Abstract
Objective:
To validate selection criteria for sublobar resection in patients with lung cancer with respect to recurrence, and to investigate predictors for recurrence in patients for whom the criteria are not suitable.
Methods:
Patients who underwent sublobar resection for lung cancer between July 2010 and December 2018 were retrospectively included. The criteria for curative sublobar resection were consolidation-to-tumor ratio ≤0.50 and size ≤3.0 cm in tumors with a ground-glass opacity (GGO) component (GGO group), and size of ≤2.0 cm and volume doubling time ≥400 days in solid tumors (solid group). Cox regression was used to identify predictors for time-to-recurrence (TTR) in tumors outside of these criteria (non-curative group).
Results:
Out of 530 patients, 353 were classified into the GGO group and 177 into the solid group. In the GGO group, the 2-year recurrence rates in curative and non-curative groups were 2.1 and 7.7%, respectively (p = 0.054). In the solid group, the 2-year recurrence rates in curative and non-curative groups were 0.0 and 28.6%, respectively (p = 0.03). Predictors of 2-year TTR after non-curative sublobar resection were pathological nodal metastasis (hazard ratio [HR], 6.63; p = 0.02) and lymphovascular invasion (LVI; HR, 3.28; p = 0.03) in the GGO group, and LVI (HR, 4.37; p < 0.001) and fibrosis (HR, 3.18; p = 0.006) in the solid group.
Conclusion:
The current patient selection criteria for sublobar resection are satisfactory. LVI was a predictor for recurrence after non-curative resection.
Advances in knowledge:
This result supports selection criteria of patients for sublobar resection. LVI may help predict recurrence after non-curative sublobar resection.
Introduction
Sublobar resection for lung cancer has been widely used for high-risk patients limited by poor cardiopulmonary function, multiple comorbidities, or history of previous lung surgery. 1 Since recent multiple trials have shown comparable outcomes between sublobar resection and lobectomy in selected patients, 2–7 sublobar resection is considered a curative option. As pre-operative imaging-based selection criteria for curative sublobar resection, the JCOG 0201 study proposed a tumor size of 0–30 mm with a consolidation-to-tumor ratio (CTR) of 0.5 or less, because such tumors rarely show pathological invasiveness. 8 The National Comprehensive Cancer Network (NCCN) guidelines recommend that sublobar resection can be considered for peripheral nodules of 2 cm or less with at least one of the following features: (1) pure adenocarcinoma in situ, (2) CTR of 0.5 or less, or (3) volume doubling time (VDT) of 400 days or greater. 9 The VDT of tumors is one of the parameters representing aggressiveness, and a 400 day cut-off has been commonly used to distinguish between indolent and malignant lesions, 10,11 and VDT is the only criterion for pre-operative selection of patients who have solid lung cancers.
A high risk of local and locoregional failure remains a major concern in patients undergoing sublobar resection, 12–14 and risk factors for tumor recurrence after sublobar resection have been widely investigated. Tumor size, lymphovascular invasion (LVI), CTR, microscopic positive surgical margin, and visceral pleural invasion (VPI) were all associated with recurrence after sublobar resection. 15–18 However, previous studies did not consider lesion type (i.e. the presence of GGO) and the suitability of patients for sublobar resection according to the recommendations. In this sense, it is unclear whether the same risk factors are associated with recurrence in patients considered not suitable according to the suggested criteria, and whether there are differences in risk factors between subsolid and solid lung cancers. Furthermore, existing criteria based on tumor size, CTR, or VDT 8,9,19 have not been well validated in a real clinical setting.
Therefore, the purpose of our study was to validate patient selection criteria for sublobar resection of lung cancer with respect to tumor recurrence, and to investigate risk factors for recurrence in patients considered not suitable according to the existing criteria.
Methods and materials
This retrospective study was approved by our institutional review board, which waived the requirement for informed consent.
