Lung Ablation

Lung cancer is the most common primary cancer, with over 230,000 new cases in 2018, and is the most common cause of cancer death, with nearly 160,000 deaths per year. Surgery is the mainstay of treatment for primary lung cancer, but it is estimated that more than 15% of all patients and 30% of patients over age 75 with stage I or stage II non–small cell lung cancer (NSCLC) are medically inoperable. Moreover, local therapy with external beam radiation has shown a best 2-year overall survival of only 51%, with newer stereotactic body radiation therapy (SBRT) showing 3-year survival rates of 42% to 60% for early-stage, medically inoperable NSCLC.

Pulmonary metastatic disease is generally an indicator of wide disease dissemination requiring systemic therapy, but when a finite number of metastatic deposits exist in the lung, resection may improve prognosis for certain pathologies, including primary sarcoma, renal cell carcinoma, colorectal carcinoma, and breast carcinoma. In the case of colorectal carcinoma with isolated pulmonary metastases, 5-year survival rates can exceed 50%. Unfortunately, patients with pulmonary metastases are also often deemed medically inoperable.

Image-guided thermal ablation has been increasingly used for both curative and palliative treatment of primary and secondary lung cancer. The safety and efficacy of this technique has been demonstrated through a decade of treatment of various solid tumors within the lung, liver, kidney, breast, bone, and adrenal gland. It may be used in conjunction with radiotherapy and systemic chemotherapy and is relatively low cost. Thermal ablation modalities include radiofrequency, microwave, laser, and cryotherapy. An increasing number of single and multicenter cohort studies have consistently established the safety and suggested efficacy for medically inoperable disease. The remainder of this chapter highlights the basic biophysics underlying thermal ablation modalities, specifically within the unique anatomy and physiology of the lung, the understood safety and efficacy of thermal lung ablation given our experience to date, newly introduced advances in thermal lung ablation techniques, and the current role of thermal ablation in the treatment of lung cancer.

Basic Biophysics of Lung Ablation

Electromagnetic energy takes form as oscillating perpendicular waves of electrical and magnetic fields traveling at the speed of light. Electromagnetic wave frequencies range from 10 Hz (waves per second) to 10 ²⁴ Hz, with radio waves having frequencies as low as 10 ⁴ Hz, followed by microwaves, infrared waves, visible light, ultraviolet waves, x-rays, and gamma rays in increasing order of wave frequency. Three of the four thermal ablation modalities utilize waves along this spectrum.

Radiofrequency Ablation

Radiofrequency (RF) ablation (RFA) is the most widely used ablation modality for the treatment of solid tumors; its safety has been firmly established in solid malignancies of the lung ( Fig. 104.1 and Table 104.1 ), liver, bone, breast, kidney, and adrenal glands. With this technique, an active RF electrode (applicator) is placed in the tumor under imaging guidance, and a grounding pad (reference electrode) is applied to the chest wall opposite the applicator or on the thigh. Most clinical RFA electrodes emit radio waves in the range of 375 to 500 kHz, generating electrical field lines between the applicator and reference electrode that oscillate with the alternating current. These fields result in collision of electrons with molecules adjacent to the applicator, generating frictional heat. Temperatures exceeding 60°C, regardless of the heating source, induce cell cytotoxicity via thermolabile protein denaturation, and this temperature is generally considered the baseline for inducing immediate coagulative necrosis. Care is taken to keep the electrode tip temperature below 100°C to avoid charring and vaporization, which occur at 110°C, as these processes increase electrical impedance and inhibit heat dissipation to surrounding tissue. The goal is to ablate an appropriate circumferential margin: 95% of microscopic neoplastic extension is within a margin of 8 mm from the tumor border for adenocarcinoma and 6 mm for squamous cell carcinoma.

