately require the conduct of randomized clinical trials.

MICROWAVE ABLATION — Microwave (MW) ablation uses a percutaneously placed needle-like antenna under computed tomography (CT) guidance to directly deliver MW energy into a tumor. The MW energy is not an electrical current and is in a much higher frequency range that extends from 300 MHz to 300 GHz, compared with that used in radiofrequency ablation (RFA). The broader deposition of MW energy creates a much larger zone of active heating.

MW applicators available for clinical use generally operate in the 900 to 2450 MHz range [25]. Microwave tissue heating occurs because of the induction of kinetic energy in water molecules. Because of their electron configuration, water molecules have highly polar properties and function as small electric dipoles with the negative charges preferentially localized around the oxygen nucleus. The rapidly alternating electric field of the MW antenna causes water molecules to spin rapidly in an attempt to align with electromagnetic charges of opposite polarity. These spinning water molecules interact with neighboring tissues, transferring a portion of their kinetic energy. This energy transfer results in local tissue hyperthermia.

There are seven MW systems that are commercially available in the United States and Europe [26]. These systems use either a 915-MHz generator [27-29] or a 2450-MHz generator [22,30-32] and straight 17-14 gauge antennae with varying active tips of 0.6 to 4.0 cm in length. Perfusion of the antenna shaft is required for five of the seven systems with either a room-temperature fluid or carbon dioxide to reduce conductive heating of the non-active portion of the antenna, thus preventing damage to the skin and tissues proximal to the active tip. There are no published data on differences between the MW systems regarding clinical safety or effectiveness. Like RFA, MW ablation can be performed with intravenous conscious sedation or general anesthesia.

In a study of 50 patients with 82 pulmonary masses treated with MW ablation, the overall survival at one, two, and three years was 65, 55, and 45 percent, respectively. Cancer-specific mortality at one, two, and three years was 83, 73, and 61 percent. Cancer-specific mortality was not significantly affected by tumor size or the presence of residual disease. Tumor necrosis with central air cavities (eg, cavitation) was associated with a lower cancer-specific mortality; the authors hypothesized that this imaging finding was indicative of a more thoroughly ablated lesion [33]. Several studies have revealed that tumor size is a significant risk factor for tumor progression or recurrence after MW treatment [34,35]. As with RFA, larger tumors can be difficult to completely control with thermal ablative techniques, and larger tumors may also have a higher likelihood of regional or systemic spread.

In a subsequent retrospective series in a larger group of 108 patients with a solitary lung malignancy treated with microwave, the recurrence rates were 22, 36, and 44 percent at one, two, and three years. Recurrence rates were estimated to be 17 percent at 13 months for tumors under 3 cm and 31 percent for tumors larger than 3 cm. Median time to tumor recurrence was 64 months. The median time to cancer-related death was 30.6 months in patients with primary or secondary assisted technical success. The 11-, 24-, and 41-month cancer-related survival rates were 89, 75, and 57 percent, respectively [36].

LASER ABLATION — Laser ablation is a thermal technique whereby light energy is converted into heat by means of tissue interactions with sources such as an Nd:YAG laser, with a wavelength of 1064 nm, or a continuous-wave infrared (820 nm) diode laser. The energy is transmitted through a flexible fiberoptic cable that is percutaneously inserted through an outer sheath. The photon delivery causes heating of the tissue and cell death due to protein denaturation [37].

The size of the ablation zone is limited by tissue carbonization near the applicator. Cooling of the fiberoptic cable in an open or closed coaxial system allows for greater energy deposition. In addition, insertion of multiple laser fibers allows the creation of a larger ablation zone. For liver tumors, magnetic resonance thermometry has been advocated to enable accurate assessment of the laser ablation zone because tumor and normal liver heating can be unpredictable. However, computed tomography guidance alone has been used for lung tumors since aerated lung provides insufficient tissue signal for temperature measurement with magnetic resonance. The development of cooled applicator systems allowed for a 50 percent greater region of thermocoagulation during energy delivery by reducing local tissue charring at the surface of the applicator [38].

The long-term safety and efficacy of laser ablation for definitive local control and tumor debulking of pulmonary metastatic disease was evaluated in a series of 64 patients with a total of 108 tumors [39]. Technical success was achieved in 85 of 108 cases (79 percent). Local tumor progression was seen in 28 percent of tumors after an initial technical success rate. The median survival for patients treated for local control (31 of 64 patients) was 32 months and overall one-, two-, three-, four-, and five-year survival rates were of 81, 59, 44, 44, and 27 percent, respectively. The pneumothorax rate was 38 percent, with chest tubes needed in 5 percent of patients, which is similar to that with other thermal modalities.

