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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 5  |  Page : 1007-1013

Effectiveness of radiofrequency ablation therapy for patients with unresected Stage IA non-small cell lung cancer


1 Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
2 Department of Health Statistics, Second Military Medical University, Shanghai 200433, China

Date of Submission27-Nov-2019
Date of Decision20-Mar-2020
Date of Acceptance11-May-2020
Date of Web Publication29-Sep-2020

Correspondence Address:
Changhui Wang
Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, #301 Mid Yanchang Rd., Shanghai 200072
China
Lihong Fan
Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1040_19

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 > Abstract 


Background: Approximately 20% of patients with resectable non-small cell lung cancer (NSCLC) are treated nonsurgically. To compare the clinical outcomes between nonsurgical patients receiving radiofrequency ablation (RFA) alone and those receiving no treatment (NT), we assessed RFA effectiveness in terms of survival using the surveillance, epidemiology, and end-results (SEER) database.
Methods: Using the SEER registry process, we identified 5268 patients who were ineligible for the surgical treatment between 2004 and 2015. Overall survival (OS) and cancer-specific survival (CSS) were compared between the groups using propensity score matching (PSM), inverse probability of treatment weight (IPTW), and overlap weight analysis. In addition, an exploratory analysis was conducted to determine RFA treatment effectiveness based on clinically relevant patient subsets.
Results: Of the 5268 patients, 189 (3.6%) received RFA. The OS and CSS in these patients were significantly better than those in the NT group (P < 0.0001). RFA was associated with a 16-month median OS improvement. Both OS and CSS improved in the nonsurgical patients (hazard ratio [HR], 0.695, 95% confidence interval [CI], 0.585–0.826, P < 0.0001; HR, 0.636; 95% CI, 0.505–0.800, P < 0.0001). The 1-, 3-, and 5-year OS in the unmatched RFA and NT groups were 84.2%, 49.0%, and 29.4% vs. 62.8%, 31.1%, and 17.1%, respectively (P < 0.001). PSM, IPTW, and overlap weight analysis showed comparable results. The odds of receiving RFA decreased with larger tumor size (>1, ≤2 cm, odds ratio [OR], 0.623, 95% CI, 0.402–0.966; >2, ≤3 cm, OR, 0.300, 95% CI, 0.186–0.483) compared to tumor size s1 cm (P < 0.05).
Conclusion: RFA improves unresected stage IA NSCLC patient survival. Our results are limited by the retrospective nature of the study; however, we believe that our findings are noteworthy for recommending local ablative therapy.

Keywords: Non-small-cell lung carcinoma, radiofrequency ablation, survival


How to cite this article:
Li M, Qin Y, Mei A, Wang C, Fan L. Effectiveness of radiofrequency ablation therapy for patients with unresected Stage IA non-small cell lung cancer. J Can Res Ther 2020;16:1007-13

How to cite this URL:
Li M, Qin Y, Mei A, Wang C, Fan L. Effectiveness of radiofrequency ablation therapy for patients with unresected Stage IA non-small cell lung cancer. J Can Res Ther [serial online] 2020 [cited 2020 Oct 26];16:1007-13. Available from: https://www.cancerjournal.net/text.asp?2020/16/5/1007/296422

Ming Li, Yingyi Qin, Aihong Mei have contributed equally to this work





 > Introduction Top


According to statistics,[1] 606,880 patients will lose their lives to cancers in the USA in 2019, suggesting that 1700 cancer-related deaths will occur daily. Lung cancer causes 25% of cancer-related deaths. In 16% of patients diagnosed early with non-small cell lung cancer (NSCLC), lobectomy remains the first-line treatment.[2] However, due to comorbidities or weakened cardiopulmonary functions, even sublobar resection is not suitable for some patients.[3]

Radiofrequency ablation (RFA) was developed to treat solid tumors starting with liver tumors and then progressing to lung tumors.[4],[5],[6],[7],[8] RFA is the latest treatment for inoperable NSCLC patients.[9],[10],[11],[12],[13] RFA causes irreversible injury or coagulation necrosis to tumors by using the biological effects of heat.[14]

Few data are available about its efficacy. Herein, the aim of the present study was to compare RFA effectiveness in Stage IA NSCLC patients deemed ineligible for surgery with the surveillance, epidemiology, and end-results (SEER) database.