TABLE 104.1

Outcomes from Leading and Supportive Studies Conducted on Various Lung Ablation Modalities

Study	Year	No. Patients	No. Tumors	Notable Findings
Radiofrequency Ablation
Huang et al.	2018	50	73	1-, 2-, 3-, 5-, and 10-year overall survival rates of patients with Ia NSCLC of 96.0%, 86.5%, 67.1%, 36.3%, and 1%, respectively, and 1-, 2-, 3-, and 5-year progression-free survival rates of 94.0%, 77.5%, 43.5%, and 10.8%, respectively.
Vogl et al.	2016	41	65 Colorectal CA lung metastases	Median survival 24 months. Overall survival rate at 1, 2, and 4 years of 76.9%, 50.8%, and 8.0%, respectively. Progression-free survival rate at 1, 2, 3, and 4 years of 77.3%, 50.2%, 30.8%, and 16.4%, respectively
Dupuy et al.	2015	51		1- and 2-year overall survival rates of 86% and 70%, respectively. Local tumor recurrence-free rate was 68.9% at 1 year and 59.8% at 2 years, worse for tumors>2 cm.
de Baère et al.	2015	566	1037	1-, 3-, and 5-year median follow-up survival rates of 92%, 68%, and 52%, respectively. Mean tumor diameter 15 mm, 90% of patients with <4 tumors.
Ridge et al.	2014	29		Estimated 1-year, 3-year, and 5-year local tumor progression-free survival was 79%, 75%, and 75%, respectively. Estimated 1-year, 3-year, and 5-year overall survival was 100%, 60%, and 14%, respectively.
Ambrogi et al.	2011	57	59	Complete response rate of 59.3% (stage IA, 65.9%; stage IB, 40%; P = .01) at mean follow-up of 47 months. Median overall survival and cancer-specific survival were 33.4 and 41.4 months, respectively. Cancer-specific actuarial survival was 89% at 1 year, 59% at 3 years, and 40% at 5 years
Hiraki et al.	2011	50	52 primary	Overall survival 94% at 1 year, 86% at 2 years, 74% at 3 years, 67% at 4 years, 61% at 5 years Stage IA survival 95% at 1 year, 89% at 2 years, 83% at 3 years, 73% at 4 years, 66% at 5 years Stage IB survival 92% at 1 year, 75% at 2 years, 50% at 3 years, 50% at 4 years, 50% at 5 years Cancer-specific survival 100% at 1 year, 93% at 2 years, 80% at 3 years, 80% at 4 years, 74% at 5 years Disease-free survival 82% at 1 year, 64% at 2 years, 53% at 3 years, 46% at 4 years, 46% at 5 years Median and mean disease-free survival 42 months
Chua et al.	2010	148		Complete response 46% (n=66) Partial response 26% (n=38) Stable disease 39% (n=57) Progressive disease 16% (n=23) Median disease-free survival 11 months
Palussiere et al.	2010	127	210	Probability of survival 72% at 2 years, 60% at 3 years, 51% at 5 years
Zemlyak et al.	2010	64 25 resection 12 RFA 27 cryo		Overall survival at 3 years for resection (wedge or segmentectomy) 87.1%, for RFA 87.5%, for cryo 77%, with no statistically significant difference Cancer-specific survival at 3 years for resection 90.6%, for RFA 87.5%, for cryo 90.2%, with no statistically significant difference Length of hospital stay significantly shorter for RFA/cryo than resection
Huang et al.	2010	329 237 primary 92 mets		Median progression-free interval 21.6 months Overall survival 68.2% at 1 year, 35.3% at 2 years, 20.1% at 5 years NSCLC survival 80.1% at 1 year, 45.8% at 2 years, 24.3% at 5 years Pulmonary mets survival 50.6% at 1 year, 30.1% at 2 years, 17.3% at 5 years Local progression in 78 (23.7%) during follow-up, most likely related to incomplete ablation due to technical issues or tumor size >4 cm
Beland et al.	2010	79	79 primary	Median disease-free survival 23 months Recurrence in 43% at mean follow-up of 17 months Larger tumor sizes associated with larger risk of recurrence, suggesting initial volume of ablation not adequate
Lanuti et al.	2009	31	34 primary	Overall survival 78% at 2 years, 47% at 3 years Median overall survival 30 months, median disease-free survival 25.5 months Disease-free survival 57% at 2 years, 39% at 3 years Mean progression-free survival 33 ± 3.8 months Local progression in 31.5%, tumors >3 cm had greatest recurrence rate, tumors <2 cm had lowest recurrence rate
