Edited by: Stephen V. Liu, Georgetown University Medical Center, United States
Reviewed by: Tim Kruser, Northwestern Medicine, United States; Heloisa De Andrade Carvalho, University of São Paulo, Brazil
This article was submitted to Thoracic Oncology, a section of the journal Frontiers in Oncology
†These authors have contributed equally to this work
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Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease and surgical resection with or without neoadjuvant therapy could be carried out in selected patients (
Moreover, there is no definite agreement on the delineation of clinical target volume (CTV) during PORT for completely resected (y)pN2 NSCLC, and it varies between different institutions and clinical trials (
In the current study, we investigated the cumulative incidence, risk factor, and prognostic significance of SCR in completely resected (y)pN2 NSCLC. Additionally, our recent study finds crucial prognostic value of routine immunohistochemical (IHC) markers in completely resected NSCLC (
Lung cancer patients who received surgery at Fudan University Shanghai Cancer Center (FUSCC) from January 2013 to December 2018 were retrospectively reviewed. Patients who underwent complete surgical resection (
For each patient, common clinic-pathological parameters were gathered from the electronic medical records, including age, sex, smoking history, the Eastern Corporative Oncology Group (ECOG) performance score, clinical TNM stage, pathological TNM stage, primary tumor size, tumor differentiation, tumor histology, tumor location, lymphovascular invasion, visceral pleural invasion, perineural invasion, and type of surgery. Pathologic TNM stage was in accordance with the eighth edition Lung Cancer Stage Classification (
Pretreatment evaluation generally included clinical assessment, blood test, bronchoscopy, contrast-enhanced chest computed tomography (CT) scan, ultrasonographic examination or CT scan of the abdomen, brain magnetic resonance imaging (MRI) and bone scans. Patients with mediastinal lymph node enlargement (>1 cm) in the short axis on CT scan or pathologically proven to be malignant, were defined as harboring clinical N2 (cN2) disease. Of note, positron emission tomography (PET)/CT, as well as invasive staging of the mediastinum, was strongly recommended for patients with cN2 disease at our cancer center.
Neoadjuvant therapy generally consisted of 3–4 cycles of platinum-based doublet regimen and surgical treatment included lobectomy, sublobectomy, and pneumonectomy, with systematic multilevel mediastinal lymph node dissection or adequate mediastinal sampling (no <3 N2 stations, must include the subcarinal station). PORT was performed according to our institutional protocol (
Follow-ups were at the discretion of the treating physicians and were generally scheduled at regular intervals: every 3 months after surgery in the first 2 years, every 6 months for the next 3 years and annually thereafter. During follow-up, blood tests, chest CT scans, and CT scans or ultrasonographic examination of abdominal and cervical regions, were routinely performed, while brain MRI and bone scans were not mandatory. Telephone calls were also implemented when necessary.
Postoperative recurrence was diagnosed considering all the evidence provided by imaging scans and pathologic confirmation. Initial disease recurrence in the supraclavicular region was defined as SCR and first relapse developed at the surgical margin, ipsilateral hilum, and/or mediastinum was considered LRR. Initial disease recurrence beyond LRR and SCR, was categorized as distant metastasis (DM).
For patients with LRR, the PTVs were restored for those who received PORT and virtual PTVs were created for those who didn't receive PORT by independent radiation oncologist, according to our institutional protocol mentioned above. Meanwhile, for patients with SCR, individual virtual PTVs were created for ipsilateral ESRT (PTV-sc) by independent radiation oncologist, according to the CT atlas proposed by Lynch et al. (
Recurrence free survival (RFS) was calculated from surgery to initial disease recurrence. Overall survival (OS1) was calculated from surgery to death of any cause in the entire cohort and OS2 was calculated from initial disease recurrence to death of any cause in patients with recurrent disease. Differences between clinical parameters were compared using the χ2 and Fisher's exact tests. The predictors of SCR were selected using competing risk methodology and Stata version 13.1 software (StataCorp, College Station, TX, USA). The associations between clinic-pathological parameters and OS were identified using the Cox proportional hazard regression model. The hazard ratio (HR) and the 95% confidence interval (CI) were calculated using coefficients from the model. Kaplan–Meier method was used to estimate survival, and differences among groups were investigated by the log-rank test. Statistical analysis was performed using SPSS 21.0 (SPSS, Chicago, IL, USA). All assessment is considered to be significant when two-sided
A total of 311 patients were finally enrolled and a flowchart for patient selection was presented in
Disease characteristics.
