Image-Guided Percutaneous and Transarterial Therapies for Primary and Metastatic Lung Cancer

Abstract

Lung cancer is the leading cause of cancer mortality in the world. A significant proportion of patients with lung cancer are not candidates for surgery and must resort to other treatment alternatives. Rapid technological advancements in fields like interventional radiology have paved the way for valid treatment modalities like image-guided percutaneous and transarterial therapies for treatment of both primary and metastatic lung cancer. The rationale of ablative therapies relies on the fact that focused delivery of energy induces tumor destruction and pathological necrosis. Image-guided percutaneous thermal ablation therapies are established techniques in the local treatment of hepatic, renal, bone, thyroid, or uterine lesions. In the lung, the 3 main indications for lung ablation include local curative intent, a strategy to achieve a chemoholiday in oligometastatic disease, and recently, oligoprogressive disease. Transarterial therapies include a set of catheter-based treatments that involve delivering embolic and/or chemotherapeutic agents directed into the target tumor via the supplying arteries. This article provides a comprehensive review of the various techniques available and discusses their applications and associated complications in primary and metastatic lung cancer.

Introduction

Despite advances in prevention and therapeutic modalities, lung cancer remains the leading cause of cancer mortality worldwide, with approximately 1.8 million deaths every year. ¹ While surgery is the preferred treatment option for resectable non-small-cell lung cancer (NSCLC), the most common type of lung cancer, not all patients are surgical candidates due to the presence of multiple comorbidities or suboptimal pulmonary function. ² Only an estimated one-third of patients diagnosed with lung cancer in the United States have stages I and II NSCLC and may be eligible for curative-intent surgery.^3–6 Furthermore, with the advent of lung cancer screening leading to earlier detection of premalignant or early-stage, locoregional tumors, there has been an expansion of the use of various minimally invasive treatment options.^7,8 Traditionally, the alternative to surgery has been radiation with stereotactic body radiation therapy (SBRT) or conventional fractionated radiotherapy. However, these modalities can expose patients to prolonged radiation, which can lead to complications.^9,10 A significant proportion of patients with lung cancer can develop recurrence after resection, with its incidence depending on the stage of disease. ¹¹ Postoperative recurrences can be classified into either locoregional or distant. Chemoradiotherapy is the standard treatment method for locoregional recurrences in patients with good performance status.^12–16 However, the optimal treatment strategy for locoregional recurrences is still not established due to a lack of data, and the prognosis remains poor.^16,17

Image-guided locoregional therapies play a critical role in the management of patients with lung tumors. Image-guided percutaneous therapies like radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation (CA) are increasingly used in the treatment of early-stage or oligometastatic lung cancer.^2,18,19 Transarterial therapies include a set of catheter-based treatments that deliver embolic and/or chemotherapeutic agents directly to the arteries supplying tumors.^20,21 Given the dual supply to the lung, the pulmonary artery or the bronchial artery can be targeted while sparing adjacent lung parenchyma and minimizing systemic adverse effects. This article provides a comprehensive review of the various percutaneous and transarterial therapies available for lung cancer.

Image-Guided Percutaneous Therapies

Several image-guided percutaneous therapies are used to ablate lung tumors and work by percutaneously introducing needle-like applicators directly or utilizing extracorporeal transducers to shrink or destroy tumors. These techniques include thermal ablations RFA, MWA, and CA. ²² Since lung tumors may extend 6-8 mm microscopically into adjacent lung parenchyma, ablation techniques are aimed to have margins at least 10 mm.^23,24 Other ablation techniques such as chemical (intratumoral ethanol or acetic acid injections), irreversible electroporation, external-energy-delivery-based methods like high-intensity frequency ultrasound and histotripsy, or laser ablation are not typically used in the treatment of lung cancer.

Given the air in the lung, computed tomography (CT) is typically the only imagining technique used to guide percutaneous therapies to the lung. However, there are 3 CT-based modalities that can be used: conventional CT (CCT), cone-beam CT (CBCT), and CT-fluoroscopy (CTF). ¹⁹ CCT uses a C-arm to provide high spatial resolution and 3-dimensional (3D) image reconstruction. Evidence has shown that CBCT may be faster than CCT for targeting and introducing the probe within the tumor site. ²⁵ In contrast, CTF pairs CT with fluoroscopy to provide real-time feedback of the probe's trajectory to the lesion.

Radiofrequency Ablation

RFA is the most commonly used ablative modality in treating lung tumors. ²⁶ It works by inserting a thin, needle-like probe through the skin, under image guidance, and is advanced until the tip is at the site of the tumor. Then, radiofrequency waves in the 375-500 kHz range thermally ablate the tissue surrounding the generator-coupled electrode, inducing an oscillating electric field that creates frictional energy by electron collision. The tissue then undergoes coagulative necrosis from the high temperatures.^27,28 Multiple ablations may be needed for large tumors by either repositioning the probe or using multiple applicators.

