ORIGINAL ARTICLE Year : 2022  |  Volume : 18  |  Issue : 7  |  Page : 1910-1918

The efficacy of postoperative radiotherapy for patients with non-small cell lung cancer: An updated systematic review and meta-analysis

Zexu Wang1, Baixia Yang2, Ping Zhan2, Li Wang1, Bing Wan1
1 Department of Respiratory and Critical Care Medicine, the Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
2 Department of Radiotherapy, Nantong Tumor Hospital, Jiangsu, China

Date of Submission20-Jan-2022Date of Decision02-Jun-2022Date of Acceptance27-Jun-2022Date of Web Publication11-Jan-2023

Correspondence Address:
Bing Wan
No. 169, Hushan Road, Jiangning District, Nanjing
China

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jcrt.jcrt_167_22

The controversy over the efficacy of postoperative radiotherapy (PORT) has existed for a long time. The present study reassessed the overall survival (OS) and disease-free survival (DFS) data to investigate whether PORT can improve survival in resectable non-small cell lung cancer (NSCLC) patients. The following databases were used to perform literature search: PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and Embase (from January 1, 1986 to July 5, 2021). The results of overall survival (OS) and disease-free survival (DFS) were calculated as hazard ratio (HR). Confidence intervals are chosen with 95% confidence intervals. A total of 12 RCTs and 19 retrospective cohort studies were found to meet the inclusion criteria. A significant DFS improvement was detected in the PORT group (4111 patients from 15 studies), although statistical difference was not detected for OS between the non-PORT and PORT groups (31 studies, 49,342 total patients). PORT prolonged OS in patients undergoing PORT plus postoperative chemotherapy (POCT) and in pN2 patients. Patients with a median radiation dose of 50.4 Gy and a median radiation dose of 54 Gy had a better OS after PORT. However, if the total radiotherapy dose went up to 60 Gy, PORT increased the risk of death in NSCLC patients. Significant difference in OS was not found in the results of studies with regard to treatment methods, pathologic stages, study type, radiation beam quality, and radiation dose. Patients undergoing postoperative chemoradiotherapy and pN2 patients can benefit from PORT. Patients exposed to median radiation doses of 50.4 and 54 Gy demonstrated relatively good efficacy. For patients with non-small-cell lung cancer, PORT has not been proven to extend OS, but its effect on DFS remains strong.

Keywords: Disease-Free Survival, non-small cell lung cancer, overall survival, postoperative radiotherapy

How to cite this article:
Wang Z, Yang B, Zhan P, Wang L, Wan B. The efficacy of postoperative radiotherapy for patients with non-small cell lung cancer: An updated systematic review and meta-analysis. J Can Res Ther 2022;18:1910-8
How to cite this URL:
Wang Z, Yang B, Zhan P, Wang L, Wan B. The efficacy of postoperative radiotherapy for patients with non-small cell lung cancer: An updated systematic review and meta-analysis. J Can Res Ther [serial online] 2022 [cited 2023 Jan 13];18:1910-8. Available from: https://www.cancerjournal.net/text.asp?2022/18/7/1910/367466

Zexu Wang and Baixia Yang contributed equally

 > Introduction 

Non-small cell lung cancer (NSCLC) patients who survived for more than 5 years accounted for only one-third of the total, and the majority of patients were in an advanced stage of cancer at the time of diagnosis.[1],[2],[3] It has been previously observed that postoperative radiotherapy (PORT) has a good promotion effect on the overall survival (OS) and disease-free survival (DFS) in NSCLC patients,[4],[5],[6],[7] while evidence from an experiment by Hui et al.[8] suggests that PORT does not increase DFS in pIIIA-N2 NSCLC patients. This uncertainty makes research on the effectiveness of PORT in NSCLC patients imminent.

Billiet et al.[4] reported an increase in OS when using a linear accelerator for PORT; cobalt additive has no effect on OS. However, this meta-analysis contains less literature, and the longevity of the publication year makes the results lack guidance for contemporary reality. Zhang et al.[5] demonstrated that PORT leads to a significantly increased DFS, but the effect of postoperative chemotherapy (POCT) on PORT was not taken into account. Liu et al.[6] focused on patients with pIIIa-N2 stage NSCLC, ignoring patients with other pathologic types of NSCLC.