Study population
The electronic medical records of our institution (Asan Medical Center) were retrospectively searched to identify patients who received sublobar resection for non-small cell lung cancer (NSCLC) between January 2010 and December 2018. The inclusion criteria were: (1) patients who underwent chest CT within 2 months before surgery; and (2) available 1 mm or 1.25 mm slice-thickness CT. The exclusion criteria were minimally invasive adenocarcinoma, recurrent or metastatic tumors, synchronous lung cancer, history of neoadjuvant chemotherapy or other primary malignancy, and recurrence or death within 1 month after surgery. Of 1562 patients, 180 were reported in a previous retrospective study investigating CT features predicative of LVI in Stage IA lung cancer after sublobar resection. 20
Chest CT protocol
Chest CT was obtained with multidetector row CT scanners from two different manufacturers. The acquisition parameters were: 120 kVp, 30–200 mAs, pitch of 0.875–1, and collimation of 1–1.25 mm. Intravenous contrast media (90–120 ml) was injected at a rate of 3 ml/s, and scanning started after a delay of 50 s. Images were reconstructed using a sharp kernel with a slice thickness/interval of 1/1 or 1.25/1.25 mm (supplementary material).
Clinical tumor staging with chest CT and evaluation of CT features
Two radiologists (S.P. and S.M.L., with 5 and 17 years of experience in thoracic radiology, respectively) who were blinded to the pathological results evaluated T descriptors and CT features in consensus. The primary tumor characteristics included: GGO, air-bronchogram/bubble lucency, lobulation, spiculation, and pleural/fissure retraction. 21 The presence of underlying emphysema was considered when mild or more severe emphysema was present. 22 The presence of fibrosis was considered when there was extensive disease involving three or more of the six lung zones: right and left upper, middle, and lower. 23
One radiologist (S.P.) measured the longest diameter of each tumor and its solid portion on axial, coronal, and sagittal planes using electronic calipers and a lung window setting on a picture archiving and communication system, and the largest measurements in the three planes were recorded to determine tumor size and solid portion size. 24 The CTR was calculated as the ratio of the longest diameter of the solid portion divided by the longest tumor diameter.
Clinical and pathologic data collection
The age, sex, and smoking history of the patients, date and type of surgery, and dates of pre-operative CT and positron emission tomography-CT (PET-CT) scans were collected from medical records. Maximum standardized uptake values (SUVmax) of the primary lung cancers were obtained from the PET-CT reports. The histologic subtype, pathological nodal status, LVI, VPI, and resection margin distance of each tumor were collected from the pathologic report.
The patients’ follow-up data were obtained from the electronic medical records of our institution (Asan Medical Center) and time-to-recurrence (TTR) was used as the end point for survival analysis. TTR was calculated from the date of surgery until the date of locoregional tumor recurrence, distant metastasis, or death from the same cancer (event), or until the date that the patient was last known to be free of events (censored). 25
Analysis of VDT
In the patients with pure-solid tumors, tumor growth was defined as an increase in tumor size ≥2 mm between two 1- or 1.25 mm slice-thickness CT scans acquired at least 30 days apart. 26 The pre-operative CT and the first CT showing a visible lesion were selected. Tumor segmentation was performed using commercial software (Aview; Coreline Soft). Two radiologists confirmed the final regions of interest in consensus. After tumor segmentation, the software calculated the VDT of each tumor using the following equation adopted from a previous study 27 : VDT = [(T1 − T0) log 2]/[log (V1/V0)], where V1 and V0 are the volumes at T1 (time 1, second examination date) and T0 (time 0, baseline examination date). Detailed information is presented in the supplementary material.
Statistical analysis
Patients were classified into the GGO or solid group according to the presence or absence of GGO components. The patients’ characteristics were compared between the two groups using independent t-tests, Mann–Whitney U-tests, or χ2 tests, as appropriate. The Kaplan–Meier method and log-rank test were also used to compare the 2-year recurrence rates of patients in different subgroups according to the presence or absence of GGO components and curative or non-curative intent.
