Definitive Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer: Current Status and Future Perspectives

*Hiroshi Doi and Kozo Kuribayashi*

## **Abstract**

Lung cancer remains one of the most common cancers, and the mortality rate is still high. Radiotherapy plays an important role in radical treatment for locally advanced non-small cell lung cancer. Treatment outcomes in lung cancer have improved over the last few decades. Several treatment regimens have been shown to be effective and safe. Further, modern technological approaches of radiotherapy have been developed along with advanced imaging and immunotherapy in order to improve outcomes and minimize radiation-induced toxicity. This chapter summarizes the historical results of the key clinical studies that were conducted in the past with the focus on various regimens of chemoradiotherapy used. In addition, we discuss future perspectives of definitive radiotherapy for locally advanced nonsmall cell lung cancer.

**Keywords:** lung cancer, radiotherapy, chemoradiotherapy, intensity modulated radiation therapy, dulvalumab

## **1. Introduction**

The lung cancer remains one of the most common cancers, and 80% of lung cancers account for non-small cell lung cancer (NSCLC) [1]. Patients diagnosed at a locally advanced stage represent 20 to 30%, and radical surgery is challenging for those patients [1]. Definitive chemoradiotherapy is a well-established treatment option for unresectable locally advanced NSCLC [2, 3]. Treatment outcomes in such patients have improved over the last few decades. Several treatment regimens have been shown to be effective and safe. Moreover, modern radiotherapy technologies have been developed along with the development of optimal chemotherapy and immunotherapy to improve outcomes and minimize radiationinduced toxicity. This chapter summarizes historical results of key clinical studies in the past in terms of various regimens of chemoradiotherapy. In addition, we discuss definitive radiotherapy, which is recommended for locally advanced NSCLC. Specifically, we address future perspectives of definitive radiotherapy for locally advanced NSCLC.

## **2. History of the development of definitive radiotherapy for locally advanced NSCLC**

Radiotherapy alone was a standard treatment for inoperable lung cancer up to the 1980s based on the results of a randomized controlled trial in the 1960s [4]. Perez et al. showed the dose–response efficacy up to 60 Gy, which had been a standard dose from the combined results of the RTOG 7101 and 73–02 study [5]. After the 1990s, definitive radiotherapy, using ≥60Gy in a conventional fractionated regimen, combined with chemotherapy, has been used as a standard treatment for unresectable locally advanced NSCLC. In the early 1990s, sequential cisplatin-based chemotherapy followed by radiotherapy had been proven to have a survival benefit over definitive radiotherapy alone and chemotherapy alone for unresectable stage III NSCLC [6–9]. Then, from the late 1990s to the 2000s, several randomized clinical trials revealed that the concurrent approach of chemoradiotherapy enhanced survival compared to the sequential approach [10–13]. After 2000, the usefulness of several new agents, such as paclitaxel, gemcitabine, vinorelbine, and docetaxel, which are called third-generation chemotherapy agents, have been studied. They have been usually administered in combination with platinum compounds, and demonstrated increased survival in patients with metastatic NSCLC [14, 15]. Although there has been no significant improvement in survival achieved with chemoradiotherapy using third-generation regimens, it has become a standard treatment with a favorable toxicity profile [16, 17].

Some clinical studies conducted between 1990s and 2000s showed that hyperfractionated, accelerated radiotherapy was superior to the conventional fractionated radiotherapy with a feasible toxicity [18–21]. However, the benefit of hyperfractionated, accelerated radiotherapy is controversial, with high risk of acute esophageal toxicity; and has been less accepted in clinical practice [2, 21, 22]. After 2000, the utility of consolidation chemotherapy following chemoradiotherapy has failed to prove a significant survival benefit [23–25]. A dose escalation of radiotherapy has been investigated because loco-regional tumor control might be associated with better survival; and there is a potential dose–response efficacy in the control of NSCLC using this approach [5, 26]. However, RTOG 0617 trial failed to prove benefits on overall survival (OS) and progression-free survival (PSF) using the escalated doses of 74 Gy compared to the standard dose of 60 Gy in an open-label randomized phase 3 study [27]. Volume prescriptions such as D95 using updated calculation algorithms in recent clinical trials could reveal a slightly escalated dose for the target, in comparison with the point prescription that has been used in previous studies. However, the standard regimen of definitive radiotherapy has been 60 Gy in 30 fractions.

As shown in **Figure 1**, the median survival time after treatment has improved with the development of chemoratiotherapy. However, the 5-year survival rate has been unsatisfactorily, reaching only up to 20%. Recently, immune checkpoint inhibitors (ICIs) have been applied in the treatment of advanced malignancies, including lung cancer [29]. ICIs block checkpoint proteins that can weaken immune responses by T cells to cancer cells. Recent systematic reviews have demonstrated the beneficial effects of ICIs on OS and PSF in advanced NSCLC [30]. The PACIFIC trial, a randomized, double-blind, placebo-controlled multi-center trial, has tested the efficacy of dulvalumab, which is a human monoclonal antibody directed against programmed cell death-ligand 1 (PD-L1), in patients with stage III NSCLC as sequential treatment following standard concurrent chemoradiotherapy [19–32]. Dulvalumab has brought a breakthrough in the treatment of locally advanced

**65**

**Table 1.**

**Figure 1.**

~ 1980s Radiotherapy alone

1990s Sequential chemoradiotherapy

*Definitive Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer: Current Status…*

NSCLC in decades, and median survival after treatment has not reached with a median follow-up of 33.3 months in a recent updated result [28]. The transition of standard definitive radiotherapy for locally advanced NSCLN and representative of the clinical outcomes of selected prospective clinical trials with time are shown in

*Improvement of survival outcome of locally advanced NSCLN. (A) Median survival and (B) 3-year overall survival per selected prospective clinical studies and meta-analyses [4–13, 16, 17, 23, 24, 27, 28]. Each bar indicates the mean value of the results. Radiotherapy group included locally advanced NSCLC patients who underwent treatment with standard radiation doses such as* ≥*60Gy in a conventional schedule.* Abbreviations: *Con-CRT, concurrent chemoradiotherapy; Con-CRT-ICI, concurrent chemoradiotherapy with consolidation* 

*immune checkpoint inhibitor; RT, radiotherapy; Seq-CRT, sequential chemoradiotherapy.*

Concurrent chemoradiotherapy (second-generation regimen)

2020~ Concurrent chemoradiotherapy followed by immune checkpoint inhibitor (dulvalumab)

2000s Concurrent chemoradiotherapy (third-generation regimen)

*Transition of standard definitive radiotherapy for locally advanced NSCLN.*

*DOI: http://dx.doi.org/10.5772/intechopen.93927*

**Table 1** and **Figure 1**.

*Definitive Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer: Current Status… DOI: http://dx.doi.org/10.5772/intechopen.93927*

NSCLC in decades, and median survival after treatment has not reached with a median follow-up of 33.3 months in a recent updated result [28]. The transition of standard definitive radiotherapy for locally advanced NSCLN and representative of the clinical outcomes of selected prospective clinical trials with time are shown in **Table 1** and **Figure 1**.

#### **Figure 1.**

*Lung Cancer - Modern Multidisciplinary Management*

**advanced NSCLC**

profile [16, 17].

been 60 Gy in 30 fractions.

**2. History of the development of definitive radiotherapy for locally** 

regimens, it has become a standard treatment with a favorable toxicity

Some clinical studies conducted between 1990s and 2000s showed that hyperfractionated, accelerated radiotherapy was superior to the conventional fractionated radiotherapy with a feasible toxicity [18–21]. However, the benefit of hyperfractionated, accelerated radiotherapy is controversial, with high risk of acute esophageal toxicity; and has been less accepted in clinical practice [2, 21, 22]. After 2000, the utility of consolidation chemotherapy following chemoradiotherapy has failed to prove a significant survival benefit [23–25]. A dose escalation of radiotherapy has been investigated because loco-regional tumor control might be associated with better survival; and there is a potential dose–response efficacy in the control of NSCLC using this approach [5, 26]. However, RTOG 0617 trial failed to prove benefits on overall survival (OS) and progression-free survival (PSF) using the escalated doses of 74 Gy compared to the standard dose of 60 Gy in an open-label randomized phase 3 study [27]. Volume prescriptions such as D95 using updated calculation algorithms in recent clinical trials could reveal a slightly escalated dose for the target, in comparison with the point prescription that has been used in previous studies. However, the standard regimen of definitive radiotherapy has

As shown in **Figure 1**, the median survival time after treatment has improved with the development of chemoratiotherapy. However, the 5-year survival rate has been unsatisfactorily, reaching only up to 20%. Recently, immune checkpoint inhibitors (ICIs) have been applied in the treatment of advanced malignancies, including lung cancer [29]. ICIs block checkpoint proteins that can weaken immune responses by T cells to cancer cells. Recent systematic reviews have demonstrated the beneficial effects of ICIs on OS and PSF in advanced NSCLC [30]. The PACIFIC trial, a randomized, double-blind, placebo-controlled multi-center trial, has tested the efficacy of dulvalumab, which is a human monoclonal antibody directed against programmed cell death-ligand 1 (PD-L1), in patients with stage III NSCLC as sequential treatment following standard concurrent chemoradiotherapy [19–32]. Dulvalumab has brought a breakthrough in the treatment of locally advanced

Radiotherapy alone was a standard treatment for inoperable lung cancer up to the 1980s based on the results of a randomized controlled trial in the 1960s [4]. Perez et al. showed the dose–response efficacy up to 60 Gy, which had been a standard dose from the combined results of the RTOG 7101 and 73–02 study [5]. After the 1990s, definitive radiotherapy, using ≥60Gy in a conventional fractionated regimen, combined with chemotherapy, has been used as a standard treatment for unresectable locally advanced NSCLC. In the early 1990s, sequential cisplatin-based chemotherapy followed by radiotherapy had been proven to have a survival benefit over definitive radiotherapy alone and chemotherapy alone for unresectable stage III NSCLC [6–9]. Then, from the late 1990s to the 2000s, several randomized clinical trials revealed that the concurrent approach of chemoradiotherapy enhanced survival compared to the sequential approach [10–13]. After 2000, the usefulness of several new agents, such as paclitaxel, gemcitabine, vinorelbine, and docetaxel, which are called third-generation chemotherapy agents, have been studied. They have been usually administered in combination with platinum compounds, and demonstrated increased survival in patients with metastatic NSCLC [14, 15]. Although there has been no significant improvement in survival achieved with chemoradiotherapy using third-generation

**64**

*Improvement of survival outcome of locally advanced NSCLN. (A) Median survival and (B) 3-year overall survival per selected prospective clinical studies and meta-analyses [4–13, 16, 17, 23, 24, 27, 28]. Each bar indicates the mean value of the results. Radiotherapy group included locally advanced NSCLC patients who underwent treatment with standard radiation doses such as* ≥*60Gy in a conventional schedule.* Abbreviations: *Con-CRT, concurrent chemoradiotherapy; Con-CRT-ICI, concurrent chemoradiotherapy with consolidation immune checkpoint inhibitor; RT, radiotherapy; Seq-CRT, sequential chemoradiotherapy.*


#### **Table 1.**

*Transition of standard definitive radiotherapy for locally advanced NSCLN.*

## **3. Utility of intensity-modulated radiotherapy, learning from RTOG 0617 and PACIFIC trials**

RTOG 0617 trial failed to demonstrate the benefit of dose-escalation of 74 Gy compared with 60 Gy, but also provided significant information for clinical practice, as it was the first phase III NSCLC study to allow intensity-modulated radiotherapy (IMRT) as a treatment modality for locally advanced NSCLC, and 46% of enrolled patients underwent IMRT [27, 33].

The disadvantage of IMRT in terms of dose distribution is increased volume of lungs receiving low-dose radiation, called "low-dose bath" because the IMRT plan is created using the increased number of beam angles [34]. Low-dose baths represented by large volumes of lung V5 (the volume of the lungs receiving ≥5 Gy) has been reported to increase the risk of acute and late pulmonary toxicity [34–36]. IMRT was used to treat larger and unfavorable tumors in RTOG 0617 [37]. Lung V5 was significantly higher in the IMRT group than in the 3D-CRT group. However, IMRT was associated with lower rates of severe pneumonitis in the RTOG 0617 prospective clinical trial. In addition, severe pneumonitis was predicted by lung V20, but not V5. Thus, V20 has been confirmed as a wellestablished risk factor of radiation pneumonitis with high reproducibility [38]. It is difficult to clarify the controversial meaning of V5 as a predictor of radiation pneumonitis. However, IMRT could improve target coverage and reduce the volume of normal lungs irradiated with intermediate doses such as V20 [34]. Grade ≥ 2 pneumonitis after chemoradiotherapy was a significant exclusion criterion in the PACIFIC trial [31]. The reduction of the risk of radiation pneumonitis by using IMRT might maximize the opportunity of receiving consolidation ICI based on the PACIFIC trial, although detailed data on radiotherapy was not collected in the PACIFIC trial [28, 31, 32, 37].

Higher doses to heart and esophagitis were associated with poor survival [37, 39]. In patients receiving heart V50 < 25% versus ≥25, the 1-year OS rates were 70.2% versus 46.8% and the 2-year OS rates were 45.9% versus 26.7% (p < 0.0001) [39]. Heart V40, which has been shown to be a prognostic factor for survival, can be substantially reduced with IMRT compared to 3D-CRT. In addition, the use of IMRT was associated with significantly less decline in quality of life [40]. These toxicities were potentially associated with poor survival in patients treated with escalated radiation doses of 74 Gy [27]. Furthermore, the correlation of institution accrual volume with the treatment outcomes is controversial but can be associated with other malignancies such as head and neck cancers [39, 41–43]. Quality assurance and institutional experience seem important in radical treatment of locally advanced NSCLC.

The benefits of proton therapy have been reported and included a better dose distribution to the lung and heart in treatment plan than in photon radiotherapy [44]. A randomized control study that compared the utility of proton therapy with that of IMRT showed no significant benefit in terms of the occurrence of radiation pneumonitis and local failure [45]. Modern proton techniques might improve clinical outcomes, but there is no significant evidence of a superiority of proton therapy over IMRT at this moment.

IMRT allows the treatment of challenging cases with dosimetric and clinical benefits. Therefore, IMRT is a current standard technique in the definitive radiotherapy for advanced NSCLC, as the use of IMRT has various advantages over 3D-CRT, which obviously outweighs the disadvantages.

**67**

**Figure 2.**

*Definitive Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer: Current Status…*

**4. Tips for using definitive radiotherapy for locally advanced NSCLC**

The European Society for Radiotherapy and Oncology recommends that metastatic nodes and the applicable margin with no further elective lymph nodes should be included in clinical tumor volume (CTV) [46]. Radiotherapy has been prescribed to the intersection point of the treatment beams [18]. An initial radiotherapy was administered to the anteroposterior parallel–opposed pair of portals and then to a pair of oblique fields during the boosted radiotherapy [16]. Traditionally, definitive radiotherapy for locally advanced NSCLC targets the primary disease and nodal metastases as well as the mediastinum and ipsilateral hilum whether or not there is clinical involvement of all nodal stations [6, 7, 9–11, 13, 17, 18, 22]. This technique is known as elective nodal irradiation (ENI). Potential dose–response has been reported, and an increased radiation dose has been believed to improve survival in NSCLC before RTOG 0617 [5, 26]. Involved field radiotherapy (IFRT) is a radiation treatment technique that minimizes the radiation dose to uninvolved areas [47]. For example, **Figure 2** indicates the difference in planning target volume (PTV) between ENI and IFRT. IFRT allows radiation doses to be increased to the primary tumor and involves mediastinal lymph nodes. Thus, landmark clinical trials testing dose escalation adopted IFRT [27, 48, 49]. Although there are limited data directly comparing IFRT and ENI, the elective nodal failure rate after IFRT has been reported to be <10% in most reports [50–56]. Generally, EFRT can decrease the risk of severe toxicities, including acute esophagitis and pneumonitis, while showing no significant differences in elective nodal failure rate and survival outcomes in comparison with ENI [54–56]. Importantly, metastatic nodes should be defined with the guidance of PET images [46, 57]. Thereafter, CTV is generated by adding 5 to 10 mm to the gross tumor volume (GTV) of the primary tumor (typically 8 mm and 6 mm for adenocarcinoma and squamous carcinoma, respectively) and

*DOI: http://dx.doi.org/10.5772/intechopen.93927*

3 mm for GTV of metastatic nodes of <20 mm [46, 58, 59].

*including the upper mediastinum enlarges the size of the PTV.*

*Differences in radiotherapy target selection in elective nodal irradiation and involved field radiotherapy. Squamous cell carcinoma in the upper lobe of the right lung with nodal metastases (cT3N2M0). Red, green, and blue indicates gross tumor volume (GTV), planning target volume (PTV) for elective nodal irradiation (ENI), and that for involved field radiotherapy (IFRT), respectively. The clinical target volume (CTV) for ENI* 

**4.1 Involved-field radiotherapy**

*Definitive Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer: Current Status… DOI: http://dx.doi.org/10.5772/intechopen.93927*

## **4. Tips for using definitive radiotherapy for locally advanced NSCLC**

## **4.1 Involved-field radiotherapy**

*Lung Cancer - Modern Multidisciplinary Management*

collected in the PACIFIC trial [28, 31, 32, 37].

ment of locally advanced NSCLC.

therapy over IMRT at this moment.

3D-CRT, which obviously outweighs the disadvantages.

**0617 and PACIFIC trials**

patients underwent IMRT [27, 33].

**3. Utility of intensity-modulated radiotherapy, learning from RTOG** 

RTOG 0617 trial failed to demonstrate the benefit of dose-escalation of 74 Gy compared with 60 Gy, but also provided significant information for clinical practice, as it was the first phase III NSCLC study to allow intensity-modulated radiotherapy (IMRT) as a treatment modality for locally advanced NSCLC, and 46% of enrolled

The disadvantage of IMRT in terms of dose distribution is increased volume of lungs receiving low-dose radiation, called "low-dose bath" because the IMRT plan is created using the increased number of beam angles [34]. Low-dose baths represented by large volumes of lung V5 (the volume of the lungs receiving ≥5 Gy) has been reported to increase the risk of acute and late pulmonary toxicity [34–36]. IMRT was used to treat larger and unfavorable tumors in RTOG 0617 [37]. Lung V5 was significantly higher in the IMRT group than in the 3D-CRT group. However, IMRT was associated with lower rates of severe pneumonitis in the RTOG 0617 prospective clinical trial. In addition, severe pneumonitis was predicted by lung V20, but not V5. Thus, V20 has been confirmed as a wellestablished risk factor of radiation pneumonitis with high reproducibility [38]. It is difficult to clarify the controversial meaning of V5 as a predictor of radiation pneumonitis. However, IMRT could improve target coverage and reduce the volume of normal lungs irradiated with intermediate doses such as V20 [34]. Grade ≥ 2 pneumonitis after chemoradiotherapy was a significant exclusion criterion in the PACIFIC trial [31]. The reduction of the risk of radiation pneumonitis by using IMRT might maximize the opportunity of receiving consolidation ICI based on the PACIFIC trial, although detailed data on radiotherapy was not

Higher doses to heart and esophagitis were associated with poor survival [37, 39]. In patients receiving heart V50 < 25% versus ≥25, the 1-year OS rates were 70.2% versus 46.8% and the 2-year OS rates were 45.9% versus 26.7% (p < 0.0001) [39]. Heart V40, which has been shown to be a prognostic factor for survival, can be substantially reduced with IMRT compared to 3D-CRT. In addition, the use of IMRT was associated with significantly less decline in quality of life [40]. These toxicities were potentially associated with poor survival in patients treated with escalated radiation doses of 74 Gy [27]. Furthermore, the correlation of institution accrual volume with the treatment outcomes is controversial but can be associated with other malignancies such as head and neck cancers [39, 41–43]. Quality assurance and institutional experience seem important in radical treat-

The benefits of proton therapy have been reported and included a better dose distribution to the lung and heart in treatment plan than in photon radiotherapy [44]. A randomized control study that compared the utility of proton therapy with that of IMRT showed no significant benefit in terms of the occurrence of radiation pneumonitis and local failure [45]. Modern proton techniques might improve clinical outcomes, but there is no significant evidence of a superiority of proton

IMRT allows the treatment of challenging cases with dosimetric and clinical benefits. Therefore, IMRT is a current standard technique in the definitive radiotherapy for advanced NSCLC, as the use of IMRT has various advantages over

**66**

The European Society for Radiotherapy and Oncology recommends that metastatic nodes and the applicable margin with no further elective lymph nodes should be included in clinical tumor volume (CTV) [46]. Radiotherapy has been prescribed to the intersection point of the treatment beams [18]. An initial radiotherapy was administered to the anteroposterior parallel–opposed pair of portals and then to a pair of oblique fields during the boosted radiotherapy [16]. Traditionally, definitive radiotherapy for locally advanced NSCLC targets the primary disease and nodal metastases as well as the mediastinum and ipsilateral hilum whether or not there is clinical involvement of all nodal stations [6, 7, 9–11, 13, 17, 18, 22]. This technique is known as elective nodal irradiation (ENI). Potential dose–response has been reported, and an increased radiation dose has been believed to improve survival in NSCLC before RTOG 0617 [5, 26]. Involved field radiotherapy (IFRT) is a radiation treatment technique that minimizes the radiation dose to uninvolved areas [47]. For example, **Figure 2** indicates the difference in planning target volume (PTV) between ENI and IFRT. IFRT allows radiation doses to be increased to the primary tumor and involves mediastinal lymph nodes. Thus, landmark clinical trials testing dose escalation adopted IFRT [27, 48, 49]. Although there are limited data directly comparing IFRT and ENI, the elective nodal failure rate after IFRT has been reported to be <10% in most reports [50–56]. Generally, EFRT can decrease the risk of severe toxicities, including acute esophagitis and pneumonitis, while showing no significant differences in elective nodal failure rate and survival outcomes in comparison with ENI [54–56]. Importantly, metastatic nodes should be defined with the guidance of PET images [46, 57]. Thereafter, CTV is generated by adding 5 to 10 mm to the gross tumor volume (GTV) of the primary tumor (typically 8 mm and 6 mm for adenocarcinoma and squamous carcinoma, respectively) and 3 mm for GTV of metastatic nodes of <20 mm [46, 58, 59].

