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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 4  |  Page : 730-744

Expert consensus workshop report: Guidelines for thermal ablation of primary and metastatic lung tumors (2018 edition)


1 Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
2 Imaging and Interventional Center, Sun Yat-Sen University Cancer Center, Guangzhou, China
3 Interventional Treatment Center, Jilin Provincial Tumor Hospital, Changchun, China
4 Department of Radiation Oncology, Peking University Third Hospital, Beijing, China
5 Department of Interventional Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
6 Department of Interventional Therapy, Hunan Provincial Tumor Hospital, Changsha, China
7 Department of Oncology, Fuxing Hospital Affiliated to the Capital University of Medical Sciences, Beijing, China
8 Department of Interventional Therapy, Jiangsu Cancer Hospital, Nanjing, China
9 Department of Thoracic Surgery, Xuanwu Hospital Affiliated to the Capital University of Medical Sciences, Beijing, China
10 Department of Tumor Minimally Invasive Therapy, Beijing Hospital, Beijing, China
11 Interventional Treatment Center, Shandong University Second Hospital, Jinan, China
12 Division of Interventional MRI, Shandong Medical Imaging Research Institute Affiliated to Shandong University, Jinan, China
13 Department of Radiology, Chinese PLA General Hospital, Beijing, China
14 Department of Interventional Radiology, The Fourth Hospital of Harbin Medical University, Harbin, China
15 Department of Tumor Minimally Invasive Therapy, 307 Hospital, Beijing, China
16 Department of Minimally Invasive Interventional Therapy, Shenzhen Hospital of Beijing University, Shenzhen, China
17 Department of Interventional Therapy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
18 Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
19 Department of Oncology, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
20 Department of Interventional Therapy, Beijing Cancer Hospital, Beijing, China
21 Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
22 Department of Interventional Therapy, Tumor Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, China
23 Department of Interventional Therapy, The Second Affiliated Hospital of Soochow University, Suzhou, China
24 Department of Thoracic Surgery, Shanxi Provincial Tumor Hospital, Xi'an, China
25 Tumor Interventional Therapy Center, Shanghai Renji Hospital, Shanghai, China

Date of Web Publication27-Jun-2018

Correspondence Address:
Weijun Fan
Imaging and Interventional Center, Sun Yat-sen University Cancer Center, Guangzhou 510060
China
Xin Ye
Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Ji'nan 250014
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_221_18

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 > Abstract 


Although surgical resection with curative intent is the main therapy for both primary and metastatic lung tumors, about 80% of lung cancers cannot be removed by surgery. Because most patients with unresectable lung cancer only receive limited benefits from traditional radiotherapy and chemotherapy, many novel local treatment modalities have emerged including local ablation therapy. The Minimally Invasive Treatment of Lung Cancer Branch, Professional Committee of Minimally Invasive Treatment of Cancer of the Chinese Anti-Cancer Association and Committee on Tumor Ablations, Chinese College of Interventionalists have organized multidisciplinary experts to develop guidelines for this treatment modality. These guidelines aim at standardizing thermal ablation procedures, describing the indications for candidates, assessing outcomes, and preventing postablation complications.

Keywords: Cryoablation, Guidelines, laser ablation, Lung tumors, microwave ablation, radiofrequency ablation, Thermal ablation


How to cite this article:
Ye X, Fan W, Wang H, Wang J, Wang Z, Gu S, Feng W, Zhuang Y, Liu B, Li X, Li Y, Li C, Xiao Y, Yang P, Yang X, Yang W, Chen J, Zhang R, Lin Z, Meng Z, Hu K, Liu C, Peng Z, Han Y, Jin Y, Lei G, Zhai B, Huang G. Expert consensus workshop report: Guidelines for thermal ablation of primary and metastatic lung tumors (2018 edition). J Can Res Ther 2018;14:730-44

How to cite this URL:
Ye X, Fan W, Wang H, Wang J, Wang Z, Gu S, Feng W, Zhuang Y, Liu B, Li X, Li Y, Li C, Xiao Y, Yang P, Yang X, Yang W, Chen J, Zhang R, Lin Z, Meng Z, Hu K, Liu C, Peng Z, Han Y, Jin Y, Lei G, Zhai B, Huang G. Expert consensus workshop report: Guidelines for thermal ablation of primary and metastatic lung tumors (2018 edition). J Can Res Ther [serial online] 2018 [cited 2019 Nov 20];14:730-44. Available from: http://www.cancerjournal.net/text.asp?2018/14/4/730/235080




