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Lung Cancer

Lung Cancer: Radiofrequency Ablation (RFA) of Lung Tumors 
  Submitted By: Baskaran Sundaram

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Radiofrequency Ablation (RFA) of Lung Tumors


Authors: Jacek Strzelczyk, MD, Aamer Chughtai, M.D., Ella A. Kazerooni, M.D., M.S., Gregory P. Kalemkerian, M.D.*, Baskaran Sundaram, M.D.


Cardiothoracic Radiology, a division of Department of Radiology, and * Thoracic Oncology, a division of Department of Internal Medicine.
University of Michigan Health System, 1500 East Medical Center drive, Ann Arbor, Michigan, USA




Introduction:

Surgery is the established treatment for early stage primary lung cancers (cancer that started in lung) or limited secondary cancers (cancer that started outside and spread to lung, also known as metastases or metastatic cancer). External beam radiation is an alternative local therapy to surgery, particularly for patients who are not candidates for surgery due to other medical conditions. Thermal ablation, using either heat or cold, is a newer treatment to destroy cells in lung tumors. Heat is most commonly used, and is referred to as Radiofrequency Ablation (RFA). RFA of tumors has gained significant interest and acceptance in the last decade due to its potential to produce a large volume of cancer cell death in a controlled fashion.

What is RFA?

RFA stands for Radio Frequency Ablation. RFA is successfully used to treat certain tumors of lung, liver, kidney, and bone. Radiofrequency energy oscillation agitates cells thereby increasing the frictional heating with in tissues resulting in cell death. The feasibility of lung RFA has been demonstrated in animals (1-3), and the feasibility, safety and long term efficacy of lung RFA to treat tumors have been reported in humans, both in the United States and internationally (4-13). During the RFA procedure, rapidly alternating current is applied with a frequency in the range of 460-500 kHz through the RFA electrode (14). The alternating current causes movement of ions in the tissue resulting in tissue heating. Applying a temperature greater than 50 degrees centigrade for five minutes results in tumor cell death. Too high a temperature is not desirable as it will cause charring and gas formation immediately adjacent to the electrode and prevent the homogeneous heating of the entire tumor. During RFA, reaching a temperature of 60-100 degrees centigrade within the tumor is generally desired, as charring and gas formation occur at approximately 105-115 degrees centigrade (14, 15). Ideally, the goal is to achieve complete cell death within the tumor, as well as in a 1 cm margin of the adjacent normal lung (14, 16).

Who is suitable for RFA?

Patients with tumors that are 3 cm or smaller are best suited for RFA treatment. A typical patient undergoing RFA is an adult who cannot undergo lung cancer surgery despite having a tumor that is at an early stage. Examples of patients who may not be able to undergo surgery include those with poor lung function, other coexisting other diseases, poor general performance status which might deteriorate further following lung surgery, and patients with lung tumors that either do not respond to maximum conventional therapy, including radiation therapy, or recur after treatment. In other words, these patients have tumors that can be potentially removed by surgery, but the presence of other additional diseases in these patients prevent them from undergoing surgery. Also in this group are patients who cannot afford to lose any more lung tissue. Although few studies report that RFA can be safely performed in tumors close to vital organs such as the heart, generally tumors that are close to the lung hilum (where the airtubes and blood vessels enter the lung) are not amenable to RFA (17, 18).

How is RFA performed?

This technique has many similarities to CT-guided lung biopsy procedures. Throughout the world, lung RFA is commonly performed in a CT scanner suite. Patients undergo this procedure either under moderate sedation with pain relief or under general anesthesia. General anesthesia has the advantage of complete control over patient's breathing pattern and motion that helps to accurately place the RFA electrode within the tumor. One study comparing conscious sedation to general anesthesia did not show any major difference in tumor control or procedure related complication rates, however the number of patients in both groups was small (19). A survey of centers performing RFA for lung tumors indicated that conscious sedation is used more commonly than general anesthesia (12). During the procedure, tumor cells are destroyed by placing a needle (RFA electrode) within the center of the tumor. The RFA electrodes come in various shapes, length and thickness, depending on the manufacturer (Figure 1). The RFA electrodes are carefully placed into the center of the tumor undergoing ablation using the guidance of images in the CT suite. Multiple CT images are taken to confirm the safe placement of RFA electrodes, and to avoid adjacent vital organs. Following placement, RFA electrodes are connected to an external RF generator (Figure 2). High-frequency alternating energy is then applied through the RF electrodes. This causes ionic agitation in tumor cells which raises tissue temperature. As the temperature increases above 45-50 degrees centigrade within the tumor, cellular proteins denature and cell structure disintegrates. This results in thermal coagulation in tumor cells, ultimately leading to tumor destruction. The entire RFA procedure session usually takes 3-4 hours or less. Following completion of therapy, RFA probes are withdrawn from the patient. Subsequently, patients are closely observed for any post procedural complications such as lung collapse. Following an uncomplicated RFA procedure, patients are discharged home mostly after overnight observation or rarely the same day.
Lung tissue characteristics may play a role in the effectiveness of RFA. The normal lung tissue surrounding the tumor is relatively resistant to heating due to its high electrical impedance (20, 21). Therefore, the heat energy created by RFA is preferentially deposited in the tumor facilitating higher temperatures. Also, large blood vessels (> 3 mm) near a tumor constantly cool the tissue due to the flowing blood that takes heat away from the area being treated, commonly known as the heat sink effect (14, 20). As a result, tumors in continuity with large blood vessels may be suboptimally treated with RFA. Some electrodes are believed to produce necrosis measuring up to 4-5 cm in diameter. This allows for the treatment of a 3 cm lesion and a 1 cm margin of normal lung (14). Tumors larger than 3 cm may require multiple electrodes to create overlapping tissue RFA zones.