≤ 65 | 151 (48.6) |
>65 | 160 (51.4) |
Female | 127 (40.8) |
Male | 184 (59.2) |
Ever smoker | 144 (46.3) |
Never smoker | 167 (53.7) |
0 | 252 (81.0) |
1 | 59 (19.0) |
cN0–1 | 147 (47.3) |
cN2 | 164 (52.7) |
Yes | 31 (10.0) |
No | 280 (90.0) |
Sublobar | 18 (5.8) |
Lobectomy | 276 (88.7) |
Pneumonectomy | 17 (5.5) |
pT0–2 | 262 (84.2) |
pT3–4 | 49 (15.8) |
Absent | 150 (48.2) |
Present | 161 (51.8) |
Absent | 195 (62.7) |
Present | 116 (37.3) |
Left lower lobe | 44 (14.1) |
Left upper lobe | 90 (29.0) |
Right lower lobe | 53 (17.0) |
Right middle lobe | 44 (14.1) |
Right upper lobe | 80 (25.7) |
Squamous cell carcinoma | 61 (19.6) |
Non-squamous non-small cell lung cancer | 250 (80.4) |
Post surgery, 94 patients received PORT and with a median follow up of 26 (range, 3–78) months, 203 patients developed recurrent disease, including 27 SCRs. Of note, 17 of the 27 SCRs were pathologically confirmed and the rest 10 were diagnosed by clinical assessments and radiographic findings. The 1, 3, and 5-year RFS were 56.9, 23.9, and 9.0%, in patients without PORT, respectively, and were 71.5, 42.7, and 27.4%, in patients with PORT, respectively. Among the 27 patients with SCR, 16 (59.3%) patients developed SCR without DM (
Patterns of supraclavicular recurrence.
The 1, 3, and 5-year cumulative incidence of SCR were 6.53, 13.0, and 24.7%, respectively (
Cumulative incidence and dynamics of supraclavicular recurrence.
Competing risk analyses of clinical-pathological variables associated with supraclavicular recurrence.
Age (>65 vs. ≤ 65) | 0.85 (0.40–1.81) | 0.671 | ||
Sex (Male vs. Female) | 1.23 (0.56–2.69) | 0.604 | ||
Smoking (Never vs. Ever) | 0.77 (0.35–1.69) | 0.577 | ||
ECOG (1 vs. 0) | 1.81 (0.62–5.26) | 0.279 | ||
cN2 (+ vs. –) | 2.58 (1.09–6.11) | |||
pT stage (T3–4 vs. T0–2) | 0.72 (0.22–2.41) | 0.599 | ||
pN1 (+ vs. –) | 0.83 (0.39–1.80) | 0.643 | ||
Multiple levels of pN2 (+ vs. –) | 1.13 (0.53–2.42) | 0.745 | ||
Histology (SCC vs. Non-SCC) | 1.24 (0.50–3.07) | 0.646 | ||
Differentiation (P vs. W/M) |
1.23 (0.57–2.65) | 0.603 | ||
LVI (+ vs. –) | 1.54 (0.72–3.31) | 0.271 | ||
VPI (+ vs. –) | 1.09 (0.49–2.43) | 0.836 | ||
PNI (+ vs. –) | 0.86 (0.20–3.64) | 0.834 | ||
ypN2 vs. pN2 | 4.61 (1.89–11.22) | 3.32 (1.30–6.50) | ||
Tumor Location (Left vs. Right) | 0.81 (0.38–1.73) | 0.582 | ||
Tumor Lobe (Upper vs. Others) | 1.25 (0.78–5.23) | 0.374 | ||
TLN (≥16 vs. <16) | 0.60 (0.28–1.29) | 0.190 | ||
PLN (≥3 vs. <3) | 0.95 (0.44–2.02) | 0.885 | ||
LNR (≥0.2 vs. <0.2) | 1.88 (0.84–4.19) | 0.123 | ||
Surgery (Others vs. Lobectomy) | 3.68 (1.61–8.42) | 1.32 (0.76–2.39) | 0.319 | |
PORT (+ vs. –) | 0.62 (0.27–1.43) | 0.260 | ||
ERCC1 (+ vs. –) | 0.90 (0.53–1.52) | 0.695 | ||
Her2 (+ vs. –) | 1.10 (0.67–1.78) | 0.715 | ||
Ki67 (≥50 vs. <50%) | 1.81 (0.84–3.88) | 0.129 | ||
TTF1 (+ vs. –) | 0.64 (0.33–1.24) | 0.181 | ||