 > Introduction Top


Lung cancer is the most common cancer and leading cause of cancer death around the world, with an incidence of about 2.5 million and over 1.6 million deaths each year.[1] Lung cancer is also the most common cancer and main cause of cancer death in China. In 2010, there were 605,900 new cases of lung cancer and 486,600 cases of death in China.[2] It is estimated that, in 2015, there would be 733,300 new cases of lung cancer and 610,200 cases of death.[3] The number absolutely ranked the first in the world. For early non-small cell lung cancer (NSCLC), surgical resection with curative intent is the main therapy,[4] but about 80% of lung cancers cannot be removed surgically due to various reasons. Most patients with unresectable lung cancer can only derive limited benefits from traditional radiotherapy and chemotherapy. Therefore, many novel local treatment modalities have emerged, including local ablation therapy. Local thermal ablation, as a precise minimally invasive technique, has been increasingly used to treat early-stage lung cancer each year.[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16] Pulmonary metastases are common in clinic as the second common site of all metastases. Percutaneous thermal ablation has been demonstrated to be effective in the treatment of pulmonary metastases.[17],[18],[19],[20] On March 1, 2014, 18 well-known experts, who are in the field of minimally invasive tumor diagnosis and treatment in China, participated in a meeting. They discussed and summarized the “Chinese expert consensus workshop report: Guidelines for thermal ablation of primary and metastatic lung tumors,” which was published at “Thoracic Cancer” in 2015.[21] The “Guidelines” has published for over 3 years and made contributions to the development of international thermal ablation treatment of lung tumors. However, in the past over 3 years of clinical practice, many shortcomings have been found in the “Guidelines,” and further improvements are needed. On April 16, 2017, the Minimally Invasive Treatment of Lung Cancer Branch, Professional Committee of Minimally Invasive Treatment of Cancer of the Chinese Anti-Cancer Association and Committee on Tumor Ablations, Chinese College of Interventionalists organized well-known Chinese experts to amend this “Guidelines.” The experts were from multiple disciplines, including thoracic surgery, radiotherapy, medical oncology, interventional medicine, imaging, and traditional Chinese medicine for oncology. The guideline aimed to provide better references for clinical practice and standardize the development of thermal ablation for treating lung tumors.


 > Local Thermal Ablation Techniques Top


With the emergence of “irreversible electroporation,”[22],[23],[24],[25] the concept of tumor ablation has undergone great changes. Thermal ablation has become one of the energy-based ablations.[26] As a precise minimally invasive treatment technology, tumor thermal ablation utilizes biological effects of heat to directly cause irreversible injury or necrosis of tumor cells in one or more tumor lesions which are located in a certain organ. The techniques include radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation, laser ablation, and high-intensity focused ultrasound (HIFU)[26],[27], although HIFU is not commonly used to treat lung tumors.

Radiofrequency ablation

Currently, RFA is the most widely used ablation technique for the treatment of solid tumors. Through inserting radiofrequency electrodes into the tumor tissue and the application of 375–500 kHz frequency alternating current, mutual friction and collisions of ions within the tumor tissue produce thermal biological effects to raise the local temperature up to 60°C–120°C. When the tissue is heated to >60°C, cell coagulation necrosis may occur. The RFA volume depends on the thermal conduction of local RFA and the thermal convection between circulating blood and extracellular fluid.[26],[27],[28] In December 2007, RFA was approved by the Food and Drug Administration for its application in lung cancer treatment.[29] Since 2009, the NSCLC National Comprehensive Cancer Network Guidelines and China's diagnosis and treatment of primary lung cancer (2015 Edition)[30] have both recommended RFA for treating patients with early-stage lung cancer who cannot tolerate surgical resection.

Microwave ablation

MWA generally uses either of the two frequencies: 915 MHz or 2450 MHz. In a microwave electromagnetic field, water molecules, protein molecules, and other polar molecules within tumor tissue vibrate at high speeds, resulting in collision and mutual friction between molecules. This can raise temperatures to 60°C–150°C in a short time, leading to coagulation necrosis of the cells.[26],[31],[32],[33] MWA has a higher convection and a lower “heat sink” effect in the lungs. However, MWA faced the continued challenges as follows: (1) there are few clinical data and experience because MWA is relatively new; (2) a learning curve is associated with using MWA safely because of the potential larger ablation zones compared with RFA; and (3) the clinical systems are heterogeneous in terms of antenna design, wavelength, frequency, power, and cooling, which leads to different performance characteristics and confusion regarding the interpretation of clinical results and the predictability of results between systems from different manufacturers.[34],[35],[36],[37]

Cryoablation

Argon-helium cryoablation is a mature cryoablation therapy up to date. The principle is that based on the Joule–Thomson theory, the target tissue could be cooled to −140°C with high-pressure argon and then rapidly heated to +20°C to +40°C from −140°C with helium. The ablation process consists of successive freezing-thawing cycles which induce cell death by protein denaturation, membrane disruption, and microvascular thrombosis.[38],[39],[40],[41],[42] The main advantage of cryoablation is that real-time computed tomography (CT) or magnetic resonance imaging (MRI) is used to monitor the ablation zone (“ice ball”) in comparison to the other techniques.[43] The “ice ball” observed under CT or MRI can directly distinguish the boundary of ablation zone and tumor, so as to determine the margin of freezing injury, which is generally within 4–6 mm of the margin of the “ice ball.”

Demonstrably, the most critical factor for a successful ablation practice is the skills of the professionals. The importance of excellent training, a thorough understanding of the indications, imaging options, techniques, complications, ablation modalities, and specific system being used cannot be emphasized enough. In addition, the ability to accurately place needles using CT and MRI guidance, as well as a thorough knowledge of the expected appearance of successful and unsuccessful ablations and complications at immediate postprocedural imaging is paramount. In deciding which ablation device to be used for a specific patient, many factors should be considered, not the least of which is availability. The unfortunate reality is that many institutions have only one ablation system available. Some rules of thumb to be kept in mind include the following: (1) for the tumor with diameter ≤3 cm, good efficacies can be obtained with all the three ablation techniques; (2) the conformability of RFA electrode is favorable because the ablation electrode can be adjusted to protect adjacent organs. However, RFA could be affected by blood flow and airflow. For tumors larger than 3 cm, particularly those larger than 5 cm, MWA is significantly better than RFA. The MWA has some potential advantages over RFA including faster ablations, higher temperature which is not limited by electric impedance, less sensitivity to tissue types with more consistent results, a relatively insensitivity to “heat sinks” compared with RFA, and the ability to create much larger ablation zones. Furthermore, multiple MWA antennas can be positioned into the target tissue and activated simultaneously, which maximize the ablation zone size; (3) the possible precision of cryoablation can be important for treatment of tumors adjacent to vulnerable structures. Cryoablation is also less likely to cause local pain. For tumors ≤1 cm from the pleura or complicated with bone destruction because of bone metastases, cryoablation is significantly better than RFA and MWA. Cryoablation consumes platelets during ablation; therefore, it should be avoided for patients with poor coagulation function.[10],[35],[44],[45],[46]