What happens to the tumor following RFA?

When CT scans are obtained immediately following RFA, a hazy (ground glass like) opacity develops surrounding the tumor (11, 22) that represents pulmonary bleeding and/or increased blood flow (23). Within one week, the hazy opacity changes to dense opacity like pneumonia (consolidation) (11). The ablation zone is frequently larger than the original tumor, which may be a reflection of ablation of normal lung adjacent to the lesion, which is the desired result. Following RFA, the tumor is monitored with the help of serial surveillance CT examinations, often accompanied by intermittent positron emission tomography (PET) scans. An increase in the size of the ablated lesion has been reported to occur within the first three months after RFA. Beyond that time, continued increase in growth of the ablation zone should be viewed as suspicious for incomplete tumor destruction and recurrent tumor (22). Based on the tumor appearance on CT examinations it may be difficult to determine if the tumor was fully ablated in the first few months after RFA.
Other approaches to evaluating the effectiveness of ablation include PET scans and enhancement of the ablation zone using intravenous contrast material-enhanced CT perfusion imaging. Immediately following RFA, the ablated tumor may show no enhancement with intravenous contrast material on CT. The presence of nodule-like enhancing areas within the ablation zone suggests residual tumor (24). Cavities develop within the ablation zone in up to one-third of patients. Most patients with cavities have no specific symptoms, and the cavities usually spontaneously contract with time (Figures 3-6). Other CT findings after RFA include bubble lucencies or pleural thickening within or near the ablation zone (22).

Pathologic correlation to prove the effectiveness of lung RFA is available from animal and human studies. Lung tissue biology following RFA is promising. In a rabbit model, the ground-glass opacity seen immediately after RFA correlated with lung thermal injury. Progressive necrosis was seen in the area of ground glass opacity and is thought to represent lung that has been effectively ablated or destroyed by the heat energy (25). A study of pig lungs demonstrated that ground glass opacity represents a combination of lung cell death and bleeding, and that the apparent initial increase in size of the ablated tumor was due to the presence of granulation tissue as a result of heat damage to lung and not continued tumor growth (26). Goldberg and colleagues have reported effective cell death in a rabbit lung sarcoma model (27). A study in which surgical resection was performed immediately following RFA in 8 patients with proven primary lung cancer (tumors 2.2 + (or) - 0.6 cm), observed that 87.5% of tumors had more than or equal to 80% cell death, while 100% cell death was noted in tumors less than 2 cm (28). Another study using similar methodology reported 65% overall cell death in 9 patients with proven primary lung cancer (20).

Figure 1:
RFA electrodes are available in various configurations. They are chosen based on the tumor morphology. The thickness of a typical RFA electrode (arrow) and a CT guided lung biopsy needle (arrow head) can be appreciated in relation to the millimeter marks on the ruler.



Figure 1


Figure 2:
Following accurate placement within a tumor, RFA electrodes are connected to an external RF generator. During RFA, display panels show ablation parameters such as tissue impedance, current flow, and target tissue temperature. A pump (arrow) maintains a constant flow of cold water inside the RFA electrodes to prevent them from overheating.



Figure 2


Figures 3-7:
A 69 year old gentleman who had undergone a partial left upper lobe resection for primary lung cancer developed a recurrent left upper lobe lung cancer (arrow in Figure 3). Due to medical reasons, RFA was preferred over the other therapeutic modalities. During RFA, probes were accurately placed in the middle of the nodule (arrow in Figure 4) along its long axis. One month after RFA, the tumor was replaced by a complex lung cavity (arrow in Figure 5). Six months after RFA there was minimal left upper lobe lung scarring on CT scan image (arrow in Figure 6) with no focal FDG-PET activity on CT/PET fusion image to suggest residual or recurrent tumor (arrow in Figure 7).


Figure 3


During RFA, probes were accurately placed in the middle of the nodule (arrow in Figure 4) along its long axis.


Figure 4


One month after RFA, the tumor was replaced by a complex lung cavity (arrow in Figure 5).