Percutaneous laser ablation systems have been in use in Europe for years; however, only one system is commercially available in the United States [40], and there are no data on its application for lung tumors.

CRYOABLATION — Cryoablation, using the local application of liquid nitrogen directly to or within sealed metal cryoprobes, has been used to treat liver tumors in the operating room setting for more than three decades [41]. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates who are eligible for local ablation", section on 'Cryoablation'.)

The development of argon-based cryoablation systems has permitted a substantial decrease in the diameter of cryotherapy applicators. This has made the percutaneous application of this technique to other sites of disease more feasible because collateral injury to the skin and structures along the insertion path is minimized.

Pressurized argon gas can cool to temperatures as low as -140°C. At temperatures colder than -40°C, cryogenic destruction of living tissue occurs due to several mechanisms, including protein denaturation, cell rupture caused by osmotic shifts in intracellular and extracellular water and ice crystal formation, and tissue ischemia from microvascular thrombosis [42].

There are two commercially available percutaneous argon-based cryoablation devices available [43,44]. These systems allow the placement of 1 to 10 individual 1.5- to 2.4-mm diameter cryoprobes. With these systems, a freeze-thaw-freeze cycle at a single probe position is typically used to achieve local tumor necrosis. Newer treatment schemes have been proposed as a means to shorten the ablation time and create a larger ablation zone. These use a three-minute freeze, three-minute thaw, seven-minute freeze, seven-minute thaw, and a final five-minute freeze. This new schema was adopted to generate interstitial fluid in the adjacent lung tissue that allowed further ice formation into the lung, and hence improved margin control.

A computed tomography (CT) scan is typically obtained after treatment, and the low-density changes within the targeted tumor are measured and used to approximate the size of the ablated region. The outer periphery of the freeze zone may not reach cytotoxic temperatures; therefore, a 3- to 7-mm margin is subtracted from the diameter of the low-density ablation region to better approximate the true volume of tissue necrosis [45]. Ice ball visualization with CT allows direct comparison of the ablative zone in relation to the tumor margins. This can give the operator greater confidence when treating tumor tissue near critical structures and allows measurement of the cytotoxic ice margin, which is typically situated 3 to 7 mm within the most peripheral aspect of the ice ball.

Multiple applicators must be used to treat large tumors. The advantages of cryoablation over radiofrequency ablation include larger tumor ablation volumes, the ability to use multiple applicators, a highly visible ablation zone, and less procedural pain due to the analgesic effect of freezing. Compared with heat-based thermal ablation therapies, cryoablation is able to preserve the collagenous tissue and cellular architecture in frozen tissue, which makes it a safer option near vasculature or bronchi [46]. In patients with underlying emphysema, cryoablation may increase the risk of pneumothorax and bleeding, which could be detrimental in patients with poor pulmonary reserve. To date, there have been no large randomized trials comparing the heat- and cold-based ablative modalities.

Bleeding along the needle tract is a theoretical disadvantage of cryoablation; tract coagulation with fibrin glue can be used in such instances, and one of the cryoablation systems contains additional radiofrequency heating of the cryoprobe shaft that allows thermocoagulation of the needle tract prior to probe removal. Another disadvantage of cryoablation is the longer procedural time required to generate adequate tumor coverage compared with heat-based ablative therapies.

Several large studies evaluating cryoablation for the treatment of intrathoracic lesions have revealed that the treatment is an effective and safe option [47-49]. The largest study evaluating cryoablation for thoracic masses demonstrated that location and size were predictive of increased tumor ice coverage [47].

The potential efficacy of cryotherapy is illustrated by the following:

A study that included 71 patients with 210 tumors (11 primary and 199 metastatic neoplasms) evaluated factors predicting progression after cryoablation treatment. Median follow-up was 454 days, and local progression was observed in 50 tumors. Local progression-free rates at one, two, and three years were 80, 69, and 68 percent, respectively. According to multivariate analysis, independent risk factors for local progression after cryoablation included tumor size greater than 20 mm and the presence of a vessel with at least a 3 mm diameter located within 3 mm of the tumor [49].