RFA has been well established for the treatment of lung malignancies since the 2008 RAPTURE trial verified its feasibility, safety, and effectiveness. ²⁹ The trial consisted of 137 ablation procedures and found correct placement and completion of the treatment protocol in 99% of patients, no procedure-related deaths, no significant worsening of pulmonary function, and a complete response that lasted at least 1 year in 88% of assessable patients. Furthermore, the trial found no significant differences in response between patients with NSCLC and lung metastases. The 1-year and 2-year overall survival (OS) was 70% and 48%, respectively, in patients with NSCLC, and 89% and 66%, respectively in patients with colorectal metastases, and 92% and 64%, respectively, in patients with other metastases. In the recent American College of Surgeons Oncology Group Z4033 (Alliance) cooperative group study that analyzed the effects and safety of RFA in patients with medically inoperable stage IA NSCLC (n = 51 patients), the 1-year and 2-year OS was 86.3% and 69.8%, respectively. ³⁰ The 1-year and 2-year local tumor recurrence rate was 68.9% and 59.8%, respectively. The study found 21 grade 3, 2 grade 4, and 1 grade 5 adverse events in a total of 12 (23.5%) patients within 90 days after the procedure, but none of the grades 4 and 5 complications were attributable to the RFA. The study also found no significant change in the forced expiratory volume in 1 second (FEV1) or the diffusion capacity of the lungs for carbon monoxide (DLCO) following the procedure.

Some of the advantages of using RFA is that there are various electrode shapes, and it is widely available and most studied. ²² Because of air's low electrical and thermal conductivity, the effectiveness of RFA is tissue-specific, which is postulated as to why RFA has larger ablation volumes than in subcutaneous tissue and kidneys.^31,32 Some disadvantages with RFA are that the ablation zone is not visible during the ablation itself, it requires more use of anesthesia for pain, requires grounding pads, and is susceptible to the heat sink effect, the phenomenon of reduced ablation volumes in tumors close to large blood vessels that have flowing blood which creates a cooling effect, making it less ideal for central tumors near the pulmonary hilum.^19,22,33

A recent systematic review and meta-analysis compared SBRT and RFA for inoperable early-stage NSCLC; 87 SBRT (n = 12 811 patients) and 18 RFA studies (n = 1535 patients) were included. ³⁴ The analysis found significantly higher local control rates at 1, 2, 3, and 5 years for SBRT when compared to RFA, but no significant differences in 1-year and 2-year OS. With regard to 3-year and 5-year OS, however, SBRT was associated with higher survival than RFA (3-year OS, 58% [95% confidence interval [CI]: 56%-59%] vs 48% [95% CI: 45%-51%], P < .01; 5-year OS 39% [95% CI: 37%-40%] vs 21% [95% CI: 19%-23%], P < .01). The most common complication in the SBRT group was radiation pneumonitis (9.1%) while pneumothorax was the most common complication in the RFA group (27.2%). Other older systematic reviews and/or meta-analyses have been performed comparing SBRT and RFA with conflicting results. A systematic review and pooled analysis of 31 studies on SBRT (n = 2767 patients) and 13 studies on RFA (n = 328 patients) from 2016 found comparable OS at 1, 2, 3, and 5 years while SBRT had higher rates of local control than ablation. ³⁵ Moreover, a National Cancer Database (NCDB) analysis found no significant difference in OS between patients treated with SBRT and patients treated with RFA in propensity score-matched analysis for stage I NSCLC. An analysis of the Surveillance, Epidemiology, and End Results (SEER) registry of patients with stage IA NSCLC who received SBRT or RFA and were ineligible for surgery found no significant difference in survival between the 2 groups despite RFA appearing to offer better survival, especially in tumors <1 cm. ³⁶

Microwave Ablation

While less popular than RFA, MWA has been gaining traction in treating lung tumors and many studies have reported its effectiveness and safety.^37,38 MWA works by utilizing microwave energy in the 300-3000 MHz range from an antenna, which creates an oscillating electromagnetic field that rotates water molecules and eventual heat by friction. This heat causes damage and results in coagulative necrosis. ²² Similar to RFA, MWA inserts needle-like probes through the skin and is advanced toward the tumor under image guidance. Figure 1 depicts a case of MWA in a patient with lung metastasis.

Figure 1.

Microwave ablation in an 80-year-old man with thymoma and lung metastasis. (A) CT scan of chest shows a lung nodule in the right middle lobe of the lung (white arrow). (B) The lung nodule measures 1.46 cm in diameter and is located 12.54 cm from the potential entry site of the probe. MWA probe is inserted into the lung nodule (C), with a 4 min MWA at the power of 65 W, and (D) post ablation CT showing limited alveolar hemorrhage. (E) Follow-up CT scan after 6 months shows scare tissue in the region of the treated tumor. Abbreviations: CT, computed tomography; MWA, microwave ablation.