Lencioni et al.	2008	106	183 33 primary 150 mets	Local control 88% at 1 year Primary lung cancer overall survival 70% at 1 year, 48% at 2 years Colorectal pulmonary mets overall survival 89% at 1 year, 60% at 2 years
Simon et al.	2007	153	189 116 primary 73 mets	Local control 83% at 1 year, 64% at 2 years, 57% at 3 years, 47% at 4 years, and 47% at 5 years for tumors ≤3 cm Local control 45% at 1 year, 25% at 2 years, 25% at 3 years, 25% at 4 years, and 25% at 5 years for tumors >3 cm Stage I NSCLC overall survival 78% at 1 year, 57% at 2 years, 36% at 3 years, 27% at 4 years, and 27% at 5 years Colorectal pulmonary mets overall survival 87% at 1 year, 78% at 2 years, 57% at 3 years, 57% at 4 years, and 57% at 5 years
de Baère et al.	2006	60	100	Local control 93% at 18 months Overall survival 71% at 18 months Lung disease free 34% at 18 months
Dupuy et al.	2006	24		Local control 92% Stage IA cumulative survival 92% at 12 months, 62% at 24 months, and 46% at 56 months Stage IB cumulative survival 73% at 12 months, 42% at 24 months, and 31% at 60 months
Yan et al.	2006	55	55 mets	Overall median survival 33 months, despite 30/55 with previously resected liver mets Actuarial survival 85% at 1 year, 64% at 2 years, and 46% at 3 years Univariate analysis: lesion size, location, repeat RFA predictive of survival Multivariate analysis: only lesion size remained predictive
Akeboshi et al.	2004	31	54 13 primary 41 mets	Complete tumor necrosis 69% in 36 lesions <3 cm Complete tumor necrosis 39% in 18 lesions >3 cm
Kang et al.	2004	50 23 primary 27 mets	120	Complete tumor necrosis in tumors >3.5 cm In tumors >3.5 cm, complete tumor necrosis area within 3.5 cm diameter PET-demonstrated tumor destruction in 70% of cases
Yasui et al.	2004	35	99 3 primary 96 mets	Complete tumor necrosis 91%, mean diameter of 1.9 cm
Microwave Ablation
Healey et al.	2017	108	108	Recurrence rates estimated at 22%, 36%, and 44% at 1, 2, and 3 years, respectively. Recurrence rates estimated at 31% at 13 months for tumors > 3 cm and 17% for those < 3 cm.
Vogl et al.	2016	47	103 Colorectal CA lung metastases	Median survival 33 months. Overall survival rate at 1, 2, and 4 years of 82.7%, 67.5%, and 16.6%, respectively. Progression-free survival rate at 1, 2, 3, and 4 years of 54.6%, 29.1%, 10.0%, and 1.0%, respectively.
Wolf et al.	2008	50		Primary local control 74% at median follow-up of 10 months Additional 6% secondary local control for total 80% local control rate Actuarial survival 65% at 1 year, 55% at 2 years, and 45% at 3 years
Laser Ablation
Vogl et al.	2016	21	25 Colorectal CA lung metastases	Median survival 22 months. Overall survival rate at 1, 2, and 4 years was 95.2%, 47.6%, and 23.8%, respectively. Progression-free survival rate at 1, 2, 3, and 4 years was 96.8%, 52.7%, 24.0%, and 19.1%, respectively.
Rosenberg et al.	2009	64	108 mets	Primary local control rate 78% Secondary local control rate of 72% Survival rate 81% at 1 year, 59% at 2 years, 44% at 3 years, 44% at 4 years, 27% at 5 years
Cryoablation
Lyons et al.	2018	42	67	Local tumor recurrence/residual disease in 9% of cases, none in nodules <1.0 cm. Estimated marginal probabilities of local recurrence were 11.4%, 11.4%, and 38.1% at 1, 2, and 3 years after ablation, respectively.
Moore et al.	2015	45	47	5-year survival rate of 67.8% ± 15.3. Cancer-specific survival rate at 5 years of 56.6% ±16.5. 5-year progression-free survival rate of 87.9% ±9.
Yashiro et al.	2013	71	210	1-, 2-, and 3-year local progression-free rates were 80.4%, 69.0%, and 67.7%, respectively.
Zemlyak et al.	2010	64 25 resection 12 RFA 27 cryo		Overall survival at 3 years for resection (wedge or segmentectomy) 87.1%, for RFA 87.5%, for cryo 77%, with no statistically significant difference Cancer-specific survival at 3 years for resection 90.6%, for RFA 87.5%, for cryo 90.2%, with no statistically significant difference Length of hospital stay significantly shorter for RFA/cryo than resection
Wang et al.	2005	187	234 196 primary 38 mets	Mean Karnofsky performance score increased from 75.2 ±1.3 before ablation to 82.6 ±1.4 at 1 week postablation

