84: Nonoperative Treatments For Lung Cancer Percutaneous Thoracic Tumor Ablation

Lung cancer remains the leading cause of cancer death for both men and women.¹ Only one-third of patients diagnosed with lung cancer are stage appropriate for surgical therapy. In addition, the rising population of elders in the United States and other Western countries has caused an increase in the number of patients with comorbidities, making primary surgical and curative therapy more complicated. In fact, a review of the California cancer registry revealed that stage I cancer patients who received no treatment have a median survival of 9 months. Eighty-nine percent of patients who were recommended for treatment but refused died within 5 years, and 78% of these patients died from cancer-specific causes. For T1 lesions, the survival rate for treated cancers was 155 months versus 26 months for untreated cancers.² For those patients treated with conventional external radiation alone, 5-year survival is 10% to 30%.³ Hence, appropriate treatment even for patients with major comorbidities should be available.

Surgical resection remains the gold standard treatment for early-stage lung cancer. In addition, the lung is a frequent site of metastasis in that pulmonary metastases occur in 30% of all malignancies.¹ However, a significant proportion of patients are unable or unwilling to undergo surgery. For these patients, ablative therapy may be an option for localized treatment. The technique of percutaneous tumor ablation has developed through the introduction of multiple modalities including microwave, cryoablation, high-intensity focused ultrasound scan, irreversible electroporation, interstitial laser, and radiofrequency ablation (RFA). The most studied and proven method among these is RFA.

Radiofrequency energy was first used in surgery with the application of cauterization in 1926, introduced by William T. Bovie, after pulsed electrical current was shown to cause coagulation in tissue, while continuous current resulted in cutting of tissue. The technique afforded precision cuts with minimal blood loss. Percutaneous RFA was first reported in 1990 for liver tumor ablation.⁴ Since then, the indications have expanded to other organs, such as kidney, bone, and lung. The mechanism of action and outcomes of treatment are reviewed.

The term, radiofrequency ablation, refers to the therapeutic use of electromagnetic radiation (EMR) for the selective destruction and removal of biologic lesions. Electromagnetic radiation exhibits wave-like behavior corresponding in magnitude to the light spectrum (e.g., microwaves, radio waves, infrared, visible light, ultraviolet, X-rays, gamma rays). RFA uses energy at the frequency and length of radio waves (2–300 Hz).⁵ A circuit is created that flows from the tip of the electrode, to a large, diffuse grounding pad placed over the patient's thighs, to an external generator. The small cross-sectional area of the electrode creates a surrounding region of high energy flux. The molecules next to the electrode, usually water, align with the direction of the current. The rapidly alternating current causes the adjacent molecules to vibrate. Molecules farther away from the probe are affected by the other vibrating molecules. The frictional loss of energy between molecules results in a temperature increase.⁶ The electrode, itself, is not a source of heat, but creates the electromagnetic field that causes molecular movement, and hence heat generation.

Temperature control is an important issue in RFA. The temperature must be managed to allow energy to be conducted through the tissues. Excessive energy can cause build-up of char around the probe that insulates conduction and limits energy dissipation. With regard to the lung, the parenchyma is thermally insulated by the air-filled alveoli. Tumors within the lung will require different amounts of energy than those attached to the pleura, as the chest wall creates different resistive patterns.⁷

Tissue is sensitive to temperatures above 40°C.⁸ Protein denaturation and coagulation occur between 60°C and 100°C. The therapeutic effect of RFA diminishes when temperatures rise above 105°C, at which point the tissue starts to boil, vaporize, and carbonize. Gas formation increases tissue impedance, preventing heat expansion and limiting the ablative area. Carbonization creates insulation around the probe that prevents heat dissipation.