Some advantages of MWA include faster ablation times and a more uniform ablation zone than RFA. Furthermore, since MWA is not as impeded by tissue, it can produce larger ablation zones than RFA, making it more suitable for larger tumors, and it can be used with pacemakers. MWA is also less susceptible to the heat sink effect than RFA and does not require grounding pads. Some disadvantages of MWA are that it is usually performed under general anesthesia, is more difficult than RFA, and is less efficient in larger tumors.^19,22

A single-center, propensity score-weighted cohort study of high-risk patients with stage I NSCLC who received CT-guided MWA (n = 32) or lung lobectomy (n = 35) ³⁹ found no significant difference in median survival (MWA: 43.8 months, 95% CI: 26.1-55 months vs lobectomy: 55.8 months, 95% CI: 49.9-76.8 months; log-rank test, P = .041) but did find improved disease-free survival estimates in the lobectomy groups and greater recurrence rates (distant + local relapses) in the MWA group (MWA: 28 (90.6%) vs lobectomy: 14 (40.0%); P < .001).

A best evidence topic review analyzed 12 out of 550 articles to assess and compare outcomes of MWA and SBRT in patients with inoperable early-stage primary lung cancer. ⁴⁰ The analysis found that while no study directly compared the 2 modalities, the best available evidence for MWA, which came from 7 studies, and that of SBRT, which came from 5 studies, were reviewed. The analysis reports a comparable range of 3-year survival (MWA: 29.2%-84.7% vs SBRT: 42.7%-63.5%) and median survival (MWA: 35-60 months vs SBRT: 32.6-48 months) between the 2 groups. The analysis found different side effects between the 2 modalities, with MWA more commonly associated with pneumothorax and fever while SBRT was more commonly associated with radiation pneumonitis and rib fractures. A recent cost-effective analysis comparing MWA and SBRT for inoperable stage I NSCLC concluded that MWA appears to be more cost-effective than SBRT with an incremental cost-effectiveness ratio of $1,480,596 per quality-adjusted life year. ⁴¹

Cryoablation

CA works by inducing sub-zero temperatures or alternating freeze-thaw cycles to form an ice ball and ablate tumors.^22,42 It employs the Joule-Thomson effect, in which gases such as nitrogen, nitrous oxide, or argon experience temperature drops when moving from high pressure to low pressure. At temperatures below −20°C, ice crystals are generated that lead to osmotic cell destruction by the increased tonicity in the extracellular space. Eventually, intracellular ice forms, which ruptures the plasma and organelle membrane, and this damage is enhanced by ischemia from damaged blood vessels and inflammation. If a thawing phase is used, either the liquefied gas is replaced with helium or the needle is heated, and this freezing-thawing cycle is repeated until successful tumor ablation. ⁴³ Figure 2 depicts a case of cryoablation in a patient with lung metastasis.

Figure 2.

Cryoablation of a lung metastasis in a 66-year-old woman with metastasis from cholangiocarcinoma. (A) CT image shows a lung nodule in the right upper lobe (white arrow). (B) The lung nodule measures 0.7 cm in largest diameter and is located 4.77 cm from the skin. (D) Cryoablation probe insertion followed by 3, 7, and 10 min freezing with interval passive thaws (total freezing time of 20 min). (E-F) Focal intranodular and limited alveolar hemorrhage occurred during and after cryoablation. (G) Follow-up CT images after 6 month shows stable lung nodule in the treated area. Abbreviation: CT, computed tomography.

The advantages of CA are that the ablation zone and Iceball are visible while ablating, allowing real-time optimization. ²² Specifically, CA preserves structures that have a collagenous matrix, which includes blood vessels and bronchial airways, making CA ideal for tumors that are near major blood vessels and the hilum. ¹⁹ Furthermore, since CA induces less pain than the other heat-based modalities, it may be preferred in subpleural lesions. Some disadvantages include inconsistent ablation sizes, longer ablation times, higher risk of bleeding, the possibility of cryoshock, some heat sink effect, and greater complexity (operator needs experience working with argon gas and sometimes requires inserting multiple probes).^19,22,44 Possible complications of CA include pneumothorax, hemoptysis, pleural effusion, and pain. ⁴⁵

The ECLIPSE trial, which was a multicenter, prospective, single-arm study that included 40 patients with 60 lung metastases who were treated with 48 CA sessions, confirmed the effectiveness of the use of CA in treating pulmonary metastases.^46,47 The study found 5-year overall local tumor control rates to be 79.2% per tumor and 75% per patient and only 5 (12.5%) of the treated patients had local progression during study duration. The literature has been sparser on the use of CA in primary lung cancer than that of RFA or MWA. In a retrospective analysis of 45 patients with medically inoperable stage I NSCLC, the 5-year OS of 67.8%, 5-year progression-free survival (PFS) of 87.9%, and combined local and regional recurrence rate of 36.2% was reported for CA of lung lesions. ⁴⁸