The mechanisms of radiotherapy damage are generally considered to appear randomly at any level of radiation exposure and vary with increasing radiotherapy doses.[9],[10],[11] Excessive irradiation doses can produce secondary damage effects that exceed the therapeutic effect, while very low dose rates are less effective because they do not counteract the proliferation of coexisting tumor cells.[12] Therefore, it is necessary to determine the optimal radiotherapy dose.

Based on these results, the OS and DFS data were reassessed to understand whether PORT can improve the survival rate of patients with NSCLC after resection.

 > Materials and Methods 

Search strategy

The following databases were used to perform literature search: PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and Embase (from January 1, 1986 to July 5, 2021). The following is the search strategy for PubMed: (”Carcinoma, Non-Small-Cell Lung”[MeSH Terms] OR “nsclc”[Title/Abstract]) AND (”radiotherapy”[MeSH Terms] OR “radiation therapy”[Title/Abstract]) AND (”Postoperat*” [Title/Abstract] OR “Post-operat*”[Title/Abstract]).

Inclusion and exclusion criteria

The included studies adhered to the following criteria:[1] patients with NSCLC who underwent a complete resection,[2] interventions consisting of PORT,[3] controls in which PORT was not performed,[4] studies with OS or DFS used as outcome indicators,[5] randomized controlled trial (RCT) or retrospective cohort study. If the same study population was used, all articles with incomplete relative data and earlier publication time were excluded and the remaining one was included. The following exclusion criteria were used for this meta-analysis:[1] letter, review, editorial, comment, case report, animal experiment, and duplicated study;[2] studies where survival data are not available;[3] and manuscripts written in Chinese.

Quality evaluation and statistical analysis

We evaluated retrospective cohort studies using the Newcastle Ottawa scale,[13] while RCTs were evaluated using the Cochran risk assessment tool.[14]

Review Manager (Cochrane Collaboration, Oxford, UK) and Stata 14.0 (Stata Corporation, College Station, TX, USA) were used to perform the analyses. The result of OS and DFS were calculated as hazard ratios (HRs). Confidence intervals were chosen with 95% confidence intervals. HRs and 95% CIs were directly extracted if they were provided in the manuscript. Otherwise, the Kaplan–Meier curve was calculated using the methods provided by Parmar et al.[15] and Tierney et al.[16] Target data were extracted from the survival curve or calculated using other available data.

Heterogeneity was evaluated using the I squared (I2) test. I2 >50% was considered to indicate significant heterogeneity, where further analysis used the random-effects model. Otherwise, the fixed-effects model was utilized. The robustness of the pooled results was measured by sensitivity analysis. Subgroup analysis was performed to further explain the heterogeneity. Potential publication bias was determined using the Duval trim-and-fill method.[17] A symmetrical image indicated no publication bias. Otherwise, publication bias existed.

 > Results 

Study selection results and included study characteristics

The literature screening procedure is shown in [Figure 1]. A total of 235 search results were obtained 204 articles from database searching and 31 articles from three meta-analyses). After removing the duplicates and reviewing the abstracts, 40 articles remained. Finally, 13 RCTs[7],[8],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28] and 19 retrospective studies[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47] were included in the meta-analysis. Full-text review revealed that two articles used the same study population.[8],[48] The study with more incomplete data was excluded.[48][Table 1] describes the characteristics of the included literature.

Study quality evaluation

A total of 19 retrospective studies were evaluated using the Newcastle-Ottawa Scale (NOS) [Table 1]. Bias assessment for 13 RCTs was carried out using the Cochrane collaboration tool [Figure 2].