#### **Figure 2.**

*Differences in radiotherapy target selection in elective nodal irradiation and involved field radiotherapy. Squamous cell carcinoma in the upper lobe of the right lung with nodal metastases (cT3N2M0). Red, green, and blue indicates gross tumor volume (GTV), planning target volume (PTV) for elective nodal irradiation (ENI), and that for involved field radiotherapy (IFRT), respectively. The clinical target volume (CTV) for ENI including the upper mediastinum enlarges the size of the PTV.*

## **4.2 Respiratory management in locally advanced NSCLC**

An important challenge for lung cancer radiotherapy treatment is the management of physiological movements related to breathing. The lung tumors can move during breathing. Usually, to ensure adequate dose delivery to the tumor, an appropriate margin is added around the tumor. Four-dimensional computed tomography (4DCT) is a technique that allows to quantify the movement of the tumor with the use of respiratory reduction equipment such as an abdominal compression device. The internal target volume (ITV) is delineated on the 4DCT scan in order to account for tumor motion, and an additional margin is added to generate PTV. However, the target is large as it covers the entire tumor motion, especially in tumors in the lower lobe of the lung [60].

The breath-hold technique has been used to minimize the target volume, which must be irradiated with high-dose radiation and can help to reduce risk of radiation pneumonitis (**Figure 3**). In particular, the deep inspiration breath hold (DIBH) technique provides an advantage to a free-breathing treatment and could reduce the dosimetric parameters of normal organs such as the lung in dose-volume histograms [61]. DIBH gating has been clinically used in thoracic and upper abdominal radiotherapy [62]. In addition, it has recently been reported that compliance and reproducibility of DIBH was sufficiently high, with a reported compliant rate of 72% in a prospective clinical study [63]. DIBH has a high potential as a standard treatment in definitive radiotherapy for locally advanced NSCLC.

### **4.3 Image-guided radiotherapy in locally advanced NSCLC**

In recent years, advancements in image-guided radiotherapy (IGRT) technology have enabled more accurate positioning and precise radiotherapy. IGRT is an essential companion to IMRT and allows the treatment to account for daily changes in target anatomy, motion, and positioning. Megavoltage (MV) portal imaging had been conventionally used to correct the setup errors and limited to verification of bony anatomy. In recent years, the X-ray source for imaging has been evolving from MV imaging to kilovoltage (kV) imaging, and from two-dimensional to three- dimensional

#### **Figure 3.**

*Breath hold technique can minimize a target volume. Non-small cell lung cancer in the lower lobe of the left lung. Red, orange blue, and green indicate gross tumor volume (GTV), accumulated GTV on four-dimensional computed tomography (4DCT), planning target volume (PTV) using the breath-hold technique (exhale), and PTV, which was generated by accounting tumor motion in 4DCT, respectively. The breath-hold technique reduces the target volume.*

**69**

NCT03348748).

*Definitive Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer: Current Status…*

imaging. Modern IGRT is performed with either gantry mounted MV or kV cone beam computed tomography (CBCT) or room-mounted kV systems for tracking during treatment. IGRT allows for easier and improved accuracy leading more frequent positioning changes with leading to a therapeutic advantage. Kilburn et al. has reported that IGRT using daily CBCT improved locoregional tumor control than radiotherapy

Three-dimensional images in CBCT are used not only for positioning but also for the evaluation of the radiotherapy planning by dose calculation on the CBCT images. It has recently been reported that dose distribution and dose volume histogram were accurately calculated on CBCT images with a deformable imaging

Further, acquired images from CBCT can be used for individualized treatment, called adaptive radiotherapy (ART). Since there are possibe changes of tumor and surround tissues during the treatment courses due to tumor shrinking and anatomical changes, it is necessary to modify the radiotherapy plan with accounting the appropriate margin, positioning, and tumor. CBCT provides significant three-dimensional information to evaluate if the patient would benefit from a re-scanning and re-planning. Indeed, ART can improve locoregional tumor control

Daily IGRT with CBCT and ART has been reported to reduce toxicity and probably increase tumor response due to a better tumor localization and reduction of an interfraction target miss due to anatomical changes [64, 66, 67]. Further studies should be conducted in order to establish the optimal systemic replanning

**5. Future perspectives of definitive radiotherapy for locally advanced** 

Approximately 40% and 50% of locally advanced NSCLC patients experience locoregional and distant failures two years after the definitive chemoradiotherapy [27]. Consolidation ICI has been proven to reduce disease progression in both the intrathoracic and extrathoracic areas [32, 68]. Time to death or distant metastasis was longer, and the frequency of new lesions was lower with the use of durvalumab in comparison with placebo [32]. Notably, distant failure occurred in one or two lesions (66.6% in durvalumab arm) in a single organ (95.2% in durvalumab arm) at first progression in both arms of durvalumab and placebo with a median followup of 25.2 months [68]. Therefore, there seems to be a window of opportunity for treating these limited failures as a salvage, which might lead to a longer survival [69–71]. Cutting-edge radiotherapies, such as stereotactic radiotherapy and particle

**5.1 Failure pattern and potential salvage after definitive radiotherapy**

therapy, have the potential to be a prospective option as a salvage modality.

The results of the PACIFIC clinical trial have led to the design of several clinical trials combining radiotherapy with ICIs, including PACIFIC-2 study, where a chemoradiotherapy plus durvalumab arm is currently studied (NCT03519971). In addition, combining chemotherapy, radiotherapy, and ICIs with surgical resection is also under investigation in clinical trials (NCT03694236, NCT03237377, NCT04073745,

There are oncological differences between pathological subtypes in NSCLC, as widely known in metastatic diseases [72]. Ito et al. showed that adenocarcinoma and squamous cell carcinoma tended to develop distant and locoregional failures, respectively, after chemoradiotherapy for locally advanced NSCLC [73].

*DOI: http://dx.doi.org/10.5772/intechopen.93927*

using weekly MV portal images [64].

over radiotherapy without ART [66].

registration [65].

technique.

**NSCLC**

*Definitive Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer: Current Status… DOI: http://dx.doi.org/10.5772/intechopen.93927*

imaging. Modern IGRT is performed with either gantry mounted MV or kV cone beam computed tomography (CBCT) or room-mounted kV systems for tracking during treatment. IGRT allows for easier and improved accuracy leading more frequent positioning changes with leading to a therapeutic advantage. Kilburn et al. has reported that IGRT using daily CBCT improved locoregional tumor control than radiotherapy using weekly MV portal images [64].

Three-dimensional images in CBCT are used not only for positioning but also for the evaluation of the radiotherapy planning by dose calculation on the CBCT images. It has recently been reported that dose distribution and dose volume histogram were accurately calculated on CBCT images with a deformable imaging registration [65].

Further, acquired images from CBCT can be used for individualized treatment, called adaptive radiotherapy (ART). Since there are possibe changes of tumor and surround tissues during the treatment courses due to tumor shrinking and anatomical changes, it is necessary to modify the radiotherapy plan with accounting the appropriate margin, positioning, and tumor. CBCT provides significant three-dimensional information to evaluate if the patient would benefit from a re-scanning and re-planning. Indeed, ART can improve locoregional tumor control over radiotherapy without ART [66].

Daily IGRT with CBCT and ART has been reported to reduce toxicity and probably increase tumor response due to a better tumor localization and reduction of an interfraction target miss due to anatomical changes [64, 66, 67]. Further studies should be conducted in order to establish the optimal systemic replanning technique.

## **5. Future perspectives of definitive radiotherapy for locally advanced NSCLC**

#### **5.1 Failure pattern and potential salvage after definitive radiotherapy**

Approximately 40% and 50% of locally advanced NSCLC patients experience locoregional and distant failures two years after the definitive chemoradiotherapy [27]. Consolidation ICI has been proven to reduce disease progression in both the intrathoracic and extrathoracic areas [32, 68]. Time to death or distant metastasis was longer, and the frequency of new lesions was lower with the use of durvalumab in comparison with placebo [32]. Notably, distant failure occurred in one or two lesions (66.6% in durvalumab arm) in a single organ (95.2% in durvalumab arm) at first progression in both arms of durvalumab and placebo with a median followup of 25.2 months [68]. Therefore, there seems to be a window of opportunity for treating these limited failures as a salvage, which might lead to a longer survival [69–71]. Cutting-edge radiotherapies, such as stereotactic radiotherapy and particle therapy, have the potential to be a prospective option as a salvage modality.

The results of the PACIFIC clinical trial have led to the design of several clinical trials combining radiotherapy with ICIs, including PACIFIC-2 study, where a chemoradiotherapy plus durvalumab arm is currently studied (NCT03519971). In addition, combining chemotherapy, radiotherapy, and ICIs with surgical resection is also under investigation in clinical trials (NCT03694236, NCT03237377, NCT04073745, NCT03348748).

There are oncological differences between pathological subtypes in NSCLC, as widely known in metastatic diseases [72]. Ito et al. showed that adenocarcinoma and squamous cell carcinoma tended to develop distant and locoregional failures, respectively, after chemoradiotherapy for locally advanced NSCLC [73].

*Lung Cancer - Modern Multidisciplinary Management*

lobe of the lung [60].

**4.2 Respiratory management in locally advanced NSCLC**

treatment in definitive radiotherapy for locally advanced NSCLC.

**4.3 Image-guided radiotherapy in locally advanced NSCLC**

An important challenge for lung cancer radiotherapy treatment is the management of physiological movements related to breathing. The lung tumors can move during breathing. Usually, to ensure adequate dose delivery to the tumor, an appropriate margin is added around the tumor. Four-dimensional computed tomography (4DCT) is a technique that allows to quantify the movement of the tumor with the use of respiratory reduction equipment such as an abdominal compression device. The internal target volume (ITV) is delineated on the 4DCT scan in order to account for tumor motion, and an additional margin is added to generate PTV. However, the target is large as it covers the entire tumor motion, especially in tumors in the lower

The breath-hold technique has been used to minimize the target volume, which must be irradiated with high-dose radiation and can help to reduce risk of radiation pneumonitis (**Figure 3**). In particular, the deep inspiration breath hold (DIBH) technique provides an advantage to a free-breathing treatment and could reduce the dosimetric parameters of normal organs such as the lung in dose-volume histograms [61]. DIBH gating has been clinically used in thoracic and upper abdominal radiotherapy [62]. In addition, it has recently been reported that compliance and reproducibility of DIBH was sufficiently high, with a reported compliant rate of 72% in a prospective clinical study [63]. DIBH has a high potential as a standard

In recent years, advancements in image-guided radiotherapy (IGRT) technology have enabled more accurate positioning and precise radiotherapy. IGRT is an essential companion to IMRT and allows the treatment to account for daily changes in target anatomy, motion, and positioning. Megavoltage (MV) portal imaging had been conventionally used to correct the setup errors and limited to verification of bony anatomy. In recent years, the X-ray source for imaging has been evolving from MV imaging to kilovoltage (kV) imaging, and from two-dimensional to three- dimensional

*Breath hold technique can minimize a target volume. Non-small cell lung cancer in the lower lobe of the left lung. Red, orange blue, and green indicate gross tumor volume (GTV), accumulated GTV on four-dimensional computed tomography (4DCT), planning target volume (PTV) using the breath-hold technique (exhale), and PTV, which was generated by accounting tumor motion in 4DCT, respectively. The breath-hold technique* 

**68**

**Figure 3.**

*reduces the target volume.*

In addition, non-squamous cell carcinoma tends to benefit more from adding durvalumab than squamous cell carcinoma, although there is a lack of direct comparison analysis [32]. The effects of histopathological and oncological differences in NSCLC on definitive chemoradiotherapy should be investigated with the aim of developing a precision treatment for locally advanced NSCLC.

### **5.2 Immune enhancement and preservation in radiotherapy**

Recent developments in immunotherapy have started a new era in the treatment of various malignancies, including NSCLC [29, 30, 74]. Induction of the expression of immune checkpoint molecules such as PD-L1 results in the inhibition of T cell function and immune tolerance of tumors.

Radiation may cause immune activation through cytokine signaling and tumor antigen release [75, 76]. However, PD-L1 expression in tumors has been reported to be upregulated by radiation exposure in both pre-clinical and clinical settings and can suppress the immunogenic effect on tumors [75–78]. ICIs block the immunosuppressive mechanisms of cancer cells and have a synergistic effect in combination with radiotherapy [75, 77]. The addition of durvalumab was proven to benefit disease control and survival after definitive chemoradiotherapy for locally advanced NSCLC [28, 31, 32]. The density of CD8+ tumorinfiltrating lymphocytes was significantly associated with favorable survival in locally advanced NSCLC patients undergoing chemoradiotherapy [79]. In their report, PD-L1 expression, which could be blocked by ICIs, was associated with inferior survival. In addition, radiation-induced lymphopenia has been reported to be associated with inferior survival [80, 81]. Therefore, radiotherapy will be


*Searched for: radiotherapy, immune | Recruiting, Not yet recruiting Studies | Non-small Cell Lung Cancer Stage III at https://clinicaltrials.gov with excluding trials including surgery on Sep. 7, 2020.*

**71**

*Definitive Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer: Current Status…*

modified to enhance the immune response to tumors. Hypofractionated regimens might have less immunosuppressive effects and are more appropriate than conventional fractionated regimens in terms of immune preservation [82, 83]. A clinical trial has been designed to test the addition of durvalumab to two schedules of radiotherapies of conventional and hypofractionated schedules (NCT03801902). Ongoing clinical trials in terms of definitive radiotherapy combined with ICIs are

PTV size can be associated with circulating blood, including the leukocytes [84].

Thus, IFRT is appropriate in terms of not only reducing the risk of pneumonitis but also preservation of the host immune system. Ladbury et al. have presented a predictive model of the estimated dose of radiation to immune cells, which was calculated using the radiation doses for heart, lung, body, and number of fractions, and was associated with cancer-specific outcomes [85]. Thereafter, sparing the host immune system will be discussed, and new optimizing theory for IMRT should be investigated in the future. Radio-immune therapy strategy is giving a new direction to radiotherapy and is warranted to explore future definitive radiotherapy for

In this chapter, the historical improvement and the current recommendation of definitive radiotherapy for locally advanced NSCLC are described. The current standard treatment for locally advanced NSCLC is definitive radiotherapy, concurrently combined with chemotherapy, followed by anti-PD-L1 treatment. In order to improve outcomes and minimize radiation-induced toxicity, IMRT using an involved-field under modern management of respiration is a present recommendation in this chapter. An optimal combination of radiotherapy and immunotherapy

This work was supported by JSPS KAKENHI Grant Number JP20K08093.

*DOI: http://dx.doi.org/10.5772/intechopen.93927*

summarized in **Table 2**.

locally advanced NSCLC.

**Acknowledgements**

should be warranted in a future investigation.

**6. Conclusions**

#### **Table 2.**

*Ongoing phase 1 to 3 clinical trials for locally advanced NSCLN in terms of definitive radiotherapy and immune therapy.*

*Definitive Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer: Current Status… DOI: http://dx.doi.org/10.5772/intechopen.93927*

modified to enhance the immune response to tumors. Hypofractionated regimens might have less immunosuppressive effects and are more appropriate than conventional fractionated regimens in terms of immune preservation [82, 83]. A clinical trial has been designed to test the addition of durvalumab to two schedules of radiotherapies of conventional and hypofractionated schedules (NCT03801902). Ongoing clinical trials in terms of definitive radiotherapy combined with ICIs are summarized in **Table 2**.

PTV size can be associated with circulating blood, including the leukocytes [84]. Thus, IFRT is appropriate in terms of not only reducing the risk of pneumonitis but also preservation of the host immune system. Ladbury et al. have presented a predictive model of the estimated dose of radiation to immune cells, which was calculated using the radiation doses for heart, lung, body, and number of fractions, and was associated with cancer-specific outcomes [85]. Thereafter, sparing the host immune system will be discussed, and new optimizing theory for IMRT should be investigated in the future. Radio-immune therapy strategy is giving a new direction to radiotherapy and is warranted to explore future definitive radiotherapy for locally advanced NSCLC.

### **6. Conclusions**

*Lung Cancer - Modern Multidisciplinary Management*

function and immune tolerance of tumors.

In addition, non-squamous cell carcinoma tends to benefit more from adding durvalumab than squamous cell carcinoma, although there is a lack of direct comparison analysis [32]. The effects of histopathological and oncological differences in NSCLC on definitive chemoradiotherapy should be investigated with the aim of

Recent developments in immunotherapy have started a new era in the treatment of various malignancies, including NSCLC [29, 30, 74]. Induction of the expression of immune checkpoint molecules such as PD-L1 results in the inhibition of T cell

Radiation may cause immune activation through cytokine signaling and tumor antigen release [75, 76]. However, PD-L1 expression in tumors has been reported to be upregulated by radiation exposure in both pre-clinical and clinical settings and can suppress the immunogenic effect on tumors [75–78]. ICIs block the immunosuppressive mechanisms of cancer cells and have a synergistic effect in combination with radiotherapy [75, 77]. The addition of durvalumab was proven to benefit disease control and survival after definitive chemoradiotherapy for locally advanced NSCLC [28, 31, 32]. The density of CD8+ tumorinfiltrating lymphocytes was significantly associated with favorable survival in locally advanced NSCLC patients undergoing chemoradiotherapy [79]. In their report, PD-L1 expression, which could be blocked by ICIs, was associated with inferior survival. In addition, radiation-induced lymphopenia has been reported to be associated with inferior survival [80, 81]. Therefore, radiotherapy will be

developing a precision treatment for locally advanced NSCLC.

**5.2 Immune enhancement and preservation in radiotherapy**

**70**

**Table 2.**

*immune therapy.*

**ClinicalTrials.gov identifier**

NCT03663166 Phase

**Study design**

1, 2

*at https://clinicaltrials.gov with excluding trials including surgery on Sep. 7, 2020.*

**Brief of treatment**

NCT04432142 Phase 2 Immune changes after concurrent chemoradiation followed by durvalumab

NCT03589547 Phase 2 Durvalumab and consolidation SBRT following chemoradiation

consolidative therapy alone

combined with durvalumab

Chemoradiotherapy with ipilimumab followed by nivolumab

NCT04092283 Phase 3 Durvalumab as concurrent and consolidative therapy or

NCT03801902 Phase 1 Accelerated or conventionally fractionated radiotherapy

NCT04310020 Phase 2 Hypofractionated radiotherapy followed by atezolizumab

NCT04249362 Phase 2 Durvalumab following radiotherapy (standard or

*Ongoing phase 1 to 3 clinical trials for locally advanced NSCLN in terms of definitive radiotherapy and* 

NCT03693300 Phase 2 Durvalumab following sequential chemotherapy and radiotherapy

NCT04392505 Phase 2 Investigating biomarkers related to chemoradiation followed by durvalumab NCT04505267 Phase 1 Reirradiation with NBTXR3 for locoregional recurrence *Searched for: radiotherapy, immune | Recruiting, Not yet recruiting Studies | Non-small Cell Lung Cancer Stage III* 

hypofractionated bioequivalent dose)

In this chapter, the historical improvement and the current recommendation of definitive radiotherapy for locally advanced NSCLC are described. The current standard treatment for locally advanced NSCLC is definitive radiotherapy, concurrently combined with chemotherapy, followed by anti-PD-L1 treatment. In order to improve outcomes and minimize radiation-induced toxicity, IMRT using an involved-field under modern management of respiration is a present recommendation in this chapter. An optimal combination of radiotherapy and immunotherapy should be warranted in a future investigation.

