Postoperative radiotherapy for patients with completely resected pathological stage IIIA-N2 non-small cell lung cancer: a preferential benefit for squamous cell carcinoma

Between October 2010 and September 2016, 288 consecutive patients with pathologically confirmed T1–3N2M0 stage IIIA NSCLC, according to the American Joint Committee on Cancer (AJCC) 7^th lung cancer TNM classification, who underwent surgery at the Department of Thoracic Surgery at Beijing Chest Hospital were included in the present retrospective study. The eligibility criteria of the patients included the following: (1) demonstrating an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1; (2) not having received neo-adjuvant chemotherapy or chemoradiotherapy; (3) information about tumor characteristics, pathology and follow-up data being available. All patients survived at least 4 months after radical resection in Beijing Chest Hospital. The medical records and follow-up data of the patients were retrospectively analyzed, including gender, age, smoking index, histology, pathological T stage, types of surgery, types of N2 (N2a1 N2a2, N2b) were based on The Eighth Edition Lung Cancer Stage Classification, number of positive nodes, positive lymph nodes ratio (PLNR), number of N2 stations, postoperative chemotherapy (POCT), PORT, patterns and times of recurrence, and survival status.18

The ethics committee of Academic Research Project Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University approved this study and consent was obtained from all participants.

Radical resection was performed as follows: (1) either sleeve resection, lobectomy or pneumonectomy; (2) microscopically negative resection margins; (3) mediastinal lymphadenectomy or systematic mediastinal LN sampling.

POCT was administered with a cisplatin- or carboplatin-based regimen, used within 4 weeks after the surgery. Patients excluded from POCT included asthenia condition, refusal of the therapy or based on physicians’ decision.

PORT, based on radiation oncologists’ decision or surgeon’s referral, was administered within 6 months after the surgery during or after the POCT cycles. Extensive mediastinal lymph node involvement was the main indication for PORT. Clinical target volume (CTV) included surgical margin, ipsilateral hilum, and high-risk ipsilateral mediastinal drainage lymph area. The planning target volume (PTV) was defined as the CTV plus 0.5–0.8 cm margins.

Patients with EGFR or ALK mutations in NSCLC were also treated with EGFR TKIs or ALK inhibitors given when tumors relapsed or metastasized. EGFR TKIs included erlotinib, gefitinib or icotinib. ALK inhibitor used was crizotinib.

The patients were followed up every 3 months after surgery for the first 2 years and every 6–12 months thereafter. The last follow-up time was December 2019. Regular follow-up included physical examination, hematology tests, chest CT scans, ultrasound of supraclavicular region, ultrasound or CT scanning of the abdomen, and other imaging procedures based on the requirement. Treatment failures were determined by the physicians based on the available information, including clinical assessments, imaging results and/or pathological examination. Follow-up information was also obtained by telephone surveys and reviewing electronic medical records. Disease recurrence at the surgical margin, ipsilateral hilum, and/or mediastinum was considered as local-regional failure (LRF). Tumors appeared at other sites, including the supraclavicular zone, contralateral hilum and distant organs, were considered distant metastasis (DM).

SPSS statistical software (version 23.0; SPSS Inc., Chicago, IL) was used for the statistical analyses. Loco-regional recurrence-free survival (LRFS) was defined from the day of surgery to the day of documented LRF or the last follow-up. Distant metastasis-free survival (DMFS) was defined from the day of surgery to the day of documented DM or the last follow-up. Overall survival (OS) was measured from the day of surgery to the date of death from any cause or the last follow-up. A χ2 test was used to determine the distribution of patient characteristics within the PORT group and the non-PORT group. The 5-year OS, LRFS and DMFS were calculated using the Kaplan-Meier method. To determine prognostic value, study variables were compared with the survival measures using log-rank tests. The prognostic factors were determined using Cox’s regression model. A statistically significant difference was set at p < 0.05.

Detailed patient clinical and pathological characteristics are presented in Tables 1 with 194 cases of LADC and 85 cases of LSCC. Among 194 cases of LADC, the median age was 58 years. The median numbers of lymph nodes resected was 18 (range: 2–57). There were 170 (87.6%) patients treated with POCT and 42 (21.6%) patients treated with PORT. The clinicopathological features of the patients were comparable between PORT and non-PORT groups, with the exception that in the PORT group, there were more patients with T1–2 tumors, treated with lobectomy and POCT. Among 85 cases of LSCC, the median age was 60 years. The median numbers of lymph nodes resected was 21 (range: 5–66). There were 72 (84.7%) patients treated with POCT and 19 (22.3%) treated with PORT. Among 61 PORT cases, the techniques used included three-dimensional conformal radiotherapy (3D-CRT, 21 cases) and intensity modulated radiotherapy (IMRT, 40 cases). The therapies were administered with a linear accelerator using 6–8 MV x-ray at 180–200 cGy per fraction, 5 days per week, to an average total radiation dose of 5918 cGy. PORT was used 4.38 months after surgery as an average and after 2 or 4 cycles of POCT.