CK20 (+ vs. –) | 1.07 (0.67–1.70) | 0.784 | ||
CK7 (+ vs. –) | 0.32 (0.15–0.68) | 0.46 (0.19–1.13) | 0.090 | |
CK5/6 (+ vs. –) | 1.24 (0.77–2.01) | 0.180 | ||
P63 (+ vs. –) | 1.13 (0.66–1.93) | 0.651 | ||
NapsinA (+ vs. –) | 0.91 (0.50–1.64) | 0.754 | ||
Syn (+ vs. –) | 1.23 (0.71–2.57) | 0.326 | ||
RRM1 (+ vs. –) | 0.99 (0.58–1.69) | 0.955 | ||
EGFR (+ vs. –) | 0.98 (0.54–1.79) | 0.946 |
In the entire cohort, 6 (6.38%) of the 94 patients who received PORT developed LRR, while 24 (11.1%) of the 217 patients who did not receive PORT developed LRR. PORT significantly reduced the risk of LRR (
Prognostic significance of postoperative radiotherapy and supraclavicular recurrence. The impact of postoperative radiotherapy (PORT) on loco-regional recurrence (LRR)
On the other hand, 8 (8.51%) of the 94 patients who received PORT developed SCR, while 19 (8.76%) of the 217 patients who did not receive PORT developed SCR in the entire cohort. PORT without ESRT didn't reduce the incidence of SCR (
By the time of data cut-off, 125 patients had died and the median OS1 was 49.0 (95CI 40.5–57.6) months. PORT was found to significant prolong OS1 in the entire cohort (
Cox analyses of clinical-pathological variables associated with overall survival (OS1).
Age (>65 vs. ≤ 65) | 1.64 (1.14–2.15) | 1.46 (1.01–2.12) | ||
Sex (Male vs. Female) | 1.49 (1.03–2.17) | 1.40 (0.94–2.08) | 0.097 | |
Smoking (Never vs. Ever) | 1.21 (0.85–1.73) | 0.285 | ||
ECOG (1 vs. 0) | 2.67 (1.71–4.19) | 2.22 (1.41–3.52) | ||
cN2 (+ vs. –) | 1.11 (0.78–1.57) | 0.575 | ||
pT stage (T3–4 vs. T0–2) | 1.19 (0.74–1.90) | 0.473 | ||
pN1 (+ vs. –) | 1.51 (1.01–2.25) | 0.042 | ||
Multiple levels of pN2 (+ vs. –) | 1.18 (0.83–1.67) | 0.366 | ||
Histology (SCC vs. Non-SCC) | 1.35 (0.88–2.08) | 0.167 | ||
Differentiation (P vs. W/M) |
1.05 (0.80–1.24) | 0.899 | ||
LVI (+ vs. –) | 1.49 (1.04–2.12) | 1.21 (0.84–1.75) | 0.297 | |
VPI (+ vs. –) | 1.29 (0.90–1.85) | 0.168 | ||
PNI (+ vs. –) | 1.22 (0.70–2.14) | 0.477 | ||
ypN2 vs. pN2 | 0.76 (0.37–1.55) | 0.445 | ||
Tumor Location (Left vs. Right) | 0.80 (0.56–1.14) | 0.217 | ||
Tumor Lobe (Upper vs. Others) | 1.17 (0.89–1.25) | 0.913 | ||
TLN (≥16 vs. <16) | 0.92 (0.63–1.33) | 0.644 | ||
PLN (≥3 vs. <3) | 1.46 (1.02–2.10) | 1.33 (0.80–2.21) | 0.274 | |
LNR (≥0.2 vs. <0.2) | 1.44 (1.01–2.07) | 1.29 (0.78–2.13) | 0.324 | |
Surgery (Others vs. Lobectomy) | 0.80 (0.43–1.49) | 0.483 | ||
PORT (+ vs. –) | 0.63 (0.42–0.93) | 0.61 (0.40–0.92) | ||
ERCC1 (+ vs. –) | 1.03 (0.80–1.32) | 0.825 | ||
Her2 (+ vs. –) | 0.92 (0.72–1.16) | 0.464 | ||
Ki67 (≥50 vs. <50%) | 1.65 (1.16–2.34) | 1.55 (1.06–2.25) | ||
TTF1 (+ vs. –) | 0.81 (0.59–1.10) | 0.181 | ||
CK20 (+ vs. –) | 0.96 (0.76–1.20) | 0.704 | ||
CK7 (+ vs. –) | 0.75 (0.49–1.14) | 0.178 | ||
CK5/6 (+ vs. –) | 1.07 (0.85–1.35) | 0.545 | ||
P63 (+ vs. –) | 1.02 (0.80–1.32) | 0.857 | ||
NapsinA (+ vs. –) | 0.79 (0.60–1.05) | 0.103 | ||
