Dr. Igor Brichkov

Division of Thoracic Surgery
Maimonides Medical Center
Brooklyn, NY

Lung cancer is currently the most common cause of adult cancer related to mortality in the United States. Surgical resection remains the gold standard therapy for resectable disease and offers the best chance for a cure. Unfortunately, age, poor lung function, and significant comorbidity preclude many patients with otherwise resectable lung cancer from surgical therapy. A conventional option for medically inoperable patients with lung cancer includes external beam radiation therapy. Long-term survival with this treatment modality is poor, with reported 5-year survival rates from 10% to 30% and 13% for stage I non-small cell lung cancer (NSCLC) (Sibley et al. Int J Radiat Oncol Biol Phys. 1998;40[1]:149).

The need to improve the treatment of this high-risk group of patients with lung cancer has prompted the development of newer treatment modalities as alternatives to conventional therapy. Radiofrequency ablation (RFA) and stereotactic radiosurgery (SRS) are two such alternative modalities that have emerged in the arena of lung cancer treatment in recent years. RFA has historically been used as an adjunct for treatment of tumors of solid abdominal viscera, and its use for pulmonary malignancy was first reported in 2000. Since that time, multiple case series have been published establishing the safety and efficacy of this treatment modality for pulmonary malignancies in high-risk patients.

SRS was a term originally coined by Leksell to describe a radiation delivery system in which multiple convergent beams of radiation could be delivered to a tumor, utilizing a three-dimensional imaging localization technique. This modality was originally applied to intracranial malignancies, and in 1994, was adapted to treat extracranial lesions as well (Song et al. Oncology. 2004;18[11]:1419). Several reports of its use for pulmonary malignancies began to emerge in the early 2000s; and since that time, refinement of imaging, tracking, and radiation delivery systems has given rise to several different commercially available SRS systems. One such system that has shown success in the treatment of pulmonary malignancy is the CyberKnife^® System (Accuray, Sunnyvale, CA).

Radiofrequency Ablation

RFA utilizes heat-induced cellular necrosis and is administered by means of an alternating current applied via an electrode. The current is supplied by a radiofrequency generator and is transferred through the patient and completed via two grounding pads. The alternating current, when applied to tissue, results in agitation of water molecules and frictional release of thermal energy within the immediate area of the electrode. At 46°C cell death occurs within 60 minutes, at 50°C to 52°C irreversible cell death occurs at 4 to 6 minutes, and at 60°C there is instantaneous irreversible cell death.

The goal of RFA is to ablate the tumor with a 0.5- to 1.0-cm margin of surrounding lung tissue. The RFA electrode, with or without tines deployed, ablates a spherical target area of tissue. The target temperature during a conventional pulmonary RFA treatment protocol is 105°C. For an electrode with multiple tines, the temperature is typically averaged across all tines, which each provide accurate real-time temperature readings at their respective locations within the tissue.

Indications for pulmonary RFA include otherwise resectable pulmonary nodules in patients who either refuse surgery or are at high risk for surgical resection. This includes patients with poor pulmonary reserve and/or medically inoperable patients, such as those who have severe coronary/valvular disease, uncompensated congestive heart failure, or other severe comorbidities, who are candidates for RFA. Patients who have failed prior modalities, including surgical resection with or without chemoradiation, would also qualify for RFA treatment.

The only absolute contraindication to RFA is a central location of a nodule, defined as being within 3 cm of the hilum. Central nodules are close to large blood vessels, which function as heat sinks, limiting the therapeutic effect of RFA. Also, the presence of larger airways with corresponding pulmonary vessels near the hilum increases the risk of potentially lethal bronchovascular fistula formation from ablation. Relative contraindications include large nodules (>3 cm) that would require multiple ablations within the same nodule as well as multiple nodules. The latter may be cumbersome to treat and may not be technically feasible, although multiple staged treatments for bilateral pulmonary nodules are possible.

The procedure of RFA for pulmonary lesions with regard to electrode placement and treatment algorithm varies according to the protocols supplied by the individual RFA system manufacturers. Either general endotracheal anesthesia or local with intravenous sedation may be used. The latter generally decreases the risk of pneumothorax with the trade-off that the patient is more likely to move spontaneously during the procedure. Typically, the electrode is placed under image guidance into the center of the nodule after a small skin incision is made to accommodate the 14-gauge needle. Imaging should be repeated between every repositioning to confirm placement. In the event of a periprocedural pneumothorax, a pleural drainage catheter should be placed immediately to evacuate it, as this may cause the lung and nodule to fall away from the chest wall and impede adequate placement of the electrode. A completion CT scan is performed after treatment to visualize the adequacy of the ablation as well as to visualize delayed pneumothorax formation. Occasionally, fiber-optic bronchoscopy may be required to clear endobronchial secretions, which can be blood-tinged after treatment.