#### **Acknowledgements**

This work was supported by JSPS KAKENHI Grant Number JP20K08093.

## **Author details**

Hiroshi Doi1 \* and Kozo Kuribayashi<sup>2</sup>

1 Department of Radiation Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan

2 Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan

\*Address all correspondence to: h-doi@med.kindai.ac.jp

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**73**

1991;83:417-423.

*Definitive Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer: Current Status…*

[7] Kubota K, Furuse K, Kawahara M, Kodama N, Yamamoto M, Ogawara M, et al. Role of radiotherapy in combined modality treatment of locally advanced non-small-cell lung cancer. Journal of Clinical Oncology. 1994;12:1547-1552.

[8] Dillman RO, Herndon J, Seagren SL, Eaton WL, Green MR. Improved Survival in Stage III Non-Small-Cell Lung Cancer: Seven-Year Follow-up of Cancer and Leukemia Group B (CALGB) 8433 Trial. JNCI Journal of the National Cancer Institute.

[9] Sause W, Kolesar P, Taylor S IV, Johnson D, Livingston R, Komaki R, et al. Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest.

[10] Furuse K, Fukuoka M, Kawahara M, Nishikawa H, Takada Y, Kudoh S, et al. Phase III Study of Concurrent Versus Sequential Thoracic Radiotherapy in Combination With Mitomycin, Vindesine, and Cisplatin in Unresectable

Stage III Non–Small-Cell Lung Cancer. Journal of Clinical Oncology.

Oncology. 2005;23:5910-5917.

[12] Auperin A, Le Pechoux C, Rolland E, Curran WJ, Furuse K, Fournel P, et al. Meta-Analysis of

[11] Fournel P, Robinet G, Thomas P, Souquet P-J, Lena H, Vergnenégre A, et al. Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. Journal of Clinical

1996;88:1210-1215.

2000;117:358-364.

1999;17:2692-2699.

*DOI: http://dx.doi.org/10.5772/intechopen.93927*

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[2] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Non-Small Cell Lung Cancer Version 6. 2020 https://www.nccn.org/professionals/ physician\_gls/pdf/nscl.pdf [Accessed:

[3] Park K, Vansteenkiste J, Lee KH, Pentheroudakis G, Zhou C, Prabhash K, et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with locally-advanced unresectable non-small-cell lung cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS. Ann Oncol. 2020;31:191-201.

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*Lung Cancer - Modern Multidisciplinary Management*

**72**

**Author details**

Osaka-Sayama, Osaka, Japan

\* and Kozo Kuribayashi<sup>2</sup>

College of Medicine, Nishinomiya, Hyogo, Japan

provided the original work is properly cited.

\*Address all correspondence to: h-doi@med.kindai.ac.jp

1 Department of Radiation Oncology, Kindai University Faculty of Medicine,

2 Division of Respiratory Medicine, Department of Internal Medicine, Hyogo

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Hiroshi Doi1

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Randomized Phase III Trial With or Without Consolidation Chemotherapy Using Docetaxel and Cisplatin After Concurrent Chemoradiation in Inoperable Stage III Non–Small-Cell Lung Cancer: KCSG-LU05-04. Journal of Clinical Oncology. 2015;33:2660-2666.

*Lung Cancer - Modern Multidisciplinary Management*

hyperfractionated, accelerated radiotherapy (CHART) versus

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Lung Cancer. 2009;65:62-67.

[21] Mauguen A, Le Pechoux C, Saunders MI, Schild SE, Turrisi AT, Baumann M, et al. Hyperfractionated

or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis. J Clin Oncol.

and Oncology. 2011;100:76-85.

Arseneau J, Ansari R, et al. Phase III Study of Cisplatin, Etoposide, and Concurrent Chest Radiation With or Without Consolidation Docetaxel in Patients With Inoperable Stage III Non–Small-Cell Lung Cancer: The Hoosier Oncology Group and U.S. Oncology. Journal of Clinical Oncology.

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[22] Baumann M, Herrmann T, Koch R, Matthiessen W, Appold S, Wahlers B, et al. Final results of the randomized phase III CHARTWEL-trial (ARO 97-1) comparing hyperfractionatedaccelerated versus conventionally fractionated radiotherapy in non-small cell lung cancer (NSCLC). Radiotherapy

2014;6:328-335.

2012;30:2788-2797.

conventional radiotherapy in non-small cell lung cancer: mature data from the randomised multicentre trial. CHART Steering committee. Radiotherapy and

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[20] Haslett K, Pöttgen C, Stuschke M, Faivre-Finn C. Hyperfractionated and accelerated radiotherapy in nonsmall cell lung cancer. J Thorac Dis.

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2010;28:2181-2190.

2011;103:1452-1460.

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Cancer Res. 1998;4:1087-1100.

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Second- and Third-Generation Regimens With Concurrent Thoracic Radiotherapy in Patients With

[18] Saunders M, Dische S, Barrett A, Harvey A, Griffiths G,

Palmar M. Continuous,

Unresectable Stage III Non–Small-Cell Lung Cancer: West Japan Thoracic Oncology Group WJTOG0105. Journal of Clinical Oncology. 2010;28:3739-3745.

[16] Segawa Y, Kiura K, Takigawa N, Kamei H, Harita S, Hiraki S, et al. Phase III Trial Comparing Docetaxel and Cisplatin Combination Chemotherapy With Mitomycin, Vindesine, and Cisplatin Combination Chemotherapy With Concurrent Thoracic Radiotherapy in Locally Advanced Non–Small-Cell Lung Cancer: OLCSG 0007. Journal of Clinical Oncology. 2010;28:3299-3306.

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**74**

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[79] Tokito T, Azuma K, Kawahara A, Ishii H, Yamada K, Matsuo N, et al. Predictive relevance of PD-L1 expression combined with CD8+ TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy. Eur J Cancer. 2016;55:7-14.

[80] Tang C, Liao Z, Gomez D, Levy L, Zhuang Y, Gebremichael RA, et al. Lymphopenia association with gross tumor volume and lung V5 and its effects on non-small cell lung cancer patient outcomes. Int J Radiat Oncol Biol Phys. 2014;89:1084-1091.

[81] Wang W, Huang L, Jin J-Y, Jolly S, Zang Y, Wu H, et al. IDO Immune Status after Chemoradiation May Predict

Survival in Lung Cancer Patients. Cancer Research. 2018;78:809-816.

[82] Wang W, Huang L, Jin J-Y, Pi W, Ellsworth SG, Jolly S, et al. A Validation Study on IDO Immune Biomarkers for Survival Prediction in Non-Small Cell Lung Cancer: Radiation Dose Fractionation Effect in Early-Stage Disease. Clin Cancer Res. 2020;26:282-289.

[83] Crocenzi T, Cottam B, Newell P, Wolf RF, Hansen PD, Hammill C, et al. A hypofractionated radiation regimen avoids the lymphopenia associated with neoadjuvant chemoradiation therapy of borderline resectable and locally advanced pancreatic adenocarcinoma. Journal for ImmunoTherapy of Cancer. 2016;4:45.

[84] Yovino S, Kleinberg L, Grossman SA, Narayanan M, Ford E. The etiology of treatment-related lymphopenia in patients with malignant gliomas: modeling radiation dose to circulating lymphocytes explains clinical observations and suggests methods of modifying the impact of radiation on immune cells. Cancer Invest. 2013;31:140-144.

[85] Ladbury CJ, Rusthoven CG, Camidge DR, Kavanagh BD, Nath SK. Impact of Radiation Dose to the Host Immune System on Tumor Control and Survival for Stage III Non-Small Cell Lung Cancer Treate d with Definitive Radiation Therapy. International Journal of Radiation Oncology\*Biology\*Physics. 2019;105:346-355.

**81**

**Chapter 6**

**Abstract**

**1. Introduction**

for Lung Tumors

tions, and providing a true "wound-less" option.

Image-Guided Ablative Therapies

While the gold standard for early stage lung cancers is still surgical resection, many patients have comorbidities or suboptimal lung function making surgery unfavorable. At the same time, more and more small lung nodules are being incidentally discovered on computer tomography (CT), leading to the discovery of pre-malignant or very early stage lung cancers without regional spread, which could probably be eradicated without anatomical surgical resection. Various ablative energies and technologies are available on the market, including radiofrequency ablation, microwave ablation, cryoablation, and less commonly laser ablation and irreversible electroporation. For each technology, the mechanism of action, advantages, limitations, potential complications and evidence-based outcomes will be reviewed. Traditionally, these ablative therapies were done under CT guidance with percutaneous insertion of ablative probes. Recently, bronchoscopic ablation under ultrasound, CT, or electromagnetic navigation bronchoscopy guidance is gaining popularity due to improved navigation precision, reduced pleural-based complica-

**Keywords:** radiofrequency ablation, microwave ablation, cryoablation, percutaneous

With the increasing availability of computer tomography (CT) scans and enlarging body of evidence for low-dose CT screening in high risk populations, a rising number of lung nodules are discovered incidentally. Many of them are small, sub-solid, and harbor pre-malignant or early stage cancers. Local therapies for these lesions are gaining evidence support, especially in patients with high surgical risks or decline surgery. Sublobar resection has been shown to confer similar 5-year survival rates, especially in older patients, tumor smaller than 2 cm, and pure bronchoalveolar carcinoma [1–3]. Stereotactic body radiation therapy (SBRT) is targeted toward patients with stage I or II non-small cell lung carcinoma (NSCLC) without lymph node involvement and who are medically inoperable. SBRT has a local control rate of more than 80% in multiple retrospective series [4], and disease-free survival of 26% and overall survival of 40% at 4 years in a multicentre phase II study [5]. However, sublobar resection still carries surgical risks while SBRT has up to 22.3% risk of radiation pneumonitis and pneumonia. Since the early 2000s, percutaneous ablation of lung tumors has been attempted [6] following reports of efficacy of local ablation in liver cancers. The subsequent decade saw the blossom

ablation, bronchoscopic ablation, electromagnetic navigation bronchoscopy

*Joyce W.Y. Chan, Rainbow W.H. Lau and Calvin S.H. Ng*

## **Chapter 6**

## Image-Guided Ablative Therapies for Lung Tumors

*Joyce W.Y. Chan, Rainbow W.H. Lau and Calvin S.H. Ng*

## **Abstract**

While the gold standard for early stage lung cancers is still surgical resection, many patients have comorbidities or suboptimal lung function making surgery unfavorable. At the same time, more and more small lung nodules are being incidentally discovered on computer tomography (CT), leading to the discovery of pre-malignant or very early stage lung cancers without regional spread, which could probably be eradicated without anatomical surgical resection. Various ablative energies and technologies are available on the market, including radiofrequency ablation, microwave ablation, cryoablation, and less commonly laser ablation and irreversible electroporation. For each technology, the mechanism of action, advantages, limitations, potential complications and evidence-based outcomes will be reviewed. Traditionally, these ablative therapies were done under CT guidance with percutaneous insertion of ablative probes. Recently, bronchoscopic ablation under ultrasound, CT, or electromagnetic navigation bronchoscopy guidance is gaining popularity due to improved navigation precision, reduced pleural-based complications, and providing a true "wound-less" option.

**Keywords:** radiofrequency ablation, microwave ablation, cryoablation, percutaneous ablation, bronchoscopic ablation, electromagnetic navigation bronchoscopy

### **1. Introduction**

With the increasing availability of computer tomography (CT) scans and enlarging body of evidence for low-dose CT screening in high risk populations, a rising number of lung nodules are discovered incidentally. Many of them are small, sub-solid, and harbor pre-malignant or early stage cancers. Local therapies for these lesions are gaining evidence support, especially in patients with high surgical risks or decline surgery. Sublobar resection has been shown to confer similar 5-year survival rates, especially in older patients, tumor smaller than 2 cm, and pure bronchoalveolar carcinoma [1–3]. Stereotactic body radiation therapy (SBRT) is targeted toward patients with stage I or II non-small cell lung carcinoma (NSCLC) without lymph node involvement and who are medically inoperable. SBRT has a local control rate of more than 80% in multiple retrospective series [4], and disease-free survival of 26% and overall survival of 40% at 4 years in a multicentre phase II study [5]. However, sublobar resection still carries surgical risks while SBRT has up to 22.3% risk of radiation pneumonitis and pneumonia. Since the early 2000s, percutaneous ablation of lung tumors has been attempted [6] following reports of efficacy of local ablation in liver cancers. The subsequent decade saw the blossom

of image-guided local ablative therapies of lung tumors, first with radiofrequency ablation (RFA), later with microwave ablation (MWA) and cryoablation. In this chapter, we discuss the preparation and procedure of lung ablative therapies, the various energy used, their pros and cons, evidence for safety and efficacy, and a glimpse into the future with a special section on bronchoscopic ablation.

### **2. Patient and nodule selection**

Image-guided lung ablation is best suited for patients who have high surgical risks, either due to underlying medical comorbidities, or due to inadequate respiratory reserve, for instance significant chronic obstructive pulmonary disease (COPD) or previous contralateral lobectomy or pneumonectomy making intra-operative one-lung ventilation difficult. In general, there are no lower limits of lung function requirement for ablation candidates [7], but patients should be expected to tolerate sedation or general anesthesia at supine, lateral decubitus or semi-prone position for at least an hour. Contraindications for ablation include severe interstitial lung disease (ILD), where exacerbation of ILD may lead to severe pulmonary failure and death [8].

When ablation is intended for local control of early stage lung cancer, the tumor should ideally be small enough to be covered by the expected ablation zone with adequate margin, and there should be no nodal or extrathoracic metastasis based on pre-operative imaging. Ablation with palliative intent is best suited for lung cancers with tumor-related symptoms, for example pain and airway obstruction. Tumor size must be considered, and numerous lung ablation studies have demonstrated increased risk of local recurrence for increasing size of tumors, with cut-off of 2 cm [9] and 3 cm [10, 11] reported. In case of larger tumors, double ablation may be required, which either involves re-ablating in the same position, after pull-back of electrode, or after repositioning of electrode. Alternatively, ablation catheters with multiple electrodes can be used to generate a larger ablation zone.

Tumor location is also important to consider before submitting patient to thermal ablation. Nodules which are not suitable candidates for CT-guided biopsy are generally not recommended for percutaneous ablation, for example those shielded by the bony scapula, very close to diaphragm or hilar structures. Tumors located close to medium to large blood vessels are susceptible to heat-sink effects and ablation efficacy may be reduced. Ablation of tumors close to the apex or mediastinal structures may risk thermal injury to brachial plexus, phrenic nerve and adjacent organs such as the heart and esophagus, although hydro-dissection or artificial pneumothorax to protect surrounding structures have been reported with success [12].

#### **3. Procedure and planning**

Pre-procedure workup includes CT imaging ideally within 4 weeks of the planned ablation date. Patients were fasted overnight before ablation to reduce risk of sedation-induced nausea and aspiration. Anti-coagulation or anti-platelet medications were stopped as per regional guidelines for invasive procedures. Implantable cardiac devices like pacemakers or defibrillators are susceptible to interference from certain ablation modalities, and should be interrogated and programed by cardiac electrophysiologist to automatic pacing modes, or by placing a magnet over the device, while defibrillation should be turned off during ablation. Grounding pads should be placed to guide the flow of current away from the cardiac device and

**83**

**Figure 1.**

*with no signs of recurrence.*

*Image-Guided Ablative Therapies for Lung Tumors DOI: http://dx.doi.org/10.5772/intechopen.94216*

emergency.

correct placement.

powerful electrodes can be performed.

electrodes should be inserted at least 5 cm away from pacemaker or defibrillator leads. External pacing and defibrillator system should be readily available in case of

The aim of all ablation modalities is to create a zone of tissue necrosis that encompasses both the tumor and a margin of normal parenchyma surrounding it. The choice of electrode length, active tip length and the number of electrodes is determined by the size and location of tumor. The actual ablation zone size may differ from the predicted size. Factors include the heat-sink effect [14], which refers to the fact that medium to large blood vessels or airways carry heat away leading to asymmetrical or truncated ablation zones. Depending on the energy used, the lung's conductivity, impedance and density also play a role in affecting the eventual ablation zone volume. In general, microwave is able to produce a larger ablation zone than radiofrequency due to its mechanism of energy deposition [15], with explanation detailed later in the chapter. After the initial ablation, a CT evaluation of ablation effect should be performed. In case of inadequate ablation volume, re-ablation with several overlapping ablation zones, or exchange to larger and more

After ablation and removal of electrode, CT images are acquired to evaluate technical success and rule out any complications, for example pneumothorax and bleeding. Patients are observed for 2–4 hours and a repeat chest x-ray confirms the absence of pneumothorax. Most patients are discharged the same day if no compli-

*(A) CT scan shows a biopsy proven left upper lobe lung metastasis in a patient with stage III colonic cancer who was treated with colectomy and chemoradiation previously. (B) CT-guided radiofrequency ablation of the lung metastasis was performed with ablation catheter in-situ and an area of surrounding ground glass opacities (GGO). (C)The ablated area evolved into a denser GGO with central cavitation at 1 month after ablation. (D) CT scan at 6 months after ablation showed evolution of the ablated area into a smaller contracted scar* 

cations arise. Median length of stay was 1 day in a nation-wide review [16].

Most ablation strategies are performed percutaneously, and nearly all are done under CT guidance. The great majority of ablation are performed with conscious sedation, while general anesthesia is reserved for pediatric patients or patients who cannot tolerate sedation alone, although some authors have reported higher feasibility rates and lower peri-procedural pain with general anesthesia [13]. For certain ablation energies, a reference electrode or grounding pad is necessary, which is attached to patient's skin usually on the opposite chest wall or thigh. Initial scout CT images are acquired; the skin entry site is determined and cross-marked on the skin by laser lights from the CT gantry. Following sterile preparation and draping, local anesthesia is injected along the tract from skin to the level of pleura. A spinal needle is advanced according to the planned trajectory with CT and/or fluoroscopy guidance, which is then exchanged to the ablation electrode after confirmation of

*Lung Cancer - Modern Multidisciplinary Management*

**2. Patient and nodule selection**

death [8].

success [12].

**3. Procedure and planning**

of image-guided local ablative therapies of lung tumors, first with radiofrequency ablation (RFA), later with microwave ablation (MWA) and cryoablation. In this chapter, we discuss the preparation and procedure of lung ablative therapies, the various energy used, their pros and cons, evidence for safety and efficacy, and a

Image-guided lung ablation is best suited for patients who have high surgical risks, either due to underlying medical comorbidities, or due to inadequate respiratory reserve, for instance significant chronic obstructive pulmonary disease (COPD) or previous contralateral lobectomy or pneumonectomy making intra-operative one-lung ventilation difficult. In general, there are no lower limits of lung function requirement for ablation candidates [7], but patients should be expected to tolerate sedation or general anesthesia at supine, lateral decubitus or semi-prone position for at least an hour. Contraindications for ablation include severe interstitial lung disease (ILD), where exacerbation of ILD may lead to severe pulmonary failure and

When ablation is intended for local control of early stage lung cancer, the tumor should ideally be small enough to be covered by the expected ablation zone with adequate margin, and there should be no nodal or extrathoracic metastasis based on pre-operative imaging. Ablation with palliative intent is best suited for lung cancers with tumor-related symptoms, for example pain and airway obstruction. Tumor size must be considered, and numerous lung ablation studies have demonstrated increased risk of local recurrence for increasing size of tumors, with cut-off of 2 cm [9] and 3 cm [10, 11] reported. In case of larger tumors, double ablation may be required, which either involves re-ablating in the same position, after pull-back of electrode, or after repositioning of electrode. Alternatively, ablation catheters with

multiple electrodes can be used to generate a larger ablation zone.