Heat transmission can also be affected by the local anatomy. Approximation to a vessel 3 mm or larger can create enough heat loss from the flow of lower temperature blood to prevent adequate ablation, the so-called “heat sink” effect. This can lead to incomplete or inadequate ablation of tumors in close proximity to vessels. Animal studies of lesions close to the heart and myocardium have demonstrated RFA to be safe with no damage to the myocardium, possibly owing to the loss of heat from the higher blood flows in the heart.⁹ Tumors in close proximity to the heart subsequently have higher rates of recurrence with a 69.3% recurrence at 1 mm distance versus 8.6% recurrence at 9 mm.¹⁰

The typical set-up for an ablation requires a generator, a probe, and a ground. The grounding pad is used to complete the circuit from the patient to the generator. It is often large and applied to both thighs to dissipate the charge without causing local heat effects. The radiofrequency generators are capable of outputting approximately 250 W with high-frequency alternating currents ranging from 460 to 500 kHz.⁵ With regard to the electrodes, three commercially available devices are the most popular. The Boston Scientific LeVeen ablation system uses an impedance-based feedback system to adjust its energy output (Fig. 84-1). The distal monopolar electrodes are deployed in an umbrella fashion with diameters of 2 to 5 cm. Covidien produces the formally Valleylab Cool-tip technology. The catheter is cooled internally with running saline to slow heating of adjacent tissue, thereby reducing tissue resistance. It uses impendence monitoring to adjust its energy output, and multiple electrodes can be clustered to allow for larger ablation zones (Fig. 84-2). Angiodynamics produces the radiofrequency interstitial tissue ablation (RITA) temperature-controlled system. They offer two probes, the StarBurst which has several electrodes that expands like a Christmas tree to a maximum size of 7 cm (Fig. 84-3). Real-time temperature readings at the distal electrodes are utilized to adjust energy output. Their Talon system is similar, but uses saline infusion into the tissue at the electrode tips to reduce charring and to allow for a more uniform distribution of heat.

We prefer the Angiodynamics RITA system with Talon probes. Patients are worked up in the standard fashion including chest CT, PET/CT, and pulmonary function testing (PFT). Early stage or localized lesions are considered appropriate for treatment. Patients are brought into the CT scanner, placed under conscious sedation with fentanyl and Versed medication, and continuously monitored. A scout scan is performed to identify the lesion. Patients are placed in various positions to allow for the shortest route to the lesion, either supine, lateral decubitus, prone, or some variation thereof. Crossing lung fissures should be avoided to decrease the risk of pneumothorax. Local anesthesia is given on the skin and intercostal space while a straight tract is probed with the needle. Then, using CT fluoroscopic guidance, the electrode is delivered into the tumor. The tines are deployed and ablation started. Our protocol calls for a 10-minute ablation at 90°C. If pneumothorax is encountered, a pigtail catheter is placed to control the chest space. Once treatment is complete, the catheter is removed without the use of tract ablation. A CT scan is performed immediately after the procedure and again at 24 hours.

CT scanning is used to follow time-related changes post-RFA. Figure 84-4 shows the typical appearance of tissues before and after the application of RFA. In a rodent model of normal lung, the appearance of RFA treatment is that of a central density surrounded by a ground-glass opacity. This corresponds to an area of tissue necrosis centrally with a surrounding zone of ongoing necrosis and tissue damage in the ground glass area.¹¹ In a case report of an ablation followed by resection 3 weeks later, an inner band of thermally coagulated blood, chronic hemostasis, and thrombosis with a focal area of lytic necrosis was seen. Surrounding this was an outer band of hemorrhage associated with lytic necrosis of lung tissue.¹² Initially, the ablation area will increase in size, but then start to condense. A baseline CT scan is advised at 3 months. Following this, the tumor should progressively shrink.¹³ Cavitation of the ablated zone can occur in about one-third of all treatments.¹⁴ To detect recurrent or persistent disease, the ablation area must be evaluated for any increase in size. This can lead to some delay. Some have demonstrated that it takes about 7 months to detect an incomplete treatment.¹⁵

Thanos et al.¹⁶ have used contrast enhancement to determine complete ablation. If the nonenhanced posttreatment scan is equal to the enhanced pretreatment area, the treatment is considered complete. They reported complete treatment in 79% of lesions, with an overall 1-year recurrence rate of 15%.

