Ablation Therapy Combined with EGFR TKIs in the Treatment of Advanced Non-Small Cell Lung Cancer: A Meta-Analysis of Randomized Controlled Trials

Objective Systematically evaluate the efficacy of physical ablation combined with TKI in the treatment of advanced non-small cell lung cancer (NSCLC). Methods We performed a comprehensive search of databases including OVID, PubMed, EMBASE, the Cochrane Library, and three Chinese databases (China National Knowledge Infrastructure, Wanfang Database, and Chongqing Weipu Database). The aim was to identify randomized controlled trials (RCT) investigating physical ablation as the treatment for advanced NSCLC. We also evaluated the methodological quality of the included studies and summarized the data extracted for meta-analysis with Review Manager 5.3. Results A total of 9 studies, including 752 patients, were evaluable. The meta-analysis results show that the complete response rate (CRR) (RR: 2.23, 95% CI: 1. 46 to 3.40, P 0.01), partial response rate (PRR) (RR: −2.25, 95% CI: 1.41 to 3.59, P 0.01), and disease control rate (DCR) (RR: −2.80, 95% CI: 1.64 to 4.80, P< 0.01) of patients with advanced NSCLC who received physical ablation combined with TKI therapy were higher than those who did not receive physical ablation therapy. The control groups from seven of the studies had a total of 606 patients with targeted therapies and chemotherapy. The complete response rate was (CRR) (RR: 2.48, 2.4895% CI: 1.55 to 2.47, P 0.01), partial response rate (PRR) (RR: −1.66, 95% CI: 1.20 to 2.31, P< 0.01), and disease control rate (DCR) (RR: −2.68, 95% CI: 1.41 to 5.06, P< 0.01) for patients with advanced NSCLC who had received physical ablation combined with targeted therapies and chemotherapy, compared to patients who had not received physical ablation therapy. This difference was statistically significant. Above all, these results showed that the clinical efficacy of physical ablation combined EGFR-TKIs therapy (regardless of whether it was combined with chemotherapy) was better than that of EGFR-TKIs therapy alone. Conclusion Physical ablation combined with TKI treatment in patients with advanced NSCLC can improve efficacy.


Background
Lung cancer is at the forefront of malignant tumors, in terms of both morbidity and mortality. Most lung cancer is diagnosed in its advanced stages such that most patients miss the opportune window for surgery. Instead, most receive multidisciplinary synthetic treatment. Combining systemic therapy with local therapy is always the focus of clinical inquiry. Since targeted treatment has become increasingly available in clinic, more and more patients with clear driver genes for non-small cell lung cancer have benefited from it. In this way, the appropriate use of molecular target drugs often achieves gratifying clinical results. However, with the passage of time, targeted drugs become resistant. Once this happens, drugs are rendered ineffective. us, methods for delaying resistance are worthy of scientific study. Physical ablation technology is a new technique for treating malignant tumors with physical technology. Common physical ablation techniques used in the clinic include radiofrequency ablation, microwave ablation, and frozen ablation [1][2][3]. e mechanism of action is similar in all forms of physical ablation. It entails inserting an electrode needle into the tumor tissue and producing a hot or cold effect based on the physical principle of denaturing tumor cell necrosis. In this way, it provides local treatment for malignant tumors. Several studies have demonstrated [4,5] the clinical efficacy of ablation techniques. Although many articles have been published, both in China and abroad, on the combination of physical ablation and targeted therapy for advanced NSCLC, high quality systematic evaluation is lacking. For this reason, this study explores the efficacy of physical ablation joint targeted therapy for advanced NSCLC. A meta-analysis is conducted, with the aim of providing evidence in support of clinical work in choosing appropriate treatment options.