Postoperatively, the patient is typically admitted for observation overnight. Chest radiographs are obtained at 6 h postoperatively and the following morning to assess for delayed pneumothorax. If a chest pigtail was required during or after the procedure, a clamp trial is usually performed the following day prior to removal. Rarely, a patient will require a chest drain for a longer period of time, resulting in a prolonged hospital stay. A follow-up chest CT scan may be done the next morning to more accurately assess the post ablation lung but is not required. Patients are typically followed with CT/PET scans at 3- to 4-month intervals.

The most common complication of pulmonary RFA is pneumothorax, occurring in 59% of patients in a recent series. This is largely attributed to the size of the electrode used and is less frequent when positive pressure ventilation is avoided. Prolonged air leak (>5 days) occurred in 7% of patients. Other complications included hemoptysis requiring bronchoscopy, myocardial infarction, deep vein thrombosis, and respiratory failure, which occurred in 1% of patients. In addition, 3% of patients required subsequent drainage of pleural effusions. No intraoperative or in-hospital mortality was observed (Pennathur et al. Ann Thorac Surg. 2009[5];88:1601).

Local recurrence for stage I NSCLC after RFA was confirmed radiographically by CT scan, PET scan, or both after 31.5% of treatments (12/38). Two patients were successfully retreated for technical failures related to pneumothorax; three underwent radiotherapy with stable disease. Three patients died of metastatic disease; five died of pneumonia remote from treatment. The 2- and 4-year survivals were 78% and 47%, respectively. Median overall survival was 30 months. Tumors larger than 3 cm were more likely to recur locally (Pennathur et al. Ann Thorac Surg. 2009[5];88:1601).

CyberKnife^® System

The rationale for SRS is based on the notion that higher doses of radiation improve local control and disease-related survival at the expense of increased toxicity in normal tissues (Sibley et al. Int J Radiat Oncol Biol Phys. 1998;40[1]:149). Initially described for the treatment of intracranial lesions, SRS utilized a rigid frame to immobilize a patient, stereotactically localize a lesion, and deliver a higher dose to a specific point with minimal dosing of surrounding normal tissue, using multiple convergent beams of radiation (Song et al. Oncology. 2004;18[11]:1419). As technology evolved, this technique was adapted for extracranial lesions. However, due to the presence of multiple critical structures in the thorax as well as the intrinsic movement of the lung, there was little interest in SRS for pulmonary lesions. Recent advances in SRS led to the development of CyberKnife, which overcame the limitations of conventional SRS in the thorax.

CyberKnife utilizes a frameless system in which the patient needs to not be immobilized. Instead, the CyberKnife System depends on tracking a tumor in real time and adjusting radiation beams accordingly, thus overcoming the limitations of respiratory movement and minimizing toxic exposure to nearby critical structures. It utilizes a 6-MV linear accelerator mounted on a robotic arm. Beams can be emitted in 12 directions from 110 arm positions. The CyberKnife System relies on internally placed radio-opaque fiducial markers that are implanted and allow tumor tracking based on internal rather than external reference points, thus eliminating the need for rigid immobilization (Pennathur et al. Ann Thorac Surg. 2007;83[5]:1820).

Indications for CyberKnife treatment are similar to those of RFA. Unlike those with RFA, patients with central nodules are also candidates for CyberKnife as there are no heat-sinking limitations.

There are no absolute contraindications to CyberKnife. Relative contraindications are similar to those of RFA. Multiple bulky nodules may be difficult to treat without surrounding radiation toxicity and may lead to treatment failure. Central lesions limit the total allowable dose.

The procedure for CyberKnife treatment begins with placement of one to four fiducials in and around the tumor. These are gold tumor markers that are 1 to 2 mm in size and allow for real-time tracking of the tumor. They are placed under image guidance, typically in an outpatient setting. Usually, a total of three fiducials (within, superior, and inferior to the tumor) will suffice. It is critical that the fiducials be placed within the lung parenchyma, as placement within the pleural space or in the fissures will allow migration, compromising tumor tracking.