Laser ablation

The clinical development and application of laser ablation for lung tumors have been relatively less than the above three ablation techniques. The most widely used laser ablation is the neodymium-doped yttrium aluminum garnet (Nd: YAG) laser with the wavelength of 1064 nm. The principle is as follows:[26],[47],[48] after the laser is introduced into the tissue, the photon can be adsorbed by chromophore, resulting in biological effects such as heat and pressure. The tumor tissue may be degenerated, coagulated, vaporized, and even carbonized with these effects; thus, the tumor can be destroyed. The characteristics of laser ablation are as follows:[49],[50] (1) ablation zone was small (1.0 cm × 1.5 cm); (2) ablation time is short due to instant release of laser energy; (3) the optical fiber is introduced with Chiba needle of 21-gauge so that there are less complications (such as hemorrhage). Laser ablation works better for tumors with the following features: multiple tumors in the lung, tumors adjacent to vulnerable structures, and the tumor diameter is <1.0 cm.[51],[52]


 > Procedure Platforms Top


Image guidance

Imaging guidance techniques for percutaneous thermal ablation include CT, MRI, positron emission tomography (PET)/CT, and C-arm cone-beam/CT.[53],[54],[55] CT is the most commonly used image-guided technique in lung tumor ablation, followed by MRI. For tumors near or adhesive to the chest wall, the ultrasound (US) guidance can be applied because the whole morphology of the tumor can be observed with US. Cone-beam/CT has also been applied in some institutions. The functional imaging can be performed with PET/CT although there are less clinical practices.

Thoracic or video-assisted thoracoscopy

Thoracotomy or video-assisted thoracoscopic-assisted techniques are generally used when (1) the tumor is adjacent to critical structures, such as large blood vessels, hilum, or heart, or (2) the result of thoracotomy indicates that the lung tumor cannot be removed.[56]


 > Indications and Contraindications Top


Indications for curative ablation

The curative ablation refers to the complete necrosis of lung tumors (i.e., achieving the goal of complete eradication of all known tumor cells within the index tumors and without any other known tumor foci in the body) [Figure 1].[26]
Figure 1: Decision chart for indications and contraindications of thermal ablation

Click here to view


Primary peripheral lung cancer

(1) The patients with poor cardiopulmonary function or advanced age, who cannot tolerate surgical resection; (2) patients refuse surgical resection; (3) patients with recurrent single lesions after other local treatment (including stereotactic body radiotherapy [SBRT]);[5],[7],[12],[14],[16],[57],[58],[59],[60],[61],[62],[63],[64] (4) lung solitary metastases after surgery or SBRT of primary lung cancer; (5) single lung;[65],[66],[67],[68],[69] (6) multiple primary lung tumors, with the number of lung tumors ≤3. The maximum tumor diameter is ≤3 cm, with no evidence of nodal or distant metastases.

Pulmonary metastases

Some tumors with pulmonary metastases show good prognosis by biological features (e.g., sarcoma, kidney cancer, colorectal cancer, breast cancer, melanoma, and hepatocellular carcinoma). If the primary tumor can be effectively treated, thermal ablation can be performed on the pulmonary metastases. The number of unilateral lung lesions is ≤3 (≤5 for bilateral lung); the maximum diameter for largest tumor of multiple metastases is ≤3 cm; the maximum diameter for unilateral single metastatic tumor is ≤5 cm, without metastases at other sites.[19],[20],[59],[70],[71],[72],[73],[74] For patients with bilateral pulmonary metastatic disease, simultaneous bilateral ablation is not recommended.

Indications for palliative ablation

The purpose of palliative thermal ablation is to minimize tumor burden, relieve symptoms caused by the tumor, and improve quality of life of the patients. For patients who cannot meet conditions of curative ablation, the indications can be appropriately widened compared to that in curative ablation.[26],[59],[75],[76],[77],[78],[79],[80],[81],[82],[83],[84] If the maximum diameter of the tumor is >5 cm or the number of unilateral pulmonary lesions is >3 (>5 for bilateral lung), multi-applicator and multisite at a session, multisite at multisession, or combination with other treatment methods is required for completing the ablation. For the refractory pain caused by tumor invasion of the ribs or vertebral body, the ablation can be performed at the local bone which is invaded by the tumor so that analgesic effects can be achieved.