Search Methods.
We performed a systematic search of the literature in OVID, PubMed, EMBASE, the Cochrane Library, and three Chinese databases (China National Knowledge Infrastructure, Wanfang Database, and Chongqing Weipu Database).
e aim was to use the subject-word retrieval method to identify articles published from database inception through April 1, 2020. e retrieval model is as follows: M � (Lung Neoplasms or Lung Cancer or Non-Small-Cell Lung or Lung Carcinoma) and (Ablation, Radiofrequency or Radio Frequency Ablation or Ablation, Radio Frequency or Radio-Frequency Ablation or Ablation, Radio-Frequency or Cryosurgeries or Cryoablation or Cryoablations or Ablation Techniques or Microwave ablation) AND (EGFR tyrosine kinase inhibitor OR tyrosine kinase inhibitor) and (Randomized Controlled or Controlled Clinical or randomized or placebo or randomly or trial or groups or drug therapy).

Inclusion Criteria. (1)
is study only includes randomized controlled clinical studies.
ere are no specific requirements for blinding methods; (2) pathological diagnosis of non-small cell lung cancer; (3) TNM phases III B to IV based onstage standards for primary lung cancer phase according to the AJCC eighth edition; and (4) age greater than 18 years old.

Treatment Means.
(1) e treatment group was treated with physical ablation joint targeted therapy; physical ablation included radiofrequency ablation, microwave ablation, or frozen ablation; (2) control group was treated with the target treatment or combined chemotherapy, not limited to the specific target treatment drug; (3) the treatment of the control group was the same as that of the treatment group, except for the physical ablation therapy.

Document
Screening and Data Extraction. Document screening and data extraction were performed by two researchers and were reviewed independently based on the inclusion criteria. e data extracted included the name of researcher, year of publication, number of cases, sex, and tumor staging. When there was questionable data, a third researcher would arbitrate.

Document Quality Evaluation.
We conducted a quality evaluation of the included studies with Cochrane System Evaluation Manual 5.1. We assessed 7 aspects of randomized controlled studies: allocation of hiding, blinding methods, outcome evaluation blinding methods, incomplete outcome indicators, selective reporting, and other bias. According to the evaluation results, the included literature was divided into "high risk," "low risk," and "unknown risk." 2.7. Statistical Methods. Meta-analysis was conducted with RevMan 5.3. Various methods were used for evaluation based on the data type. Two classification variables (e.g., CR rate, PR rate, and DCR) were analyzed with a relative risk (RR) and 95% CI as the effect analysis statistic. We used a fixed effects model for consolidation and analysis. e literature's heterogeneity was evaluated by a Q test and I 2 statistical evaluation. If I 2 ≤50% and P ≥ 0.10, the studies had better homogeneity. I 2 >50% or P < 0.1 indicated that there was heterogeneity in the studies. us, we used a random effects model to analyze the factors that may have led to heterogeneity. is was assessed with sensitivity analysis and subgroup analysis. e published bias was evaluated by funnel plots, when there were over 10 research articles. Figure 1 is a flowchart of the literature retrieval. According to the search strategy, a total of 154 articles were retrieved, after excluding 24 duplicates, 38 reviews, 58 retrospective studies, and 5 case reports. An additional 20 articles were dropped after reading the full text and discovering their treatment had combined other local treatments such as radiotherapy or surgery. We were left with 9 randomized controlled clinical studies which were used in our analysis [6][7][8][9][10][11][12][13][14].