A week after placement of fiducials, the patient is brought back for a contrast-enhanced CT scan of the chest and upper abdomen with 1.25-mm sections. The treatment plan is then jointly formulated by a thoracic surgeon and radiation oncologist. The tumor volume as well as a 0.5- to 1.0-cm margin of surrounding tissue is outlined using dosimetry software. The treatment area need not be spherical and in fact may be molded to encompass irregularly shaped nodules and to avoid neighboring critical structures. Precise doses at each point within and away from the planned treatment area may be calculated, thus avoiding reaching toxic thresholds in nearby critical structures.

During the treatment phase, the patient is typically positioned according to the previously formulated treatment plan. Fiducials are tracked in real time using two ceiling-mounted radiographic fluoroscopes, and these oblique dual images are combined with the CT scan data, using tracking software to direct or readjust the beams of radiation at frequent intervals. For peripheral lesions, 60 Gy is delivered in three fractions; and for central lesions, 48 Gy is delivered in four fractions to minimize toxicity to surrounding critical structures (Pennathur et al. Ann Thorac Surg. 2009;88[5]:1594).

Patients are followed at 3- to 4-month intervals with PET/CT scans. Nodules are assessed for response/progression based on size, mass quality (cavitation, replacement with scar, etc.), and PET avidity. In addition, treatment-related toxicity is assessed with each follow-up visit with pulmonary function testing and quality-of-life assessment.

Early complications of treatment are mainly related to placement of fiducials. In a recent series, 26% of patients developed a pneumothorax requiring tube thoracostomy. Late complications are mainly due to treatment-related toxicity. This is particularly true for central tumors (Pennathur et al. Ann Thorac Surg. 2009;88[5]:1594). In a phase II trial of 70 patients treated with 60 to 66 Gy in three fractions, only 54% of patients with central tumors were free from severe toxicity compared with 83% of patients with peripheral tumors at 2 years. In summary, 8.6% of patients died of treatment-related toxicity (Timmerman et al. J Clin Oncol. 2006[30];24:4833). Therefore, lower doses are required for central tumors, particularly those near larger central airways.

Using this modality, the overall 2-year survival for primary lung cancer (all stages) was 44%. The median overall survival was 22 months. In conclusion, 62% of patients had progression, which was observed at a median time of 9 months. Patients treated with 60-Gy doses (i.e., those with peripheral lesions) showed significantly improved survival and time to disease progression compared with those treated with 20-Gy doses (Pennathur et al. J Thorac Cardiovasc Surg. 2009;137[3]:597).

Conclusion

RFA and SRS each provide a minimally invasive alternative for high-risk patients with pulmonary malignancy. Studies are ongoing in their application to pulmonary metastases and as part of multimodality treatment protocols. As technology improves, RFA delivery probes will be smaller and can potentially be delivered endobronchially. Similarly, tumor-tracking technology in the spontaneously ventilating lung continues to improve, and fiducial placement may soon be unnecessary in SRS. As the technology evolves, the use of these modalities may expand beyond use only for the high-risk patients.

Dr. Brichkov is with the division of thoracic surgery at Maimonides Medical Center in Brooklyn, N.Y. He has disclosed that he has no significant relationships with the companies/organizations whose products or services are discussed within this Pulmonary Perspectives.

Division of Thoracic Surgery
Maimonides Medical Center
Brooklyn, NY

Lung cancer is currently the most common cause of adult cancer related to mortality in the United States. Surgical resection remains the gold standard therapy for resectable disease and offers the best chance for a cure. Unfortunately, age, poor lung function, and significant comorbidity preclude many patients with otherwise resectable lung cancer from surgical therapy. A conventional option for medically inoperable patients with lung cancer includes external beam radiation therapy. Long-term survival with this treatment modality is poor, with reported 5-year survival rates from 10% to 30% and 13% for stage I non-small cell lung cancer (NSCLC) (Sibley et al. Int J Radiat Oncol Biol Phys. 1998;40[1]:149).

The need to improve the treatment of this high-risk group of patients with lung cancer has prompted the development of newer treatment modalities as alternatives to conventional therapy. Radiofrequency ablation (RFA) and stereotactic radiosurgery (SRS) are two such alternative modalities that have emerged in the arena of lung cancer treatment in recent years. RFA has historically been used as an adjunct for treatment of tumors of solid abdominal viscera, and its use for pulmonary malignancy was first reported in 2000. Since that time, multiple case series have been published establishing the safety and efficacy of this treatment modality for pulmonary malignancies in high-risk patients.

