Lung cancer has the highest morbidity and mortality rate among malignant tumors, and non-small cell lung cancer accounts for more than 80%, and its 5-year survival rate is only 15%. Surgical resection is the main treatment for early stage non-small cell lung cancer, and the 5-year survival rate for stage I–IIIA surgery ranges from 67% to 19%. Approximately one-third of patients are diagnosed with advanced disease or lose any chance of surgery due to complications. These patients mainly choose radiation therapy alone or combined with chemotherapy. The remission rate of radical radiotherapy for stage I and II lung cancer is 33%–61%, and the 5-year survival rate is 0–42%, while the recurrence rate is 6%–70%. Chemotherapy is the mainstay or combined with radiotherapy for patients with advanced disease. The improvement rate of survival with preoperative neoadjuvant chemotherapy is 12%–15%, which shows that systemic chemotherapy is not effective for early lesions. For the many patients who cannot be surgically resected or treated with radiotherapy, alternative therapies are necessary to maximize the destruction of tumor tissue. ImagingguidedRadiofrequencyAblation (RFA) has been used as a minimally invasive treatment for various solid tumors, including liver, kidney, bone and adrenal gland, and has been highly evaluated in clinical studies, and RF ablation is beginning to be recognized as curative. The NCCN 2009 clinical practice guidelines have listed ablation as one of the treatment options for resectable hepatocellular carcinoma along with surgical resection, and radiofrequency ablation is the most commonly used among various ablation therapies. In recent years, the clinical practice of lung cancer treatment by radiofrequency ablation has been increasing all over the world. Radiofrequency ablation is not only used for local control of tumor but also used to relieve systemic symptoms. nCCN 2009 clinical practice guideline for non-small cell lung cancer states that radiofrequency ablation can be chosen for those who are lymph node negative, refuse surgery or cannot tolerate surgery, especially for isolated peripheral lesions ≤3 cm. This article introduces the application of radiofrequency ablation in non-small cell lung cancer. I. Treatment technology of radiofrequency ablation The basic principle of radiofrequency ablation is to form a current circuit between the electrode inserted into the tumor and the external electrode plate, using the radiofrequency alternating current with the output power of 10-300W at 200-500kHz to excite the ions in the tumor tissue to rotate at high speed and generate heat by friction. When the tumor tissue is heated over 50℃ for 5 minutes, above 70℃, coagulative necrosis is produced immediately. Since the current density of the electrode on the tumor side is much higher than that of the external electrode plate, a large amount of heat energy is generated inside the tumor and the tumor tissue dies due to protein coagulation. Radiofrequency ablation, through temperature measurement feedback, enables the computer to automatically control the optimal temperature within the range of 50–100℃ to prevent the tissue heating from boiling and gas production beyond 100℃ and from coking and charring beyond 115℃ to affect the treatment. In order to make the tumor tissue cells die completely, the ablation should include the lung tissue adjacent to the tumor 0.5–1cm. The RF ablation system consists of RF generator, tumor electrode and extracorporeal electrode plate, and there are several models of domestic and foreign equipment available. The RF generator should have temperature measurement feedback and computerized automatic control function. A good tumor electrode should have the following characteristics: (1) equipped with puncture guidance and support system to facilitate accurate hitting of target points; (2) multi-pole electrode with conformal release function, which can adjust the length of electrode according to the shape of tumor to achieve the treatment range and protect the surrounding normal tissues; (3) with injection function to inject saline or drugs to increase the therapeutic effect. Radiofrequency ablation mainly adopts CT image guidance, not only because CT has good resolution and spatial display function, which can better guide and monitor the treatment process, but also because the lung tumor has a certain contrast with the surrounding air-containing lung tissue. Local anesthesia is usually used and the choice of puncture route is the same as that of puncture biopsy. During the treatment, CT monitors the lung tissue around the tumor with hairy glass-like changes, which means that the radiofrequency ablation treatment can be ended. Experimental study of radiofrequency ablation of lung cancer In 1995, Goldberg et al. firstly used radiofrequency in the ablation experiment of rabbit lung, and the CT showed a uniform opaque circular area immediately after ablation, and the density further increased after three days. Pathologically the central area of the ablation was fibrous in composition and an inflammatory response encircled this central area, showing congestion and edema. After ten days, the central area was hypodense or even hollow, surrounded by encapsulated fibrous granulation tissue. Since the current impedance of lung tissue is higher than that of liver tissue, the coagulation range is significantly smaller than that of liver. MRI images also confirmed that the central part of the lung tissue in the early stage of RF ablation was coagulative necrosis without vascular strengthening, and the surrounding tissue had circumferential strengthening. The coagulative necrosis gradually resolved over several months. Radiofrequency ablation of transplanted tumors in the rabbit lung resulted in tumor necrosis rates of more than 95%, but 43% of the treated margins still had tumor remnants. FDG-PET showed a significant decrease in glucose metabolism in the treated area, and the delayed period could