Thermal Ablation Versus Surgical Resection

To our knowledge, there has been only 1 systematic review and meta-analyses that compared surgery to ablation for patients with lung cancer. ⁴⁹ Out of 816 potential articles, only 8 were included in this meta-analysis, resulted in enrollment of 679 patients treated by sublobar resection and 468 patients treated with ablation for stage I NSCLC. ⁴⁹ The study found that the pooled OS, PFS, and cancer-specific survival rates were significantly higher in the sublobar resection group; however, this finding was associated with significant heterogeneity (I² of 73% for OS, 76% for PFS, and 74% for cancer-specific survival). Additionally, pooled local recurrence rates were significantly higher in the ablation group than in the sublobar resection group (25.4% vs 5.0%, P < .0001; I² = 0%). Of the 2 studies that reported distance recurrence, pooled distance recurrence rates were similar between the 2 groups (P = .75; I² = 0%). Of the 3 studies that included complication rates, there was no significant difference in complication rates. Of the 5 articles that specifically compared sublobar resection and RFA, pooled hazard ratios for survival remained more favorable for the surgical resection group. While this study found that surgery was more beneficial than thermal ablation, the included studies were all retrospective and thus vulnerable to selection bias.

There have been a few registry-based cohort studies that have compared the 2 modalities but with conflicting results.^50,51 In the SEER Medicare-linked database, 1897 patients with stages IA and IB NSCLC who were aged ≥65 years were analyzed. ⁵⁰ While patients who received sublobar resection had better OS and lung cancer-specific survival than thermal ablation in unadjusted analysis, multivariable Cox proportional hazards model and propensity score-matched analysis (n = 69) found no significant difference in OS and lung cancer-specific survival between the 2 groups. Analysis of the NCDB to assess outcomes for patients with clinical stage I NSCLC found that patients undergoing sublobar resection experienced improved survival when compared with ablation in both unadjusted and adjusted analyses. ⁵¹ Comparison of thermal ablation to wedge resection for stage I NSCLC in another study utilizing the US SEER database reported that wedge resection had better OS and cancer-specific survival than thermal ablation in propensity score-matched analysis. ⁵² However, for patients aged >75 years, thermal ablation had similar OS and cancer-specific survival as wedge resection.

Thermal Ablation Versus Radiation

In the most recent NCDB propensity score-matched analysis, comparing the thermal ablation to SBRT found no difference in OS of the patients with stage I NSCLC. However, rates of unplanned readmission within 30 days were higher in the thermal ablation cohort, mainly for pneumothoraxes. ⁵³ Similar findings were seen in another NCDB analysis in patients with early-stage NSCLC that found that despite patients being older and more likely to have clinical stage IB (vs IA) lung cancer, SBRT was associated with a higher median OS and 1-year, 2-year, and 5-year OS than those with ablation. ⁵⁴ Another retrospective analysis queried the NCDB for nonsurgically managed early-stage NSCLC concluded improved OS for SBRT when compared to ablation, but there was no significant difference in OS in tumor sizes <2 cm. ⁵⁵

Table 1 summarizes the major studies comparing thermal ablation to other modalities discussed. It is worth noting that none of these comparisons come from randomized controlled trials (RCTs), and, therefore, the superiority of 1 treatment over another cannot be determined. Furthermore, most of the large analyses are limited to the NCDB, which often include general categories for thermal ablation, like laser ablation, cryosurgery, electrocautery/fulguration, local tumor destruction not otherwise specified, and various percutaneous ablation techniques like RFA and MWA are not explicitly recorded.

Table 1.

Major Studies Comparing Thermal Ablation to Surgical Resection and/or Stereotactic Body Radiation Therapy.

Reference	Comparison	Type of study	Disease	n	Outcomes
Li et al 49	Thermal ablation vs Sublobar resection	Systematic review and meta-analysis	Stage I NSCLC	679 SR vs 468 TA (8 studies)	Pooled LR rates: 5.0% (SR) vs 25.4% (TA), P < .01 Pooled DR rates: 25.7% (SR) vs 23.1% (TA), P = .75 Pooled HRs for OS (1.23), PFS (1.34), and CSS (1.39), all Ps < .01 [ie, better survival rates in SR] Pooled complication rates: 27.7% (SR) vs 43.8% (TA), P = .27 Pooled postoperative hospitalization shorter in TA (mean difference 5.93, P = .02).
Kwan et al 50	Thermal ablation vs Sublobar resection	Observational study using SEER-Medicare	Stage I NSCLC in pts ≥ 65 years old	1822 SR vs 75 TA	No significant difference in OS in adjusted analysis, P = .56
Wu et al 51	Sublobar resection vs SBRT vs ablation	Observational study using NCDB	Stage I NSCLC	30 451 pts with SR vs 22 134 SBRT vs 1388 ablations	Propensity score matching found that SBRT and ablation had shorter OS when compared with SR. Results were consistent in pts with tumor size ≤2 cm
Zeng et al 52	Thermal ablation vs wedge resection	Observational study using SEER	Stage I NSCLC	108 TA vs 4264 wedge resection	Propensity score matching found that wedge resection had better OS (44.5% vs 30.1%, P = .03) and CSS (63.5% vs 46%, P = .04) than TA. Results showed comparable OS and CSS for pts aged >75 years
Uhlig et al 53	Thermal ablation vs SBRT	Observational study using NCDB	Stage I NSCLC	947 TA vs 27 478 SBRT	Propensity score matching showed that OS was overall comparable for TA and SBRT (P = .13), however, OS was higher for TA in non-small-cell NETs (P = .04)
Baine et al 54	Thermal ablation vs SBRT	Observational study using NCDB	Stage I NSCLC	1009 TA vs 26 725 SBRT	Propensity score matching showed that SBRT had higher OS than TA (P < .01)
Ager et al 55	Thermal ablation vs SBRT	Observational study using NCDB	cT1-2N0M0 (primary tumors ≤5 cm)	1141 TA vs 14 651	Propensity score matching showed that SBRT was associated with improved OS relative to TA (P < .01). No significant difference in OS was seen in tumors ≤2 cm (P = .23)