SRS was a term originally coined by Leksell to describe a radiation delivery system in which multiple convergent beams of radiation could be delivered to a tumor, utilizing a three-dimensional imaging localization technique. This modality was originally applied to intracranial malignancies, and in 1994, was adapted to treat extracranial lesions as well (Song et al. Oncology. 2004;18[11]:1419). Several reports of its use for pulmonary malignancies began to emerge in the early 2000s; and since that time, refinement of imaging, tracking, and radiation delivery systems has given rise to several different commercially available SRS systems. One such system that has shown success in the treatment of pulmonary malignancy is the CyberKnife^® System (Accuray, Sunnyvale, CA).

Radiofrequency Ablation

RFA utilizes heat-induced cellular necrosis and is administered by means of an alternating current applied via an electrode. The current is supplied by a radiofrequency generator and is transferred through the patient and completed via two grounding pads. The alternating current, when applied to tissue, results in agitation of water molecules and frictional release of thermal energy within the immediate area of the electrode. At 46°C cell death occurs within 60 minutes, at 50°C to 52°C irreversible cell death occurs at 4 to 6 minutes, and at 60°C there is instantaneous irreversible cell death.

The goal of RFA is to ablate the tumor with a 0.5- to 1.0-cm margin of surrounding lung tissue. The RFA electrode, with or without tines deployed, ablates a spherical target area of tissue. The target temperature during a conventional pulmonary RFA treatment protocol is 105°C. For an electrode with multiple tines, the temperature is typically averaged across all tines, which each provide accurate real-time temperature readings at their respective locations within the tissue.

Indications for pulmonary RFA include otherwise resectable pulmonary nodules in patients who either refuse surgery or are at high risk for surgical resection. This includes patients with poor pulmonary reserve and/or medically inoperable patients, such as those who have severe coronary/valvular disease, uncompensated congestive heart failure, or other severe comorbidities, who are candidates for RFA. Patients who have failed prior modalities, including surgical resection with or without chemoradiation, would also qualify for RFA treatment.

The only absolute contraindication to RFA is a central location of a nodule, defined as being within 3 cm of the hilum. Central nodules are close to large blood vessels, which function as heat sinks, limiting the therapeutic effect of RFA. Also, the presence of larger airways with corresponding pulmonary vessels near the hilum increases the risk of potentially lethal bronchovascular fistula formation from ablation. Relative contraindications include large nodules (>3 cm) that would require multiple ablations within the same nodule as well as multiple nodules. The latter may be cumbersome to treat and may not be technically feasible, although multiple staged treatments for bilateral pulmonary nodules are possible.

The procedure of RFA for pulmonary lesions with regard to electrode placement and treatment algorithm varies according to the protocols supplied by the individual RFA system manufacturers. Either general endotracheal anesthesia or local with intravenous sedation may be used. The latter generally decreases the risk of pneumothorax with the trade-off that the patient is more likely to move spontaneously during the procedure. Typically, the electrode is placed under image guidance into the center of the nodule after a small skin incision is made to accommodate the 14-gauge needle. Imaging should be repeated between every repositioning to confirm placement. In the event of a periprocedural pneumothorax, a pleural drainage catheter should be placed immediately to evacuate it, as this may cause the lung and nodule to fall away from the chest wall and impede adequate placement of the electrode. A completion CT scan is performed after treatment to visualize the adequacy of the ablation as well as to visualize delayed pneumothorax formation. Occasionally, fiber-optic bronchoscopy may be required to clear endobronchial secretions, which can be blood-tinged after treatment.

Postoperatively, the patient is typically admitted for observation overnight. Chest radiographs are obtained at 6 h postoperatively and the following morning to assess for delayed pneumothorax. If a chest pigtail was required during or after the procedure, a clamp trial is usually performed the following day prior to removal. Rarely, a patient will require a chest drain for a longer period of time, resulting in a prolonged hospital stay. A follow-up chest CT scan may be done the next morning to more accurately assess the post ablation lung but is not required. Patients are typically followed with CT/PET scans at 3- to 4-month intervals.

The most common complication of pulmonary RFA is pneumothorax, occurring in 59% of patients in a recent series. This is largely attributed to the size of the electrode used and is less frequent when positive pressure ventilation is avoided. Prolonged air leak (>5 days) occurred in 7% of patients. Other complications included hemoptysis requiring bronchoscopy, myocardial infarction, deep vein thrombosis, and respiratory failure, which occurred in 1% of patients. In addition, 3% of patients required subsequent drainage of pleural effusions. No intraoperative or in-hospital mortality was observed (Pennathur et al. Ann Thorac Surg. 2009[5];88:1601).

