Study of Outcomes of Radiofrequency Ablation of Lung Tumors

The use of RF ablation in pulmonary tissue is not new. However previous reports have
primarily been descriptions of technique and early procedural outcomes. Follow-up studies
have been lacking. This study will provide information on outcomes such as rates of clinical
response, overall survival, progression-free survival, dyspnea and QOL.

The determination of the efficacy of this technique with this study could make an important
contribution to the management of patients with pulmonary malignancies with high operative
risk for resection. A minimally invasive alternative for tumor destruction could potentially
improve quality of life by controlling local tumor progression and could provide longer
survival when compared to current non-surgical options. This pilot study will determine the
potential utility and effectiveness of RFA treatment of lung tumors, and whether to further
evaluate this therapy in prospective randomized clinical trials compared to other
conventional modalities.

Lung cancer is currently the most common cause of cancer-related death in the USA and
represents the second most common malignancy in both men and women with 171,400 new cases in
the year 1999. Unfortunately, the majority of patients present with advanced disease. Despite
advances in the management of this disease, the best 5-year survival for stage I remains
around 70% for patients who have undergone surgical resection. Complete resection provides
the best chance for cure and remains the gold standard of therapy for patients with
acceptable surgical risk.

The role of surgical resection of pulmonary metastasis in selected patients is widely
accepted, and a survival advantage of aggressive surgical therapy has been demonstrated.
Surgical series have demonstrated 5-year survival of 25-42% in the surgical treatment of
pulmonary metastasis from different primaries including colorectal cancer osteogenic sarcoma,
melanoma, and others. In a prospective study of 5,206 cases of lung metastasectomy, the
International Registry of Lung Metastases reported an actuarial survival of 36% at 5 years
and 26% at 10 years. These results compared favorably with those who had an incomplete
resection achieving a survival of 13% at 5 years and 7% at 10 years.

The standard resections for primary lung cancer include lobectomy or pneumonectomy depending
on the size and location of the tumor. Limited resections, including segmentectomy or wedge
resection of the lung, are the standard treatment for limited metastases and are good
alternatives for patients with primary lung cancer and poor lung function who cannot tolerate
a larger resection. However, a prospective randomized trial to address the role of limited
resection for primary lung cancer was performed by the Lung Cancer Study Group in 276
patients with T1N0 NSCLC. Patients in the limited resection group suffered a 50-75% increase
in local recurrence rate, but no survival difference was seen between the two groups. Limited
resection however should continue to be viewed as a good option for metastasectomy but a
compromising operation for primary lung cancer.

The treatment options for patients with pulmonary malignancies who have severe comorbidities
or poor pulmonary function are limited. These patients are many times not considered for
surgical resection because of the excessive risk of undergoing an invasive operation and are
often treated with external beam radiation and/or chemotherapy. In the case of pulmonary
metastases occurring after previous pulmonary resection, further resection is sometimes not
feasible due to limited residual pulmonary parenchyma or dense adhesions.

After the widespread application of radiofrequency ablation (RFA) for the destruction of
unresectable liver tumors, this technique has been considered as an alternative therapy for
the ablation of other solid tumors. The initial experience in the treatment of lung tumors
with RFA indicates that the technique appears to be safe and feasible for ablation of
peripheral lung nodules.

The U.S. Food and Drug Administration approved RFA for coagulation necrosis of soft tissue
tumors. In addition, RFA has been widely used for treatment of pulmonary nodules in France,
Germany, Japan, Korea, and the People's Republic of China.

Radiofrequency ablation systems are comprised of three components: a radiofrequency
generator, an active electrode, and dispersive electrodes. The RF energy is introduced into
the tissue via the active electrode. As the RF energy (alternating current) moves from the
active electrode to the dispersive electrode (i.e., the electrosurgical return pad) and then
back to the active electrode, the ions within the tissue oscillate in an attempt to follow
the change in the direction of the alternating current. This movement results in frictional
heating of the tissue, and as the temperature within the tissue becomes elevated beyond 60°C,
cells begin to die. It is this phenomenon that causes the region of necrosis surrounding the
electrode.

The advantage of such a thermal intervention system is the capacity to heat tissue to a
lethal temperature in a specific anatomic location. The advantages of such a procedure in the
treatment of non-resectable hepatic and renal lesions are reduced surgical trauma, shorter
procedure time, shorter hospitalization, and a faster recovery time. In the treatment of lung
nodules, this allows for destruction of lung tumors with minimal damage to surrounding normal
lung tissue.

Coagulation necrosis of soft tissue due to RF ablation has been reported in liver, kidney,
breast, and lung tissues. Radiofrequency ablation of primary and metastatic hepatic lesions
has been reported to result in necrosis encompassing 70% to 98% of tumors treated. To date,
little has been reported on the use of RF ablation to address pulmonary nodules. In a
presentation of three case studies, follow-up CT imaging noted that cells within the region
of the thermal lesions were fibrotic and in only one of the three patients was residual
disease detected. Using positron emission tomography (PET) imaging of the lung, a series of
ten patients noted that within the boundaries of the thermal lesions there was no evidence of
metabolic activity.