Tumor location is also important to consider before submitting patient to thermal ablation. Nodules which are not suitable candidates for CT-guided biopsy are generally not recommended for percutaneous ablation, for example those shielded by the bony scapula, very close to diaphragm or hilar structures. Tumors located close to medium to large blood vessels are susceptible to heat-sink effects and ablation efficacy may be reduced. Ablation of tumors close to the apex or mediastinal structures may risk thermal injury to brachial plexus, phrenic nerve and adjacent organs such as the heart and esophagus, although hydro-dissection or artificial pneumothorax to protect surrounding structures have been reported with

Pre-procedure workup includes CT imaging ideally within 4 weeks of the planned ablation date. Patients were fasted overnight before ablation to reduce risk of sedation-induced nausea and aspiration. Anti-coagulation or anti-platelet medications were stopped as per regional guidelines for invasive procedures. Implantable cardiac devices like pacemakers or defibrillators are susceptible to interference from certain ablation modalities, and should be interrogated and programed by cardiac electrophysiologist to automatic pacing modes, or by placing a magnet over the device, while defibrillation should be turned off during ablation. Grounding pads should be placed to guide the flow of current away from the cardiac device and

glimpse into the future with a special section on bronchoscopic ablation.

**82**

electrodes should be inserted at least 5 cm away from pacemaker or defibrillator leads. External pacing and defibrillator system should be readily available in case of emergency.

Most ablation strategies are performed percutaneously, and nearly all are done under CT guidance. The great majority of ablation are performed with conscious sedation, while general anesthesia is reserved for pediatric patients or patients who cannot tolerate sedation alone, although some authors have reported higher feasibility rates and lower peri-procedural pain with general anesthesia [13]. For certain ablation energies, a reference electrode or grounding pad is necessary, which is attached to patient's skin usually on the opposite chest wall or thigh. Initial scout CT images are acquired; the skin entry site is determined and cross-marked on the skin by laser lights from the CT gantry. Following sterile preparation and draping, local anesthesia is injected along the tract from skin to the level of pleura. A spinal needle is advanced according to the planned trajectory with CT and/or fluoroscopy guidance, which is then exchanged to the ablation electrode after confirmation of correct placement.

The aim of all ablation modalities is to create a zone of tissue necrosis that encompasses both the tumor and a margin of normal parenchyma surrounding it. The choice of electrode length, active tip length and the number of electrodes is determined by the size and location of tumor. The actual ablation zone size may differ from the predicted size. Factors include the heat-sink effect [14], which refers to the fact that medium to large blood vessels or airways carry heat away leading to asymmetrical or truncated ablation zones. Depending on the energy used, the lung's conductivity, impedance and density also play a role in affecting the eventual ablation zone volume. In general, microwave is able to produce a larger ablation zone than radiofrequency due to its mechanism of energy deposition [15], with explanation detailed later in the chapter. After the initial ablation, a CT evaluation of ablation effect should be performed. In case of inadequate ablation volume, re-ablation with several overlapping ablation zones, or exchange to larger and more powerful electrodes can be performed.

After ablation and removal of electrode, CT images are acquired to evaluate technical success and rule out any complications, for example pneumothorax and bleeding. Patients are observed for 2–4 hours and a repeat chest x-ray confirms the absence of pneumothorax. Most patients are discharged the same day if no complications arise. Median length of stay was 1 day in a nation-wide review [16].

#### **Figure 1.**

*(A) CT scan shows a biopsy proven left upper lobe lung metastasis in a patient with stage III colonic cancer who was treated with colectomy and chemoradiation previously. (B) CT-guided radiofrequency ablation of the lung metastasis was performed with ablation catheter in-situ and an area of surrounding ground glass opacities (GGO). (C)The ablated area evolved into a denser GGO with central cavitation at 1 month after ablation. (D) CT scan at 6 months after ablation showed evolution of the ablated area into a smaller contracted scar with no signs of recurrence.*

#### *Lung Cancer - Modern Multidisciplinary Management*

Subsequent follow up required interval CT scans for evaluation of treatment response, usually every 3 months although no international guideline exists [17]. Typical early CT appearances following heat-based thermal ablation (eg. RFA, MWA) include ground glass opacities (GGO) or cavities, with or without soft tissue components. The GGO is typically concentric with three layers, the central consolidation represents ablated tumor tissue, the middle layer of faint GGO represents necrotic surrounding parenchyma, and an outer rim of denser GGO contains congested lung tissue and hemorrhage than may retain viability [17]. Cavitation, which is considered a positive response, is most likely to appear in the intermediate phase (1 week to 2 months after ablation). At 3 to 6 months post-ablation, the ablated area continues to involute and shrink down to a linear or nodular scar, or even a thinwalled cavity. Enlarging ablation zone beyond 6 months is highly suggestive for tumor recurrence. Central enhancement >10 mm or > 15HU suggests progression of incompletely ablated disease on contrast CT scans [18], while increased metabolic

#### **Figure 2.**

*(A): At 2 weeks after microwave ablation of a small right lower lobe lung tumor, there was a largerthan-expected cavity noted in chest x-ray upon follow up. CT showed a large thick-walled cavity with central soft tissue likely representing necrotic lung and tumor tissue. There was no pneumothorax. (B) CT scan at 3 months post-ablation showed reduction in size of the cavity and soft tissue component. (C) CT scan at 6 months post-ablation showed disappearance of cavity and further reduction in overall size of the ablated area, now consisting of soft tissue density. (D) CT scan at 9 months post-ablation showed a contracted scar representing good treatment response.*

#### **Figure 3.**

*(A) A cavity with soft tissue component surrounded by patchy ground-glass consolidations at 1 month after microwave ablation of a left upper lobe lung cancer. (B) Complete response as the ablation zone turned into a thin-walled cavity without soft tissue component at 6 months after ablation, which persisted with static appearance thereafter.*

**85**

illustrated in **Figure 4**.

**Figure 4.**

**4. Ablation energies**

ablation modalities in the lung.

*Image-Guided Ablative Therapies for Lung Tumors DOI: http://dx.doi.org/10.5772/intechopen.94216*

activity or new uptake inside the ablation zone beyond 2 months post-ablation are worrisome of recurrence on PET/CT scans [19]. Patients with local recurrence can undergo repeated ablation to improve local control. **Figures 1**–**3** show the typical appearance of successfully ablated lung tumors over serial CT imagings. CT-guided ablation of centrally located metastasis can be combined with surgical resection of other more peripheral lung metastases as part of lung-preserving strategy, as

*lobulated scar remaining at the ablated area, and no recurrence of lung metastasis.*

*(A) A 43 year old patient had curative resection of a hepatocellular carcinoma, but was found to have 5 lung metastases on surveillance CT, 3 of which in the right lower lobe (RLL) (as shown), and 2 more in the right middle lobe (not shown). The deepest lung metastasis in the RLL (\*) would be difficult to palpate intraoperatively, making wedge resection difficult. Patient was keen for lung-preserving treatment, thus a combined strategy of CT-guided ablation and surgical wedge resection was planned. (B) CT guided radiofrequency ablation of the deepest RLL lung metastasis was performed. (C) The ablation zone evolved into a welldemarcated ground glass opacity with soft tissue component 2 weeks after ablation. (D) Wedge resection of the remaining 4 lung metastases located in peripheral right lower and middle lobe was performed with videoassisted thoracoscopic surgery. CT scan at 3 months after ablation showed contraction of the ablation zone (#) and disappearance of the other 2 RLL lung metastases after surgery. (E) CT scan at 7 months after ablation showed further contraction of the ablated area. (F) CT scan at 1 year after ablation showed a small contracted* 

Ablation techniques can be divided into thermal or non-thermal ablations (e.g. irreversible electroporation). Among thermal ablations, heat-based techniques include radiofrequency ablation, microwave ablation and laser ablation, while coldbased technique includes cryoablation. **Table 1** shows the comparison of thermal

*Image-Guided Ablative Therapies for Lung Tumors DOI: http://dx.doi.org/10.5772/intechopen.94216*

#### **Figure 4.**

*Lung Cancer - Modern Multidisciplinary Management*

Subsequent follow up required interval CT scans for evaluation of treatment response, usually every 3 months although no international guideline exists [17]. Typical early CT appearances following heat-based thermal ablation (eg. RFA, MWA) include ground glass opacities (GGO) or cavities, with or without soft tissue components. The GGO is typically concentric with three layers, the central consolidation represents ablated tumor tissue, the middle layer of faint GGO represents necrotic surrounding parenchyma, and an outer rim of denser GGO contains congested lung tissue and hemorrhage than may retain viability [17]. Cavitation, which is considered a positive response, is most likely to appear in the intermediate phase (1 week to 2 months after ablation). At 3 to 6 months post-ablation, the ablated area continues to involute and shrink down to a linear or nodular scar, or even a thinwalled cavity. Enlarging ablation zone beyond 6 months is highly suggestive for tumor recurrence. Central enhancement >10 mm or > 15HU suggests progression of incompletely ablated disease on contrast CT scans [18], while increased metabolic

*(A) A cavity with soft tissue component surrounded by patchy ground-glass consolidations at 1 month after microwave ablation of a left upper lobe lung cancer. (B) Complete response as the ablation zone turned into a thin-walled cavity without soft tissue component at 6 months after ablation, which persisted with static* 

*(A): At 2 weeks after microwave ablation of a small right lower lobe lung tumor, there was a largerthan-expected cavity noted in chest x-ray upon follow up. CT showed a large thick-walled cavity with central soft tissue likely representing necrotic lung and tumor tissue. There was no pneumothorax. (B) CT scan at 3 months post-ablation showed reduction in size of the cavity and soft tissue component. (C) CT scan at 6 months post-ablation showed disappearance of cavity and further reduction in overall size of the ablated area, now consisting of soft tissue density. (D) CT scan at 9 months post-ablation showed a contracted scar* 

**84**

**Figure 3.**

**Figure 2.**

*representing good treatment response.*

*appearance thereafter.*

*(A) A 43 year old patient had curative resection of a hepatocellular carcinoma, but was found to have 5 lung metastases on surveillance CT, 3 of which in the right lower lobe (RLL) (as shown), and 2 more in the right middle lobe (not shown). The deepest lung metastasis in the RLL (\*) would be difficult to palpate intraoperatively, making wedge resection difficult. Patient was keen for lung-preserving treatment, thus a combined strategy of CT-guided ablation and surgical wedge resection was planned. (B) CT guided radiofrequency ablation of the deepest RLL lung metastasis was performed. (C) The ablation zone evolved into a welldemarcated ground glass opacity with soft tissue component 2 weeks after ablation. (D) Wedge resection of the remaining 4 lung metastases located in peripheral right lower and middle lobe was performed with videoassisted thoracoscopic surgery. CT scan at 3 months after ablation showed contraction of the ablation zone (#) and disappearance of the other 2 RLL lung metastases after surgery. (E) CT scan at 7 months after ablation showed further contraction of the ablated area. (F) CT scan at 1 year after ablation showed a small contracted lobulated scar remaining at the ablated area, and no recurrence of lung metastasis.*

activity or new uptake inside the ablation zone beyond 2 months post-ablation are worrisome of recurrence on PET/CT scans [19]. Patients with local recurrence can undergo repeated ablation to improve local control. **Figures 1**–**3** show the typical appearance of successfully ablated lung tumors over serial CT imagings. CT-guided ablation of centrally located metastasis can be combined with surgical resection of other more peripheral lung metastases as part of lung-preserving strategy, as illustrated in **Figure 4**.

#### **4. Ablation energies**

Ablation techniques can be divided into thermal or non-thermal ablations (e.g. irreversible electroporation). Among thermal ablations, heat-based techniques include radiofrequency ablation, microwave ablation and laser ablation, while coldbased technique includes cryoablation. **Table 1** shows the comparison of thermal ablation modalities in the lung.


#### **Table 1.**

*Comparison between different modalities of lung cancer thermal ablation.*

#### **4.1 Radiofrequency ablation (RFA)**

Radiofrequency ablation is the most widely used ablative modality in the lung, and utilizes heat as a form of thermal ablation. Radiofrequency refers to a section in the electromagnetic spectrum with frequency ranging between 20 kHz to 30 MHz, but most clinically available devices function in the 375-500KHz range. A grounding pad or reference electrode is required in RFA, while the active electrode placed inside the tumor is coupled to an RF generator. The RF generator establishes a voltage between the active electrode and reference electrode, producing electric field lines that oscillate with alternating current. At the area closest to the applicator, electrons collide with adjacent molecules under the influence of oscillating electric field, inducing frictional heating [20]. Immediate cell death occurs at temperatures greater than 60°C. RF electrodes have an internal thermocouple that measures the temperature at the tip. Charring and desiccation at the electrode increases impedance and reduces heat conduction, thus most commercially available electrodes are coupled with infusion pumps that pump cold saline to internally cool the electrode tip. Treatments usually range between 4 and 12 minutes, and RFA electrodes may be single-tip applicators or cluster electrodes.

Multiple RFA systems are commercially available (Boston Scientific, Watertown, MA, USA; StarBurst (RITA) Medical Systems, Mountain View, CA, USA; Cool-Tip, Covidien, Boulder, CO, USA). The first two use a deployable radiofrequency array electrode with 4–16 small wires tines through a 14- to 17-gauge needle. The

**87**

*Image-Guided Ablative Therapies for Lung Tumors DOI: http://dx.doi.org/10.5772/intechopen.94216*

thermocoagulation in a single application.

*4.1.1 Efficacy of radiofrequency ablation*

3 years and 40% at 5 years [22].

**4.2 Microwave ablation (MWA)**

third system consists of a single or triple cluster (3 electrodes spaced 5 mm apart) electrode perfused with saline, and a switching controller allow for simultaneous placement of up to three separate single electrodes to create a greater volume of

The local control and survival rates of RFA have been examined in a handful of non-randomized single-institutional series and a few multicenter trials. The RAPTURE study published in 2008 is a prospective, intention-to-treat, multicenter trial involving seven centres in Europe, USA and Australia [21]. It included 106 patients with 183 biopsy-proven lung tumors, although there was a mixture of NSCLC and lung metastases. Technical success rate was 99%, and a confirmed complete response lasting at least 1 year was achieved in 88% of patients. For patients with NSCLC, overall survival was 70% at 1 year and 48% at 2 years, cancer-specific survival was 92% at 1 year and 73% at 2 years. Selecting those with stage 1 NSCLC, the 2-year overall survival was 75% and cancer-specific survival was 92%. More recently, another multicenter trial, the ALLIANCE Trial, was published in 2015 [9]. The overall survival was 86.3% at one year and 69.8% at two years, while local

Regarding long term efficacy, a retrospective study revealed that for stage I NSCLC, the overall survival rate was 36% and 27% at 3 and 5 years respectively [10]. In another prospective intention-to-treat study, the complete response rate was 59.3% at a mean follow-up of 47 months, with a mean local recurrence interval of 25.9 months [22]. Median overall survival and cancer-specific survival were 33.4 and 41.4 months respectively, while cancer-specific actuarial survival was 59% at

Tumor diameter was found to be a negative prognostic factor. The difference between survival curves associated with large (>3 cm) and small (<=3 cm) lung tumors was significant (p = 0.002, 10], and there was a trend toward better efficacy for tumors smaller than 2 cm in diameter (p = 0.066, 23]. Tumor size less than 2 cm was associated with a statistically significant improved survival of 83% at two years in the ALLIANCE Trial [9]. In another study, complete necrosis was attained in all tumors less than 3 cm but only in 23% of larger tumors, and the mean survival of patients with complete necrosis was significantly better than that with partial necrosis [11]. An ablation area of at least 4 times larger than initial tumor was

To date, there are no properly powered prospective trials comparing one RFA system with another or comparing RFA with other treatment modalities. There has been a propensity-matched analysis comparing RFA and surgery for stage 1 NSCLC, and the mean survival duration of RFA group and surgery group was 33.2 +/− 7.9 and 45.4 +/− 7.2 months respectively, although the difference is not statistically significant [24]. A large propensity-matched retrospective study comparing thermal ablation (mostly RFA) with SBRT using the National Cancer Database reported no significant difference in overall survival at a mean follow up of 52.4 months, however unplanned hospital readmission rates were high in the thermal ablation group [25]. In a systemic analysis and pooled review, the local control rate was significantly lower in the RFA group compared to SBRT, although the overall survival remained similar [26].

Microwave ablation for lung tumors has been gaining increasing momentum since the mid-2000s. Microwave occupies a much higher frequency range in the

recurrence-free rate was 68.9% at one year and 59.8% at two years.

reported to be predictive of complete ablation treatment [23].

*Lung Cancer - Modern Multidisciplinary Management*

Mechanism of action Frictional heating

History of application in lung cancer

Dependence on impedance

Affected by tissue charring

Ablation time per ablation

Preservation of bronchovascular structures

*GGO, ground glass opacity.*

**Table 1.**

**Radiofrequency ablation**

from electron collisions under oscillating electric

Temperature (°C) 60 to 100 Around 150 −20 to −40 Grounding pad Required Not required Not required Ablation zone size Smaller Larger Larger

Visibility on CT/MRI Fair (concentric GGO) Fair (concentric GGO) Best (iceballs)

Heat sink effect Larger Smaller —

Procedural pain Fair Less Least

field

Medium (10–15 minutes)

*Comparison between different modalities of lung cancer thermal ablation.*

**Microwave Ablation Cryoablation**

Ultracold temperature when pressurized argon gas expands (Joule Thomson effect)

Longest (25 minutes)

Frictional heating from rapidly realigning polar water molecules under oscillating electric field

Since early 2000s Since mid 2000s Since mid 2000s

Yes No No

Yes No No

Shortest (2–10 minutes)

Fair Fair Best

**4.1 Radiofrequency ablation (RFA)**

applicators or cluster electrodes.

Radiofrequency ablation is the most widely used ablative modality in the lung, and utilizes heat as a form of thermal ablation. Radiofrequency refers to a section in the electromagnetic spectrum with frequency ranging between 20 kHz to 30 MHz, but most clinically available devices function in the 375-500KHz range. A grounding pad or reference electrode is required in RFA, while the active electrode placed inside the tumor is coupled to an RF generator. The RF generator establishes a voltage between the active electrode and reference electrode, producing electric field lines that oscillate with alternating current. At the area closest to the applicator, electrons collide with adjacent molecules under the influence of oscillating electric field, inducing frictional heating [20]. Immediate cell death occurs at temperatures greater than 60°C. RF electrodes have an internal thermocouple that measures the temperature at the tip. Charring and desiccation at the electrode increases impedance and reduces heat conduction, thus most commercially available electrodes are coupled with infusion pumps that pump cold saline to internally cool the electrode tip. Treatments usually range between 4 and 12 minutes, and RFA electrodes may be single-tip

Multiple RFA systems are commercially available (Boston Scientific, Watertown,

MA, USA; StarBurst (RITA) Medical Systems, Mountain View, CA, USA; Cool-Tip, Covidien, Boulder, CO, USA). The first two use a deployable radiofrequency array electrode with 4–16 small wires tines through a 14- to 17-gauge needle. The

**86**

third system consists of a single or triple cluster (3 electrodes spaced 5 mm apart) electrode perfused with saline, and a switching controller allow for simultaneous placement of up to three separate single electrodes to create a greater volume of thermocoagulation in a single application.

## *4.1.1 Efficacy of radiofrequency ablation*

The local control and survival rates of RFA have been examined in a handful of non-randomized single-institutional series and a few multicenter trials. The RAPTURE study published in 2008 is a prospective, intention-to-treat, multicenter trial involving seven centres in Europe, USA and Australia [21]. It included 106 patients with 183 biopsy-proven lung tumors, although there was a mixture of NSCLC and lung metastases. Technical success rate was 99%, and a confirmed complete response lasting at least 1 year was achieved in 88% of patients. For patients with NSCLC, overall survival was 70% at 1 year and 48% at 2 years, cancer-specific survival was 92% at 1 year and 73% at 2 years. Selecting those with stage 1 NSCLC, the 2-year overall survival was 75% and cancer-specific survival was 92%. More recently, another multicenter trial, the ALLIANCE Trial, was published in 2015 [9]. The overall survival was 86.3% at one year and 69.8% at two years, while local recurrence-free rate was 68.9% at one year and 59.8% at two years.

Regarding long term efficacy, a retrospective study revealed that for stage I NSCLC, the overall survival rate was 36% and 27% at 3 and 5 years respectively [10]. In another prospective intention-to-treat study, the complete response rate was 59.3% at a mean follow-up of 47 months, with a mean local recurrence interval of 25.9 months [22]. Median overall survival and cancer-specific survival were 33.4 and 41.4 months respectively, while cancer-specific actuarial survival was 59% at 3 years and 40% at 5 years [22].