Abbreviations: CSS, cancer-specific survival; DR, distant recurrence; HR, hazard ratio; LR, local recurrence; NCDB, National Cancer Database; NET, neuroendocrine tumors; NSCLC, non-small-cell lung cancer; OS, overall survival; PFS, progression-free survival pts, patients; SBRT, stereotactic body radiation therapy; SEER, Surveillance, Epidemiology, and End Results; SR, sublobar resection; TA, thermal ablation.

Radiofrequency Ablation Versus Microwave Ablation Versus Cryoablation

There have been various systematic reviews and meta-analysis conducted that compares the different energy modalities in lung cancer^56–59 and an RCT. ⁶⁰

The LUMIRA trial included 52 patients with stage IV lung cancer who went 1:1 randomization between RFA and MWA. ⁶⁰ The study found that within the RFA group there was only a significant decrease in tumor size between 6 and 12 months but in the RFA group, there was a significant reduction in tumor size both between 6 and 12 months and between pretherapy and 12 months. The study further found no significant difference between the 2 groups in terms of survival but did find significantly lower intraprocedural pain levels in the MWA group.

A systematic review and meta-analysis comprising 7 comparative studies with 246 patients who received RFA versus 319 controls who received MWA found no significant difference in the 6-month, 1-year, 2-year, and 3-year OS between the 2 groups. ⁵⁶ There was also no significant difference in complication rates. Another meta-analysis that included 53 studies with a total of 3432 patients with lung cancer found no significant difference in the complete ablation rates, median local tumor PFS, and median survival between RFA and MWA. ⁵⁷ However, the analysis found higher estimated OS rates in RFA-treated patients than that in MWA-treated patients. Upon subgroup analyses, they found that RFA had a significantly higher median OS for pulmonary metastases, but no significant difference was found in the median OS in patients with primary lung cancer. There were also no significant differences in adverse effects. Another meta-analysis compared RFA, MWA, and CA and comprised of 24 studies with 1840 patients and 2520 lung malignancies (1318 primary lung tumors and 1202 pulmonary metastases). ⁵⁸ The analysis found RFA and MWA to be significantly more effective than CA in terms of local progression rate but comparable between RFA and MWA. The study also found comparable safety profiles, finding no significant difference in rates of major complications between the 3 ablation modalities. However, this analysis was limited by its inability to distinguish subgroups based on stages of lung cancer, and it acknowledges the very low quality of evidence ratings in most of its included comparisons. In a retrospective, case-controlled observational study and meta-analysis to compare MWA and RFA, the observational study found no significant difference in complete ablation rate, median progression-free, or OS between the 2 modalities, and these comparable outcomes were seen in the meta-analysis. ⁵⁹

Image-Guided Transarterial Therapies

Pulmonary Vasculature Anatomy

The blood supply to the lung comes from 2 main sources, the bronchial and pulmonary arteries.^61–63 The pulmonary arterial system (Figure 3) arises from the right ventricle and courses posteriorly and superiorly to the aorta, bifurcating to the left and right main pulmonary arteries at the level of the carina. The pulmonary arteries then divide into 2 lobar branches followed by segmental and subsegmental branches. The pulmonary arterial circuit is connected in series to an extensive parallel capillary bed and a subsequent pulmonary venous circuit that drains the capillaries to create smaller veins followed by the main pulmonary veins into the left atrium, forming a low pressure, high capacitance system that provides a vast surface area for gas exchange.

Figure 3.

The pulmonary artery and its branches.

The bronchial circulatory system, which accounts for approximately 1% of the cardiac output, provides nutrients and oxygenated blood to the lung parenchyma in a low capacitance, high-pressure system. These bronchial arteries mostly originate from either the anterolateral aspect of the proximal descending thoracic aorta or from intercostal arteries, forming a rich anastomotic network with the pulmonary arterial circulation. There exists a lot of variability in the bronchial arteries, with 4 common anatomical variations, ⁶⁴ described in Figure 4. A significant amount of the bronchial venous flow from the lung enters the pulmonary circulation and drains via the pulmonary veins into the left atrium, and the rest drains into the systemic circulation via the azygos vein, superior intercostal vein, or hemiazygos vein.^61–63

Figure 4.