Among 194 cases of LADC, the median survival time was 44.50 months. A total of 112 (57.7%) patients succumbed during follow-up. The 1-, 3-, and 5-year OS rates in the PORT group were 95.2, 61.9 and 40.0%, respectively, whereas the non-PORT group exhibited 1-, 3- and 5-year OS rates of 90.1, 63.3 and 45.0%, respectively (p = 0.948; Figure 1A). On the other hand, among 85 cases of LSCC, the median survival time was 38.00 months. A total of 52 (61.2%) patients succumbed during follow-up. The 1-, 3-, and 5-year OS rates in the PORT group were 94.7, 63.2 and 63.2%, respectively, whereas the non-PORT group exhibited 1-, 3- and 5-year OS rates of 86.4, 48.5 and 37.1%, respectively (p = 0.026; Figure 1B).

Figure 1

Univariate analyses were performed to determine the association between clinicopathological factors and the patients’ 5-year OS, LRFS and DMFS in LADC and LSCC cases. The results of 194 cases of LADC are presented in Table 2. The 5-year OS in this patient group was significantly increased with a smoking index < 400 (p = 0.001), a lower T stage (p = 0.032), lower rate (or a single) N2 station metastasis (p = 0.001), lower number of positive nodes (p = 0.000), and lower percentage of positive nodes (p = 0.000). In addition, a lower smoking index < 400 (p = 0.001), a lower T stage (p = 0.020), lower number (or a single) N2 station metastasis (p = 0.002), lower number of positive nodes (p = 0.000), and lower percentage of positive nodes (p = 0.001) were as-sociated with improved 5-year LRFS. Furthermore, the 5-year DMFS were significantly increased in patients with lower smoking index < 400 (p = 0.006), lower T stage (p = 0.001), lower (or a single) N2 station metastasis (p = 0.000), lower number of positive nodes (p = 0.000), and lower percentage of positive nodes (p = 0.000). The results of 85 cases of LSCC are presented in Table 3. It was noteworthy that only PORT improved the 5-year OS, LRFS and DMFS, with p values of 0.026, 0.008 and 0.018 respectively.

Multivariate analyses using Cox’s regression model were performed to determine independent prognostic factors for patient survival and disease control. The results of 194 cases of LADC were presented in Table 4. Use of POCT (HR, 0.417; 95% CI, 0.230–0.757; p = 0.004), multiple N2 stations (HR, 2.065; 95% CI, 1.148–3.714; p = 0.015) and smoking index ≥ 400 (HR, 2.172; 95% CI, 1.471–3.207; p = 0.000) were identified as significant independent predictors of OS. The use of POCT (HR, 0.524; 95% CI, 0.291–0.942; p = 0.031), multiple N2 stations (HR, 1.818; 95% CI, 1.010–3.272; p = 0.046) and smoking index ≥ 400 (HR, 2.098; 95% CI, 1.421– 3.099; p = 0.000) were identified as significant independent predictors of LRFS. Likewise, use of POCT (HR, 0.554 95% CI, 0.310–0.992; p = 0.047), T3 stage (HR, 2.120; 95% CI, 1.308–3.435; p = 0.002) and smoking index ≥ 400 (HR, 1.739; 95% CI, 1.181– 2.560; p = 0.005) were identified as significant independent predictors of DMFS. The results of 85 cases of LSCC were presented in Table 5, which indicates that only patients with the use of PORT showed significantly improved OS (HR, 0.364; 95% CI, 0.159–1.832; p = 0.017), LRFS (HR, 0.308; 95% CI, 0.133–0.712; p = 0.006) and DMFS (HR, 0.349; 95% CI, 0.152–0.802; p = 0.013) (Figure 2).

Twelve patients (19.6%) experienced Common Terminology Criteria for Adverse Events (CTCAE) v4.0 Grade 2 (10 patients) or Grade 3 (2 patients) acute pneumonitis. No patients experienced Grade 4 or higher acute pneumonitis. There were 46 patients (75.4%) experiencing CTCAE v4.0 Grade 1 (35 patients) or higher acute esophagitis (10 with Grade 2 and 1 with Grade 3 toxicity). No patients experienced Grade 4 or higher acute esophagitis.

Figure 2

All patients completed symptomatic radiotherapy with planned doses. As late radiation toxicity, 2 patients (3.2%) were observed with pulmonary fibrosis.