Tumor diameter was found to be a negative prognostic factor. The difference between survival curves associated with large (>3 cm) and small (<=3 cm) lung tumors was significant (p = 0.002, 10], and there was a trend toward better efficacy for tumors smaller than 2 cm in diameter (p = 0.066, 23]. Tumor size less than 2 cm was associated with a statistically significant improved survival of 83% at two years in the ALLIANCE Trial [9]. In another study, complete necrosis was attained in all tumors less than 3 cm but only in 23% of larger tumors, and the mean survival of patients with complete necrosis was significantly better than that with partial necrosis [11]. An ablation area of at least 4 times larger than initial tumor was reported to be predictive of complete ablation treatment [23].

To date, there are no properly powered prospective trials comparing one RFA system with another or comparing RFA with other treatment modalities. There has been a propensity-matched analysis comparing RFA and surgery for stage 1 NSCLC, and the mean survival duration of RFA group and surgery group was 33.2 +/− 7.9 and 45.4 +/− 7.2 months respectively, although the difference is not statistically significant [24]. A large propensity-matched retrospective study comparing thermal ablation (mostly RFA) with SBRT using the National Cancer Database reported no significant difference in overall survival at a mean follow up of 52.4 months, however unplanned hospital readmission rates were high in the thermal ablation group [25]. In a systemic analysis and pooled review, the local control rate was significantly lower in the RFA group compared to SBRT, although the overall survival remained similar [26].

### **4.2 Microwave ablation (MWA)**

Microwave ablation for lung tumors has been gaining increasing momentum since the mid-2000s. Microwave occupies a much higher frequency range in the

electromagnetic spectrum between 300 MHz to 300 GHz. Compared to radiofrequency, microwave energy is able to create a much larger zone of active heating due to broader deposition of energy. Clinically available microwave applicators generally operate in the 900-245 MHz range [27]. MWA directly heats tissue to lethal temperatures greater than 150°C through dielectric hysteresis, which is a process in which the polar water molecules realign with the oscillating electric field generating kinetic energy, which is then transferred to neighboring tissues [28]. Being completely independent from electrical conductance, microwave energy deposition is less susceptible to tissue impedance, and is able to produce faster, larger and more predictable ablation zones than RFA [15]. The aerated lung has a relatively high impedance among all solid organs, thus making MWA a better modality than RFA in lungs [15, 29]. Heat-sink effect is also smaller with microwave [28].

There are 7 microwave systems commercially available in the United States and Europe, using either 915 MHz or 2450 MHz generators [30]. The antennae are generally straight, ranging from 14 to 17 gauge, with varying active tips of 0.6–4.0 cm in length. Five out of seven systems require perfusion of antenna shaft with room-temperature fluid or carbon dioxide to reduce conductive heating of the non-active portion of the antennae, which protects the skin and other tissues from thermal damage.

#### *4.2.1 Efficacy of microwave ablation*

The majority of evidence supporting the efficacy of MWA comes from retrospective data. The earlier studies reported an actuarial survival of 65% at 1 year, 55% at 2 years and 45% at 3 years, while cancer-specific survival was 83%, 73% and 61% at 1, 2 and 3 years respectively [31]. A more recent retrospective study reported cancer-specific survival of 69%, 54% and 49% at 1, 2 and 3 years respectively, and the mean survival was 27.8 months [32]. Local control rate was 84.4% at a mean follow-up of 446 days in another retrospective series [33]. A larger retrospective review of 108 patients reported that the median time to tumor recurrence was 62 months, and recurrence rates were 22%, 36% and 44% at 1, 2 and 3 years respectively [34]. It should be noted that the majority of the studies include both primary and secondary lung tumors, and results for NSCLC may not be separately reported. Longer term results were reported in a study involving large NSCLC (mean tumor size of 5.0+/− 1.8 cm). Owing to the larger tumor size, only 44.6% of cases achieved complete tumor ablation after first ablation, and 18.5% required a re-do MWA session. The 3- and 5-year cancer-specific survival rates were 42.1% and 30.0% respectively, and the median cancer-specific survival was 25 months [35].

Similar to RFA, tumor size is associated with poorer prognosis. For every millimeter increase in tumor maximal diameter, the odds of not attaining technical success increased by 7% [34]. Tumor size >4 cm is a significant predictor for local tumor progression and poorer survival [35]. Recurrence rate was 17% for tumors smaller than 3 cm, and increased to 31% for those greater than 3 cm [34]. A risk-factor analysis demonstrated that local tumor progression was significantly correlated with tumor diameter of more than 15.5 mm, irregular shape of index tumor, pleural contact and low energy deployed per unit volume of index tumor [36]. On the other hand, cavitation was associated with reduced cancer-specific mortality [31].

Again, there are no prospective studies comparing one MWA system with another, or with other modalities. There was a propensity-score matched analysis comparing MWA with lobectomy for stage I NSCLC, which reported no significant difference in overall survival and disease free survival (1,3 and 5-year disease free survival of 98.1%, 79.6% and 37.0% for MWA group and 98.1%, 81.5% and 29.6%

**89**

*Image-Guided Ablative Therapies for Lung Tumors DOI: http://dx.doi.org/10.5772/intechopen.94216*

tion in tumor mass [39].

**4.3 Percutaneous Cryoablation**

intrathoracic or percutaneous routes.

for lobectomy group) [37]. The complication rate in MWA group was significantly lower than lobectomy group (p = 0.008). However, the power of this study is undermined by the relatively poor results in lobectomy group when compared to international standard, probably due to poor patient premorbid. In a best evidence topic review, the best available evidence for MWA (7 studies) was compared to that for SBRT (5 studies) [38]. The 3-year survival was 29.2–84.7% for MWA and 42.7–63.5% for SBRT, while the median survival was 35–60 months for MWA and 32.6–48 months for SBRT. The authors concluded that MWA appears comparable to SBRT in terms of local control and survival rates. In the randomized controlled LUMIRA trial, 52 patients with stage IV lung tumors were recruited, and there was no significant difference in survival between the MWA group and RFA group, but MWA was found to produce less intraprocedural pain and a more significant reduc-

Cryoablation makes use of the Joule-Thomson effect by distributing pressured argon gas to an area of lower pressure and reaching ultracold temperatures when the gas expands [40]. As low as −140°C can be achieved, although living tissue destruction already happens at −40°C. Cryogenic destruction occurs via a number of mechanisms, including protein denaturation, cell rupture due to osmotic shifts, and tissue ischemia from microvascular thrombosis [41]. Meanwhile, the term "cryosurgery" includes cryoablation performed through endobronchial, direct

Traditionally, each cryoablation consists of a dual freeze cycle, involving a 10-minute freeze, followed by 8-minute helium thaw and another 10-minute freeze. Early animal models suggest that air leaks and bleeding could be reduced with this protocol [42]. Current commercially available cryoablation devices (for example Cryocare CS® system, Endocare, Irvine, CA, USA) use a faster cycle of 3-minute freeze, 3-minute thaw, 7-minute freeze, 7-minute thaw and a final 5-minute freeze. These systems allow placement of 1–10 individual 1.5–2.4 mm diameter cryoprobes, and one freeze–thaw–freeze cycle at a single probe position usually suffice. The faster cycle produces interstitial fluid in adjacent lung tissue and improves margin control. Radiologically, a visible "ice ball" and surrounding edematous changes can be seen on CT and serve as an estimation of ablation zone. The true volume of tissue necrosis has been shown to be 3-7 mm from the ice-ball edge [43], and should be taken into consideration when determining cytotoxic ice margin clearance.

Compared with heat-based thermoablation like RFA and MWA, cryoablation has the advantage of larger ablation volumes, availability of multiple applicators, a highly visible ablation zone (a clearly defined ice ball as opposed to concentric ground glass opacities in RFA or microwave), and less pain due to analgesic effect of freezing [44]. Another benefit is its safety near vasculature or bronchi due to the ability to preserve collagenous tissue and cellular architecture in frozen tissue [45]. Disadvantages of cryoablation include a longer procedural time (25 minutes per freeze–thaw–freeze cycle compared to roughly 5 to 10 minutes per ablation in MWA) and a higher incidence of pneumothorax up to 62% [46]. The latter can be tackled with fibrin glue tract coagulation or radiofrequency thermocoagulation of

A retrospective review of 25 stage I NSCLC treated with cryoablation reported 3-year overall survival of 88% and mean overall survival of 62+/−4 months [47].

needle tract provided by one of the cryoablation systems.

*4.3.1 Efficacy of Cryoablation*

*Lung Cancer - Modern Multidisciplinary Management*

thermal damage.

*4.2.1 Efficacy of microwave ablation*

cancer-specific mortality [31].

electromagnetic spectrum between 300 MHz to 300 GHz. Compared to radiofrequency, microwave energy is able to create a much larger zone of active heating due to broader deposition of energy. Clinically available microwave applicators generally operate in the 900-245 MHz range [27]. MWA directly heats tissue to lethal temperatures greater than 150°C through dielectric hysteresis, which is a process in which the polar water molecules realign with the oscillating electric field generating kinetic energy, which is then transferred to neighboring tissues [28]. Being completely independent from electrical conductance, microwave energy deposition is less susceptible to tissue impedance, and is able to produce faster, larger and more predictable ablation zones than RFA [15]. The aerated lung has a relatively high impedance among all solid organs, thus making MWA a better modality than RFA

in lungs [15, 29]. Heat-sink effect is also smaller with microwave [28].

There are 7 microwave systems commercially available in the United States and Europe, using either 915 MHz or 2450 MHz generators [30]. The antennae are generally straight, ranging from 14 to 17 gauge, with varying active tips of 0.6–4.0 cm in length. Five out of seven systems require perfusion of antenna shaft with room-temperature fluid or carbon dioxide to reduce conductive heating of the non-active portion of the antennae, which protects the skin and other tissues from

The majority of evidence supporting the efficacy of MWA comes from retrospective data. The earlier studies reported an actuarial survival of 65% at 1 year, 55% at 2 years and 45% at 3 years, while cancer-specific survival was 83%, 73% and 61% at 1, 2 and 3 years respectively [31]. A more recent retrospective study reported cancer-specific survival of 69%, 54% and 49% at 1, 2 and 3 years respectively, and the mean survival was 27.8 months [32]. Local control rate was 84.4% at a mean follow-up of 446 days in another retrospective series [33]. A larger retrospective review of 108 patients reported that the median time to tumor recurrence was 62 months, and recurrence rates were 22%, 36% and 44% at 1, 2 and 3 years respectively [34]. It should be noted that the majority of the studies include both primary and secondary lung tumors, and results for NSCLC may not be separately reported. Longer term results were reported in a study involving large NSCLC (mean tumor size of 5.0+/− 1.8 cm). Owing to the larger tumor size, only 44.6% of cases achieved complete tumor ablation after first ablation, and 18.5% required a re-do MWA session. The 3- and 5-year cancer-specific survival rates were 42.1% and 30.0% respectively, and the median cancer-specific survival was 25 months [35].

Similar to RFA, tumor size is associated with poorer prognosis. For every millimeter increase in tumor maximal diameter, the odds of not attaining technical success increased by 7% [34]. Tumor size >4 cm is a significant predictor for local tumor progression and poorer survival [35]. Recurrence rate was 17% for tumors smaller than 3 cm, and increased to 31% for those greater than 3 cm [34]. A risk-factor analysis demonstrated that local tumor progression was significantly correlated with tumor diameter of more than 15.5 mm, irregular shape of index tumor, pleural contact and low energy deployed per unit volume of index tumor [36]. On the other hand, cavitation was associated with reduced

Again, there are no prospective studies comparing one MWA system with another, or with other modalities. There was a propensity-score matched analysis comparing MWA with lobectomy for stage I NSCLC, which reported no significant difference in overall survival and disease free survival (1,3 and 5-year disease free survival of 98.1%, 79.6% and 37.0% for MWA group and 98.1%, 81.5% and 29.6%

**88**

for lobectomy group) [37]. The complication rate in MWA group was significantly lower than lobectomy group (p = 0.008). However, the power of this study is undermined by the relatively poor results in lobectomy group when compared to international standard, probably due to poor patient premorbid. In a best evidence topic review, the best available evidence for MWA (7 studies) was compared to that for SBRT (5 studies) [38]. The 3-year survival was 29.2–84.7% for MWA and 42.7–63.5% for SBRT, while the median survival was 35–60 months for MWA and 32.6–48 months for SBRT. The authors concluded that MWA appears comparable to SBRT in terms of local control and survival rates. In the randomized controlled LUMIRA trial, 52 patients with stage IV lung tumors were recruited, and there was no significant difference in survival between the MWA group and RFA group, but MWA was found to produce less intraprocedural pain and a more significant reduction in tumor mass [39].

## **4.3 Percutaneous Cryoablation**

Cryoablation makes use of the Joule-Thomson effect by distributing pressured argon gas to an area of lower pressure and reaching ultracold temperatures when the gas expands [40]. As low as −140°C can be achieved, although living tissue destruction already happens at −40°C. Cryogenic destruction occurs via a number of mechanisms, including protein denaturation, cell rupture due to osmotic shifts, and tissue ischemia from microvascular thrombosis [41]. Meanwhile, the term "cryosurgery" includes cryoablation performed through endobronchial, direct intrathoracic or percutaneous routes.

Traditionally, each cryoablation consists of a dual freeze cycle, involving a 10-minute freeze, followed by 8-minute helium thaw and another 10-minute freeze. Early animal models suggest that air leaks and bleeding could be reduced with this protocol [42]. Current commercially available cryoablation devices (for example Cryocare CS® system, Endocare, Irvine, CA, USA) use a faster cycle of 3-minute freeze, 3-minute thaw, 7-minute freeze, 7-minute thaw and a final 5-minute freeze. These systems allow placement of 1–10 individual 1.5–2.4 mm diameter cryoprobes, and one freeze–thaw–freeze cycle at a single probe position usually suffice. The faster cycle produces interstitial fluid in adjacent lung tissue and improves margin control. Radiologically, a visible "ice ball" and surrounding edematous changes can be seen on CT and serve as an estimation of ablation zone. The true volume of tissue necrosis has been shown to be 3-7 mm from the ice-ball edge [43], and should be taken into consideration when determining cytotoxic ice margin clearance.

Compared with heat-based thermoablation like RFA and MWA, cryoablation has the advantage of larger ablation volumes, availability of multiple applicators, a highly visible ablation zone (a clearly defined ice ball as opposed to concentric ground glass opacities in RFA or microwave), and less pain due to analgesic effect of freezing [44]. Another benefit is its safety near vasculature or bronchi due to the ability to preserve collagenous tissue and cellular architecture in frozen tissue [45]. Disadvantages of cryoablation include a longer procedural time (25 minutes per freeze–thaw–freeze cycle compared to roughly 5 to 10 minutes per ablation in MWA) and a higher incidence of pneumothorax up to 62% [46]. The latter can be tackled with fibrin glue tract coagulation or radiofrequency thermocoagulation of needle tract provided by one of the cryoablation systems.

## *4.3.1 Efficacy of Cryoablation*

A retrospective review of 25 stage I NSCLC treated with cryoablation reported 3-year overall survival of 88% and mean overall survival of 62+/−4 months [47].

Another study involving 27 cryoablated stage I NSCLC demonstrated 3-year survival of 77%, 3-year cancer-specific survival of 90.2% and cancer-free survival of 45.6% [48]. In a study comprising of cryoablation of both primary and secondary lung tumors, the 1-, 2- and 3-year local progression free rates were reported to be 80.4%, 69.0% and 67.7% respectively [49]. In a long-term analysis of 47 stage I NSCLC treated with cryoablation, the 5-year cancer-specific survival rate was 56.6+/−16.5% and 5-year progression free survival rate was 87.9+/−9% [50]. There were two randomized controlled trials, the ECLIPSE trial [51] and SOLSTICE trial [52], evaluating cryoablation of metastatic lung tumors, which report favorable safety and efficacy, but are out of the scope of this chapter.

Cryoablation has been performed for stage IV lung cancer for palliation of symptoms. In a comparative study between cryoablation and palliative treatment alone, the overall survival of the cryoablation group was significantly longer, with median survival of 14 months compared to 7 months [53]. The same group has performed cryosurgery in various stages of NSCLC yielding an overall survival of 64%, 45% and 32% at 1, 2 and 3 years respectively [54].

Few studies have compared cryoablation with other treatment modalities. In 64 patients with stage I NSCLC deemed medically unfit for lobectomy, 25 were treated with sublobar resection, 12 with RFA and 27 with cryoablation. The 3-year survival rate was similar for the three groups (87.1% for sublobar resection, 87.5% for RFA and 77% for cryoablation) [48]. In a comparative study for stage IIIB or IV NSCLC treated with cryoablation or MWA, the overall survival and progression-free survival were similar for tumors ≤3 cm in diameter, but were poorer in tumors greater than 3 cm which are treated with cryoablation [44].

#### **4.4 Percutaneous laser ablation**

Laser ablation is a thermal technique where light energy is converted into heat by interaction with sources such as an Nd: YAG laser. Typically, energy is transmitted through a flexible fiberoptic cable which is percutaneously inserted into the lung through an outer sheath. Cooling of the fiberoptic cable enables greater energy deposition and a 50 percent increase in size of thermocoagulation [55], as the size of ablation zone is limited by tissue carbonization near the applicator. To date, there have been limited reports on the efficacy of laser ablation in humans [56]. A long term analysis of laser ablation for lung metastases reported 1-, 3- and 5-year survival of 81%, 44% and 27% respectively [57], with a relatively high rate of pneumothorax (38%). No data is available for primary lung cancers.

### **4.5 Irreversible electroporation (IRE)**

Electroporation is a phenomenon in which cell membrane permeability to ions and macromolecules is increased by exposure to high voltage electric pulses. It can be reversible or irreversible, with the latter leading to cell death from loss of homeostasis and osmotic effects. Since IRE is a non-thermal ablation modality, its theoretical advantage includes overcoming the heat-sink effect [58] and preservation of structural integrity of nearby bronchovascular structures [59]. Although there have been reports on its efficacy in animal models [60] and in other organs such as the liver [61], there were few reports on its use in human lungs [62]. In fact, in the multicenter phase II ALICE trial for treatment of primary and secondary lung malignancies, IRE failed to meet the expected efficacy and the trial was terminated prematurely after inclusion of 23 patients, in which 61% showed progressive disease [63]. The disappointing results may be explained by high differences in electric

**91**

**Table 2.**

*Image-Guided Ablative Therapies for Lung Tumors DOI: http://dx.doi.org/10.5772/intechopen.94216*

tract seeding happened in 13% of cases.

for bleeding [64].

Pleural effusion/aseptic

Thermal injury to nearby structures

Pulmonary artery pseudoaneurysm

*Complications following thermal ablation in the lung.*

pleuritis

**5. Safety and complications of percutaneous ablation**

conductivity between normal lung parenchyma and tumor tissue. Of note, needle

Percutaneous ablation of lung tumors is generally considered safe. A list of potential complications is presented in **Table 2**. In a nationwide analysis of 3344 patients who underwent percutaneous lung ablation in the United States [16], in-hospital mortality was 1.3%, and patients with more comorbidities (Charlson comorbidity index score ≥ 4) was associated with significantly higher mortality. The most common complication was pneumothorax (38.4%), followed by pneumonia (5.7%) and effusion (4.0%). In a Japanese review of 1000 RFA sessions [64], there was a 0.4% procedure-related mortality, of which three died of interstitial pneumonia and another died of hemothorax. Major complication rate was 9.8%, consisting of 2.3% aseptic pleuritis, 1.9% pneumonia, 1.6% lung abscess (**Figure 5**), 1.6% pneumothorax requiring pleural sclerosis, 0.4% bronchopleural fistula and 0.3% brachial nerve injury. Previous radiotherapy and age were significant risk factors for pneumonia, as were emphysema for lung abscess, and platelet count and tumor size

Pneumothorax occurs as a result of pleural puncture by the ablation catheter leading to air leak. Hence, unlike standard lung biopsy technique, in which the shortest path to tumor is preferred, some operators advocated a longer distance between pleura puncture site and tumor is more desirable for ablation. An indirect approach that leaves an unablated tract of at least 2 cm of normal lung is preferable [29], because

Bleeding 1.6–18% Rarely require emergency arterial embolization

Bronchopleural fistula 0.4–0.6% Prolonged chest tube drainage, chemical

Needle tract seeding 0.3–0.7% Associated with biopsy prior to RFA

Only 6–29% require chest tube insertion

or surgery

pleurodesis, endobronchial valves/ embolization

Phrenic nerve injury can lead to significant reduction in vital capacity and referred pain to shoulder

2.3–19% Only a minority require drainage

0.2% Transcatheter coil embolization

**Complications Treatment/remarks**

delayed pneumothorax)

Pneumonia 1.8% Antibiotics Lung abscess 1.6% Antibiotics, drainage

> 0.3–0.5% (brachial plexus) 1.3% (phrenic nerve) 0.1% (diaphragm)

Pneumonitis 0.4% Pulse steroid

Systemic air embolism Very rare Hyperbaric oxygen

Pneumothorax 3.5–54% (Up to 10%

*Lung Cancer - Modern Multidisciplinary Management*

safety and efficacy, but are out of the scope of this chapter.