Local recurrence for stage I NSCLC after RFA was confirmed radiographically by CT scan, PET scan, or both after 31.5% of treatments (12/38). Two patients were successfully retreated for technical failures related to pneumothorax; three underwent radiotherapy with stable disease. Three patients died of metastatic disease; five died of pneumonia remote from treatment. The 2- and 4-year survivals were 78% and 47%, respectively. Median overall survival was 30 months. Tumors larger than 3 cm were more likely to recur locally (Pennathur et al. Ann Thorac Surg. 2009[5];88:1601).

CyberKnife^® System

The rationale for SRS is based on the notion that higher doses of radiation improve local control and disease-related survival at the expense of increased toxicity in normal tissues (Sibley et al. Int J Radiat Oncol Biol Phys. 1998;40[1]:149). Initially described for the treatment of intracranial lesions, SRS utilized a rigid frame to immobilize a patient, stereotactically localize a lesion, and deliver a higher dose to a specific point with minimal dosing of surrounding normal tissue, using multiple convergent beams of radiation (Song et al. Oncology. 2004;18[11]:1419). As technology evolved, this technique was adapted for extracranial lesions. However, due to the presence of multiple critical structures in the thorax as well as the intrinsic movement of the lung, there was little interest in SRS for pulmonary lesions. Recent advances in SRS led to the development of CyberKnife, which overcame the limitations of conventional SRS in the thorax.

CyberKnife utilizes a frameless system in which the patient needs to not be immobilized. Instead, the CyberKnife System depends on tracking a tumor in real time and adjusting radiation beams accordingly, thus overcoming the limitations of respiratory movement and minimizing toxic exposure to nearby critical structures. It utilizes a 6-MV linear accelerator mounted on a robotic arm. Beams can be emitted in 12 directions from 110 arm positions. The CyberKnife System relies on internally placed radio-opaque fiducial markers that are implanted and allow tumor tracking based on internal rather than external reference points, thus eliminating the need for rigid immobilization (Pennathur et al. Ann Thorac Surg. 2007;83[5]:1820).

Indications for CyberKnife treatment are similar to those of RFA. Unlike those with RFA, patients with central nodules are also candidates for CyberKnife as there are no heat-sinking limitations.

There are no absolute contraindications to CyberKnife. Relative contraindications are similar to those of RFA. Multiple bulky nodules may be difficult to treat without surrounding radiation toxicity and may lead to treatment failure. Central lesions limit the total allowable dose.

The procedure for CyberKnife treatment begins with placement of one to four fiducials in and around the tumor. These are gold tumor markers that are 1 to 2 mm in size and allow for real-time tracking of the tumor. They are placed under image guidance, typically in an outpatient setting. Usually, a total of three fiducials (within, superior, and inferior to the tumor) will suffice. It is critical that the fiducials be placed within the lung parenchyma, as placement within the pleural space or in the fissures will allow migration, compromising tumor tracking.

A week after placement of fiducials, the patient is brought back for a contrast-enhanced CT scan of the chest and upper abdomen with 1.25-mm sections. The treatment plan is then jointly formulated by a thoracic surgeon and radiation oncologist. The tumor volume as well as a 0.5- to 1.0-cm margin of surrounding tissue is outlined using dosimetry software. The treatment area need not be spherical and in fact may be molded to encompass irregularly shaped nodules and to avoid neighboring critical structures. Precise doses at each point within and away from the planned treatment area may be calculated, thus avoiding reaching toxic thresholds in nearby critical structures.

During the treatment phase, the patient is typically positioned according to the previously formulated treatment plan. Fiducials are tracked in real time using two ceiling-mounted radiographic fluoroscopes, and these oblique dual images are combined with the CT scan data, using tracking software to direct or readjust the beams of radiation at frequent intervals. For peripheral lesions, 60 Gy is delivered in three fractions; and for central lesions, 48 Gy is delivered in four fractions to minimize toxicity to surrounding critical structures (Pennathur et al. Ann Thorac Surg. 2009;88[5]:1594).

Patients are followed at 3- to 4-month intervals with PET/CT scans. Nodules are assessed for response/progression based on size, mass quality (cavitation, replacement with scar, etc.), and PET avidity. In addition, treatment-related toxicity is assessed with each follow-up visit with pulmonary function testing and quality-of-life assessment.