Contraindications of thermal ablation

Because of excellent tolerance of percutaneous thermal ablation therapy, it is difficult to identify an absolute contraindication for lung thermal ablation, except for patients with untreatable coagulopathies.[59],[85] The contraindications for thermal ablation are as follows: (1) the patients with poorly controlled infection or radioactive inflammation around the lesions and puncture site infection or ulceration; (2) the patients with severe pulmonary fibrosis, especially drug-induced pulmonary fibrosis;[85],[86] (3) the patients with severe hemorrhage tendency, with the platelet of ≤50 × 109/L and severe coagulation dysfunction. Anticoagulant therapy and/or antiplatelet agents should be withdrawn for at least 5–7 days before ablation; (4) the patients with poorly controlled malignant pleural effusion ipsilaterally in the ablation lesions; (5) the patients with severe dysfunction of liver, kidney, heart, lung, and brain, severe anemia and dehydration, and severe disorders of nutritional metabolism, which cannot be corrected or improved in short term and the patients with severe systemic infection and high fever (>38.5°C); (6) the patients with extensive extrapulmonary metastases, with an expected survival of <3 months;[87] (7) the patients with ECOG score of >3; (8) the patients with implanted pacemakers are not recommended to use RFA [Figure 1].[88],[89],[90]


 > Procedure Preparation Top


Patient assessment and imaging

The patients should be evaluated by carefully reviewing their medical history, physical examinations, and recent imaging data. The multidisciplinary professionals (thoracic surgery, medical oncology, radiotherapy, interventional medicine, imaging, etc.) should work together to select the indications, make the decision, and record the discussion of procedure.[26],[59],[84],[91] Thoracic contrast-enhanced CT (within 2 weeks) is the key preprocedure imaging assessment. The size and location of the tumor, as well as its relationship with vital organs, blood vessels, trachea, or bronchus, can be observed through CT. The relevant staging examinations such as bone scan and cerebral MR should be completed. PET-CT scans are recommended if it is applicable to exclude or detect distant metastases. The pathologic biopsy can be conducted on mediastinal lymph nodes with suspected metastasis. For patients who can achieve curative ablation, PET-CT examination is recommended before the procedure for determining accurate staging.[26],[59],[92],[93],[94],[95],[96]

Laboratory tests

Laboratory tests should include blood routine, stool routine, urinary routine, coagulation function, liver and kidney function, blood glucose, tumor biological markers, blood type and other tests, electrocardiograph (ECG), pulmonary function, and ultrasonic cardiogram (optional for elderly patients).

Pathological examination

For primary lung cancer, percutaneous biopsy of lesion or fiberoptic bronchoscopy should be performed as confirmation of diagnosis before the procedure. When the metastatic lesion is not typical, biopsy on lesions is recommended to perform before the procedure.[26],[59],[97]

Drugs and monitoring equipment

Drugs for anesthesia and analgesia, antitussives, hemostatics, and vasodilators and antihypertensive drugs, as well as rescue medicines and monitoring equipment, should be prepared before the procedure.

Patient preparation

The patient and/or his/her family or representative must sign informed consent form. The patient should fast for 4 h before local anesthesia or abstain from solid food for 12 h and liquids for 4 h before general anesthesia. The patient should also undergo surgical skin preparation and oral antitussive before the procedure. The patient should receive preprocedure education (such as breathing training).


 > Anesthesia and Disinfection Top


According to the patient's condition, general anesthesia or local anesthesia can be applied for the procedure.[12],[16],[21],[98],[99],[100] The puncture point is locally infiltrated with 1%–2% lidocaine until the pleura. General anesthesia is recommended for the following patients: children, patients who cannot cooperate during the procedure, patients with expected long procedure time, and patients with tumor close to the wall of the pleura which may cause intensive pain. During the procedure, strict aseptic technique standard should be followed.


 > Procedure Top


After the appropriate ablation technique is selected, imaging techniques (e.g., CT, US, PET, MRI, and cone-beam/CT) are used during the procedure. CT is one of the most commonly applied and accurate image-guided techniques. Imaging is used in six separate and distinct ways including planning, targeting, ablation, monitoring, intraprocedural modification, and assessing treatment response. Ablation for lung tumors in outpatient is not recommended [Figure 2], shown in Appendix [Additional file 1].
Figure 2: Chart ablation procedure

Click here to view


Planning

Preprocedure planning is critical for ensuring the success of the procedure, which mainly includes the following steps: (1) determining the “gross tumor region (GTR)” which can be defined by imaging, including the location, size, shape, and its relationship with adjacent organs; (2) selecting the appropriate body position and the punctured sites on body surface; (3) determining the puncture path: the path from puncture site to the deepest border of the lesion (“target–skin distance”); (4) preliminarily determining the ablation parameters.

Targeting

After the anesthesia, in accordance with the GTR in preprocedure planning, the ablation applicator (electrode, antenna, probe, or fiber) is used to puncture at the punctured site on body surface layer by layer along the puncture path which is the “target–skin distance” determined in preprocedure planning. The CT scans which are confirmed with the three-dimensional reconstructed image are applied to observe whether the ablation applicator punctures into the target ablation lesion.

Ablation

According to the size and location of the tumor, multiple modes can be applied for ablation of target tissues: (1) single site at a session for completing the ablation (such as for the tumor with diameter of ≤3 cm); (2) multisite at a session for completing the ablation (such as for the tumor with diameter of 3–5 cm); (3) multi-applicator and multisite at a session or multisite at multisession for completing the ablation (such as for the tumor with diameter >5 cm or palliative ablation). The ablation parameters (temperature, power, time, cycle, etc.,) vary between different devices.