Syn (+ vs. –) | 0.521 (0.23–1.41) | 0.324 | ||
RRM1 (+ vs. –) | 0.891 (0.62–1.42) | 0.897 | ||
EGFR (+ vs. –) | 0.82 (0.62–1.08) | 0.155 |
Cox analyses of clinical-pathological variables associated with OS2 in patients with recurrent disease.
Age (>65 vs. ≤ 65) | 1.70 (1.17–2.47) | 1.49 (1.02–2.19) | ||
Sex (Male vs. Female) | 1.57 (1.07–2.30) | 1.74 (1.19–2.56) | ||
Smoking (Never vs. Ever) | 1.23 (0.86–1.77) | 0.260 | ||
ECOG (1 vs. 0) | 1.95 (1.22–3.10) | 2.02 (1.25–3.26) | ||
cN2 (+ vs. –) | 1.12 (0.78–1.61) | 0.534 | ||
pT stage (T3–4 vs. T0–2) | 1.15 (0.71–1.86) | 0.572 | ||
pN1 (+ vs. –) | 1.11 (0.74–1.65) | 0.622 | ||
Multiple levels of pN2 (+ vs. –) | 0.89 (0.62–1.27) | 0.517 | ||
Histology (SCC vs. Non-SCC) | 1.56 (0.99–2.42) | 0.051 | ||
Differentiation (P vs. W/M) |
1.04 (0.71–1.51) | 0.851 | ||
LVI (+ vs. –) | 1.35 (0.94–1.94) | 0.104 | ||
VPI (+ vs. –) | 1.07 (0.74–1.55) | 0.732 | ||
PNI (+ vs. –) | 0.96 (0.55–1.67) | 0.875 | ||
ypN2 vs. pN2 | 0.56 (0.28–1.16) | 0.118 | ||
Tumor Location (Left vs. Right) | 1.05 (0.73–1.50) | 0.810 | ||
Tumor Lobe (Upper vs. Others) | 1.03 (0.79–2.17) | 0.874 | ||
TLN (≥16 vs. <16) | 0.85 (0.65–1.42) | 0.849 | ||
PLN (≥3 vs. <3) | 1.14 (0.78–1.65) | 0.485 | ||
LNR (≥0.2 vs. <0.2) | 1.03 (0.72–1.50) | 0.361 | ||
Surgery (Others vs. Lobectomy) | 1.45 (0.76–2.77) | 0.266 | ||
PORT (+ vs. –) | 0.85 (0.66–1.23) | 0.414 | ||
DM (+ vs. –) | 6.49 (2.36–17.85) | 7.43 (2.67–20.68) | ||
ERCC1 (+ vs. –) | 1.04 (0.81–1.33) | 0.765 | ||
Her2 (+ vs. –) | 0.83 (0.65–1.07) | 0.152 | ||
Ki67 (≥50 vs. <50%) | 1.19 (0.83–1.70) | 0.356 | ||
TTF1 (+ vs. –) | 0.73(0.53–1.02) | 0.061 | ||
CK20 (+ vs. –) | 0.92 (0.72–1.16) | 0.472 | ||
CK7 (+ vs. –) | 0.87 (0.63–1.20) | 0.403 | ||
CK5/6 (+ vs. –) | 1.01 (0.80–1.27) | 0.955 | ||
P63 (+ vs. –) | 0.91 (0.71–1.18) | 0.484 | ||
NapsinA (+ vs. –) | 0.76 (0.57–1.02) | 0.063 | ||
Syn (+ vs. –) | 1.37 (0.92–2.35) | 0.781 | ||
RRM1 (+ vs. –) | 0.97 (0.71–1.42) | 0.971 | ||
EGFR (+ vs. –) | 0.84 (0.64–1.11) | 0.226 |
In order to investigate the prognostic significance of SCR, patients with recurrent disease were further divided into three groups: Group A consisted of patients who had DM (
To the best of our knowledge, this is the first comprehensive study specifically focusing on SCR in completely resected (y)pN2 NSCLC with a relatively large sample size, in the era of modern radiation technique. SCR was not uncommon and had imperative prognostic significance, indicating that treatment modalities able to reduce the incidence of SCR may be beneficial. Additionally, PORT without ESRT significantly reduced LRR and prolonged OS, but did not decrease SCR in our study, suggesting that the clinical value of ESRT may be reconsidered in selected patients with high risks of SCR.