 > Methods Top


Data source

Using the National Cancer Institute SEER database, a retrospective analysis was conducted by exempting the data from the institutional review board's oversight. The SEER project was started in the USA in 1973 as a population-based cancer registry which involves about one-tenth of the country's population. The patient sample in the present study was selected from de-identified patients in the NCI SEER 18 Registries whose data included no personal identifiers and were submitted to the NCI through electronic channels. The researchers in the present study obtained approval from the ethics committee and institutional review board before using the data which included the clinicopathological patient features, tumor histology, cancer stage, timing and type of the first treatment course, and therapeutic outcomes. A yearly follow-up rate of 90% for all involved patients whose cancer was diagnosed in the most recent 5 years was required for accreditation.

Study population

Of the 618,830 male and female patients with primary NSCLC who were diagnosed with lung adenocarcinoma, squamous cell carcinoma, and large cell carcinoma during a 10-year period from 2004 to 2015, 68,651 patients with clinical stage I NSCLC (T1N0M0) who did not receive surgical treatment such as hepatectomy, surgical resection, extended lobectomy, and lobectomy but received RFA were selected as participants. All patients had only one primary tumor. Patients with 12 or more primary tumors were excluded. Patients who were treated with (neo) adjuvant chemotherapy, radiotherapy, or had unknown chemotherapy information were also excluded from the study. A total of 5,268 patients met the inclusion criteria and were recruited for the study [Figure 1].
Figure 1: Flow chart of patient selection for the study. RFA = Radiofrequency ablation, NT = No treatment

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Covariates

During the analysis, variables on the tumor, facility, and patient level were considered. Variables on the tumor level included the year of diagnosis, tumor size, and TNM stage, with the tumor grade available to patients undergoing tumor evaluation biopsy. Variables on the facility level included the geographic region, quarterly case volume, distance from the treatment facilities to the patient residences, and the facility type as assigned by the Cost Optimization Committee (COC). Major treatment facilities could be seen in the accreditation category assigned by the COC based on services available and case volume, including the integrated network cancer program, comprehensive community, and community. Variables on the patient level included ethnicity, gender, age at the time of diagnosis, insurance status, percentage of patients with less than a high-school diploma, and median family income based on patient ZIP code. The SEER data dictionary provides a comprehensive description of all included variables for reference.

Objectives

The present study was conducted primarily to compare overall survival (OS) and cancer-specific survival (CSS) in early diagnosed inoperable NSCLC patients who underwent RFA treatment. CSS and OS were defined as the period from patient diagnosis date to death date. In addition, this study also attempted to determine RFA treatment effectiveness based on clinically relevant patient subsets.

Statistical analysis

The Wilcoxon Rank sum test, Chi-square test, or Cochran–Mantel–Haenszel test were applied to assess the correlations between different treatment methods and all of the above-mentioned variables. The primary outcomes included survival rate and survival curve estimated using the Kaplan-Meier estimator. OS and CSS between patients receiving RFA (RFA group) and those receiving no treatment (NT group) were compared using univariable and multivariable Cox-proportional hazard models adjusted for all baseline covariates. In addition, three PS models (propensity score matching [PSM], inverse probability of treatment weight [IPTW], and overlap weight method) were used in our study. PS of receiving RFA was estimated through multivariable logistic regression model. The final PS model was determined using stepwise variable selection with an initial inclusion of P < 0.20 and P > 0.10 to remain in the model. Patients in the RFA and NT groups were matched based on the nearest available matching method with a ratio of 3:1 (R package MatchIt). The IPTWs and overlap weights were calculated by using R package PSW with the covariates in the previous final PS model. We included the absolute mean differences to evaluate the balance of covariates between the two groups, and the criterion for covariate unbalance was set to 0.1 in [Figure S1]. For the PS models of OS and CSS, all patients were subjected to Kaplan–Meier estimator calculations, and the comparison of the results in the different groups was performed by conducting the log-rank test. We conducted a subgroup analysis to further explore the therapeutic outcomes based on age, sex, ethnicity, diagnosis year, tumor size, histology, education, and median income level among the patients in the matched group. The R software package (version 3.4.1) and SAS software (version 9.4; SAS Institute, Cary, NC, USA) were used to perform the calculations.