64%, 45% and 32% at 1, 2 and 3 years respectively [54].

than 3 cm which are treated with cryoablation [44].

**4.4 Percutaneous laser ablation**

**4.5 Irreversible electroporation (IRE)**

Another study involving 27 cryoablated stage I NSCLC demonstrated 3-year survival of 77%, 3-year cancer-specific survival of 90.2% and cancer-free survival of 45.6% [48]. In a study comprising of cryoablation of both primary and secondary lung tumors, the 1-, 2- and 3-year local progression free rates were reported to be 80.4%, 69.0% and 67.7% respectively [49]. In a long-term analysis of 47 stage I NSCLC treated with cryoablation, the 5-year cancer-specific survival rate was 56.6+/−16.5% and 5-year progression free survival rate was 87.9+/−9% [50]. There were two randomized controlled trials, the ECLIPSE trial [51] and SOLSTICE trial [52], evaluating cryoablation of metastatic lung tumors, which report favorable

Cryoablation has been performed for stage IV lung cancer for palliation of symptoms. In a comparative study between cryoablation and palliative treatment alone, the overall survival of the cryoablation group was significantly longer, with median survival of 14 months compared to 7 months [53]. The same group has performed cryosurgery in various stages of NSCLC yielding an overall survival of

Few studies have compared cryoablation with other treatment modalities. In 64 patients with stage I NSCLC deemed medically unfit for lobectomy, 25 were treated with sublobar resection, 12 with RFA and 27 with cryoablation. The 3-year survival rate was similar for the three groups (87.1% for sublobar resection, 87.5% for RFA and 77% for cryoablation) [48]. In a comparative study for stage IIIB or IV NSCLC treated with cryoablation or MWA, the overall survival and progression-free survival were similar for tumors ≤3 cm in diameter, but were poorer in tumors greater

Laser ablation is a thermal technique where light energy is converted into heat by interaction with sources such as an Nd: YAG laser. Typically, energy is transmitted through a flexible fiberoptic cable which is percutaneously inserted into the lung through an outer sheath. Cooling of the fiberoptic cable enables greater energy deposition and a 50 percent increase in size of thermocoagulation [55], as the size of ablation zone is limited by tissue carbonization near the applicator. To date, there have been limited reports on the efficacy of laser ablation in humans [56]. A long term analysis of laser ablation for lung metastases reported 1-, 3- and 5-year survival of 81%, 44% and 27% respectively [57], with a relatively high rate of

Electroporation is a phenomenon in which cell membrane permeability to ions and macromolecules is increased by exposure to high voltage electric pulses. It can be reversible or irreversible, with the latter leading to cell death from loss of homeostasis and osmotic effects. Since IRE is a non-thermal ablation modality, its theoretical advantage includes overcoming the heat-sink effect [58] and preservation of structural integrity of nearby bronchovascular structures [59]. Although there have been reports on its efficacy in animal models [60] and in other organs such as the liver [61], there were few reports on its use in human lungs [62]. In fact, in the multicenter phase II ALICE trial for treatment of primary and secondary lung malignancies, IRE failed to meet the expected efficacy and the trial was terminated prematurely after inclusion of 23 patients, in which 61% showed progressive disease [63]. The disappointing results may be explained by high differences in electric

pneumothorax (38%). No data is available for primary lung cancers.

**90**

conductivity between normal lung parenchyma and tumor tissue. Of note, needle tract seeding happened in 13% of cases.

## **5. Safety and complications of percutaneous ablation**

Percutaneous ablation of lung tumors is generally considered safe. A list of potential complications is presented in **Table 2**. In a nationwide analysis of 3344 patients who underwent percutaneous lung ablation in the United States [16], in-hospital mortality was 1.3%, and patients with more comorbidities (Charlson comorbidity index score ≥ 4) was associated with significantly higher mortality. The most common complication was pneumothorax (38.4%), followed by pneumonia (5.7%) and effusion (4.0%). In a Japanese review of 1000 RFA sessions [64], there was a 0.4% procedure-related mortality, of which three died of interstitial pneumonia and another died of hemothorax. Major complication rate was 9.8%, consisting of 2.3% aseptic pleuritis, 1.9% pneumonia, 1.6% lung abscess (**Figure 5**), 1.6% pneumothorax requiring pleural sclerosis, 0.4% bronchopleural fistula and 0.3% brachial nerve injury. Previous radiotherapy and age were significant risk factors for pneumonia, as were emphysema for lung abscess, and platelet count and tumor size for bleeding [64].

Pneumothorax occurs as a result of pleural puncture by the ablation catheter leading to air leak. Hence, unlike standard lung biopsy technique, in which the shortest path to tumor is preferred, some operators advocated a longer distance between pleura puncture site and tumor is more desirable for ablation. An indirect approach that leaves an unablated tract of at least 2 cm of normal lung is preferable [29], because


#### **Table 2.**

*Complications following thermal ablation in the lung.*

#### **Figure 5.**

*A small pneumothorax and a large cavity with soft tissue content at 2 weeks after microwave ablation of a left upper lobe lung tumor. If the patient had fever and air-fluid level was seen in the cavity, a suspicion for lung abscess should be raised, and the abscess should be drained with contents sent for culture and intravenous antibiotics should be commenced.*

#### **Figure 6.**

*(A) A large right pneumothorax immediately after CT-guided radiofrequency ablation of a right lower lobe lung cancer. (B) Shows the lung re-expands after right chest drain insertion in the same patient.*

#### **Figure 7.**

*(A) A patient with right lower lobe lung cancer was treated with CT-guided microwave ablation, but complicated by persistent air leak for 2 weeks despite chest drain insertion. CT scan showed a moderate right pneumothorax and an area of ground glass opacity in the anterior right lower lobe representing the ablation zone. (B) CT scan performed at 3 weeks after ablation demonstrated a bronchopleural fistula (yellow arrow) joining a lobar bronchus to the pleural space through the ablated needle tract.*

**93**

**Figure 9.**

**Figure 8.**

*marked by (\*) on this chest x-ray.*

*Image-Guided Ablative Therapies for Lung Tumors DOI: http://dx.doi.org/10.5772/intechopen.94216*

bronchoscopic embolization of relevant fistulae [68].

unablated pleura contracts less and heals quicker. Emphysema is the most significant risk factor for pneumothorax in multiple studies [65, 66]. Other risk factors include male gender, no previous lung surgery, high number of tumors ablated, advanced age, and traversal of major fissure by electrode [67]. The rate of pneumothorax ranges from 3.5–54%, but only 6–29% required chest tube placement [68] (**Figure 6**). Delayed pneumothorax could occur in up to 10% of cases [69, 70]. Around 0.4–0.6% of all patients develop bronchopleural fistula [64, 71] leading to intractable pneumothorax not resolving with chest drainage (**Figure 7**). Treatment strategies include repeated chemical pleurodesis, placement of endobronchial valves (**Figure 8**), and

Aseptic pleuritis and pleural effusion is postulated to be due to ablation zone reaching pleura leading of pleural inflammation, and is associated with higher

*Resolution of pneumothorax after implantation of an endobronchial valve (faint metallic shadow surrounded by yellow arrows) for bronchopleural fistula. This is the same patient as Figure 7 And the ablation zone is* 

*(A) Moderate right pleural effusion that has accumulated for 3 days following CT-guided microwave ablation of a right lower lobe lung tumor. The patient had low grade fever and complained of shortness of breath. (B) partial drainage of the effusion by a medium bore chest drain. The pleural fluid was exudative but sterile, and* 

*the patient was discharged home after a course of antibiotics and complete drainage of the effusion.*

#### *Image-Guided Ablative Therapies for Lung Tumors DOI: http://dx.doi.org/10.5772/intechopen.94216*

unablated pleura contracts less and heals quicker. Emphysema is the most significant risk factor for pneumothorax in multiple studies [65, 66]. Other risk factors include male gender, no previous lung surgery, high number of tumors ablated, advanced age, and traversal of major fissure by electrode [67]. The rate of pneumothorax ranges from 3.5–54%, but only 6–29% required chest tube placement [68] (**Figure 6**). Delayed pneumothorax could occur in up to 10% of cases [69, 70]. Around 0.4–0.6% of all patients develop bronchopleural fistula [64, 71] leading to intractable pneumothorax not resolving with chest drainage (**Figure 7**). Treatment strategies include repeated chemical pleurodesis, placement of endobronchial valves (**Figure 8**), and bronchoscopic embolization of relevant fistulae [68].

Aseptic pleuritis and pleural effusion is postulated to be due to ablation zone reaching pleura leading of pleural inflammation, and is associated with higher

#### **Figure 8.**

*Lung Cancer - Modern Multidisciplinary Management*

**92**

**Figure 7.**

**Figure 6.**

**Figure 5.**

*antibiotics should be commenced.*

*(A) A patient with right lower lobe lung cancer was treated with CT-guided microwave ablation, but complicated by persistent air leak for 2 weeks despite chest drain insertion. CT scan showed a moderate right pneumothorax and an area of ground glass opacity in the anterior right lower lobe representing the ablation zone. (B) CT scan performed at 3 weeks after ablation demonstrated a bronchopleural fistula (yellow arrow)* 

*(A) A large right pneumothorax immediately after CT-guided radiofrequency ablation of a right lower lobe* 

*lung cancer. (B) Shows the lung re-expands after right chest drain insertion in the same patient.*

*A small pneumothorax and a large cavity with soft tissue content at 2 weeks after microwave ablation of a left upper lobe lung tumor. If the patient had fever and air-fluid level was seen in the cavity, a suspicion for lung abscess should be raised, and the abscess should be drained with contents sent for culture and intravenous* 

*joining a lobar bronchus to the pleural space through the ablated needle tract.*

*Resolution of pneumothorax after implantation of an endobronchial valve (faint metallic shadow surrounded by yellow arrows) for bronchopleural fistula. This is the same patient as Figure 7 And the ablation zone is marked by (\*) on this chest x-ray.*

#### **Figure 9.**

*(A) Moderate right pleural effusion that has accumulated for 3 days following CT-guided microwave ablation of a right lower lobe lung tumor. The patient had low grade fever and complained of shortness of breath. (B) partial drainage of the effusion by a medium bore chest drain. The pleural fluid was exudative but sterile, and the patient was discharged home after a course of antibiotics and complete drainage of the effusion.*

pleural temperatures [72]. Repeated punctures and previous systemic chemotherapy were significant risk factors [64]. Aseptic pleuritis gives rise to pleuritic pain, but most resolve spontaneously. Only a minority of pleural effusion required drainage (**Figure 9**).

The incidence of hemoptysis after percutaneous RFA is 3–9% [68], while the incidence of all forms of hemorrhage is approximately double that rate. Risk factors for intraparenchymal hemorrhage include basal and middle lung zone lesions, needle track traversing lung parenchyma by more than 2.5 cm, electrode traversing pulmonary vessels and the use of multi-tined electrodes [73]. Although most hemorrhages are self-limiting, rarely ablation injury to intercostal artery may occur leading to massive bleeding [68].

## **6. Bronchoscopic ablation techniques**

Most of the thermal ablative techniques in literature involved percutaneous placement of electrodes. Since 2010, a Japanese group pioneered a bronchoscopyguided cooled RFA technique for lung tumors in humans [74, 75], followed by a Chinese group using electromagnetic navigation bronchoscopy (ENB) guidance [76]. Compared to percutaneous approach, a major advantage of bronchoscopic ablation is lack of pleural puncture, and hence fewer pleural-based complications. The Japanese group reported no pneumothorax, bronchopleural fistula nor pleural effusion in 28 cases of bronchoscopic RFA [75], while the rate of pneumothorax for percutaneous ablation ranges from 3.5–54% as mentioned above. Bronchoscopic ablation also eliminates the risk of needle tract seeding. Another edge of bronchoscopic ablation is its ability to reach certain regions of lung which are otherwise difficult or dangerous for percutaneous access, for instance areas near mediastinal pleura, diaphragm, lung apex, or areas shielded by scapula.

#### **Figure 10.**

*The set-up for microwave ablation of lung nodules under electromagnetic navigation bronchoscopy (ENB) is shown. Within the hybrid theater, the patient lies supine and is intubated with single lumen endotracheal tube. With the help of navigation software like SuperDimension™ (@), and fine adjustment of position with conebeam CT (#), the target lung lesion is localized with a ENB bronchoscope. The microwave ablation catheter is inserted through the bronchoscope into the lung tumor, which is then connected to the microwave generator (\*). The yellow arrow is pointing to the external part of microwave ablation catheter.*

**95**

**Figure 12.**

*0.8 cm from the tip of the locatable guide.*

**Figure 11.**

*of navigation software like SuperDimension™.*

*Image-Guided Ablative Therapies for Lung Tumors DOI: http://dx.doi.org/10.5772/intechopen.94216*

With evidence of safety and technical success of bronchoscopic ablation in animal models [77], and the above-mentioned advantages in mind, the author's institute is one of the first to perform ENB-guided microwave ablation on patients in the hybrid operating room (**Figure 10**). Navigation precision has been much improved following the advent of ENB with the help of navigation systems like SuperDimension™ (Covidien, Plymouth, MN, USA) (**Figures 11** and **12**), supplemented by position confirmation by fluoroscopy and cone beam CT. The microwave catheter (Emprint™ Ablation Catheter with Thermosphere™ technology, Covidien, Plymouth, MN, USA) is inserted within the lung tumor via bronchoscopy and ablated for up to 10 minutes per burn (**Figure 13**). Since early

*The planned navigation pathway (pink) from trachea to the target lung lesion in left upper lobe with the help* 

*The SuperDimension™ software allows multiple views to guide navigation to a target lung lesion (green ball). The upper left panel shows the navigation pathway (pink) in virtual bronchoscopy view, while the lower left panel shows it in 3D map view. On the right side panel, the Centre of the target lung lesion is shown to be* 

*Image-Guided Ablative Therapies for Lung Tumors DOI: http://dx.doi.org/10.5772/intechopen.94216*

*Lung Cancer - Modern Multidisciplinary Management*

**6. Bronchoscopic ablation techniques**

drainage (**Figure 9**).

massive bleeding [68].

pleural temperatures [72]. Repeated punctures and previous systemic chemotherapy were significant risk factors [64]. Aseptic pleuritis gives rise to pleuritic pain, but most resolve spontaneously. Only a minority of pleural effusion required

The incidence of hemoptysis after percutaneous RFA is 3–9% [68], while the incidence of all forms of hemorrhage is approximately double that rate. Risk factors for intraparenchymal hemorrhage include basal and middle lung zone lesions, needle track traversing lung parenchyma by more than 2.5 cm, electrode traversing pulmonary vessels and the use of multi-tined electrodes [73]. Although most hemorrhages are self-limiting, rarely ablation injury to intercostal artery may occur leading to

Most of the thermal ablative techniques in literature involved percutaneous placement of electrodes. Since 2010, a Japanese group pioneered a bronchoscopyguided cooled RFA technique for lung tumors in humans [74, 75], followed by a Chinese group using electromagnetic navigation bronchoscopy (ENB) guidance [76]. Compared to percutaneous approach, a major advantage of bronchoscopic ablation is lack of pleural puncture, and hence fewer pleural-based complications. The Japanese group reported no pneumothorax, bronchopleural fistula nor pleural effusion in 28 cases of bronchoscopic RFA [75], while the rate of pneumothorax for percutaneous ablation ranges from 3.5–54% as mentioned above. Bronchoscopic ablation also eliminates the risk of needle tract seeding. Another edge of bronchoscopic ablation is its ability to reach certain regions of lung which are otherwise difficult or dangerous for percutaneous access, for instance areas near mediastinal

**94**

**Figure 10.**

*The set-up for microwave ablation of lung nodules under electromagnetic navigation bronchoscopy (ENB) is shown. Within the hybrid theater, the patient lies supine and is intubated with single lumen endotracheal tube. With the help of navigation software like SuperDimension™ (@), and fine adjustment of position with conebeam CT (#), the target lung lesion is localized with a ENB bronchoscope. The microwave ablation catheter is inserted through the bronchoscope into the lung tumor, which is then connected to the microwave generator (\*).* 

*The yellow arrow is pointing to the external part of microwave ablation catheter.*

pleura, diaphragm, lung apex, or areas shielded by scapula.

With evidence of safety and technical success of bronchoscopic ablation in animal models [77], and the above-mentioned advantages in mind, the author's institute is one of the first to perform ENB-guided microwave ablation on patients in the hybrid operating room (**Figure 10**). Navigation precision has been much improved following the advent of ENB with the help of navigation systems like SuperDimension™ (Covidien, Plymouth, MN, USA) (**Figures 11** and **12**), supplemented by position confirmation by fluoroscopy and cone beam CT. The microwave catheter (Emprint™ Ablation Catheter with Thermosphere™ technology, Covidien, Plymouth, MN, USA) is inserted within the lung tumor via bronchoscopy and ablated for up to 10 minutes per burn (**Figure 13**). Since early

#### **Figure 11.**

*The planned navigation pathway (pink) from trachea to the target lung lesion in left upper lobe with the help of navigation software like SuperDimension™.*

#### **Figure 12.**

*The SuperDimension™ software allows multiple views to guide navigation to a target lung lesion (green ball). The upper left panel shows the navigation pathway (pink) in virtual bronchoscopy view, while the lower left panel shows it in 3D map view. On the right side panel, the Centre of the target lung lesion is shown to be 0.8 cm from the tip of the locatable guide.*

**Figure 13.**

*(A) The target lung lesion (yellow tracing) in 3 axes on CT before bronchoscopic microwave ablation. The green, red and blue ovals mark the expected ablation zone margins. (B) The post-ablation appearance of the same lung nodule. The lung tumor has been encompassed in the ablation zone, represented by ground-glass opacities.*

2019, we have performed 45 cases with 100% technical success rate. Similar to percutaneous approach, the median length of stay was 1 day only. Only 2 patients (4.4%) developed pneumothorax requiring chest drainage. Post-ablation reaction and fever occurred in 8.9%, minor hemoptysis or hemorrhage in 4.4%, and pleural effusion in 2.2%. As of the time of writing, there was no progressive disease at a mean follow up of 290 days. We believe that bronchoscopic ablation represents the future for lung cancer ablation as it offers a truly wound-less option with likely fewer complications.

## **7. Conclusions**

Image-guided ablative therapy is an important armamentarium in the treatment of lung cancers, either for early stage lung cancers in patients who are medically inoperable or refuse surgery, or for palliation of late stage lung cancers. Radiofrequency ablation is the most studied modality with a large body of evidence supporting its safety and efficacy, with comparable outcomes to sublobar resections and stereotactic radiation therapy in select patients. Nonetheless, microwave ablation is quickly catching up in popularity due to its superior properties over RFA. Traditionally, lung ablation was performed percutaneously, but the latest development of bronchoscopic ablation techniques are promising and may drive the future of lung cancer ablation research.

## **Conflict of interest**

Dr. Joyce WY Chan and Dr. Rainbow WH Lau declare no conflict of interest. Professor Calvin SH Ng is a consultant for Johnson and Johnson; Medtronic, USA.

**97**

**Author details**

Joyce W.Y. Chan, Rainbow W.H. Lau and Calvin S.H. Ng\*

provided the original work is properly cited.