distinguish the inflammatory response in the surrounding lung tissue, suggesting that PET/CT could be used to evaluate the therapeutic effect of radiofrequency ablation, and it is recommended to perform metabolic examination after 4 weeks of radiofrequency ablation. Metabolic examination is recommended 4 weeks after RF ablation, which can distinguish tumor or inflammation. With the improvement of treatment technology and the accumulation of experience, the chance of complete ablation of tumor is increasing. The clinical application of radiofrequency ablation for lung cancer Radiofrequency ablation for lung tumor is a new technique for clinical application, and there have been a lot of reports in the literature since Dupuy et al. reported three cases of lung cancer patients treated with radiofrequency ablation in 2000. (I) Selection of cases Radiofrequency ablation minimally invasive treatment ultimately controls local tumor and is mainly used for patients who are inoperable. Radiofrequency ablation is used as a measure to relieve lesions: reduce tumor load before chemotherapy; relieve local symptoms due to infiltrative tumor growth, such as chest pain, chest wall pain or dyspnea; relieve pain from bone metastases; tumor recurrence is not suitable for re-radiation or surgery. Radiofrequency ablation for primary and metastatic lung cancer is most suitable for tumors ≤3 cm in diameter, which are inoperable due to poor cardiopulmonary function, or severe comorbidities, or patients refuse surgical resection. Lung cancer, including adenocarcinoma, squamous carcinoma, and a small amount of small cell carcinoma, is pathologically proven by percutaneous puncture biopsy or transbronchial lung biopsy. Staging included all stages I to IV. In 1/3 cases, radiofrequency ablation was chosen after receiving radiotherapy and chemotherapy at the time of initial treatment due to treatment failure. Patients had no coagulation disorders or distant metastases. Radiofrequency ablation mainly targets peripheral tumors within each lung parenchyma, and treatment can still be safely completed for some tumors close to important organs such as the heart and lung hilum. With the improvement of treatment technology and accumulation of experience, the treatment range of isolated peripheral lung cancer can be considered to increase to 5cm. (II) Implementation of radiofrequency ablation Patients with radiofrequency ablation of lung cancer are mainly under local anesthesia with moderate sedation and pain relief to keep awake and under the guidance of CT. The ablation electrode is punctured and inserted into the center of the tumor, and the microelectrode is released in the right shape according to the shape of the tumor. The treatment process of radiofrequency ablation is usually controlled automatically by the target temperature measurement and feedback computer, and the treatment power is from low to high, depending on the size of the tumor, the treatment process takes 10 – 30 minutes. Repeat the treatment for multiple times for single lesions or multiple lesions. (C) Imaging and pathological changes after radiofrequency ablation of lung cancer The anatomical features of lung tissues are suitable for ablation to work effectively. The normal lung tissue around the tumor is of high electrical impedance, and the alveolar air-containing structures have an insulating effect. Therefore, radiofrequency generates thermal energy that is retained within the tumor to promote temperature increase. The blood flowing in the large vessels ≥3mm in diameter in the surrounding lung tissue has a cooling and heat dissipation effect, and radiofrequency ablation does not damage such vessels. Such vessels at the tumor margins, however, are prone to tumor remnants due to the heat dissipation effect. CT scan immediately after tumor ablation showed hypodense changes in the ablated area and hairy glass-like changes in the tumor surrounding tissues, which became dense with pneumonia-like changes after one week. Enhanced CT of the treated area showed hypodensity without enhancement and a vacuolated cavity within the lesion. The pathology showed radiofrequency thermal injury, increased blood flow to lung tissue and congestion, inflammatory congestion, granulation tissue proliferation, cancer cell death and loss of growth ability, indicating that heat can effectively ablate or destroy lung cancer tissue. Intensive CT scan 2 months after ablation showed that the non-enhanced area of the tumor increased by 50% to double compared with the original tumor. On CT scan within 3 months after ablation, the extent of ablation often exceeded the original tumor, reflecting that the ablation went beyond the tumor boundary to reach the normal lung tissue adjacent to the lesion. The area should shrink back to its original size about 3 months after treatment. However, if the ablation area continues to increase after 3 months and the lesion appears to intensify, it indicates incomplete ablation and tumor recurrence. In the surgically resected specimens of primary lung cancer after ablation, 65%–87% of tumor cells die, especially when the tumor is ≤2cm, the cancer cells are more likely to reach complete death. (D) Efficacy assessment of radiofrequency ablation Radiofrequency ablation leads to tumor necrosis and inflammatory response, and the treatment scope often exceeds the tumor itself. The extent of tumor on imaging increases for a short period of time and slowly decreases in extent over time. Since necrotic tissue is absorbed over time or even persists, it is clinically difficult to assess the efficacy of ablation by the criteria of surgical resection or even by the efficacy of radiotherapy. It is difficult to determine whether the tumor is completely inactivated by CT scan densitometry alone within a few months after ablation. Intensive CT, PET/CT or biopsy histology are commonly used to evaluate the efficacy of radiofrequency ablation. Intensive CT immediately after ablation shows no enhancement