 > Results Top


Factors associated with radiofrequency ablation and no treatment

A total of 5268 nonsurgical, nonrational, and nonchemotherapy patients with stage IA NSCLC were identified during a 10-year period from 2004 to 2015, of whom 189 (3.6%) received RFA as the primary treatment modality. Details about the treatment selection are presented in [Figure 1].

The baseline patient characteristics are shown in [Table 1]. Patients who accepted RFA treatment were more likely to be white (P = 0.0025), medically insured (P < 0.000), and married (P = 0.0090). Patients who were admitted to hospitals in Northwest or West China (P < 0.0001) between 2004 and 2007 (P < 0.0001) were more likely to accept RFA treatment. RFA was also more frequent in patients with a tumor size between 1 and 2 cm. There were also significant differences in household income and education level between the NT and RFA groups in the unadjusted cohorts. There were no significant differences in the unadjusted cohort characteristics including gender, primary label, grade, and laterality. With respect to the covariate, the two groups reached a sound balance in propensity-score matched treatment [Figure S1]. Nonetheless, the clinical characteristics showed little significant difference in the adjusted cohorts.
Table 1: Demographic and clinical characteristics of patients with lung cancer

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Factors affecting treatment selection

As shown in [Table 2], treatment method selection was related not only to the clinicopathological patients' features but also their socioeconomic conditions. The probability of choosing RFA as the treatment decreased with the tumor size increasing (>1, ≤2 cm, odds ratio [OR]; 0.623; 95% confidence interval [CI], 0.402–0.966; >2, ≤3 cm, OR; 0.300; 95% CI, 0.186–0.483) compared with the tumor size <1 cm. Patients who were admitted to hospitals in Northwest and West China and between 2004 and 2007 were more likely to accept RFA (OR; 2.213: 95% CI, 1.499–3.269 and OR; 2.342: 95% CI, 0.255–0.504, P < 0.001). There were no significant differences in the household income, ethnicity, and marital status between the two groups [Table 2].
Table 2: Propensity modeling of receipt of radiofrequency ablation

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Survival analysis

The median posttreatment follow-up period was 15 months (interquartile range 5–32 months). The median OS was 36 months for RFA versus 20 months for NT. OS of the patients who received RFA was significantly better than that of the NT patients (P < 0.0001). The 1-, 3- and 5-year OS rates were 84.2%, 49.0%, and 29.4% for RFA vs. 62.8%, 31.1%, and 17.1% for NT, respectively. PSM, IPTW and overlap weight analysis revealed similar results [Table 3]. The stage-specific OS curves are illustrated in [Figure 2].
Table 3: Overall survival with radiofrequency ablation versus no treatment in patients with lung cancer

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Figure 2: Overall survival in nonsurgically managed patients with stage IA nonsmall cell lung cancer. (a) Unmatched analysis. (b) Propensity score-matched analysis. (c) Inverse probability of treatment weight–adjusted analysis. (d) Overlap weight analysis. RFA = Radiofrequency ablation, NT = No treatment

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The CSS curve results of are shown in [Figure S2] and [Table S1]. The median CSS time was 35 months for NT versus 62 months for RFA. RFA was associated with significant improvements in lung cancer-specific survival (LCSS) in the unadjusted cohort (P < 0.001). The 1-, 3- and 5-year OS rates were 901.5%, 67.1%, and 52.3% for RFA versus 76.3%, 48.2%, and 33.8% for NT, respectively. PSM, IPTW, and overlap weight analysis revealed similar results.



The results of the exploratory sub-group analysis in the matched cohort showed consistent results on the impact of RFA on OS in examined subgroups. The propensity-matched hazard ratios based on different facilities, clinical, and demographic features between NT and RFA groups are shown in [Figure 3]. Patients receiving RFA had better OS than those receiving NT. RFA OS benefits were even more pronounced in males, patients aged ≥65 years, or tumors 1–3 cm in diameter (P < 0.05) [Figure 3].
Figure 3: Forest plot depicting hazard ratios of radiofrequency ablation versus no treatment for nonsurgically managed stage IA non-small cell lung cancer in the propensity score-matched population

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 > Discussion Top


In this study, we identified a total of 5,268 IA NSCLC patients between 2004 and 2015 who were ineligible for surgical intervention for various reasons in an attempt to validate the effectiveness of RFA versus NT. The 5-year OS in the RFA and NT groups was 29.4% versus 17.1%, indicating that RFA offered significant improvement in terms of OS and CSS as compared with NT before and after IPTW, PSM and overlap weight method.