Hospital, The Chinese University of Hong Kong, Hong Kong SAR

\*Address all correspondence to: calvinng@surgery.cuhk.edu.hk

Division of Cardiothoracic Surgery, Department of Surgery, Prince of Wales

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Image-Guided Ablative Therapies for Lung Tumors DOI: http://dx.doi.org/10.5772/intechopen.94216*

*Image-Guided Ablative Therapies for Lung Tumors DOI: http://dx.doi.org/10.5772/intechopen.94216*

*Lung Cancer - Modern Multidisciplinary Management*

2019, we have performed 45 cases with 100% technical success rate. Similar to percutaneous approach, the median length of stay was 1 day only. Only 2 patients (4.4%) developed pneumothorax requiring chest drainage. Post-ablation reaction and fever occurred in 8.9%, minor hemoptysis or hemorrhage in 4.4%, and pleural effusion in 2.2%. As of the time of writing, there was no progressive disease at a mean follow up of 290 days. We believe that bronchoscopic ablation represents the future for lung cancer ablation as it offers a truly wound-less option with likely

*(A) The target lung lesion (yellow tracing) in 3 axes on CT before bronchoscopic microwave ablation. The green, red and blue ovals mark the expected ablation zone margins. (B) The post-ablation appearance of the same lung nodule. The lung tumor has been encompassed in the ablation zone, represented by ground-glass* 

Image-guided ablative therapy is an important armamentarium in the treatment of lung cancers, either for early stage lung cancers in patients who are medically inoperable or refuse surgery, or for palliation of late stage lung cancers. Radiofrequency ablation is the most studied modality with a large body of evidence supporting its safety and efficacy, with comparable outcomes to sublobar resections and stereotactic radiation therapy in select patients. Nonetheless, microwave ablation is quickly catching up in popularity due to its superior properties over RFA. Traditionally, lung ablation was performed percutaneously, but the latest development of bronchoscopic ablation techniques are promising and may drive the future

Dr. Joyce WY Chan and Dr. Rainbow WH Lau declare no conflict of interest. Professor Calvin SH Ng is a consultant for Johnson and Johnson; Medtronic,

**96**

USA.

fewer complications.

of lung cancer ablation research.

**Conflict of interest**

**7. Conclusions**

**Figure 13.**

*opacities.*

## **Author details**

Joyce W.Y. Chan, Rainbow W.H. Lau and Calvin S.H. Ng\* Division of Cardiothoracic Surgery, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR

\*Address all correspondence to: calvinng@surgery.cuhk.edu.hk

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[2] El-SherifA, GoodingWE, SantosR, et al. Outcomes of Sublobar Resection Versus Lobectomy for Stage I Non-Small Cell Lung Cancer: A 13-Year Analysis. Annals of Thoracic Surgery 2006; 82(2): 408-416. DOI: 10.1016/j. athoracsur.2006.02.029.

[3] BerfieldKS, WoodDE. Sublobar resection for stage IA non-small cell lung cancer. Journal of Thoracic Disease 2017; 9(Suppl 3): 208-210. DOI: 10.21037/jtd.2017.03.135.

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[12] SolomonSB, ThorntonRH, DupuyDE, DowneyRJ. Protection of the Mediastinum and Chest Wall with an Artificial Pneumothorax during Lung Ablations. Journal of Vascular and Interventional Radiology 2008; 19(4): 610-615. DOI: 10.1016/j. jvir.2008.01.004.

[13] YasuiK, KanazawaS, SanoY, et al. Thoracic tumors treated with CT-guided radiofrequency ablation: Initial experience. Radiology 2004; 231(3): 850-857. DOI: 10.1148/ radiol.2313030347.

[14] KimC. Understanding the nuances of microwave ablation for more accurate post-treatment assessment. Future Oncology 2018; 14(17): 1755-1764. DOI: 10.2217/fon-2017-0736.

[15] BraceCL, HinshawJL, LaesekePF, SampsonLA, LeeFT. Pulmonary thermal ablation: Comparison of radiofrequency

**99**

*Image-Guided Ablative Therapies for Lung Tumors DOI: http://dx.doi.org/10.5772/intechopen.94216*

> Journal of Thoracic Oncology 2011; 6(12): 2044-2051. DOI: 10.1097/

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[16] WelchBT, BrinjikjiW, SchmitGD, et al. A national analysis of the complications, cost, and mortality of percutaneous lung ablation. Journal of Vascular and Interventional Radiology 2015; 26(6): 787-791. DOI: 10.1016/j.

[17] ChheangS, AbtinF, GuteirrezA, GenshaftS, SuhR. Imaging features following thermal ablation of lung malignancies. Seminars in Interventional Radiology 2013; 30(2): 157-168. DOI: 10.1055/s-0033-1342957.

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[19] AbtinFG, EradatJ, GutierrezAJ,

[20] OrganLW. Electrophysiologic principles of radiofrequency lesion making. Applied Neurophysiology 1976; 32(2): 69-76. DOI: 10.1159/000102478.

[21] LencioniR, CrocettiL, CioniR, et al. Response to radiofrequency ablation of pulmonary tumours: a prospective, intention-to-treat, multicentre clinical trial (the RAPTURE study). The Lancet Oncology 2008; 9(7): 621-628. DOI: 10.1016/S1470-2045(08)70155-4.

[22] AmbrogiMC, FanucchiO, CioniR, et al. Long-term results of radiofrequency ablation treatment of stage i non-small cell lung cancer: A prospective intention-to-treat study.

Radiofrequency ablation of lung tumors: Imaging features of the postablation zone. Radiographics 2012; 32(4): 947- 969. DOI: 10.1148/rg.324105181.

LeeC, FishbeinMC, SuhRD.

DOI: 10.1148/radiol.2513081564.

jvir.2015.02.019.

radiol.2293021756.

*Image-Guided Ablative Therapies for Lung Tumors DOI: http://dx.doi.org/10.5772/intechopen.94216*

and microwave devices by using gross pathologic and CT findings in a swine model. Radiology 2009; 251(3): 705-711. DOI: 10.1148/radiol.2513081564.

[16] WelchBT, BrinjikjiW, SchmitGD, et al. A national analysis of the complications, cost, and mortality of percutaneous lung ablation. Journal of Vascular and Interventional Radiology 2015; 26(6): 787-791. DOI: 10.1016/j. jvir.2015.02.019.

[17] ChheangS, AbtinF, GuteirrezA, GenshaftS, SuhR. Imaging features following thermal ablation of lung malignancies. Seminars in Interventional Radiology 2013; 30(2): 157-168. DOI: 10.1055/s-0033-1342957.

[18] SuhRD, WallaceAB, SheehanRE, HeinzeSB, GoldinJG. Unresectable Pulmonary Malignancies: CT-guided Percutaneous Radiofrequency Ablation - Preliminary Results. Radiology 2003; 229(3): 821-829. DOI: 10.1148/ radiol.2293021756.

[19] AbtinFG, EradatJ, GutierrezAJ, LeeC, FishbeinMC, SuhRD. Radiofrequency ablation of lung tumors: Imaging features of the postablation zone. Radiographics 2012; 32(4): 947- 969. DOI: 10.1148/rg.324105181.

[20] OrganLW. Electrophysiologic principles of radiofrequency lesion making. Applied Neurophysiology 1976; 32(2): 69-76. DOI: 10.1159/000102478.

[21] LencioniR, CrocettiL, CioniR, et al. Response to radiofrequency ablation of pulmonary tumours: a prospective, intention-to-treat, multicentre clinical trial (the RAPTURE study). The Lancet Oncology 2008; 9(7): 621-628. DOI: 10.1016/S1470-2045(08)70155-4.

[22] AmbrogiMC, FanucchiO, CioniR, et al. Long-term results of radiofrequency ablation treatment of stage i non-small cell lung cancer: A prospective intention-to-treat study.

Journal of Thoracic Oncology 2011; 6(12): 2044-2051. DOI: 10.1097/ JTO.0b013e31822d538d.

[23] DeBaèreT, PalussièreJ, AupérinA, et al. Midterm local efficacy and survival after radiofrequency ablation of lung tumors with minimum follow-up of 1 year: Prospective evaluation. Radiology 2006; 240(2): 587-596. DOI: 10.1148/ radiol.2402050807.

[24] KimSR, HanHJ, ParkSJ, et al. Comparison between surgery and radiofrequency ablation for stage i nonsmall cell lung cancer. European Journal of Radiology 2012; 81(2): 395-399. DOI: 10.1016/j.ejrad.2010.12.091.

[25] UhligJ, LudwigJM, GoldbergSB, ChiangA, BlasbergJD, KimHS. Survival rates after thermal ablation versus stereotactic radiation therapy for stage 1 non–small cell lung cancer: A national cancer database study. Radiology 2018; 289(3): 862-870. DOI: 10.1148/ radiol.2018180979.

[26] BiN, SheddenK, ZhengX, KongFMS. Comparison of the Effectiveness of Radiofrequency Ablation With Stereotactic Body Radiation Therapy in Inoperable Stage I Non-Small Cell Lung Cancer: A Systemic Review and Pooled Analysis. In International Journal of Radiation Oncology Biology Physics, vol 95. Elsevier Inc., 2016; 1378-1390. DOI: 10.1016/j.ijrobp.2016.04.016.

[27] SimonCJ, DupuyDE, Mayo-SmithWW. Microwave ablation: Principles and applications. In Radiographics, vol 25. Radiographics, 2005. DOI: 10.1148/rg.25si055501.

[28] LubnerMG, BraceCL, HinshawJL, LeeFT. Microwave tumor ablation: Mechanism of action, clinical results, and devices. Journal of Vascular and Interventional Radiology 2010; 21(SUPPL. 8): S192. DOI: 10.1016/j. jvir.2010.04.007.

**98**

*Lung Cancer - Modern Multidisciplinary Management*

2002; 22(SPEC. ISS). DOI: 10.1148/ radiographics.22.suppl\_1.g02oc03s259.

10.1002/cncr.29507.

radiol.2431060088.

jvir.2008.01.004.

radiol.2313030347.

10.2217/fon-2017-0736.

[9] DupuyDE, FernandoHC, HillmanS, et al. Radiofrequency ablation of stage IA non-small cell lung cancer in medically inoperable patients: Results from the American College of Surgeons Oncology Group Z4033 (Alliance) trial. Cancer 2015; 121(19): 3491-3498. DOI:

[10] SimonCJ, DupuyDE, DiPetrilloTA, et al. Pulmonary radiofrequency ablation: Long-term safety and efficacy in 153 patients. Radiology 2007; 243(1): 268-275. DOI: 10.1148/

[11] LeeJM, JinGY, GoldbergSN, et al. Percutaneous Radiofrequency Ablation for Inoperable Non-Small Cell Lung Cancer and Metastases: Preliminary Report. Radiology 2004; 230(1): 125- 134. DOI: 10.1148/radiol.2301020934.

[12] SolomonSB, ThorntonRH, DupuyDE, DowneyRJ. Protection of the Mediastinum and Chest Wall with an Artificial Pneumothorax during Lung Ablations. Journal of Vascular and Interventional Radiology 2008; 19(4): 610-615. DOI: 10.1016/j.

[13] YasuiK, KanazawaS, SanoY, et al. Thoracic tumors treated with CT-guided radiofrequency ablation: Initial experience. Radiology 2004; 231(3): 850-857. DOI: 10.1148/

[14] KimC. Understanding the nuances of microwave ablation for more accurate post-treatment assessment. Future Oncology 2018; 14(17): 1755-1764. DOI:

[15] BraceCL, HinshawJL, LaesekePF, SampsonLA, LeeFT. Pulmonary thermal ablation: Comparison of radiofrequency

[1] Rami-PortaR, TsuboiM. Sublobar resection for lung cancer. European Respiratory Journal 2009; 33(2): 426- 435. DOI: 10.1183/09031936.00099808.

[2] El-SherifA, GoodingWE, SantosR, et al. Outcomes of Sublobar Resection Versus Lobectomy for Stage I Non-Small Cell Lung Cancer: A 13-Year Analysis. Annals of Thoracic Surgery 2006; 82(2): 408-416. DOI: 10.1016/j.

[3] BerfieldKS, WoodDE. Sublobar resection for stage IA non-small cell lung cancer. Journal of Thoracic Disease 2017; 9(Suppl 3): 208-210. DOI:

athoracsur.2006.02.029.

**References**

10.21037/jtd.2017.03.135.

[4] AbreuCECV, FerreiraPPR, deMoraesFY, NevesWFP, GadiaR, CarvalhoH de A. Radioterapia estereotáxica extracraniana em câncer de pulmão: Atualização. Jornal Brasileiro de Pneumologia 2015; 41(4): 376-387. DOI: 10.1590/ S1806-37132015000000034.

[5] Anon. Long-term Results of

Cell Lung Cancer - PubMed.

Stereotactic Body Radiation Therapy in Medically Inoperable Stage I Non-Small

[6] DupuyDE, ZagoriaRJ, AkerleyW, Mayo-SmithWW, KavanaghPV., SafranH. Technical innovation: Percutaneous radiofrequency ablation of malignancies in the lung. American Journal of Roentgenology 2000; 174(1): 57-59. DOI: 10.2214/ajr.174.1.1740057.

[7] AlexanderE, DupuyD. Lung cancer ablation: Technologies and techniques. Seminars in Interventional Radiology 2013; 30(2): 141-150. DOI:

[8] DupuyDE, Mayo-SmithWW, AbbottGF, DiPetrilloT. Clinical applications of radio-frequency tumor ablation in the thorax. Radiographics

10.1055/s-0033-1342955.

[29] Louis HinshawJ, LubnerMG, ZiemlewiczTJ, LeeFT, BraceCL. Percutaneous tumor ablation tools: Microwave, radiofrequency, or cryoablation-what should you use and why? Radiographics 2014; 34(5): 1344- 1362. DOI: 10.1148/rg.345140054.

[30] WardRC, HealeyTT, DupuyDE. Microwave ablation devices for interventional oncology. Expert Review of Medical Devices 2013; 10(2): 225-238. DOI: 10.1586/erd.12.77.

[31] WolfFJ, GrandDJ, MachanJT, DiPetrilloTA, Mayo-SmithWW, DupuyDE. Microwave ablation of lung malignancies: Effectiveness, CT findings, and safety in 50 patients. Radiology 2008; 247(3): 871-879. DOI: 10.1148/radiol.2473070996.

[32] BelfioreG, RonzaF, BelfioreMP, et al. Patients' survival in lung malignancies treated by microwave ablation: Our experience on 56 patients. European Journal of Radiology 2013; 82(1): 177- 181. DOI: 10.1016/j.ejrad.2012.08.024.

[33] KoWC, LeeYF, ChenYC, et al. CT-guided percutaneous microwave ablation of pulmonary malignant tumors. Journal of Thoracic Disease 2016; 8(Suppl 9): S659–S665. DOI: 10.21037/jtd.2016.09.44.

[34] HealeyTT, MarchBT, BairdG, DupuyDE. Microwave Ablation for Lung Neoplasms: A Retrospective Analysis of Long-Term Results. Journal of Vascular and Interventional Radiology 2017; 28(2): 206-211. DOI: 10.1016/j.jvir.2016.10.030.

[35] PuscedduC, MelisL, SotgiaB, GuerzoniD, PorcuA, FancelluA. Usefulness of percutaneous microwave ablation for large non-small cell lung cancer: A preliminary report. Oncology Letters 2019; 18(1): 659-666. DOI: 10.3892/ol.2019.10375.

[36] VoglTJ, WorstTS, NaguibNNN, AckermannH, Gruber-RouhT,

Nour-EldinNEA. Factors influencing local tumor control in patients with neoplastic pulmonary nodules treated with microwave ablation: A riskfactor analysis. American Journal of Roentgenology 2013; 200(3): 665-672. DOI: 10.2214/AJR.12.8721.

[37] YaoW, LuM, FanW, et al. Comparison between microwave ablation and lobectomy for stage I non-small cell lung cancer: a propensity score analysis. International Journal of Hyperthermia 2018; 34(8): 1329-1336. DOI: 10.1080/02656736.2018.1434901.

[38] WatsonRA, TolI, GunawardanaS, TsakokMT. Is microwave ablation an alternative to stereotactic ablative body radiotherapy in patients with inoperable early-stage primary lung cancer? Interactive Cardiovascular and Thoracic Surgery 2019; 29(4): 539-543. DOI: 10.1093/icvts/ivz123.

[39] MacchiM, BelfioreMP, FloridiC, et al. Radiofrequency versus microwave ablation for treatment of the lung tumours: LUMIRA (lung microwave radiofrequency) randomized trial. Medical Oncology 2017; 34(5). DOI: 10.1007/s12032-017-0946-x.

[40] ErinjeriJP, ClarkTWI. Cryoablation: Mechanism of action and devices. Journal of Vascular and Interventional Radiology 2010; 21(SUPPL. 8): S187. DOI: 10.1016/j.jvir.2009.12.403.

[41] GageAA, BaustJ. Mechanisms of Tissue Injury in Cryosurgery. Cryobiology 1998; 37(3): 171-186. DOI: 10.1006/cryo.1998.2115.

[42] IzumiY, OyamaT, IkedaE, KawamuraM, KobayashiK. The acute effects of transthoracic cryoablation on normal lung evaluated in a porcine model. Annals of Thoracic Surgery 2005; 79(1): 318-322. DOI: 10.1016/j. athoracsur.2003.09.082.

[43] HinshawJL, LittrupPJ, DurickN, et al. Optimizing the protocol for

**101**

*Image-Guided Ablative Therapies for Lung Tumors DOI: http://dx.doi.org/10.5772/intechopen.94216*

> lung cancer in medically inoperable patients. Journal of Vascular and Interventional Radiology 2015; 26(3): 312-319. DOI: 10.1016/j.jvir.2014.12.006.

[51] DeBaereT, TselikasL, WoodrumD, et al. Evaluating cryoablation of metastatic lung tumors in patients-safety and efficacy the ECLIPSE trial-interim analysis at 1 year. Journal of Thoracic Oncology 2015; 10(10): 1468-1474. DOI: 10.1097/JTO.0000000000000632.

[52] CallstromMR, WoodrumDA, NicholsFC, et al. Multicenter Study of Metastatic Lung Tumors Targeted by Interventional Cryoablation Evaluation (SOLSTICE). In Journal of Thoracic Oncology, vol 15. Elsevier Inc, 2020; 1200-1209. DOI: 10.1016/j.

jtho.2020.02.022.

[53] NiuL, ChenJ, YaoF, et al.

10.1016/j.cryobiol.2013.06.005.

issn.2072-1439.2012.07.13.

10.1055/s-2004-813465.

10.18632/oncotarget.13901.

Percutaneous cryoablation for stage IV lung cancer: A retrospective analysis. Cryobiology 2013; 67(2): 151-155. DOI:

[54] NiuL, XuK, MuF. Cryosurgery for lung cancer. Journal of Thoracic Disease 2012; 4(4): 408-419. DOI: 10.3978/j.

[55] VoglTJ, StraubR, LehnertT, et al. Perkutane thermoablation von lungenmetastasen - Erfahrungen mit dem einsatz der LITT, der radiofrequenzablation (RFA) und literaturübersicht. RoFo Fortschritte auf dem Gebiet der Rontgenstrahlen und der Bildgebenden Verfahren 2004; 176(11): 1658-1666. DOI:

[56] ZhaoQ, TianG, ChenF, ZhongL, JiangT. CT-guided percutaneous laser ablation of metastatic lung cancer: Three cases report and literature review. Oncotarget 2017; 8(2): 2187-2196. DOI:

[57] RosenbergC, PuisR, HegenscheidK, et al. Laser Ablation of Metastatic

pulmonary cryoablation: A comparison of a dual- and triple-freeze protocol. CardioVascular and Interventional Radiology 2010; 33(6): 1180-1185. DOI:

10.1007/s00270-010-9868-0.

[45] MaiwandMO. The role of cryosurgery in palliation of tracheobronchial carcinoma. European Journal of Cardio-thoracic Surgery 1999; 15(6): 764-768. DOI: 10.1016/

S1010-7940(99)00121-9.

jvir.2011.11.019.

pone.0033223.

[44] DasSK, HuangYY, LiB, YuXX, XiaoRH, YangHF. Comparing

cryoablation and microwave ablation for the treatment of patients with stage IIIB/IV non-small cell lung cancer. Oncology Letters 2020; 19(1): 1031- 1041. DOI: 10.3892/ol.2019.11149.

[46] InoueM, NakatsukaS, YashiroH, et al. Percutaneous cryoablation of lung tumors: Feasibility and safety. Journal of Vascular and Interventional Radiology 2012; 23(3): 295-302. DOI: 10.1016/j.

[47] YamauchiY, IzumiY, HashimotoK, et al. Percutaneous cryoablation for the treatment of medically inoperable Stage I non-small cell lung cancer. PLoS ONE 2012; 7(3). DOI: 10.1371/journal.

[48] ZemlyakA, MooreWH, BilfingerTV. Comparison of Survival after Sublobar Resections and Ablative Therapies for Stage I Non-Small Cell Lung Cancer. Journal of the American College of Surgeons 2010; 211(1): 68-72. DOI: 10.1016/j.jamcollsurg.2010.03.020.

[49] YashiroH, NakatsukaS, InoueM, et al. Factors affecting local progression after percutaneous cryoablation of lung tumors. Journal of Vascular and Interventional Radiology 2013; 24(6): 813-821. DOI: 10.1016/j.jvir.2012.12.026.