Monitoring

During the procedure, the applicator is monitored with CT for observing any “off-target,” whether the applicator should be adjusted, whether the preplanning range of ablation is achieved, or whether there are any complications (such as hemorrhage, pneumothorax) during the procedure. During the procedure, due to the damage of thermal ablation for lung tissue adjacent to the tumor, there could be an opaque high-density area around the tumor, which is called “ground-glass opacity (GGO).” When the GGO around the GTR is greater than the GTR boundary before ablation, the ablation applicator can be pulled out. The target tissue at this time is defined as postablation target zone (PTZ).

During the procedure, the heart rate, blood pressure, and oxygen saturation should be monitored. Meanwhile, the conditions of the patient should also be observed, such as breathing, pain, cough, and hemoptysis. Symptomatic treatment should be provided if necessary.

Intraprocedural modification

The operator can utilize the image-based information obtained during monitoring to modify the ablation treatment as needed to control the ablation. Intraprocedural modification may simply be repositioning an applicator and adjusting the parameters of the ablation based on professional experience and imaging findings, or it could be as sophisticated as an automated system that automatically terminates the ablation at a critical point during the procedure. For example, according to the professional experience, the border of tumor surrounding the blood vessels may indicate incomplete ablation so that the operator can adjust the applicator for ablation of tumor border.

Assessment of immediate treatment response

A repeat large-range (preferably whole-lung) CT scan should be carried out at the end of the procedure to assess immediate response: (1) preliminarily evaluating the technical success; (2) observing the ablation margin. When ablation is performed with curative intent, assessment should demonstrate that the PTZ encompasses the GTR including a circumferential ablative margin (GGO – at least 5 mm, and ideally 10 mm all around the tumor).[26],[59],[101],[102] For palliative ablation, it is not necessary to achieve the requirements of curative intent ablation in accordance with clinical practice, and it even does not require ablation margin (refractory pain caused by tumor invasion of the ribs or thoracic vertebral body); (3) identifying any complications. The patient can return to the ward if the blood pressure, heart rate, and blood oxygen saturation are normal, and there are no hemoptysis, shortness of breath, chest tightness, dyspnea, and other symptoms.


 > Postprocedure Top


Vital signs are recommended to be monitored, and the chest radiograph or CT scan should be taken after 24–48 h, which is aimed to observe the occurrence of complications (such as asymptomatic pneumothorax or pleural effusion).


 > Auxiliary Techniques Top


During the procedure, the fluid and gas should be injected between the target tissue and the nontarget tissue to separate the target tissue from the nontarget tissue, which is very helpful to protect critical nontarget tissues (such as pleura, pericardium, and mediastinum) and relieve pain during the procedure. These techniques mainly include artificial hydrothorax or artificial pneumothorax.[101],[103],[104],[105],[106],[107]


 > Follow-Up and Outcome Evaluation Top


Follow-up

Monthly contrast-enhanced chest CT scans are performed for the first 3 months after the procedure. After that, contrast-enhanced chest CT or PET/CT scans and tumor markers are examined every 3 months to detect whether local lesions have been completely ablated or if any new pulmonary lesions or extrapulmonary metastases have emerged. Contrast-enhanced chest CT is the standard method of evaluating technique efficacy at present. The potential use of PET-CT in combination with contrast-enhanced CT can provide a more accurate assessment of the technique efficacy after ablation.

Postprocedure imaging characteristics and response assessment

Local response by computed tomography

CT imaging characteristics

After thermal ablation, due to bleeding, edema, exudation, and infiltration of inflammatory cells around the ablation zone, PTZ will be significantly larger than the original tumor GTR. These imaging characteristics will last for 3 months. Therefore, the traditional Response Evaluation Criteria in Solid Tumors is not suitable for the evaluation of local efficacy after thermal ablation.[26],[59],[108],[109],[110] After the ablation, CT characteristics are as follows: PTZ will be enlarged in first 1–3 months and remain stable or gradually involute and decrease in size after 3 months. (1) Early phase (within 1 week): There are three layers: (a) the first layer: Solid, honeycomb-like or hypoattenuating bubbles can be observed within PTZ; (b) the second layer: GGO. It is generally believed that GGO should be at least 5 mm (ideally 10 mm all around the tumor) beyond GTR border, indicating that the tumor has been ablated completely;[26],[59],[102] (c) the third layer (outer layer): There is a reaction zone outside the GGO layer, with the density slightly higher than the GGO.[110] These typical imaging characteristics are called “cockade” or “fried eggs” sign which is more obvious 24–48 h after ablation. (2) Intermediate phase (1 week to 3 months): As the ablation zone increases constantly, the GGO disappears and a sharp-enhanced ring may appear around the perimeter (benign periablation enhancement), which is known as the “egg shell” sign (a thin rim peripheral to PTZ, a relatively symmetric and uniform process with smooth inner margin, that can be measured 0.5–3 mm).[21] (3) Late phase (after 3 months): The PTZ remains stable compared with the baseline, which is generally found by CT at about 4–6 weeks after ablation.[26],[70],[110] Subsequent follow-up CT results of PTZ may present several different patterns such as fibrosis, cavities, nodules, atelectasis, disappearance, and enlargement (possible recurrence, progression, or hyperplastic fibrosis).[111]