A pre-clinical study was undertaken in a porcine model in order to determine the capacity of
RF energy to induce necrosis of lung tissue. Using differing power settings and length of
application times, it was determined that the thermal lesions produced in the porcine lung
tissue were complete and entire, with no procedure-related complications. Animals survived to
3, 7 and 28 days post-RF ablation were active and showed no evidence of detrimental effects
of the RF-induced necrosis on respiratory capacity or function. The regions of necrosis were
affected by conductive heat loss via air and blood flow and the presence of bronchi, which
resulted in invagination of the thermal lesion boundary; however, all cells within the
boundaries were nonviable.

Determining the effectiveness of the RF ablation usually involves follow-up computed
tomography (CT) scans. CT imaging provides an assessment of tissue changes following an
ablation, which can manifest as central cavitation of the lesion with decreased tissue
density measured by a decrease in Hounsfield units (Hu). As complementary modality, positron
emission tomography (PET) can be used to determine tissue viability within the lesion, which
can be useful in the follow-up of these patients. In particular, patients with questionable
response to RFA as determined by CT scan can benefit from PET scanning, by determining the
presence of residual disease. The patient is injected with a radio-labeled sugar (typically
18 Fluoro-deoxyglucose or FDG) prior to the PET scan and viability is determined based upon
the uptake of the FDG by cells, since FDG is taken up by cells with high metabolic activity,
such as tumors, infection, or inflammation. In a small pilot study, monitoring with PET noted
no viable tissue within the boundaries of the thermal lesions induced in pulmonary nodules.

In the investigators' initial experience at the University of Pittsburgh Medical Center, they
treated 18 patients with RFA and included primary and metastatic lung tumors. Selected
patients were not candidates for complete surgical resection based on surgical risk, multiple
lesions, poor pulmonary reserve or refusal of further surgery. Twenty-eight lung nodules were
treated with RFA in 18 patients (12 male, 6 female). Tumors included metastatic carcinoma
(9), sarcoma (6) or lung cancer (3). Mean age was 52 years (range, 27-95). Thoracic surgeons
performed RFA by mini-thoracotomy (5) or CT-guided percutaneously (13) under general
anesthesia in the operating room. In both approaches, the patient was positioned in the
lateral decubitus position. In the CT-guided procedures we employ the services of a CT
technician and the thoracic surgeon places a small finder needle into the center of the lung
nodule. The surgeon confirms successful central placement of the finder needle during CT
imaging, and the LeVeen™ needle electrode size is chosen according to the diameter of the
target lesion. The needle electrode has a diameter of 14 gauge with a 15 cm shaft length and
is introduced in the center of the lesion under CT guidance. Several applications in
different locations within the lesion may be required for larger masses, with the therapy
beginning at the most distal area and progressing proximally. Chest tubes were required in
46% (n=13) of percutaneous procedures. Mean length of stay was 3 days (range, 1-7 days).
Complications included recurrent pneumothorax (1/18), pneumonitis (6/18), small pleural
effusion (7/18) and transient renal failure (1/18). One death occurred from hemoptysis 19
days post-RFA of a central nodule. This patient had also received recent brachytherapy. After
a mean follow-up of 4 months (range, 1-11 months), computed tomography revealed resolution
with decreased density of treated sites less than 4 cm. Six patients (33%) died of
progressive metastatic disease during the follow-up period.

Even though RFA has been used to treat lung tumors in over 300 patients worldwide, there is
still a need to further define the role of RFA for pulmonary malignancies. In particular the
effects of RFA on dyspnea and quality of life as well as follow-up studies are lacking.

Inclusion Criteria:

- Have stage I or II primary lung cancer and who are felt not to be candidates for
resection based upon co-morbid disease or who refuse lung resection.

- Have metastatic tumors to the lung, and who meet criteria for metastasectomy but who
are felt not to be candidates for resection of all metastases. All metastases should
be treatable by RFA alone or in combination with resection.

- Have positive tissue diagnosis by previous resection (less than 6 months) or by
radiologic biopsy.

- Have clinically suspicious disease defined as a new lesion on chest CT or a suspicious
PET scan.

- Have RF ablation target lesions of 4 centimeters or less in diameter.

Exclusion Criteria:

- If the lesion is centrally located, less than 3 centimeters from the hilum.

- If the target lesion is greater than 4 centimeters in diameter.

- If the lesion is metastatic and the primary site is not controlled.

- If extra-thoracic metastatic disease is present.

- If there are more than 3 tumors in one lung.

- If there are greater than 6 metastatic tumors in total (bilateral).

- If it is felt that all metastases cannot be treated by RFA alone or in combination
with resection.

- If the patient is pregnant or nursing at the time of the procedure.

- If the patient has malignant pleural effusion.

- If the patient is unwilling or unable to provide consent for the procedure.

- If the patient is less than 18 years of age (the short form [SF]-36 is not designed
for patients less than 18 years of age).