cryo, Cryoablation; mets, metastases; NSCLC, non–small cell lung cancer; PET, positron emission tomography; RFA, radiofrequency ablation.

Three RFA systems are currently commercially available in the United States. The LeVeen system (Boston Scientific, Watertown, MA) consists of an array of electrode tines that are deployed through a 14- to 17-gauge needle and curve backward toward the device handle. The device measures impedance. The StarBurst system (AngioDynamics, Latham, NY), formerly called the RITA system, is also composed of an array of electrode tines that are deployed through a 14- to 17-gauge needle, but these tines course forward and laterally. The StarBurst system measures temperature through multiple peripheral thermocouples and includes perfusion electrodes that infuse saline into the tissue to enhance energy distribution. The Cool-tip system (Medtronic, Minneapolis, MN) consists of either a single electrode or a triple “cluster” of three electrodes spaced 5 mm apart. The Cool-tip electrodes are perfused with cold saline or water to minimize charring and include a thermocouple at the tip for temperature measurement. There have been no head-to-head comparisons of safety or efficacy between these devices in the lung.

The lung presents unique considerations for RFA because of the large quantities of air between thin layers of parenchyma, continuous air flow, and high volume of pulmonary vascular flow. Air acts as an insulator, so RF energy is concentrated in the tumor. However, the air exchange and vascular flow dissipate heat from normal surrounding parenchyma, creating difficulty in establishing a therapeutic ablation margin. Compared with solid organs, the lung has less water per unit volume of tissue, so the infusion of saline may be warranted to help promote conduction of electric current.

Microwave Ablation

Microwave ablation (MWA) has been established as a treatment option for many tumors of the lung ( Fig. 104.2 ; also see Table 104.1 ), liver, kidney, and bone. Most MWA antennae (applicators) available for clinical use emit microwaves in the range of 900 to 2450 MHz. Unlike RF waves, which generate heat via the friction induced by an electric current, microwaves generate heat by increasing the kinetic energy of water molecules: water molecules in the tissue adjacent to a microwave antenna function as electrical dipoles that repeatedly rotate to align with the applied oscillating electromagnetic field, thus raising the heat of the tissue. Microwave energy is transferred to a much larger area, up to 2 cm surrounding the antenna, than RF wave energy, so MWA creates a larger zone of active heating.

Six MWA systems are currently available in the United States. Three systems use a 915-MHz generator (Evident [Medtronic, Minneapolis, MN], AveCure [MedWaves, San Diego, CA], MicroThermX [Perseon, Salt Lake City, UT]), four systems use a 2450-MHz generator (NEUWAVE [Ethicon, a subsidiary of Johnson & Johnson, Bridgewater, NJ], Amica [Hospital Service, Rome, Italy], Acculis MTA [AngioDynamics]), Emprint [Medtronic], and all use straight antennae. Two of the systems (MicroThermX, NEUWAVE) allow synchronous delivery of microwave energy in three antennae simultaneously. One system (AveCure) does not require shaft cooling to protect the skin. The other six manufacturers use antennae that are perfused with room-temperature fluid or carbon dioxide gas (NEUWAVE) to reduce heating of the nonactive proximal portion of the applicator and prevent damage to the skin and other proximal tissues.

Microwaves behave differently than RF waves in the lung. Microwave propagation is not insulated by air and not hindered by the limited water content of lung parenchyma. In theory MWA may have some advantages over RFA in the lung, including a greater convection profile, resistance to heat-sinks, lack of charring and related impedance limitations, and the ability to more rapidly create larger ablative volumes by using multiple applicators simultaneously. Such advantages could theoretically improve ablation of the tumor margin and thus reduce recurrence rates. One study examined MWA and RFA in normal porcine lung parenchyma and revealed MWA lesion diameters were larger and more circular than those created by RFA. A retrospective study of thermal ablation of colorectal lung metastases showed improved local tumor control at 18 months with MWA compared with RFA and laser ablation, but similar overall survival rates with all three modalities.

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