Assessment local response

The response is determined with the baseline of lesion 4–6 weeks after ablation. (1) Complete ablation (with any one of the following patterns): (a) lesion disappears, (b) cavity completely forms, (c) fibrosis or scar, (d) solid nodule involution or no change, without contrast-enhanced signs on the CT and/or no fludeoxyglucose (FDG) uptake on the PET/CT, (e) atelectasis, lesion in atelectasis without contrast-enhanced signs on the CT and/or no FDG uptake on the PET/CT; (2) Incomplete ablation (with any one of the following patterns): (a) cavity partially forms, with some solid parts or liquid components remaining, and with irregular peripheral or internal enhancement signs on the CT and/or intense FDG uptake on the PET/CT, (b) partial fibrosis, with solid residues in the fibrotic lesion, which presents as irregular peripheral or internal enhancement signs on CT and/or intense FDG uptake on the PET/CT, (c) solid nodules with no changed or increased size, which also present as irregular peripheral or internal enhancement signs on CT and/or intense FDG uptake on the PET/CT, (d) atelectasis, lesion in atelectasis with contrast-enhanced signs on the CT and/or intense FDG uptake on the PET/CT; (3) Local progression (with any one of the following patterns): (a) enlarged by 10 mm, with enlarged irregular or internal enhancement signs on the CT and/or enlarged intense FDG uptake on the PET/CT; (b) local newly developed lesion, with newly enhancement signs on the CT and/or newly developed intense FDG uptake on the PET/CT.

Local response by PET-CT

PET-CT may be the most accurate assessment of the local response after ablation, which is useful for finding tumor residue, progression, recurrence, and distant metastasis. Due to inflammatory response after ablation, PET-CT has a high false-positive rate at 3 months after ablation,[112] but it may discover distant metastasis. The significance of PET-CT examination is limited in determining whether there are local residue and progress. Three months after ablation, the PET-CT scan objectively reflects the metabolic activity of the tumor after ablation due to reduction or regression of the inflammatory response in the ablation zone. If no FDG uptake in the tumor is observed by PET/CT after ablation, it indicates that the tumor is completely ablated. If intense FDG uptake in the tumor is observed by PET/CT after ablation, it indicates tumor residue or progression caused by incomplete ablation or tumor local progression. A variety of patterns on the PET/CT image can reflect the metabolic activity of the tumor.[113] Sometimes, it is very difficult to determine whether the enlargement of hilar or mediastinal lymph node is the metastasis or inflammatory response. If no FDG uptake or significantly lower FDG uptake is observed in enlarged lymph node 3 months after ablation, it indicates inflammatory response, and vice versa the metastasis.

Clinical outcome assessment

The regular follow-up should be performed based on the assessment of local response. The followings are longitudinal follow-up guidelines: (1) technical success and early safety data – minimum 6-month follow-up; (2) preliminary clinical outcomes – minimum 1-year follow-up; (3) intermediate-term data – minimum 3-year follow-up; (4) long-term data – at least 5-year follow-up.[114] Overall survival (OS) is the most important indicator for clinical outcome, and OS of patients at 1, 2, 3, and 5 years is recorded. For patients with palliative ablation, quantification of outcomes should be evaluated by assessment tools such as quality-of-life indices and medication usage (e.g., morphine-equivalent dose).


 > Complications and Side Effects Top


Percutaneous lung tumor ablation is a relatively safe local therapy. The complications are reported according to the classifications of the American Society of Interventional Radiology (SIR) criteria.[26] The definition of major complication is an event that leads to substantial morbidity and disability (e.g., results as the unexpected loss of an organ), which increases the level of care, or leads to hospital admission, or substantially lengthens the hospital stay (SIR classifications C–E). The complication includes any conditions that require blood transfusion or interventional drainage procedure. Any patient death within 30 days of image-guided tumor ablation should be addressed (SIR classification F). All other complications are considered minor. According to the time of occurrence, the complications are classified into: immediate complication (<24 h after ablation), perioperative complication (24 h to 30 days after ablation), and delayed complications (>30 days after ablation).

Side effects

Pain

After a procedure under local anesthesia, patients may experience varying degrees of pain (especially for the ablation of lesions near pleura where the analgesic therapy is generally necessary). If the pain is severe, increased dose of analgesic drug (such as opioid) as well as appropriate amount of sedatives should be used. Postprocedural pain is usually mild, which can last for several days. The pain can also last for 1–2 weeks for some patients, and moderate or severe pain is rare. The nonsteroidal drugs can also be applied for relieving the pain.

Postablation syndrome

Postablation syndrome occurs in approximately two-thirds of the patients because of the absorption of necrotic substances and release of inflammatory cytokines. This syndrome is a transient and self-limiting symptom/sign consisting of low-grade fever (<38.5°C), nausea, vomiting, and general malaise. If small lesions are treated, the patient is unlikely to experience postablation syndrome at all. If the very large lesions of lung tumors are ablated, syndrome may persist for 1–2 weeks. The majority of patients who get this syndrome will experience some malaise for 2–7 days, depending on the volume of tumor, surrounding tissue ablated, and integrity of the patient's immune system. If necessary, nonsteroidal drugs and glucocorticoid can be applied for short term.