RFA is the latest, most promising treatment for inoperable NSCLC patients because it can directly cause coagulation necrosis or irreversible injury to tumor cells in one or more lesions in a specific organ by utilizing the biological effects of heat.[9] Some recent studies [15] demonstrated that the efficacy of RFA treatment was similar to SBRT in early-stage NSCLC patients. In addition, OS of RFA was similar to sublobar resection in early-stage NSCLC patients.[16] A long follow-up observational study by Lee et al. also showed that the median survival of RFA patients was comparable to surgical intervention in stage I–II lung cancer patients (28.5 vs. 34 months).[17] Several retrospective case reports have summarized the outcomes of patients with stage I NSCLC treated with RFA alone,[15],[16],[17],[18],[19],[20],[21],[22],[23] showing that the 3-year OS rate was 58.33%–74% in clinical stage I NSCLC patients receiving RFA vs. 20%–35% in NT patients.

Although the above studies have shown the clinical efficacy of RFA treatment, none of them included an untreated control group. In this study, we were the first to show that RFA improved survival compared to the NT group in inoperable IA NSCLC patients. Our study found that both OS and CSS of the patients receiving RFA were significantly better than those in the NT group (P < 0.0001). The 1-, 3- and 5-year OS rates were 84.2%, 49.0%, and 29.4% for RFA versus 62.8%, 31.1%, and 17.1% for NT, respectively.

Other studies have also shown the clinical feasibility and safety of RFA treatment. Pneumothorax (13%), bleeding (6.9%), pneumonia (16%), and pleural effusion (21%) were the most common complications of RFA;[11],[12],[20] however, these adverse events are usually short-lived and can be managed with drugs and other therapies. There were no significant changes in global health status or quality of life following RFA. RFA does not seem to abate pulmonary function.[15],[16] Patients receiving RFA are not subject to radiation pneumonitis compared to those receiving SBRT. RFA can also be used repeatedly on lung lesions. Above all, RFA is an efficient and safe treatment for inoperable stage IA NSCLC patients.

The present study has some obvious strength. First, to the best of our knowledge, this is the largest cohort study to compare the therapeutic efficacy of RFA for the treatment of inoperable NSCLC patients. Second, we showed that RFA improved survival compared to the NT group in inoperable IA NSCLC patients. Finally, although the SEER database did not have patient PS scores or patient status, IPTW, PSM and overlap weight methods are efficient for minimizing the effects of observed confounders.





This is the largest and first study to show that RFA improved survival compared to the NT group in inoperable IA NSCLC patients. Data provided in this study are noteworthy for recommending local ablative therapy for unresectable patients with stage IA NSCLC.

Acknowledgments

We would like to thank the staff of the National Cancer Institute for their efforts in the SEER program.

Financial support and sponsorship

This work was financially supported by the National Natural Science Foundation of China (No. 81802262, 31770131, 81473469), the Fundamental Research Funds for the Central Universities (No. 22120180584), Shanghai Tenth Hospital's Improvement Plan for NSFC (No. 04.03.17.032, 04.01.18. 048, SYGZRPY2017014), Shanghai Municipal Health Planning Commission Project (No. ZHYY-ZXYJHZX-201607), Shanghai Shen Kang Hospital Development Center Plan (SHDC12018119) and Scientific Research Projects of Shanghai Municipal Commission of Health and Family Planning (201840056), Shanghai Municipal Health Planning Commission Project (No. ZHYY-ZXYJHZX-201607), and the National Natural Science Foundation of China (31770131, 81473469).

Conflicts of interest

There are no conflicts of interest.



 
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Kwan SW, Mortell KE, Talenfeld AD, Brunner MC. Thermal ablation matches sublobar resection outcomes in older patients with early-stage non-small cell lung cancer. J Vasc Interv Radiol 2014;25:1-90.  Back to cited text no. 15
    
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