Figure 5


Six months after RFA there was minimal left upper lobe lung scarring on CT scan image (arrow in Figure 6) with no focal FDG-PET activity on CT/PET fusion image to suggest residual or recurrent tumor (arrow in Figure 7).



Figure 6



Figure 7


What are the potential complications of RFA procedure?

Like any other medical or surgical therapy, RFA also has complications. Many studies have reported that the complication rates are quite similar to those of CT-guided lung biopsy procedures. The most common complication is pneumothorax (lung collapse). The reported incidence of pneumothorax in the larger series is 10-50%, but a smaller number of patients require chest tube insertion to facilitate lung re-expansion (13, 29-32). Other relatively common complications that occur in 10-30% of patients include hemoptysis (coughing blood-tinged sputum) and pleural effusion (fluid accumulation outside the lung within the pleura) (33-35). More serious, but rare complications include severe bleeding in the lung, hemothorax (blood accumulation outside the lung within the pleura), air-leak from lung into the chest wall, empyema (infected fluid accumulation outside the lung within the pleura), bronchopleural fistula (a connection between airways in lungs and the pleural space outside the lung), continuous chest wall pain, and acute respiratory distress syndrome (30, 33, 36). Very rarely, urgent surgery may need to be performed to deal with one of these complications. Other reported complications, such as death and stroke, are rare.

What is the impact of RFA in the treatment of primary lung cancer?

To date, studies evaluating RFA have included patients with a mixture of both primary lung tumors and metastases. Dupuy et al reported on 24 patients with stage I non-small cell lung cancer who uncerwent RFA followed by radiation therapy. Two years later, 50% of the study patients were alive, and at five years at 39% were alive (37). A similar study by Grieco et al of 41 patients with stage I or II lung cancer treated with both RFA and external beam radiation therapy or brachytherapy demonstrated a median survival of 19.5 months, with survival at one, two, and three years of 87%, 70%, and 57%, respectively (36). Simon et al in a study of 75 patients undergoing RFA for stage I lung cancers who were not surgical candidates reported survival rates of 78 % at one year, 36% at three years and 27% at five years, with a median survival of 29 months (13). A similar median survival was reported in a smaller study involving 36 patients with stage I lung cancers (31).
The survival rates reported in patients treated with RFA for stage I and II lung cancer appears to compare favorably with published data for external beam conventional radiation treatment. However, given the lack of randomized studies, such historical comparisons are of limited value. Surgery is the optimal treatment for these patients. However, those who are unable to undergo surgery may benefit from RFA.

What is the impact of RFA in the treatment of metastases?

Surgical removal of metastatic lung tumors is an accepted curative therapy provided the primary tumor is fully cured or controlled. Complete surgical removal of lung metastases in patients with selected types of cancer is associated with overall survival rates of 36% at 5 years, 26% at 10 years, and 22% at 15 years (38). Simon et al reported that RFA of metastatic lung nodules results in overall survival rates of 70%, 54%, and 44% at 1, 2, and 5 years, respectively. For metastases from colon cancer, they also report 1, 2, and 5 year overall survival rates of 87%, 78%, and 57%, respectively (13). After RFA of metastases in 55 patients, Yan et al reported median overall survival of 33 months, with 1, 2, and 3 year overall survival rates of 85%, 64%, and 46%, respectively (39). The same group of authors reported that larger size of the lung metastasis, location of the lung metastasis, and repeat RFA of recurrent tumors were associated with significantly lower overall survival (40).

Conclusion:

RFA is a promising local therapy that has evolved rapidly in recent years for the treatment of primary and secondary cancers in the lung. The feasibility and safety profile in humans are well established. Complications following RFA are similar to those of CT-guided lung biopsies. However, sufficient long term results beyond 5 years are not yet available due to the relatively short time that this technology has been in use. Patients with smaller tumors (less than or equal to three cm) and fewer tumor nodules (less than or equal to five lesions) who are considered poor surgical candidates or who develop residual or recurrent disease despite maximal conventional therapy, and have tumors that are away from vital structures are the best candidates for RFA. Hence, RFA can be safely offered to patients who cannot undergo surgical resection. However the role of RFA in patients who are candidates for surgical resection is unproven, and there is no evidence on whether RFA is more or less effective that focused radiation (sterotactic body radiation therapy). Overall, RFA is a highly promising modality that may be used to our patients' advantage either as a solitary treatment or in combination with conventional therapy.


Corresponding Author: Baskaran Sundaram, M.D.
Contact information:
Department of Radiology, University of Michigan Health System
Cardiovascular Center #5481, 1500 East Medical Center Drive
Ann Arbor, MI 48109-5868, USA
Phone: (1) 734-936-4366, Fax: (1) 734-232-5055
Email: sundbask@med.umich.edu 


 


Additional Authors:  

Works Cited:  
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