Early complications of treatment are mainly related to placement of fiducials. In a recent series, 26% of patients developed a pneumothorax requiring tube thoracostomy. Late complications are mainly due to treatment-related toxicity. This is particularly true for central tumors (Pennathur et al. Ann Thorac Surg. 2009;88[5]:1594). In a phase II trial of 70 patients treated with 60 to 66 Gy in three fractions, only 54% of patients with central tumors were free from severe toxicity compared with 83% of patients with peripheral tumors at 2 years. In summary, 8.6% of patients died of treatment-related toxicity (Timmerman et al. J Clin Oncol. 2006[30];24:4833). Therefore, lower doses are required for central tumors, particularly those near larger central airways.

Using this modality, the overall 2-year survival for primary lung cancer (all stages) was 44%. The median overall survival was 22 months. In conclusion, 62% of patients had progression, which was observed at a median time of 9 months. Patients treated with 60-Gy doses (i.e., those with peripheral lesions) showed significantly improved survival and time to disease progression compared with those treated with 20-Gy doses (Pennathur et al. J Thorac Cardiovasc Surg. 2009;137[3]:597).

Conclusion

RFA and SRS each provide a minimally invasive alternative for high-risk patients with pulmonary malignancy. Studies are ongoing in their application to pulmonary metastases and as part of multimodality treatment protocols. As technology improves, RFA delivery probes will be smaller and can potentially be delivered endobronchially. Similarly, tumor-tracking technology in the spontaneously ventilating lung continues to improve, and fiducial placement may soon be unnecessary in SRS. As the technology evolves, the use of these modalities may expand beyond use only for the high-risk patients.

Dr. Brichkov is with the division of thoracic surgery at Maimonides Medical Center in Brooklyn, N.Y. He has disclosed that he has no significant relationships with the companies/organizations whose products or services are discussed within this Pulmonary Perspectives.

Division of Thoracic Surgery
Maimonides Medical Center
Brooklyn, NY

Lung cancer is currently the most common cause of adult cancer related to mortality in the United States. Surgical resection remains the gold standard therapy for resectable disease and offers the best chance for a cure. Unfortunately, age, poor lung function, and significant comorbidity preclude many patients with otherwise resectable lung cancer from surgical therapy. A conventional option for medically inoperable patients with lung cancer includes external beam radiation therapy. Long-term survival with this treatment modality is poor, with reported 5-year survival rates from 10% to 30% and 13% for stage I non-small cell lung cancer (NSCLC) (Sibley et al. Int J Radiat Oncol Biol Phys. 1998;40[1]:149).

The need to improve the treatment of this high-risk group of patients with lung cancer has prompted the development of newer treatment modalities as alternatives to conventional therapy. Radiofrequency ablation (RFA) and stereotactic radiosurgery (SRS) are two such alternative modalities that have emerged in the arena of lung cancer treatment in recent years. RFA has historically been used as an adjunct for treatment of tumors of solid abdominal viscera, and its use for pulmonary malignancy was first reported in 2000. Since that time, multiple case series have been published establishing the safety and efficacy of this treatment modality for pulmonary malignancies in high-risk patients.

SRS was a term originally coined by Leksell to describe a radiation delivery system in which multiple convergent beams of radiation could be delivered to a tumor, utilizing a three-dimensional imaging localization technique. This modality was originally applied to intracranial malignancies, and in 1994, was adapted to treat extracranial lesions as well (Song et al. Oncology. 2004;18[11]:1419). Several reports of its use for pulmonary malignancies began to emerge in the early 2000s; and since that time, refinement of imaging, tracking, and radiation delivery systems has given rise to several different commercially available SRS systems. One such system that has shown success in the treatment of pulmonary malignancy is the CyberKnife^® System (Accuray, Sunnyvale, CA).

Radiofrequency Ablation

RFA utilizes heat-induced cellular necrosis and is administered by means of an alternating current applied via an electrode. The current is supplied by a radiofrequency generator and is transferred through the patient and completed via two grounding pads. The alternating current, when applied to tissue, results in agitation of water molecules and frictional release of thermal energy within the immediate area of the electrode. At 46°C cell death occurs within 60 minutes, at 50°C to 52°C irreversible cell death occurs at 4 to 6 minutes, and at 60°C there is instantaneous irreversible cell death.

The goal of RFA is to ablate the tumor with a 0.5- to 1.0-cm margin of surrounding lung tissue. The RFA electrode, with or without tines deployed, ablates a spherical target area of tissue. The target temperature during a conventional pulmonary RFA treatment protocol is 105°C. For an electrode with multiple tines, the temperature is typically averaged across all tines, which each provide accurate real-time temperature readings at their respective locations within the tissue.