The most common anatomical variations of the bronchial arteries with reported incidences. Type I is the most common variant with two left bronchial arteries and one right bronchial artery off an (ICBT). Type II has one left bronchial artery and one right bronchial artery off an ICBT. Type III has two left bronchial arteries and two right bronchial arteries with one from an ICBT. Type IV is the least common variant with one left bronchial artery and two right bronchial arteries with one from an ICBT. Abbreviation: ICBT, intercostal-bronchial trunk.

Transarterial Therapies for Lung Cancers

There are several transarterial therapies employed in treating lung tumors. Historically, transarterial embolization like bronchial artery embolization, the catheter-based method of identifying and injecting embolic material to a bronchial artery, was done to control hemoptysis in patients with primary lung cancer and metastatic disease.^65,66 Until recently, however, image-guided catheter-based transarterial delivery have adapted from liver cancer management and developed transarterial chemoembolization (TACE), a technique performed to embolize tumor feeding pulmonary or bronchial arteries while delivering local chemotherapy, either via beads or mixed with lipiodol, to not only control hemoptysis but also the underlying lung malignancy.^67–69 However, one of the main downsides of conventional TACE (cTACE) is that by utilizing emulsions of lipiodol, the chemotherapy does not reside for long, and local concentrations are reduced, increasing the risk of systemic adverse effects.^67,70 Drug-eluting beads TACE (DEB-TACE), a recent novel technique, aims to solve this problem by taking advantage of the slow and sustained release of the chemotherapy from the beads into the local tumor environment.^67,71–73 Moreover, different kinds of drugs can be used for DEB-TACE, such as doxorubicin, ⁷⁴ gemcitabine,^67,75 oxaliplatin,^76,77 and pirarubicin. ⁷⁸ These methods work because the lung has a dual blood supply, as previously described.

Iodine-125 (¹²⁵I) seeds insertion (ISI) is a useful and effective local treatment. In a recent meta-analysis of 8 studies, ISI was combined with transarterial chemical infusion (TCI) for advanced NSCLC or small-cell lung cancer. ⁷⁹ The pooled complete response rate, treatment success rate, disease control rate, 1-year survival, OS in the ISI combined with TCI group (377 patients) was significantly greater (all Ps < .001) than TCI alone (397 patients). The pooled 2-year survival rate (P = .08) and myelosuppression rates (P = .29) were comparable between the 2 groups. In another meta-analysis of 6 studies, 2 of which were RCTs, the complete response rate, treatment response, and disease control rates were significantly greater (all Ps < .001) for the 272 patients receiving both ISI and second-line chemotherapy when compared to the 257 patients who received second-line chemotherapy alone. Pooled progression-free and OS (both P < .001) were also higher in the combined group with comparable myelosuppression rates and gastrointestinal response. ⁸⁰

It is worth noting that most of the transarterial therapies are still palliative in nature, and more data needs to be generated to determine its best clinical utility. ⁸¹

Transbronchial Artery Transarterial Therapies

Bronchial artery embolization (BAE) is a safe and effective technique that is commonly indicated for patients with hemoptysis, regardless of etiology. ⁸² However, since approximately 20% of patients ⁸³ with lung cancer acquire hemoptysis during their clinical course and because pulmonary hemorrhages are often caused by lung cancer,^83,84 BAE is often utilized in patients with lung cancer. ⁸⁵ BAE has a very high (>80%) success rate at stopping hemoptysis^66,84–86 and is associated with prolonged survival. ⁸⁴ In a review of 84 patients with primary lung cancer-related hemoptysis that while prognosis was relatively poor, technical (98.8%), and clinical success (82.1%) were high, and those with clinical success had much higher median OS (99 days) when compared to the clinical-failure group (9 days, P < .001). ⁸⁷ Another small retrospective study on 18 patients with lung metastasis from hepatocellular carcinoma showed that BAE is not only safe and effective for controlling hemoptysis in patients with lung metastases but also decreased the size of lung metastases. ⁸² Of the 8 patients who had any antitumor effect evaluated, 3 (38%) had a partial response, 4 (50%) had stable disease, and 1 (12%) had progressive disease. The study observed a significant decrease in the mean size of the largest metastatic tumor from 5.1 to 3.7 cm (P = .035). The most common minor complications reported for BAE include chest pain and pyrexia, with an estimated prevalence of 20%-50%, and are believed to be related to embolization-induced transient ischemia. ⁸⁵