Figure 2: Quality evaluation results of RCTs. RCT = randomized controlled trial

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OS and DFS

OS data were obtained from 31 studies, and DFS data were extracted from 16 studies. PORT, in comparison with the non-PORT group, improved DFS in NSCLC patients (16 studies with 4111 patients; HR: 0.84, 95% CI: 0.75–0.93). But PORT did not reveal an evident difference in OS when compared with the non-PORT group (31 studies with 49,342 patients; HR: 0.94, 95% CI: 0.86–1.04). The random-effects model was used because the heterogeneity test result of OS was significant, while DFS revealed small heterogeneity when fixed-effect model was used [Figure 3] and [Figure 4].

Figure 3: Forest plots of HRs for OS in the 31 studies included. HR = hazard ratio, OS = overall survival

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Figure 4: Forest plots of HRs for DFS in the studies analyzed. DFS = disease-free survival, HR = hazard ratio

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Sensitivity analysis [Figure 5] showed that Pang et al.[40] significantly affects the heterogeneity, which suggests the presence of publication bias according to the nonparametric trim-and-fill method [Figure 6].

Figure 6: Presence of published bias analyzed by nonparametric trim-and-fill method

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OS by chemotherapy

As shown in [Supplementary Figure 1], 10 and five studies reported the efficacy of PORT in NSCLC patients who did not receive POCT and who received POCT, respectively. In patients who did not receive POCT, the combined HR was 1.03 and the 95% CI was 0.84–1.23, indicating no difference. A survival benefit was detected for PORT in patients who underwent POCT (HR: 0.89, 95% CI: 0.80–0.98), and the heterogeneity was moderate.

OS by pathology type

PORT significantly promoted OS (HR: 0.89, 95% CI: 0.83–0.96) in patients with pathologic lymph node stage of pN2 (22 studies with 32,719 patients) [Supplementary Figure 2]. The remaining studies on patients with other pathologic types (nine studies with 16,623 patients) showed a significant heterogeneity. The pooled HR was 1.10, and the 95% CI was 0.92–1.31.

OS by study type

Nineteen retrospective studies that included 46,682 patients and 12 RCTs that included 2660 patients were used to explore the efficacy of PORT in NSCLC patients. No significant difference was observed in both RCTs and retrospective studies. The pooled HR for OS in retrospective cohort studies was 0.9 (95% CI: 0.80–1.01). The combined HR for RCT studies was 1.07, and the 95% CI was 0.91–1.25 [Supplementary Figure 3].

OS by beam quality

Fifteen studies investigated the curative efficacy of PORT with a linear accelerator, where the combined HR was 0.89 and the 95% confidence interval was 0.75–1.04 [Supplementary Figure 4]. Four studies investigated the curative efficacy of PORT with a linear accelerator and cobalt. The combined HR was 1.17, and the 95% confidence interval was 0.95–1.45 (I2 = 51.0%, P = 0.106). No meaningful result was found.

OS by radiation dose

Nineteen studies showed an association between PORT efficacy and radiation dose [Supplementary Figure 5]. Patients with median radiotherapy dose of 50.4 Gy (three studies; HR: 0.66, 95% CI: 0.51–0.87), 50 Gy (one study; HR: 0.62, 95% CI: 0.45–0.85), and 54 Gy (three studies; HR: 0.88, 95% CI: 0.81–0.95) had a better OS after PORT. A rise in the death risk was demonstrated in patients exposed to a total radiation dose of 60 Gy (three studies; HR: 1.18, 95% CI: 1.02–1.37). In patients with a total dose of 50 Gy (HR: 1.07, 95% CI: 0.85–1.34), <50 Gy (HR: 0.97, 95% CI: 0.76–1.23), and 50.4 Gy (HR: 0.88, 95% CI: 0.61–1.27), no evidence showed a difference in OS between PORT and non-PORT.

 > Discussion 

As far as we know, this meta-analysis investigating whether PORT is effective for NSCLC patients contains the largest number of published materials. We confirmed that PORT plays a critical role in improving DFS. Although no statistical difference was detected in OS between the PORT group and the non-PORT group, pN2 patients and patients undergoing concurrent POCT still experience OS improvement from PORT. The OS of patients receiving median radiation doses of 50.4 and 54 Gy improves from PORT, when compared to non-PORT patients. However, a worse OS for PORT was found in patients whose total radiation dose was 60 Gy.