To mitigate this delay, the feasibility of using PET/CT to detect incomplete ablations has been investigated. PET uses fluorine-18-fluorodeoxyglucose (FDG) uptake to indicate cellular activity. Uptake can increase in the first 3 weeks following ablation as the ablative zone is infiltrated by phagocytes and cellular repair cells.¹⁷ In some studies, FDG uptake was shown to increase for up to 12 months following treatment; hence, differentiation between fibrosis and tumor can be difficult.¹⁸ Residual uptake or less than 60% reduction of uptake relative to baseline at 2 months may be associated with tumor recurrence.¹⁹ Baere et al. reported a true negative rate of 100% with PET/CT in 41 patients followed by PET/CT at 1 month and 3 months. They also noted that in 15% of patients, the central lymph nodes were FDG avid, reportedly related to the inflammatory process.²⁰

RFA has been used to ablate primary lung tumors as well as a multitude of pulmonary metastases. In fact, most publications reported a mixed bag of pathology. In addition, reported recurrence rates vary in definition. Most surgical publications relating to surgical resection consider regional lymph nodes as a recurrence, whereas, in most radiologic reports, recurrence is only measured at the site of the tumor. Hence, overall recurrence rates must be viewed more closely. A review of 17 publications reported a complete ablation rate of 90% ranging from 38% to 97%.²¹ Tumors <2 cm in size had higher rates of complete ablation.^22,23 As tumor sizes increase, rates of tumor ablation tend to decrease. Lee et al.²⁴ noted ablation rates of 38% in tumors 3 to 5 cm and 8% for those larger than 5 cm. Simon reported a statistically significant difference in tumor progression for tumors <3 cm compared to those >3 cm (p = 002).²⁵ The 1-year progression-free rate was 83% for tumors <3 cm versus 45% for those >3 cm. At 3 years, it was 57% versus 25%. Median time to progression was 12 months for larger tumors versus 45 months. Lee notes that all tumors <3 cm had a complete response with a survival of 19.7 months in complete responders versus 8.7 months in partial responders.²⁴ Herrera reported a complete or partial response in 67% of tumors smaller than 5 cm but only 33% control for those >5 cm.²⁶

Others have demonstrated that when the ratio of ablation volume to tumor volume was ≥3, the complete ablation rate at 1 year was 83% compared to 61% when the ratio was <3.²² In fact, a margin of 4.5 mm of ground glass opacity surrounding the tumor zone results in a complete ablation.²⁷ As most catheters extend to a 5 cm diameter, tumors <3 cm are best treated to provide the 0.5 cm to 1 cm margin of additional tissue ablation. In addition, electrode configuration may have an effect on recurrence with a lower success rate for the straight electrode, such as the LeVeen, compared with the expandable electrode, although this difference may be more related to tumor location than electrode selection.²²

A prospective multicenter intent to treat study (RAPTURE) was published in 2008.²⁸ The study included 106 patients with 183 treated tumors. Complete response at 1 year was 88%. Lung cancer patients had 1- and 2-year survivals of 70% and 48%, respectively. Most of these patients were at high risk and died of non–cancer-related diseases. Stage I patients had a 2-year survival of 75% and a cancer-specific survival of 92%.

Simon et al.²⁵ reported on 75 primary non–small-cell lung cancer (NSCLC) cases, stages IA and IB, treated with RFA. Median survival was 29 months. The 1-, 2-, 3-, 4-, and 5-year survivals were 78%, 57%, 36%, 27%, and 27%, respectively. With smaller tumors <3 cm, the progress-free survival rate was 47% at 5 years. Fernando²⁹ reported a mean survival of 21 months for NSCLC patients with a median progression-free survival of 18 months. Beland³⁰ demonstrated a 23-month, disease-free survival. Of the recurrences, 38% were local, 18% intrapulmonary, 18% nodal, and 21% distal. Zemlyak³¹ compared RFA to surgical resection for stage I lung cancer. The 3-year survival was 87.1% for surgery and 87.5% for RFA.