Bronchial arterial infusion (BAI) chemotherapy is another transbronchial artery transarterial therapy that works by delivering chemotherapy directly to the lung cancer via the bronchial artery supplying lung tumors. In 2008, a randomized trial in China of 107 patients with advanced NSCLC compared BAI, traditional vein chemotherapy, and BAI plus vein chemotherapy sequential therapy. ⁸⁸ They found that response rates of primary lesions in BAI (59.22%) and sequential therapy (69.05%) groups were significantly higher than that of the traditional vein chemotherapy group (30.23%, P < .01) but there were no significant differences between BAI and sequential therapy group (P > .05). However, the response rate of metastasis in the BAI group (18.19%) was significantly lower than both traditional vein chemotherapy (53.58%) and sequential therapy (60.00%) groups (P < .05), and there were no significant differences between traditional vein chemotherapy and sequential therapy groups. A retrospective study of 120 patients with advanced NSCLC also found that “super-selective” BAI chemotherapy was associated with improved disease control rate, 3-month (96.67% vs 73.33%, P < .01) and 6-month (86.67 vs 56.67%, P < .01) PFS, and higher Functional Assessment of Cancer Therapy-Lung (FACT-L) scores (P < .05) with significantly lower adverse reactions (P < .05) than patients receiving systemic intravenous chemotherapy. ⁸⁹

Recent developments show the combination of BAE with BAI chemotherapy to get Bronchial Artery Chemoembolization (BACE), which has shown to be effective in pulmonary metastases.^85,90 Figure 5 introduces a case of BACE in a patient with metastatic colon cancer. Moreover, the use of DEB-TACE, which employs the use of microspheres to not only serve as carriers of chemotherapy but also as embolization agents, has been shown to be effective in safe in patients with metastatic lung cancer and advanced NSCLC.^91,92 A recent retrospective study analyzed 36 patients with lung cancer and hemoptysis who were treated by either DEB-BACE or conventional BACE (cBACE). ⁶⁸ The analysis found that while there were no significant differences in the technical and clinical successes of hemoptysis treatment (P > .050), DEB-BACE was associated with increased total clinical response (P = .021), greater objective response rate (P = .035), and greater hemoptysis relapse-free survival (P = .013) when compared to cBACE. Additionally, there were no significant differences in the rates of adverse events between the 2 modalities.

Figure 5.

Bronchial artery chemoembolization in a 65-year-old woman with metastatic colon cancer. (A) Bronchial angiogram shows hypervascular lung metastases. (B) After chemoembolization using lipiodol/mitomycin emulsion, noncontrast CT shows dense lipiodol retention in the lung metastases. Follow-up scan showed decreased size and metabolic activity of the treated tumors. Abbreviation: CT, computed tomography.

Some researchers have even combined transarterial with percutaneous therapies to optimize the efficacy of treatments. A recent comparative study was conducted to compare DEB-BACE with MWA (n = 28 patients) versus DEB-BACE without MWA (n = 49 patients) for patients with advanced and standard treatment-refractory/ineligible NSCLC. ⁹³ The study found that DEB-BACE with MWA was associated with a greater overall disease control rate (85.7%) than DEB-BACE alone (46.9%, P = .002). Furthermore, DEB-BACE with MWA was associated with improved median PFS but not OS than in DEB-BACE alone (median PFS: 7 vs 4 months, P = .037; OS: 8 vs 8 months, P = .318).

Transpulmonary Artery Transarterial Therapies

While pulmonary arterial embolization (PAE) is commonly used to manage rare diseases like aneurysms, pseudoaneurysms, and arteriovenous fistulas, it can also, like BAE, be utilized for the management of hemoptysis. While hemoptysis usually arises from the bronchial artery it can also arise from the pulmonary arteries in <10% of cases.^94–96 Therefore, despite BAE being the first-line treatment, PAE can in theory be utilized for hemoptysis management as well, especially since hemoptysis recurrence and mortality are poor in patients receiving BAE. ⁹⁶ A multicenter, retrospective analysis of PAE in 19 patients with massive or recurrent hemoptysis with transarterial PAE found that of the patients with technical success (84.2%), all had received clinical success without further hemoptysis, complications, or pulmonary infarctions. ⁹⁶ Pulmonary artery infusion (PAI), the injection of chemotherapy directly to the lung tumor via the pulmonary artery, has also been shown to improve outcomes in several case reports and case series.^97,98 In a randomized study that included 90 patients treated with lobectomy for lung cancer who underwent either PAI or received chemotherapy via peripheral vein (VI group) found that PAI was associated with improved 3-year and 5-year survival rates when compared to the VI group (PAI: 77.8%, 47.4 vs VI: 53.3%, 20.5%, respectively; P < .05). ⁹⁷ Furthermore, the PAI group was associated with a lower 3-year local recurrence rate than the VI group (12.8% vs 35.0%; P < .05) and lower 3-year and 5-year metastatic rates (PAI: 20.0%, 26.3% vs VI: 35.6%, 51.3%, respectively; P < .05).