Cough

Coughing is a common symptom during the procedure. Severe cough can aggravate pneumothorax or subcutaneous emphysema and even cause ablation applicator “off target.” Some patients might not be able to tolerate the procedure due to severe cough. The reasons for cough may be the stimulation on alveoli, bronchial intima, or pleura caused by increased local temperature during the procedure. Postprocedure cough is caused by inflammation of the tumor tissue necrosis and heat injury around the lung tissue. Oral codeine can prevent coughing if given 1 h before the procedure. The procedure will not be affected with mild cough. For the postprocedure cough, antitussive and expectorant as well as the necessary antibiotics should be given as appropriate.

Pleural response

During the procedure, the vagus nerve of the parietal pleura is stimulated. Then, the excited vagus nerve can slow down the heart rate or even cause cardiac arrest. For this situation, the procedure should be temporarily stopped with sufficient local anesthesia. The atropine, sedatives, and other drugs should be properly applied.

Complications

Pneumothorax

Pneumothorax is the most common complication after ablation, with an incidence of 10%–67%.[19],[115],[116],[117],[118],[119],[120] Pneumothorax is more common in the following conditions: emphysema, male, aged >60 years, tumor <1.5 cm in diameter, tumor in the lower lobe, more than three punctures for a single tumor in lung tissue, multiple tumors and multiple puncture and ablations, and a long part of the ablation path through lung tissue or through a large lobe fissure. Most cases of pneumothorax can be easily treated or are self-limiting. In 3.5%–40% of pneumothorax cases, chest tube placement for drainage is required.[19],[115],[117],[118] If there is still a gas leakage after thoracic drainage, continuous negative suction, pleurodesis, endoscopic injection sclerotherapy, tracheal valve implantation, and other measures can be used.[121] In addition, occurrence of delayed pneumothorax should be concerned. The delayed pneumothorax refers to pneumothorax occurred 72 h after ablation.[122]

Pleural effusion

The incidence of pleural effusion is reported to be 1%–60%.[117],[120] The occurrence of pleural effusion was associated with increase of pleural temperatures during the procedure, which may indicate that pleural effusion is related to pleuritis induced by thermal injury. Significant risk factors for the development of pleural effusion are the use of a cluster applicator, decreased distance to the nearest pleura (<10 mm), ablation of multiple lesions at one session, decrease in the length of the aerated lung that is traversed by the applicator, and long ablation time.[123] Nevertheless, aseptic pleural effusion after ablation can usually be treated conservatively. For 1%–7% of pleural effusion cases, chest tube placement for drainage is required.

Hemorrhage

The incidence of hemorrhage during ablation is 3%–8%.[117],[124],[125] Hemorrhage may present as hemoptysis, hemothorax, hemorrhagic shock, and acute respiratory failure but mainly present as hemoptysis and hemothorax.

Hemoptysis

The incidence of massive hemoptysis is very low during ablation. Risk factors for intraparenchymal hemorrhage include as follows:[124],[125] (a) lesions have diameter less than 1.5 cm that the applicator will be adjusted for entering the targeted small lesions; (b) lesions in the middle and lower lung where the lesions are more easily influenced by respiratory movement and more difficult to be punctured. In addition, the blood vessels are more easily damaged by the movement of the applicator tip; (c) the path of applicator penetrating the lung tissue is more than 2.5 cm where these lesions are closer to the hilum and surrounded by large blood vessels; (d) the pulmonary vessels are penetrated through the ablation path. Up to 80% of pulmonary hemorrhage can be avoided by avoiding passing through the blood vessels. The applicator can be inserted parallel to the blood vessels so that risk factors of pulmonary hemorrhage can be avoided; (e) application of multipolar ablation applicator. If there is moderate hemoptysis, the ablation should be performed immediately with intravenous administration of hemostatic drugs. Because ablation itself can make the blood coagulation, hemorrhage will gradually stop during the ablation. During the puncture, the larger blood vessels or atelectasis in the lung tissue should be avoided. Most cases of postprocedure hemoptysis are self-limiting and only last for 3–5 days. For the patients who are not suitable for conservative treatment, interventional embolization or thoracotomy can be conducted.

Hemothorax the internal thoracic artery, intercostal artery, or other arteries are damaged during puncture. During puncture, the aforementioned arteries should be avoided. If there is hemothorax, the patient should be closely monitored and actively treated with conservative treatment. For the patients who are not candidates for conservative treatment, interventional embolization or thoracotomy can be conducted.

Infection

The incidence of pulmonary infection caused by ablation is 1%–6%.[115],[116],[117],[120],[124],[126] Prophylactic antibiotics can be used 30–60 min before the procedure and once again in 24 h and can be extended to 48–72 h for patients older than 70 years or those with chronic obstructive pulmonary disease, poorly controlled diabetes, tumors >4 cm, or low immunity. If the body temperature is still >38.5°C for 5 days after the procedure, lung infections should be suspected. Antibiotics should be adjusted according to sputum, blood, or pus culture results. Pulmonary or chest abscesses can be drained using chest tube. In addition, it is worthy to mention that because interstitial pneumonia often occurs after radiotherapy, ablation increases the risk of secondary infection.

Cavitation

The formation of cavitation is common after lung ablation, which may be regarded as a natural outcome after ablation and the causes for serious complications such as infection and hemorrhage. The incidence of the cavitation is about 14%–17%.[120],[127],[128] Most patients developed cavitation without symptoms. Risk factors for cavitation were the proximity of the tumor to the chest wall, primary lung cancer, and pulmonary emphysema. The cavitation infection and abscess formation should be considered when there are fever and weakness. In addition, the Aspergillus infection [129],[130],[131] should be noted. Cavitation-induced recurrent hemorrhage can be treated with interventional embolization if patients are not suitable for conservative treatment.