SCR is not uncommon in completely resected (y)pN2 NSCLC, especially among those with extra risk factors. Although there was limited historical data published that could be directly compared, the incidence of SCR in our study was reliable, since the overall recurrence rate and the percentage of SCR among patients with recurrent disease were in accordance with previous findings. The cumulative incidence of postoperative recurrence in the PORT group and non-PORT group, were generally comparable with recent studies (
Compared with patients developing only LRR and those developing DM, patients developing SCR but without DM had intermediate OS2, highlighting the vital prognostic significance of SCR in curatively resected (y)pN2 NSCLC. The TNM staging system is one of the most powerful indicators of patient's prognosis in NSCLC, among which patients having supraclavicular lymph node metastasis (N3) generally have intermediate prognosis when compared with those having distant metastasis (M1) and those harboring metastatic tumor lesions limited to the ipsilateral hilar (N1) or mediastinal (N2) lymph nodes (
The clinical value of PORT in completely resected (y)pN2 NSCLC was demonstrated again in our study, but the delineation of CTV remain controversial. In the current study, PORT significantly reduced LRR and improved OS1, which have been demonstrated in various studies (
Our study also has some limitations. Firstly, since ESRT is not routinely performed in our cancer center, we could not directly examine the clinical value and prognostic significance of ESRT. Secondly, as this was a retrospectively study, treatment decisions and follow-up strategies were at the discretion of the treating physicians. Different neoadjuvant and adjuvant chemotherapy regimens were used and the protocols of follow-up were not identical. Moreover, since brain MRI and bone scans were not mandatory, asymptomatic brain and/or bone metastasis may be underestimated. Despite these limitations, we believe our study provided valuable information about the cumulative incidence and prognostic significance of SCR in completely resected (y)pN2 NSCLC, which may guide better design of adjuvant treatment modalities and individualized surveillance strategies.
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
The studies involving human participants were reviewed and approved by the institutional review board of Fudan University Shanghai Cancer Center. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.
LL, ZZ, and JN: conceptualization. LL and ZZ: methodology, validation, and writing—original draft preparation. LL, ZZ, and JL: formal analysis and investigation. LL, ZZ, and YL: resources and data curation. LL and JN: writing—review and editing. All the authors have approved the final manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The Supplementary Material for this article can be found online at:
Flowchart of patient enrollment. NSCLC, non-small cell lung cancer.