Another study analyzed the long-term outcomes in 45 patients with 47 primary stage I (T1N0M0) non-small cell lung cancers treated with cryoablation between 2006 and 2011 (table 1) [50]. The five-year overall survival rate was 68 percent, and the five-year progression-free survival rate was 88 percent. Pneumothoraces occurred in 51 percent of cases, including six cases requiring a chest tube and one necessitating more prolonged intervention. Bleeding occurred in 40 percent of cases, most of which were minor. There were two major hemoptyses and one prolonged bronchopleural fistula. There were no deaths associated with the cryoablation.

A prospective multicenter trial evaluating the safety and efficacy of cryoablation for the treatment of metastatic lung tumors (SOLSTICE trial) showed local tumor control rates of 85.1 and 77.2 percent at 12 and 24 months with a Kaplan-Meier overall survival rate of 97.6 and 86.6 percent at one and two years [51].

IRREVERSIBLE ELECTROPORATION — Irreversible electroporation (IRE) is a novel ablation technology being investigated for the treatment of solid malignancies. It utilizes direct electrical pulses to create nanoscale defects or pores in cell membranes; these defects disrupt cellular homeostasis leading to apoptotic cell death [52,53]. Electroporation can either be reversible or irreversible, the latter leading to cell death.

The direct electrical pulses in IRE are deposited using an applicator; this forms an electrical field whose magnitude decreases from the applicators outward to the tissue. Cells immediately adjacent to the applicator undergo cell death by virtue of irreversibly increased permeability. There is one IRE system approved for use in the United States [54]. The system utilizes monopolar electrodes with a retractable sheath, which allows the active tip to be adjusted between 1 and 4 cm. The generator allows for the simultaneous use of up to six electrodes with a maximum delivery of 50 A and 3000 V.

Since IRE is a non-thermal ablation technique, its purported benefits include overcoming the heat sink effect and the ability to treat near bronchovascular structures without causing structural injury [55,56]. Theoretically, IRE would be a well-suited ablation modality for lung lesions close to the chest wall, hilum, and mediastinum due to the low potential for collateral structural damage. To date, there have been few published clinical studies evaluating electroporation of lung tissue in humans [57,58]. One study was a prospective trial across two academic centers named the ALICE trial. This trial was stopped prematurely due to failing to meet expected efficacy at interim analysis based on high recurrence rates in 61 percent within one year of treatment [59].

SAFETY — Overall, percutaneous image-guided lung ablation is generally safe. It is associated with a moderate risk of pneumothorax, although this complication is not associated with increased mortality [60]. In a retrospective study of 3344 patients in the Nationwide Inpatient Sample (NIS) database (61.9 percent treated for primary lung carcinomas and 38.1 percent treated for pulmonary metastatic disease), complication rates following percutaneous image-guided lung ablation were as follows [60]:

Pneumothorax (38.4 percent)

Pneumonia (5.7 percent)

Effusion (4 percent)

In-hospital mortality (1.3 percent)

Conversion to thoracoscopy/thoracotomy (0.9 percent)

Given this low rate of surgical reintervention, image-guided ablation may be an acceptable option for patients who are not candidates for primary surgical resection.

For risks associated with specific modalities of image-guided ablation, refer to the relevant sections above. (See 'Cryoablation' above and 'Radiofrequency ablation' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of lung cancer".)

SUMMARY AND RECOMMENDATIONS

Multiple image-guided ablative techniques are being developed for use in patients with primary non-small cell lung cancer (NSCLC) or oligometastatic pulmonary lesions in whom surgery is not an option. Radiofrequency ablation is the most studied technique, but other approaches under development include microwave ablation, laser ablation, cryoablation, and irreversible electroporation.

Surgical resection is the standard treatment for patients with stage I and II NSCLC if pulmonary function is adequate and medical comorbidity does not preclude surgery. (See "Management of stage I and stage II non-small cell lung cancer".)

For select patients with lung metastases in whom surgical removal has shown benefit and who are surgical candidates and have a single or limited number of lung metastases and no uncontrolled systemic disease, surgical resection is the standard therapeutic approach. (See "Surgical resection of pulmonary metastases: Outcomes by histology" and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques".)

For patients who have either a small primary NSCLC or a limited number of pulmonary metastases, and who are not candidates for surgery, use of radiofrequency ablation or another image-guided technique (eg, stereotactic body radiotherapy) may be appropriate, depending on available expertise. There are no comparative trials comparing these techniques with each other or with external beam stereotactic radiation therapy. (See "Radiation therapy techniques in cancer treatment", section on 'External beam radiation therapy' and "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques'.)

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Topic 4624 Version 35.0

References

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