Data Extraction and Quality Assessment.
is study included 8 Chinese articles, 1 English article, and a total of 752 patients with advanced NSCLC. Among them, 376 patients had received physical ablation combined with targeted therapy or chemotherapy; the other 376 had received only targeted therapy or targeted therapy combined with chemotherapy. Of the 9 articles, 7 [7][8][9][11][12][13][14] were about either image-guided percutaneous cluster electrode radiofrequency ablation (PRFA) or joint targeted therapy and chemotherapy, compared with targeted and chemotherapy treatment. 2 articles compared only microwave ablation joint targeted therapy and targeted therapy alone [6,10]. One of the articles, in which the author's name was Zhang Wisdom, did not mention the randomization method. One paper [8] used a computer-aided random 2 Evidence-Based Complementary and Alternative Medicine grouping method. e other 7 each used the random number table method to divide the experiment and control groups. Nine articles did not report a blinding method. One article reported the follow-up results, including overall survival (OS). Nine articles indicated that baseline data were comparable in both patient groups, but only 1 document [13] details the baseline data of the two patient groups. e basic characteristics of inclusion in the literature are shown in Table 1, and the quality evaluation is shown in Figure 2 3.3. Analysis Results: CR Rates. CR rates, PR rates, and DCR rates were reported in nine of the articles in this study. e results of the fixed effects model for the meta-analysis, as well as the forest plots, showed complete response rate (CRR) (RR � 2.23, 95% CI: 1. 46∼3.40, P < 0.01), partial response rate (PRR) (RR � 2.25, 95% CI: 1. 41∼3.59, P < 0.01), and disease control rate (DCR) (RR � 2.80, 95% CI: 1.64∼4.80, P < 0.01) among patients with advanced NSCLC who had received physical ablation combined with TKI therapy. ese were all higher than for those patients who had not received physical ablation therapy. All of these findings were statistically significant. e control group had received targeted therapy combined with chemotherapy, in seven articles, with a total of 606 patients. Meta-analysis of the results for physical ablation combination therapy in patients with advanced NSCLC (compared to those accepting physical ablation) showed complete response rate (RR � 2.48, 95% CI: 1. 55∼2.47, P < 0.01), partial remission rate (RR � 1.66, 95% CI: 1. 20∼2.31, P < 0.01), disease control rates (RR � 2.68, 95% CI: 1.41∼5.06, P < 0.01), showing statistically significant difference, as shown in Figure 3.

Quality of Life (QOL).
Six articles reported on quality of life [7][8][9]14], of which [11] 4 were based on the QLQ-C30 scale. One article adopted the quality of life score standard for tumor patients, including appetite, spirit, sleep, daily activities, and interpersonal communication. Patients' quality of life (QOL) was scored based on a total score of 25.
ose with scores over 15 were rated as having good QOL. e proportion of patients with good QOL was compared between the two groups. One article [12] utilized a quality of life index questionnaire with six items-activities, daily life, health, total quality of life index, recent support, and overall spirit. Each item was rated either 0, 1, or 2. e scores were tabulated and categorized as follows: excellent (11 to 12 points), good (8 to 10 points), average (5 to 7 points), and poor (3 to 5 points). ose with <3 points were considered as having extremely poor quality of life. e latter two articles     Evidence-Based Complementary and Alternative Medicine were inconsistent in their use of the scale. erefore, we proposed combining the four articles [7][8][9]14]. Finally, after reading the full texts of the 4 articles, it was demonstrated that study [8] only recorded five general functions and a total score for 3 symptoms in the quality of life scale. Individual scores for each item were not given. us, combination analysis was impossible. Study [7] recorded only one total score on the quality of life scale; the changes for each group and each score before and after treatment were unclear. erefore, the second analysis could not be conducted. Two articles [9,13] recorded the detailed score for five functions. However, the former recorded the specific value of the two groups of patients before and after treatment, while the latter only recorded the final score of the two patient groups. us, it was impossible to conduct a meta-analysis on the quality of life reports in the abovementioned literature. Although different recording scales were used, and the means of recording were inconsistent across studies, all of the studies showed that the quality of life scores for patients in the treatment group improved more than those of the control group after treatment.
e results of the fixed effects model showed that the incidence of pain in patients receiving physical ablation therapy combined with targeted therapy or chemotherapy was higher than that of patients receiving targeted therapy or chemotherapy alone.
is difference was statistically significant (RR � 5.79, 95% CI: 2.49∼13.47, P < 0.01) (Figure 4(a)). ree articles [6,11,12] reported the incidence of diarrhea, with low homogeneity (I 2 � 0%, P � 0.88). is showed that, with a random effects model, there was no statistically significant difference between the incidence of diarrhea among patients that had received physical ablation combined with targeted therapy or chemotherapy and those that had received targeted therapy or chemotherapy alone (RR � 0.92, 95% CI: 0.53∼1.61, P � 0.77) (Figure 4(b)). Rash incidence was recorded in 3 articles [6,11,12] with no statistically significant difference between the patients that had received physical ablation combined with targeted therapy or chemotherapy and those that had received targeted therapy or chemotherapy alone (RR � 0.75, 95% CI: 0.47-1.20, P � 0.23) (Figure 4(c)). is was relatively homogenous (I 2 � 0%, P � 0.90). e 4 articles [6, 11-13] recorded incidence of fever and had low homogeneity (I 2 −0%, P, 0.87) according to the fixed effects model. is showed that the incidence of fever in patients receiving physical ablation therapy combined with targeted therapy or chemotherapy exceeded that of patients receiving targeted therapy or chemotherapy alone. is difference was statistically significant (RR � 4.61, 95% CI: 1.83∼11.66, P < 0.01) (Figure 4(d)). Adverse pneumothorax reactions were also reported with low homogeneity (I 2 � 0%, P � 0.53). ere were no significant differences in the incidence of pneumothorax in patients that had received physical ablation combined with targeted therapy or chemotherapy compared with those that received targeted therapy or chemotherapy alone (RR � 7.43, 95% CI: 0.90∼61.13, P � 0.06) (Figure 4(e)). Yu Bo et al. [15] reported the incidence of liver damage and hemoptysis in patients that had received physical ablation combined with targeted therapy and chemotherapy. ey found no statistically significant differences with patients that had received targeted therapy and chemotherapy alone (P > 0.05). Chen et al. [13] reported that the incidence of bone marrow inhibition in patients receiving physical ablation therapy combined with targeted therapy and chemotherapy was statistically significant (P > 0.05), compared with that of patients who had received targeted therapy and chemotherapy alone.