Indications for pulmonary RFA include otherwise resectable pulmonary nodules in patients who either refuse surgery or are at high risk for surgical resection. This includes patients with poor pulmonary reserve and/or medically inoperable patients, such as those who have severe coronary/valvular disease, uncompensated congestive heart failure, or other severe comorbidities, who are candidates for RFA. Patients who have failed prior modalities, including surgical resection with or without chemoradiation, would also qualify for RFA treatment.

The only absolute contraindication to RFA is a central location of a nodule, defined as being within 3 cm of the hilum. Central nodules are close to large blood vessels, which function as heat sinks, limiting the therapeutic effect of RFA. Also, the presence of larger airways with corresponding pulmonary vessels near the hilum increases the risk of potentially lethal bronchovascular fistula formation from ablation. Relative contraindications include large nodules (>3 cm) that would require multiple ablations within the same nodule as well as multiple nodules. The latter may be cumbersome to treat and may not be technically feasible, although multiple staged treatments for bilateral pulmonary nodules are possible.

The procedure of RFA for pulmonary lesions with regard to electrode placement and treatment algorithm varies according to the protocols supplied by the individual RFA system manufacturers. Either general endotracheal anesthesia or local with intravenous sedation may be used. The latter generally decreases the risk of pneumothorax with the trade-off that the patient is more likely to move spontaneously during the procedure. Typically, the electrode is placed under image guidance into the center of the nodule after a small skin incision is made to accommodate the 14-gauge needle. Imaging should be repeated between every repositioning to confirm placement. In the event of a periprocedural pneumothorax, a pleural drainage catheter should be placed immediately to evacuate it, as this may cause the lung and nodule to fall away from the chest wall and impede adequate placement of the electrode. A completion CT scan is performed after treatment to visualize the adequacy of the ablation as well as to visualize delayed pneumothorax formation. Occasionally, fiber-optic bronchoscopy may be required to clear endobronchial secretions, which can be blood-tinged after treatment.

Postoperatively, the patient is typically admitted for observation overnight. Chest radiographs are obtained at 6 h postoperatively and the following morning to assess for delayed pneumothorax. If a chest pigtail was required during or after the procedure, a clamp trial is usually performed the following day prior to removal. Rarely, a patient will require a chest drain for a longer period of time, resulting in a prolonged hospital stay. A follow-up chest CT scan may be done the next morning to more accurately assess the post ablation lung but is not required. Patients are typically followed with CT/PET scans at 3- to 4-month intervals.

The most common complication of pulmonary RFA is pneumothorax, occurring in 59% of patients in a recent series. This is largely attributed to the size of the electrode used and is less frequent when positive pressure ventilation is avoided. Prolonged air leak (>5 days) occurred in 7% of patients. Other complications included hemoptysis requiring bronchoscopy, myocardial infarction, deep vein thrombosis, and respiratory failure, which occurred in 1% of patients. In addition, 3% of patients required subsequent drainage of pleural effusions. No intraoperative or in-hospital mortality was observed (Pennathur et al. Ann Thorac Surg. 2009[5];88:1601).

Local recurrence for stage I NSCLC after RFA was confirmed radiographically by CT scan, PET scan, or both after 31.5% of treatments (12/38). Two patients were successfully retreated for technical failures related to pneumothorax; three underwent radiotherapy with stable disease. Three patients died of metastatic disease; five died of pneumonia remote from treatment. The 2- and 4-year survivals were 78% and 47%, respectively. Median overall survival was 30 months. Tumors larger than 3 cm were more likely to recur locally (Pennathur et al. Ann Thorac Surg. 2009[5];88:1601).

CyberKnife^® System

The rationale for SRS is based on the notion that higher doses of radiation improve local control and disease-related survival at the expense of increased toxicity in normal tissues (Sibley et al. Int J Radiat Oncol Biol Phys. 1998;40[1]:149). Initially described for the treatment of intracranial lesions, SRS utilized a rigid frame to immobilize a patient, stereotactically localize a lesion, and deliver a higher dose to a specific point with minimal dosing of surrounding normal tissue, using multiple convergent beams of radiation (Song et al. Oncology. 2004;18[11]:1419). As technology evolved, this technique was adapted for extracranial lesions. However, due to the presence of multiple critical structures in the thorax as well as the intrinsic movement of the lung, there was little interest in SRS for pulmonary lesions. Recent advances in SRS led to the development of CyberKnife, which overcame the limitations of conventional SRS in the thorax.