The effect of concurrent chemoradiotherapy on unresectable NSCLC has been well described.[49],[50],[51] The treatment of early NSCLC is still based on immunotherapy and targeted therapy.[52] Radiotherapy and chemotherapy are not clear for other stages of NSCLC. A British meta-analysis reported that chemoradiotherapy had a good efficacy on stage I–III NSCLC patients.[53] However, another research reported on eight studies that used emerging radiotherapy techniques which may produce better results.[54] Our study included the largest number of participants and focused more widely on conventional radiotherapy techniques rather than emerging radiotherapy techniques, further confirming the effectiveness of postoperative chemoradiotherapy for NSCLC patients.

Radiation Therapy Oncology Group (RTOG) previously recommended a radiotherapy dose of 60–63 Gy for patients with stage III NSCLC, based on the results of one of their experiments.[55] However, according to our results, the total radiation dose of 60 Gy has adverse effects on patients with NSCLC. This is because the use of neoadjuvant chemotherapy was not controlled in our experiment. As a consensus treatment for NSCLC patients, it is essential to consider the effect of adjuvant chemotherapy on radiotherapy dose. On the other hand, different from the traditional radiotherapy dose scheme, hyperfractionated radiotherapy, with its more refined dose distribution and larger total dose, has been proven to be an effective radiotherapy regimen.[56] An RCT study published in Journal of Cancer Research and Therapeutics (JCRT) in 2020 showed that continuous hyperfractionated accelerated radiotherapy in combination with neoadjuvant chemotherapy can improve the locoregional disease control of NSCLC patients, but no obvious survival advantage was found.[57] Larger multivariate clinical trials are still needed.

Our findings indicated that PORT is in favor for pN2 patients. A previous study from Europe reported that the use of concurrent PORT resulted in a worse OS compared to chemotherapy alone in pN1 patients, while demonstrating a better OS than chemotherapy alone in pN2 patients.[58] It is possible that this may be due to an appropriate radiation dose that offsets the complication effect of radiotherapy in patients with pN2.[59],[60],[61],[62] However, patients with pathologic features of pN2 are a heterogeneous group. The efficacy of PORT may vary with the number of positive nodes, lymphatic metastasis type, and pathologic lymph status.[38],[63] Considering this, more experiments with comprehensive pathologic subgroups need to be conducted to determine the effect of PORT on pN2 patients.

Sensitivity analysis revealed that the studies by Pang et al.[40] and Mankuzhy et al.[47] may have been the cause of significant heterogeneity. On comparison with the data from other investigations, it was found that these two studies differed significantly from others in the types of pathology and surgical procedures included in the population. They accounted for 47% of the total number of participants (Pang et al. 29%).[64] Thus, differences in patient characteristics might result in greater heterogeneity in the results.

Our meta-analysis has several limitations. First, the nonparametric scissor-complement method showed that the included studies have a strong publication bias, which may lead to bias in the results. Second, most of the included RCTs were conducted before 2000, which may provide outdated information. Third, NSCLC patients are not a homogeneous group, but due to the difficulty in obtaining data, it is impossible to carry out an accurate classification based on the pathologic characteristics of the included population. It is difficult to determine the efficacy of PORT in NSCLC patients with different pathologic features. Fourth, most of the radiotherapy methods included in the study used traditional radiotherapy equipment, while emerging radiotherapy techniques with less toxicity, such as stereotactic radiotherapy, may change these results. Finally, some reports did not provide HRs. The HR calculation method using the Kaplan–Meier curve has errors and uncertainties, which may lead to deviations and errors.

 > Conclusion 

Our analysis confirmed that PORT extended DFS, but not OS in patients with NSCLC. Patients receiving POCT and pN2 patients can benefit from PORT. Median radiotherapy doses of 50.4 and 54 Gy had a relatively good efficacy in NSCLC patients. However, conclusions should be drawn with caution due to the high heterogeneity present in the study. Further research is needed to confirm, expand, and deepen our observations.

Ethics statement

No ethics approval was need for meta-analysis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 

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