Published Bias Analysis.
Nine articles in this study were included in the funnel plot. Due to the asymmetry on both sides of the funnel plot, there may have been publication bias. Moreover, it is also possible that articles with negative results were not published ( Figure 5).

Discussion
Of all malignant tumors, lung cancer has the highest incidence, causing immense financial costs at the population level. Many patients are already in advanced stages at the time of initial diagnosis and thus have missed the window for radical surgery. How to optimize the treatment strategy of advanced NSCLC and how to choose reasonable treatment at a specific time are the focus of clinical research. Since the IPASS study brought targeted therapy to clinical practice, patients with non-small cell lung cancer with clear driving genes have benefited. IPASS research has led to a series of studies that have established EGFR TKI as a first-line treatment for EGFR-positive patients. e median PFS for precision targeted therapy is 10-12 months, and many clinical studies have demonstrated the importance of targeted treatment in driving gene-positive nonsmall cell lung cancer [16][17][18][19][20]. Questions have arisen over what to do when resistance occurs. Appropriate targeted drugs can be identified for patients with the relevant drug resistance mechanisms, such as an ARUR3 study which brought ositinib to the clinic. is is the treatment for the first and second generations of TKI drug-resistant patients with the T790 M mutation. Data shows that about 60% of patients with the T90 M mutation can be administered targeted therapy with ositinib. However, due to various factors such as testing methods, drug availability, health policy, and other problems, far less than 60% of patients may actually be candidates for second-tier ositinib. Many patients have no drug for precise posttreatment drug resistance. ere are various theories about this. One is that, based on clinical observations, approximately one-quarter of patients who discontinue TKI after progression experience explosive tumor growth. is is based on which TKI is recommended for continued use after progression.
Targeted therapy combined with chemotherapy has some advantages. However, several studies have demonstrated that this combination has limitations, and OS benefits are not obvious [16][17][18][19][20]. ese results can be improved at this time by combining targeted therapy with local therapy [21]. Common physiotherapy ablation includes radiofrequency ablation therapy, microwave ablation therapy, and frozen ablation therapy. ese are all forms of local physiotherapy; different physiotherapy methods have been demonstrated in a number of studies of the clinical efficacy of solid tumor therapy [22,23].
In order to verify the role and safety of physical ablation therapy in patients with advanced NSCLC, this study conducted a rigorous and systematic meta-analysis. e results of this study show that patients who received physical ablation combined with TKI treatment have the following total remission rates, compared with patients who did not receive physical ablation therapy: CR: ( ese were all statistically significant. ese results show that the clinical efficacy of physical ablation combined with TKI targeted therapy (regardless of whether it is combined with chemotherapy) was better than that of simple targeted therapy or combination with chemotherapy. For long-term efficacy, the PFS of the physical ablation therapy combined with targeted therapy and chemotherapy was higher than that of the purely targeted therapy combined with chemotherapy (P < 0.01). However, the OS and 1-year survival rates were not available for meta quantitative analysis due to incomplete data in the literature. As for the quality of life, it was difficult to conduct meta-quantitative analysis because of the incomplete data on the scale and records of each aspect of the literature evaluation. However, each study showed that adding physical ablation therapy improved patients' quality of life scores. e meta-analysis results showed that the incidence of pain and fever in combination therapy was higher than that of pure targeted therapy and chemotherapy. Diarrhea, rash, and pneumothorax incidence made no significant difference in the incidence of common adverse reactions. Higher incidence of pain than that of the simple treatment group may have been due to minimally invasive operations. e high incidence of fever may have been related to the absorption heat caused by tumor necrosis after physical ablation, which is quicker and easier to treat.