in the ablated area, and PET/CT shows no metabolism of the tumor. The complete necrosis rate was 69%-100% for tumor diameter ≤3cm, and 23%-39% for tumor diameter over 3cm. FDG-PET/CT showed that ablation was more complete for tumor diameter ≤3.5cm, and tumor diameter ≥3.5cm often had residual. fine needle biopsy within 3 months showed tumor necrosis, glassy changes, fibrotic scar formation, and inflammatory cell infiltration. (v) Studies of surgical resection after radiofrequency ablation Surgical resection after radiofrequency ablation can understand whether radiofrequency ablation is complete and can assess the extent of radiofrequency ablation. nguyen et al. prospective study of 8 patients with stage I or II non-small cell lung cancer showed that 38% of tumors were completely ablated and 87% of tumors were largely inactivated. ambrogi et al. CT-guided ablation of 9 lung cancers and surgical resection two weeks later Pathology showed a complete ablation rate of 67%. An average of 8 mm beyond the complete ablation margin still showed ablation without histological changes in the surrounding lung parenchyma, confirming the safety and controllability of radiofrequency ablation. (vi) Effectiveness of radiofrequency ablation in the treatment of non-small cell lung cancer The use of radiofrequency ablation for the treatment of lung tumors is safe and effective and has shown momentum. Herrera et al. reported that patients with inoperable resectable non-small cell lung cancer were treated with radiofrequency ablation with an efficiency of 40%, with stable disease accounting for 60% and no disease progression or death. Kotaro et al. treated 99 cases of thoracic malignancies (3 primary and 96 metastases) and achieved a complete ablation rate of 91% with a single treatment. Approximately 9% of tumors with local recurrence or residual were treated with repeat radiofrequency ablation. Lee et al. had a higher rate of complete necrosis of lung cancer ≤3 cm in diameter by CT-guided radiofrequency ablation, and the mean survival time was significantly increased in patients who achieved complete necrosis compared with those with partial necrosis (19.7 months versus 8.7 months). Radiofrequency ablation combined with radiotherapy provides local treatment opportunities for inoperable patients, increasing local control rates and survival benefit. dupuy et al. reported 24 cases of stage I non-small cell lung cancer treated with radiofrequency ablation combined with radiation therapy, 50% of patients survived more than two years and 39% survived more than 5 years. grieco et al. radiofrequency ablation therapy combined with external radiation therapy or brachytherapy for stage I and II lung cancer. The median survival was 19.5 months, with 1-, 2- and 3-year survival rates of 87%, 70% and 57%, respectively. The survival rates for radiofrequency ablation for stage I lung cancer that was lost to surgery were 78% at 1 year, 36% at 3 years, and 27% at 5 years, with a median survival of 29 months. For early stage lung cancer radiofrequency ablation treatment has survival rates comparable to conventional radiation therapy. Therefore, radiofrequency ablation may be beneficial for early-stage non-small cell lung cancer that cannot receive surgical treatment. Safety and complications of radiofrequency ablation for lung cancer Like any other medical and surgical treatments, radiofrequency ablation also has complications. Complications of radiofrequency ablation are similar to those of CT-guided lung biopsy. The most common complication is pneumothorax, with an incidence of 15–45% and no more than 20% requiring drainage tube placement. Usually RF uses a 15–17 G ablation electrode needle that is slightly thicker than the biopsy needle, and the incidence of pneumothorax is not higher than that of lung biopsy in 35%. Feng Weijian et al. applied a CT-guided device to assist RF ablation electrode puncture, hitting the target once, and complications were low especially pneumothorax rarely occurred. Pleural effusion and pleurisy associated with radiofrequency ablation therapy resulted in fever 19%. Other rare complications are pneumonia, lung abscess, hematochezia, pulmonary hemorrhage, and acute respiratory distress syndrome. Predicted potentially fatal complications include massive hemothorax, bronchopleural fistula, and air embolism, but they have not been reported. Intraoperative monitoring of carotid ultrasound during radiofrequency ablation reveals microbubble formation, which is more likely to occur especially with larger masses, higher output power, and prolonged ablation time. However, post-ablation CT or MRI examination did not reveal clinical abnormalities. Control of ablation temperature not exceeding 100°C during treatment can reduce the occurrence of bubbles. V. Conclusion Radiofrequency ablation, whether applied alone or in combination with conventional methods, has shown its advantages as a treatment option for patients with tumors that have lost the opportunity for surgery. Surgical resection is still the main treatment for lung cancer. When the tumor is ≤2–6 cm and complete ablation is expected to be obtained for early stage non-small cell lung cancer, or slow growing isolated lung metastases, radiofrequency ablation can yield radical results. For larger tumors, palliative radiofrequency ablation is feasible. Advantages of ablation over surgery include precise control, complete destruction, repeated use, disease control and reduced mortality, relatively low cost, ease of approach, and even outpatient performance. Radiofrequency ablation has important clinical applications in local control of tumors and relief of systemic symptoms. In the future, long-term multicenter controlled trial studies are needed to establish treatment principles, improve techniques, monitor the treatment process, strict indications for treatment, and prevent complications so that radiofrequency ablation can develop from an alternative means to a standard treatment method.