Similar survival rates have been reported for metastatic disease, although extrathoracic metastasis is an independent factor in overall survival.³² Several studies looking at colorectal metastasis reported a 2-year survival rate of 64% to 78%.^15,32 The RAPTURE study reported a 1-year survival of patients with colorectal metastasis of 89% and 2-year survival of 66%.²⁸ Simon noted a 1-year survival of 87%, and 3- and 5-year survival of 57% for colorectal metastasis.²⁵ Other studies have demonstrated higher 1-year survival at 95% and 3-year survival at 50%.³³ For sarcoma, renal cell, and head and neck cancers, 5-year survival is in the range of 45% with disease-free survival of 36 months or more.³⁴

Overall lung function is preserved. Baere evaluated PFTs at 1 month and showed no difference between pretreatment and posttreatment function.¹⁵ Lencioni also saw no difference in pulmonary function at 12 months.²⁸ In addition, Lee noted good symptom control in noncurative patients who had hemoptysis (80%), chest pain (36%), and cough (25%).²⁴

Lee et al.³⁵ evaluated the utility of RFA as an adjuvant treatment for lung cancer. Patients with stage III and IV disease were treated with either chemotherapy alone or chemotherapy and RFA. Survival for the chemotherapy alone was 29 months. Those who received both chemotherapy and RFA had a survival of 42 months (p = 0.03). Although a small study, there may be some utility in using RFA in the adjuvant setting.

Pain is the most common postprocedure complaint and is more common in lesions close to the parietal pleura versus those that lie deep in the lung parenchyma. It is generally limited to the periprocedural period. Patients may also experience transient hyperthermia, with temperatures rising to 38°C during the ablation treatment. Pulmonary hemorrhage occurs in approximately 5% of patients, similar to those undergoing core needle biopsy.³⁶

Pneumothorax can be seen on CT scan in approximately 50% of treatments.^31,37 However, only 4% to 16% require placement of a chest tube. The rates of delayed and recurrence pneumothorax are reported to be 10.3% and 6.7%, respectively.³⁸ However, only 4 of 33 patients required intervention with an overall rate of <2%. Fernando reported a 38.9% pneumothorax rate although not all cases required intervention.²⁹ Risk factors for pneumothorax are age more than 60 years, presence of emphysema, lesions smaller than 1.5 cm, lower lobe lesions, lesions deeper than 2.6 cm, and crossing fissures.^37,39

Hemoptysis can present in about 15% of patients.²⁶ Most incidences are minor and self-limited. Severe hemorrhage has been reported with central lesions and tumors in close proximity to major pulmonary vessels.⁴⁰ Simon et al.²⁵ demonstrated a mortality of 2.6% (4 of 153 patients) related to the RFA treatment. Two of the four patients had had prior pneumonectomy.

Other thermal techniques include cryotherapy which uses a probe to cause selective freezing. This causes ice crystals to form within the cells, which ruptures the cellular membranes, causing overall cellular damage.⁴¹ The 3-year survival in stage I NSCLC has been reported as 77% with a 37% rate of pneumothorax.³¹ Microwave technology has demonstrated a mean diameter of ablation that is 25% larger than single-cooled RFA probes.⁴² Combined microwave probes can treat larger volumes. However, studies have not demonstrated the superiority of microwave over RFA. A study of 50 patients noted a 1-year local control rate of 67% with a mean time to recurrence at 16.2 months. The 1-year survival was 65% with a cancer-specific survival of 83%.⁴³ Certainly, this technology as well as others require further assessment.

As patients become older, comorbidity increases and lung function decreases, raising the need for less invasive yet effective therapies for treating pulmonary malignancies. RFA is a cost-effective, minimally invasive option that can be performed on an outpatient basis.¹⁶ Many centers observe patients for 1 or 2 days after the procedure, as is our practice. The indications for RFA include early stage disease, single site recurrence, limited metastases, and palliation for some symptoms. Combination treatment with adjuvant chemotherapy or radiation may improve outcomes and provide further options for patients.