Limitations
e principle of treatment for advanced non-small cell lung cancer can be comprehensive and based on systemic therapy. Physical ablation is characterized by minimal treatment, which has small surgical wounds and fewer effects on normal tissue, and requires less operating time than with surgery. As a minimally invasive local surgery, physical ablation can reduce the load of tumors in a short period of time. Additionally, it causes little delay in targeted therapy, chemotherapy, or other systemic treatments.
is analysis consisted of comprehensive literature retrieval and strict control of the inclusion standards. Regardless, there 8 Evidence-Based Complementary and Alternative Medicine are still the following shortcomings: because this article is a secondary study of data from other literature, there are deficiencies: (1) only 1 corresponding English language study was retrieved, and all of the included studies were single-center. As a result, they need further confirmation. (2) e therapeutic effect's evaluation time after combination treatment varied in the included literature. is resulted in time bias. (3) e scale used to evaluate the quality of life was not uniform. Although most using the QLQ-C30 scale, there were variations in how each study recorded data. As a result, they could not be analyzed quantitatively. Also, the included literature reported less on long-term efficacy such as PFS and the OS of the combination of physical ablation and targeted therapy. is means that there is no evidence of physical ablation combination therapy's long-term efficacy. erefore, the evaluation specification for the efficacy of physical ablation treatment for advanced NSCLC needs further exploration.

Conclusion
Physical ablation therapy has good near term clinical efficacy in patients with advanced NSCLC. Compared with purely targeted therapy or combined with chemotherapy, physical ablation combined therapy can improve patients' PR rates, DCR, and CR rates, assuming their safety is within the acceptable range. However, its long-term efficacy needs further assessment. New treatment options are available for patients with advanced NSCLC who cannot be treated with therapeutic surgery. However, there is still a need for large samples, and multicenter, high-quality randomized controlled trials, for further validation.
Only then can it be included in the guidelines to benefit more patients with advanced non-small cell lung cancer.

Data Availability
e data used to support the findings of this study are available from the corresponding author upon reasonable request.

Disclosure
Lu-Zhen Li and Jia-Ming Wu are co-first authors of this article.

Conflicts of Interest
e authors declare that they have no conflicts of interest.

Authors' Contributions
Lu-Zhen Li and Jia-Ming Wu are co-first authors of this article Ting Chen and Liang-Chen Zhao performed the experiments and extracted the data. Other authors reviewed the data quality. Can-Tu Fang conceived and designed the study. All the authors read and approved the final manuscript. Evidence-Based Complementary and Alternative Medicine 9