CyberKnife utilizes a frameless system in which the patient needs to not be immobilized. Instead, the CyberKnife System depends on tracking a tumor in real time and adjusting radiation beams accordingly, thus overcoming the limitations of respiratory movement and minimizing toxic exposure to nearby critical structures. It utilizes a 6-MV linear accelerator mounted on a robotic arm. Beams can be emitted in 12 directions from 110 arm positions. The CyberKnife System relies on internally placed radio-opaque fiducial markers that are implanted and allow tumor tracking based on internal rather than external reference points, thus eliminating the need for rigid immobilization (Pennathur et al. Ann Thorac Surg. 2007;83[5]:1820).

Indications for CyberKnife treatment are similar to those of RFA. Unlike those with RFA, patients with central nodules are also candidates for CyberKnife as there are no heat-sinking limitations.

There are no absolute contraindications to CyberKnife. Relative contraindications are similar to those of RFA. Multiple bulky nodules may be difficult to treat without surrounding radiation toxicity and may lead to treatment failure. Central lesions limit the total allowable dose.

The procedure for CyberKnife treatment begins with placement of one to four fiducials in and around the tumor. These are gold tumor markers that are 1 to 2 mm in size and allow for real-time tracking of the tumor. They are placed under image guidance, typically in an outpatient setting. Usually, a total of three fiducials (within, superior, and inferior to the tumor) will suffice. It is critical that the fiducials be placed within the lung parenchyma, as placement within the pleural space or in the fissures will allow migration, compromising tumor tracking.

A week after placement of fiducials, the patient is brought back for a contrast-enhanced CT scan of the chest and upper abdomen with 1.25-mm sections. The treatment plan is then jointly formulated by a thoracic surgeon and radiation oncologist. The tumor volume as well as a 0.5- to 1.0-cm margin of surrounding tissue is outlined using dosimetry software. The treatment area need not be spherical and in fact may be molded to encompass irregularly shaped nodules and to avoid neighboring critical structures. Precise doses at each point within and away from the planned treatment area may be calculated, thus avoiding reaching toxic thresholds in nearby critical structures.

During the treatment phase, the patient is typically positioned according to the previously formulated treatment plan. Fiducials are tracked in real time using two ceiling-mounted radiographic fluoroscopes, and these oblique dual images are combined with the CT scan data, using tracking software to direct or readjust the beams of radiation at frequent intervals. For peripheral lesions, 60 Gy is delivered in three fractions; and for central lesions, 48 Gy is delivered in four fractions to minimize toxicity to surrounding critical structures (Pennathur et al. Ann Thorac Surg. 2009;88[5]:1594).

Patients are followed at 3- to 4-month intervals with PET/CT scans. Nodules are assessed for response/progression based on size, mass quality (cavitation, replacement with scar, etc.), and PET avidity. In addition, treatment-related toxicity is assessed with each follow-up visit with pulmonary function testing and quality-of-life assessment.

Early complications of treatment are mainly related to placement of fiducials. In a recent series, 26% of patients developed a pneumothorax requiring tube thoracostomy. Late complications are mainly due to treatment-related toxicity. This is particularly true for central tumors (Pennathur et al. Ann Thorac Surg. 2009;88[5]:1594). In a phase II trial of 70 patients treated with 60 to 66 Gy in three fractions, only 54% of patients with central tumors were free from severe toxicity compared with 83% of patients with peripheral tumors at 2 years. In summary, 8.6% of patients died of treatment-related toxicity (Timmerman et al. J Clin Oncol. 2006[30];24:4833). Therefore, lower doses are required for central tumors, particularly those near larger central airways.

Using this modality, the overall 2-year survival for primary lung cancer (all stages) was 44%. The median overall survival was 22 months. In conclusion, 62% of patients had progression, which was observed at a median time of 9 months. Patients treated with 60-Gy doses (i.e., those with peripheral lesions) showed significantly improved survival and time to disease progression compared with those treated with 20-Gy doses (Pennathur et al. J Thorac Cardiovasc Surg. 2009;137[3]:597).

Conclusion

RFA and SRS each provide a minimally invasive alternative for high-risk patients with pulmonary malignancy. Studies are ongoing in their application to pulmonary metastases and as part of multimodality treatment protocols. As technology improves, RFA delivery probes will be smaller and can potentially be delivered endobronchially. Similarly, tumor-tracking technology in the spontaneously ventilating lung continues to improve, and fiducial placement may soon be unnecessary in SRS. As the technology evolves, the use of these modalities may expand beyond use only for the high-risk patients.

Dr. Brichkov is with the division of thoracic surgery at Maimonides Medical Center in Brooklyn, N.Y. He has disclosed that he has no significant relationships with the companies/organizations whose products or services are discussed within this Pulmonary Perspectives.