Other rare complications

There were cases reporting complications such as bronchial pleural fistula, acute respiratory distress syndrome, bronchiolitis obliterans organizing pneumonia, nontarget thermal injury or frostbite, rib fractures, cold shock, thrombocytopenia, needle tract seeding, nerve injury (brachial plexus, intercostal, phrenic, laryngeal), pulmonary embolism, systemic air embolism, and pericardial tamponade.[121],[133],[134],[135],[136],[137],[138],[139] These cases should be treated individually.

Ablation-related death

Although thermal ablation for lung tumors is generally safe, it may cause significant complications. Most complications can be treated conservatively or with minimal therapy; however, there is also a certain incidence of serious or even fatal complications. According to the current literature, mortality associated with lung tumors ablation was reported to be 0%–2.6%.[117],[139] National (nationwide) inpatient sample from the United States reported an in-hospital-related mortality rate of 1.3% for a group of 3344 cases of lung tumor ablation.[115] The main causes of death are various pneumonia (including fungal pneumonia), lung abscess, massive hemorrhage/massive hemoptysis (including pulmonary artery pseudoaneurysm rupture), bronchial pleural fistula, air embolism, and acute respiratory distress syndrome.


 > Ablation in Combination with other Therapies Top


Ablation in combination with other therapies is one of the important focuses in the current cancer researches, including the combination of ablation with surgery, radiotherapy, chemotherapy, and molecular targeted drugs. (1) Ablation combination with radiotherapy can improve the local control of the tumor and prolong survival of patients with lung cancer, and meanwhile, the adverse event has no significant increase;[140],[141],[142] (2) the researches on combination of ablation and chemotherapy for treating NSCLC in advanced stage have been gradually increased. Ablation combined with chemotherapy provides some benefits such as improving local control rate of the tumor and prolonging the survival of patients.[63],[143],[144],[145],[146],[147],[148],[149],[150],[151] It is potential to become a new model for the treatment of advanced NSCLC; (3) tyrosine-kinase inhibitor (TKI) is one of the main methods for treating advanced NSCLC with epidermal growth factor receptor (EGFR) mutations. The following drugs, such as gefitinib, erlotinib, or afatinib, have led to remarkable tumor shrinkage and improvement in progression-free survival (PFS) and quality of life compared with standard chemotherapy. EGFR-sensitizing mutant-advanced NSCLC patients should receive the first-line TKI treatment. Despite the initial advancement of these agents, most patients ultimately develop acquired resistance to TKIs after 1–1.5 years. Different patterns of progressive disease may represent different biological molecular mechanisms. Therefore, it is important to distinguish among these patterns as different therapeutic strategies may apply. Considering the growth rate and the number of growing tumor lesions, progressive disease during TKI treatment can be generally distinguished in three patterns: intracranial disease progression, development of one or few distant metastatic sites while the patient remains asymptomatic, and systematic and/or symptomatic disease progression. The first two patterns fall into the general term of oligoprogressive disease. Typically, the definition of oligoprogressive disease refers to the presence of fewer than five discrete metastatic sites. Local ablation with continued EGFR inhibition has shown efficacy for treating patients with oligoprogressive disease and associated with long PFS and OS. Local ablation with continued TKI can be used as a treatment strategy in advanced NSCLC that developed extra-central nervous system oligoprogressive disease during EGFR TKI treatment.[152],[153],[154],[155],[156]


 > Conclusions Top


For the treatment of lung tumors, minimally invasive therapy is one of the development directions in the future, especially the image-guided percutaneous thermal ablation technology. Thermal ablation has shown safety, efficacy, and cost-effectiveness in the treatment of both primary and metastatic lung tumors in nonsurgical candidates. Recent studies have shown that for the early NSCLC patients who cannot tolerate surgery, the 1-, 3-, and 5-year survival rates of percutaneous thermal ablation (tumor diameter of 2–3 cm) can be 97.4%, 72.9%, and 55.7%, respectively, with a mortality rate of <1%.[157] This clinical evidence allows us to believe that this technology will be more and more widely used in the comprehensive treatment of lung cancer. It may become a new model following the surgery, radiotherapy, and chemotherapy.

Currently, there are many problems of thermal ablation technology in the treatment of primary and metastatic lung tumors: (1) from the perspective of clinical practice, the number of cases of thermal ablation for treating primary and metastatic lung tumors is relatively less than that of surgery, radiotherapy, and chemotherapy;[26],[155] (2) however, the efficacy and safety of thermal ablation still need to be validated in prospective, randomized, and multicenter clinical trials. It is necessary to compare thermal ablation with other traditional therapies (e.g., surgery, SBRT); (3) there are few clinical trials on the combination of thermal ablation and other treatment methods (such as radiotherapy, chemotherapy, and molecular targeted drug); (4) one direction of the future study should be focused on improving local control and reducing local recurrence;[14],[158],[159],[160] (5) the role of palliative ablation in the comprehensive treatment of lung cancer needs to be further defined; (6) basic research is lagging behind, such as the complex thermal field distribution [161],[162],[163] and the effects of immune.[164],[165],[166],[167],[168]

Acknowledgment

We are grateful to Prof. Gaojun Teng (Department of Radiology, Zhongda Hospital, Southeastern University) for critical discussion of the Guidelines.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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