[50] MooreW, TalatiR, BhattacharjiP, BilfingerT. Five-year survival after cryoablation of stage I non-small cell *Image-Guided Ablative Therapies for Lung Tumors DOI: http://dx.doi.org/10.5772/intechopen.94216*

*Lung Cancer - Modern Multidisciplinary Management*

Nour-EldinNEA. Factors influencing local tumor control in patients with neoplastic pulmonary nodules treated with microwave ablation: A riskfactor analysis. American Journal of Roentgenology 2013; 200(3): 665-672.

DOI: 10.2214/AJR.12.8721.

[37] YaoW, LuM, FanW, et al. Comparison between microwave ablation and lobectomy for stage I non-small cell lung cancer: a propensity score analysis. International Journal of Hyperthermia 2018; 34(8): 1329-1336. DOI: 10.1080/02656736.2018.1434901.

[38] WatsonRA, TolI, GunawardanaS, TsakokMT. Is microwave ablation an alternative to stereotactic ablative body radiotherapy in patients with inoperable

[39] MacchiM, BelfioreMP, FloridiC, et al. Radiofrequency versus microwave ablation for treatment of the lung tumours: LUMIRA (lung microwave radiofrequency) randomized trial. Medical Oncology 2017; 34(5). DOI:

[40] ErinjeriJP, ClarkTWI. Cryoablation: Mechanism of action and devices. Journal of Vascular and Interventional Radiology 2010; 21(SUPPL. 8): S187. DOI: 10.1016/j.jvir.2009.12.403.

[41] GageAA, BaustJ. Mechanisms of Tissue Injury in Cryosurgery. Cryobiology 1998; 37(3): 171-186. DOI:

10.1006/cryo.1998.2115.

athoracsur.2003.09.082.

[43] HinshawJL, LittrupPJ, DurickN, et al. Optimizing the protocol for

[42] IzumiY, OyamaT, IkedaE, KawamuraM, KobayashiK. The acute effects of transthoracic cryoablation on normal lung evaluated in a porcine model. Annals of Thoracic Surgery 2005; 79(1): 318-322. DOI: 10.1016/j.

early-stage primary lung cancer? Interactive Cardiovascular and Thoracic Surgery 2019; 29(4): 539-543. DOI:

10.1093/icvts/ivz123.

10.1007/s12032-017-0946-x.

[29] Louis HinshawJ, LubnerMG, ZiemlewiczTJ, LeeFT, BraceCL. Percutaneous tumor ablation tools: Microwave, radiofrequency, or

cryoablation-what should you use and why? Radiographics 2014; 34(5): 1344- 1362. DOI: 10.1148/rg.345140054.

[30] WardRC, HealeyTT, DupuyDE. Microwave ablation devices for

[31] WolfFJ, GrandDJ, MachanJT, DiPetrilloTA, Mayo-SmithWW, DupuyDE. Microwave ablation of lung malignancies: Effectiveness, CT findings, and safety in 50 patients. Radiology 2008; 247(3): 871-879. DOI:

10.1148/radiol.2473070996.

DOI: 10.1586/erd.12.77.

interventional oncology. Expert Review of Medical Devices 2013; 10(2): 225-238.

[32] BelfioreG, RonzaF, BelfioreMP, et al. Patients' survival in lung malignancies treated by microwave ablation: Our experience on 56 patients. European Journal of Radiology 2013; 82(1): 177- 181. DOI: 10.1016/j.ejrad.2012.08.024.

[33] KoWC, LeeYF, ChenYC, et al. CT-guided percutaneous microwave ablation of pulmonary malignant tumors. Journal of Thoracic Disease 2016; 8(Suppl 9): S659–S665. DOI:

[34] HealeyTT, MarchBT, BairdG, DupuyDE. Microwave Ablation for Lung Neoplasms: A Retrospective Analysis of Long-Term Results. Journal of Vascular and Interventional Radiology 2017; 28(2): 206-211. DOI:

[35] PuscedduC, MelisL, SotgiaB, GuerzoniD, PorcuA, FancelluA. Usefulness of percutaneous microwave ablation for large non-small cell lung cancer: A preliminary report. Oncology Letters 2019; 18(1): 659-666. DOI:

[36] VoglTJ, WorstTS, NaguibNNN, AckermannH, Gruber-RouhT,

10.21037/jtd.2016.09.44.

10.1016/j.jvir.2016.10.030.

10.3892/ol.2019.10375.

**100**

pulmonary cryoablation: A comparison of a dual- and triple-freeze protocol. CardioVascular and Interventional Radiology 2010; 33(6): 1180-1185. DOI: 10.1007/s00270-010-9868-0.

[44] DasSK, HuangYY, LiB, YuXX, XiaoRH, YangHF. Comparing cryoablation and microwave ablation for the treatment of patients with stage IIIB/IV non-small cell lung cancer. Oncology Letters 2020; 19(1): 1031- 1041. DOI: 10.3892/ol.2019.11149.

[45] MaiwandMO. The role of cryosurgery in palliation of tracheobronchial carcinoma. European Journal of Cardio-thoracic Surgery 1999; 15(6): 764-768. DOI: 10.1016/ S1010-7940(99)00121-9.

[46] InoueM, NakatsukaS, YashiroH, et al. Percutaneous cryoablation of lung tumors: Feasibility and safety. Journal of Vascular and Interventional Radiology 2012; 23(3): 295-302. DOI: 10.1016/j. jvir.2011.11.019.

[47] YamauchiY, IzumiY, HashimotoK, et al. Percutaneous cryoablation for the treatment of medically inoperable Stage I non-small cell lung cancer. PLoS ONE 2012; 7(3). DOI: 10.1371/journal. pone.0033223.

[48] ZemlyakA, MooreWH, BilfingerTV. Comparison of Survival after Sublobar Resections and Ablative Therapies for Stage I Non-Small Cell Lung Cancer. Journal of the American College of Surgeons 2010; 211(1): 68-72. DOI: 10.1016/j.jamcollsurg.2010.03.020.

[49] YashiroH, NakatsukaS, InoueM, et al. Factors affecting local progression after percutaneous cryoablation of lung tumors. Journal of Vascular and Interventional Radiology 2013; 24(6): 813-821. DOI: 10.1016/j.jvir.2012.12.026.

[50] MooreW, TalatiR, BhattacharjiP, BilfingerT. Five-year survival after cryoablation of stage I non-small cell lung cancer in medically inoperable patients. Journal of Vascular and Interventional Radiology 2015; 26(3): 312-319. DOI: 10.1016/j.jvir.2014.12.006.

[51] DeBaereT, TselikasL, WoodrumD, et al. Evaluating cryoablation of metastatic lung tumors in patients-safety and efficacy the ECLIPSE trial-interim analysis at 1 year. Journal of Thoracic Oncology 2015; 10(10): 1468-1474. DOI: 10.1097/JTO.0000000000000632.

[52] CallstromMR, WoodrumDA, NicholsFC, et al. Multicenter Study of Metastatic Lung Tumors Targeted by Interventional Cryoablation Evaluation (SOLSTICE). In Journal of Thoracic Oncology, vol 15. Elsevier Inc, 2020; 1200-1209. DOI: 10.1016/j. jtho.2020.02.022.

[53] NiuL, ChenJ, YaoF, et al. Percutaneous cryoablation for stage IV lung cancer: A retrospective analysis. Cryobiology 2013; 67(2): 151-155. DOI: 10.1016/j.cryobiol.2013.06.005.

[54] NiuL, XuK, MuF. Cryosurgery for lung cancer. Journal of Thoracic Disease 2012; 4(4): 408-419. DOI: 10.3978/j. issn.2072-1439.2012.07.13.

[55] VoglTJ, StraubR, LehnertT, et al. Perkutane thermoablation von lungenmetastasen - Erfahrungen mit dem einsatz der LITT, der radiofrequenzablation (RFA) und literaturübersicht. RoFo Fortschritte auf dem Gebiet der Rontgenstrahlen und der Bildgebenden Verfahren 2004; 176(11): 1658-1666. DOI: 10.1055/s-2004-813465.

[56] ZhaoQ, TianG, ChenF, ZhongL, JiangT. CT-guided percutaneous laser ablation of metastatic lung cancer: Three cases report and literature review. Oncotarget 2017; 8(2): 2187-2196. DOI: 10.18632/oncotarget.13901.

[57] RosenbergC, PuisR, HegenscheidK, et al. Laser Ablation of Metastatic

Lesions of the Lung: Long-Term Outcome. American Journal of Roentgenology 2009; 192(3): 785-792. DOI: 10.2214/AJR.08.1425.

[58] MaorE, IvorraA, LeorJ, RubinskyB. The effect of irreversible electroporation on blood vessels. Technology in Cancer Research and Treatment 2007; 6(4): 307-312. DOI: 10.1177/153303460700600407.

[59] ThomsonKR, CheungW, EllisSJ, et al. Investigation of the safety of irreversible electroporation in humans. Journal of Vascular and Interventional Radiology 2011; 22(5): 611-621. DOI: 10.1016/j.jvir.2010.12.014.

[60] SongZ, XuX, LiuM, et al. Efficacy and mechanism of steep pulse irreversible electroporation technology on xenograft model of nude mice: a preclinical study. World journal of surgical oncology 2018; 16(1): 84. DOI: 10.1186/s12957-018-1386-6.

[61] VroomenLGPH, PetreEN, CornelisFH, SolomonSB, SrimathveeravalliG. Irreversible electroporation and thermal ablation of tumors in the liver, lung, kidney and bone: What are the differences? Diagnostic and Interventional Imaging 2017; 98(9): 609-617. DOI: 10.1016/j. diii.2017.07.007.

[62] UsmanM, MooreW, TalatiR, WatkinsK, BilfingerTV. Irreversible electroporation of lung neoplasm: A case series. Medical Science Monitor 2012; 18(6). DOI: 10.12659/ MSM.882888.

[63] RickeJ, JürgensJHW, DeschampsF, et al. Irreversible Electroporation (IRE) Fails to Demonstrate Efficacy in a Prospective Multicenter Phase II Trial on Lung Malignancies: The ALICE Trial. CardioVascular and Interventional Radiology 2015; 38(2): 401-408. DOI: 10.1007/s00270-014-1049-0.

[64] KashimaM, YamakadoK, TakakiH, et al. Complications After 1000 Lung Radiofrequency Ablation Sessions in 420 Patients: A Single Center's Experiences. American Journal of Roentgenology 2011; 197(4): W576– W580. DOI: 10.2214/AJR.11.6408.

[65] YamagamiT, KatoT, HirotaT, YoshimatsuR, MatsumotoT, NishimuraT. Pneumothorax as a complication of percutaneous radiofrequency ablation for lung neoplasms. Journal of Vascular and Interventional Radiology 2006; 17(10): 1625-1629. DOI: 10.1097/01. RVI.0000236607.05698.4A.

[66] OkumaT, MatsuokaT, YamamotoA, et al. Frequency and risk factors of various complications after computed tomography-guided radiofrequency ablation of lung tumors. CardioVascular and Interventional Radiology 2008; 31(1): 122-130. DOI: 10.1007/ s00270-007-9225-0.

[67] KennedySA, MilovanovicL, DaoD, FarrokhyarF, MidiaM. Risk factors for pneumothorax complicating radiofrequency ablation for lung malignancy: A systematic review and meta-analysis. Journal of Vascular and Interventional Radiology 2014; 25(11): 1671-1681.e1. DOI: 10.1016/j. jvir.2014.07.025.

[68] HirakiT, GobaraH, FujiwaraH, et al. Lung cancer ablation: Complications. Seminars in Interventional Radiology 2013; 30(2): 169-175. DOI: 10.1055/s-0033-1342958.

[69] ClasenS, KettenbachJ, KosanB, et al. Delayed development of pneumothorax after pulmonary radiofrequency ablation. CardioVascular and Interventional Radiology 2009; 32(3): 484-490. DOI: 10.1007/ s00270-008-9489-z.

[70] YoshimatsuR, YamagamiT, TerayamaK, MatsumotoT, MiuraH,

**103**

*Image-Guided Ablative Therapies for Lung Tumors DOI: http://dx.doi.org/10.5772/intechopen.94216*

> 2017; 94(3): 293-298. DOI: 10.1159/000477764.

10.21037/tlcr.2019.10.12.

[77] YuanHBin, WangXY, SunJY, et al. Flexible bronchoscopy-guided microwave ablation in peripheral porcine lung: A new minimally-invasive ablation. Translational Lung Cancer Research 2019; 8(6): 787-796. DOI:

NishimuraT. Delayed and recurrent pneumothorax after radiofrequency ablation of lung tumors. Chest 2009; 135(4): 1002-1009. DOI: 10.1378/

[71] SakuraiJ, HirakiT, MukaiT, et al. Intractable Pneumothorax Due to Bronchopleural Fistula after Radiofrequency Ablation of Lung Tumors. Journal of Vascular and Interventional Radiology 2007; 18(1): 141-145. DOI: 10.1016/j.jvir.2006.10.011.

[72] TajiriN, HirakiT, MimuraH, et al. Measurement of pleural temperature during radiofrequency ablation of lung tumors to investigate its relationship to occurrence of pneumothorax or pleural effusion. CardioVascular and Interventional Radiology 2008; 31(3): 581-586. DOI: 10.1007/

[73] Nour-EldinNEA, NaguibNNN, MacKM, AbskharonJE, VoglTJ. Pulmonary hemorrhage complicating radiofrequency ablation, from mild hemoptysis to life-threatening pattern. European Radiology 2011; 21(1): 197- 204. DOI: 10.1007/s00330-010-1889-1.

[74] TanabeT, KoizumiT, TsushimaK, et al. Comparative study of three different catheters for ct imaging-bronchoscopyguided radiofrequency ablation as a potential and novel interventional therapy for lung cancer. Chest 2010; 137(4): 890-897. DOI: 10.1378/

[75] KoizumiT, TsushimaK, TanabeT, et al. Bronchoscopy-Guided Cooled Radiofrequency Ablation as a Novel Intervention Therapy for Peripheral Lung Cancer. Respiration 2015; 90(1): 47-55. DOI: 10.1159/000430825.

[76] XieF, ZhengX, XiaoB, HanB, HerthFJF, SunJ. Navigation

Bronchoscopy-Guided Radiofrequency Ablation for Nonsurgical Peripheral Pulmonary Tumors. Respiration

chest.08-1499.

s00270-007-9283-3.

chest.09-1065.

*Image-Guided Ablative Therapies for Lung Tumors DOI: http://dx.doi.org/10.5772/intechopen.94216*

NishimuraT. Delayed and recurrent pneumothorax after radiofrequency ablation of lung tumors. Chest 2009; 135(4): 1002-1009. DOI: 10.1378/ chest.08-1499.

*Lung Cancer - Modern Multidisciplinary Management*

[64] KashimaM, YamakadoK, TakakiH, et al. Complications After 1000 Lung Radiofrequency Ablation Sessions in 420 Patients: A Single Center's Experiences. American Journal of Roentgenology 2011; 197(4): W576– W580. DOI: 10.2214/AJR.11.6408.

[65] YamagamiT, KatoT, HirotaT, YoshimatsuR, MatsumotoT, NishimuraT. Pneumothorax as a complication of percutaneous radiofrequency ablation for lung neoplasms. Journal of Vascular and Interventional Radiology 2006; 17(10): 1625-1629. DOI: 10.1097/01.

RVI.0000236607.05698.4A.

and Interventional Radiology 2008; 31(1): 122-130. DOI: 10.1007/

s00270-007-9225-0.

jvir.2014.07.025.

Seminars in Interventional

10.1055/s-0033-1342958.

s00270-008-9489-z.

[66] OkumaT, MatsuokaT, YamamotoA, et al. Frequency and risk factors of various complications after computed tomography-guided radiofrequency ablation of lung tumors. CardioVascular

[67] KennedySA, MilovanovicL, DaoD, FarrokhyarF, MidiaM. Risk factors for pneumothorax complicating radiofrequency ablation for lung malignancy: A systematic review and meta-analysis. Journal of Vascular and Interventional Radiology 2014; 25(11): 1671-1681.e1. DOI: 10.1016/j.

[68] HirakiT, GobaraH, FujiwaraH, et al. Lung cancer ablation: Complications.

Radiology 2013; 30(2): 169-175. DOI:

[69] ClasenS, KettenbachJ, KosanB, et al. Delayed development of pneumothorax

after pulmonary radiofrequency ablation. CardioVascular and Interventional Radiology 2009; 32(3): 484-490. DOI: 10.1007/

[70] YoshimatsuR, YamagamiT, TerayamaK, MatsumotoT, MiuraH,

Lesions of the Lung: Long-Term Outcome. American Journal of Roentgenology 2009; 192(3): 785-792.

DOI: 10.2214/AJR.08.1425.

[58] MaorE, IvorraA, LeorJ,

10.1016/j.jvir.2010.12.014.

and mechanism of steep pulse

10.1186/s12957-018-1386-6.

diii.2017.07.007.

MSM.882888.

[61] VroomenLGPH, PetreEN, CornelisFH, SolomonSB, SrimathveeravalliG. Irreversible electroporation and thermal ablation of tumors in the liver, lung, kidney and bone: What are the differences? Diagnostic and Interventional Imaging 2017; 98(9): 609-617. DOI: 10.1016/j.

[62] UsmanM, MooreW, TalatiR, WatkinsK, BilfingerTV. Irreversible electroporation of lung neoplasm: A case series. Medical Science Monitor 2012; 18(6). DOI: 10.12659/

[63] RickeJ, JürgensJHW, DeschampsF, et al. Irreversible Electroporation (IRE) Fails to Demonstrate Efficacy in a Prospective Multicenter Phase II Trial on Lung Malignancies: The ALICE Trial. CardioVascular and Interventional Radiology 2015; 38(2): 401-408. DOI:

10.1007/s00270-014-1049-0.

RubinskyB. The effect of irreversible electroporation on blood vessels. Technology in Cancer Research and Treatment 2007; 6(4): 307-312. DOI: 10.1177/153303460700600407.

[59] ThomsonKR, CheungW, EllisSJ, et al. Investigation of the safety of irreversible electroporation in humans. Journal of Vascular and Interventional Radiology 2011; 22(5): 611-621. DOI:

[60] SongZ, XuX, LiuM, et al. Efficacy

irreversible electroporation technology on xenograft model of nude mice: a preclinical study. World journal of surgical oncology 2018; 16(1): 84. DOI:

**102**

[71] SakuraiJ, HirakiT, MukaiT, et al. Intractable Pneumothorax Due to Bronchopleural Fistula after Radiofrequency Ablation of Lung Tumors. Journal of Vascular and Interventional Radiology 2007; 18(1): 141-145. DOI: 10.1016/j.jvir.2006.10.011.

[72] TajiriN, HirakiT, MimuraH, et al. Measurement of pleural temperature during radiofrequency ablation of lung tumors to investigate its relationship to occurrence of pneumothorax or pleural effusion. CardioVascular and Interventional Radiology 2008; 31(3): 581-586. DOI: 10.1007/ s00270-007-9283-3.

[73] Nour-EldinNEA, NaguibNNN, MacKM, AbskharonJE, VoglTJ. Pulmonary hemorrhage complicating radiofrequency ablation, from mild hemoptysis to life-threatening pattern. European Radiology 2011; 21(1): 197- 204. DOI: 10.1007/s00330-010-1889-1.

[74] TanabeT, KoizumiT, TsushimaK, et al. Comparative study of three different catheters for ct imaging-bronchoscopyguided radiofrequency ablation as a potential and novel interventional therapy for lung cancer. Chest 2010; 137(4): 890-897. DOI: 10.1378/ chest.09-1065.

[75] KoizumiT, TsushimaK, TanabeT, et al. Bronchoscopy-Guided Cooled Radiofrequency Ablation as a Novel Intervention Therapy for Peripheral Lung Cancer. Respiration 2015; 90(1): 47-55. DOI: 10.1159/000430825.

[76] XieF, ZhengX, XiaoB, HanB, HerthFJF, SunJ. Navigation Bronchoscopy-Guided Radiofrequency Ablation for Nonsurgical Peripheral Pulmonary Tumors. Respiration

2017; 94(3): 293-298. DOI: 10.1159/000477764.

[77] YuanHBin, WangXY, SunJY, et al. Flexible bronchoscopy-guided microwave ablation in peripheral porcine lung: A new minimally-invasive ablation. Translational Lung Cancer Research 2019; 8(6): 787-796. DOI: 10.21037/tlcr.2019.10.12.

**105**

Section 4

Systemic Therapy

Personalization

Section 4