While established for primary and secondary liver tumors, transpulmonary chemoembolization (TPCE), which works to block off a tumor's blood supply while injecting chemotherapy, ⁹⁹ is starting to become more acceptable as a palliative treatment option. ¹⁰⁰ It was proposed as a less invasive and more feasible treatment option than isolated lung perfusion, which was shown to be superior to systemic therapy in animal models. ¹⁰¹ TPCE was also similar in effectiveness to isolated lung perfusion when one-third of the normal dosage is used in a rat model. ¹⁰² TPCE works via a transfemoral approach where a catheter is advanced into the segmental branches of the pulmonary artery, via fluoroscopy guidance, where chemotherapy is infused with embolic agents. One of the first reported studies of TPCE was in 2005, where TPCE with mitomycin C was analyzed in 23 patients with unresectable lung metastases who had no response to systemic chemotherapy. ¹⁰³ The study found no major side effects, volume regression of embolized areas in 8 patients, stable disease at follow up in 6 patients, and progression of metastases in 9 patients. ¹⁰³ In 2008, another study evaluated TPCE in 52 patients with 106 unresectable lung metastases who were treated with 2 to 10 sessions. ¹⁰⁴ The study also found no major side effects, with 16 patients receiving a partial response, 11 patients with stable disease, and 25 patients with progressive disease under response evaluation criteria in solid tumors (RECIST) criteria. Now, TPCE is sometimes used to prevent the progression of lung tumors without systemic side effects or as a neoadjuvant treatment combined with thermal ablation. ¹⁰⁵

Limitations

A main limitation behind transarterial therapies is that while the lung has a dual blood supply like the liver, lung tumors are supplied by either the pulmonary or bronchial arteries, unlike liver tumors that are predominately supplied by the hepatic artery. ⁶⁹ It has been hypothesized that the low response rates with transarterial therapies arise from this dual blood supply. ⁶⁹ In fact, the phase I clinical trial of lung chemoembolization for unresectable and unablatable lung metastases in patients with failed systemic chemotherapy found that by performing both bronchial and pulmonary angiography to examine the blood supply to the lung tumor to tailor treatment, they were able to achieve a technical success rate of intratumoral drug delivery in 100% of the patients (n = 10) with no severe adverse events. ⁶⁹ The trial found a 10% response rate of treated tumors according to the Response Evaluation Criteria in Solid Tumors and 40% according to the PET Response Criteria in Solid Tumors. They also found that ethiodized oil retention after 4 to 6 weeks correlated with reduced tumor size and metabolic activity. Although the study was limited by a small sample size, the efficacy and safety profile with partial response rates warrant the need for future studies.

Society Guidelines

There are various society clinical practice guidelines on the use of image-guided thermal ablation (IGTA) for NSCLC. National Comprehensive Cancer Network (NCCN) guidelines recommend IGTA as an option for patients who are considered “high risk,” or “those with tumors that are for the most part surgically resectable but rendered medically inoperable due to comorbidities,” and recommend a multidisciplinary evaluation. ² They affirm the use of IGTA as a treatment option for patients with NSCLC tumors <3 cm, patients with multiple primary lung cancers for which definitive local therapy is possible, and patients with locoregional recurrence of symptomatic local thoracic disease. Their recommendation of the specific energy modality used for IGTA is to take into consideration the size and location of the tumor, complication risk, local expertise, and/or operator familiarity. ²

Cardiovascular and Interventional Radiology Society of Europe (CIRSE) guidelines recommend that lung ablation be limited to patients with primary lung cancer that is not suitable for surgery or patients with oligometastatic lung disease (mainly colorectal) with radical intent. ¹⁰⁶ While they acknowledge the comparable efficacy between RFA and MWA, they affirm that MWA is typically tolerated better and is more suitable for larger tumors. They affirm better results when lesion size is ≤2 cm with a tumor margin recommendation of ≥1 cm. CIRSE also recommends using contrast-enhanced CT and FDG-PET/CT for accurate preoperative locoregional staging in patients with primary NSCLC. They also recommend pulmonary function tests in patients with a history of pulmonary disease or lung surgery, and while no lower limit of forced expiratory volume in 1 s or diffusion capacity in candidates for IGTA, spirometry should still be discussed by a multidisciplinary tumor board.

The Society of Interventional Radiology (SIR) released a multidisciplinary position statement on percutaneous ablation of NSCLC and metastatic disease to the lungs that is endorsed by the Canadian Association for Interventional Radiology, the Cardiovascular and Interventional Radiological Society of Europe, and the Society of Interventional Oncology. ¹⁰⁷ In their statement, SIR affirms the use of IFTA as a viable treatment option for patients with inoperable stage I NSCLC, recurrent NSCLC, and metastatic lung disease. They also consider lesion characteristics and risk mitigation as the primary determinants for deciding on which energy modality to use.

Conclusion

With the advances in minimally invasive treatment modalities, image-guided percutaneous and transarterial therapies have proven to be highly promising for primary and metastatic lung cancer. However, careful patient selection in a multidisciplinary team setting is required to tailor effective treatments and minimize complications. More clinical trials and multicenter large cohort studies are still required to further optimize and validate their roles in lung cancer management.