After excluding a subset of patients considered to have undergone curative sublobar resection according to JCOG trial and NCCN guidelines, 8,9 univariable and multivariable Cox proportional hazards models were used to identify potential predictive factors for TTR in the patients who underwent non-curative sublobar resection. Variables with p < 0.1 in the univariable analysis were entered into the multivariable analysis. The Kaplan–Meier method stratified by risk factors was used to describe the TTR rates. Analysis of risk factors for recurrence in the patients, including those who underwent curative sublobar resection, is presented in the supplementary material.
All statistical analyses were performed using SPSS software (v. 22.0, IBM Corporation), with p < 0.05 being considered to indicate statistical significance.
Results
Demographic and clinical characteristics
Out of 1562 patients who underwent sublobar resection for NSCLC, 530 (mean age, 64 ± 10 years; 279 men) were included in the final study population (Figure 1); 291 (54.9%) of these patients underwent wedge resection and 239 (45.1%) segmentectomy. Of the 530 patients, 353 were classified into the GGO group and 177 into the solid group. All collected clinical characteristics except for resection margin distance showed significant differences between the two groups (Table 1). The mean tumor size was 19 ± 7 mm (mean solid portion size, 13 ± 7 mm) in the GGO group and 21 ± 10 mm in the solid group.
Figure 1.
Flow diagram of patient inclusion. AIS, adenocarcinoma in situ; NSCLC, non-small cell lung cancer; MIA, minimal invasive adenocarcinoma.
Table 1.
Demographic and clinical characteristics of the total study population
| All patients (n = 530) |
GGO (n = 353) |
Solid (n = 177) |
p-value | |
|---|---|---|---|---|
| Age (mean ± SD, years) | 64 ± 10 | 63 ± 11 | 68 ± 9 | <0.001 a |
| Sex | <0.001 b | |||
| Male | 279 (52.6%) | 151 (42.8%) | 128 (72.3%) | |
| Female | 251 (47.4%) | 202 (57.2%) | 49 (27.7%) | |
| Tumor size
d
(mean ± SD, mm) |
20 ± 8 | 19 ± 7 | 21 ± 10 | 0.006 a |
| Solid portion size
d
(mean ± SD, mm) |
13 ± 7 | |||
| Smoking history | <0.001 b | |||
| Non-smoker | 294 (55.5%) | 241 (68.3%) | 53 (29.9%) | |
| Ex/current smoker | 236 (44.5%) | 112 (31.7%) | 124 (70.1%) | |
| Smoking amount (mean ± SD, pack-years) |
14.9 ± 21.7 | 8.6 ± 16.7 | 27.3 ± 25.1 | <0.001 a |
| cT category | <0.001 b | |||
| T1 | 494 (93.2%) | 348 (98.6%) | 146 (82.5%) | |
| T1a | 177 (33.4%) | 162 (45.9%) | 15 (8.5%) | |
| T1b | 226 (42.6%) | 141 (39.9%) | 85 (48.0%) | |
| T1c | 91 (17.2%) | 45 (12.7%) | 46 (26.0%) | |
| T2 | 34 (6.4%) | 5 (1.4%) | 29 (16.4%) | |
| T3 | 2 (0.4%) | 0 | 2 (1.1%) | |
| pN category | 0.004 b | |||
| N0 | 490 (92.5%) | 332 (94.1%) | 158 (89.3%) | |
| N1/2 | 19 (3.6%) | 6 (1.7%) | 13 (7.3%) | |
| Nx | 21 (4.0%) | 15 (4.2%) | 6 (3.4%) | |
| Pathological type | <0.001 b | |||
| Adenocarcinoma | 460 (86.8%) | 352 (99.7%) | 108 (61.0%) | |
| Squamous cell carcinoma | 46 (8.7%) | 0 (0.0%) | 46 (26.0%) | |
| Others | 24 (4.5%) | 1 (0.3%) | 23 (13.0%) | |
| SUVmax e | 3.7 ± 2.9 | 2.7 ± 1.9 | 6.8 ± 4.6 | <0.001 a |
| Resection margin distance (median [IQR], cm) |
1.00 [0.50, 1.80] |
1.00 [0.50, 1.80] |
1.00 [0.50, 1.70] |
0.71 c |
| Surgical method | <0.001 b | |||
| Wedge resection | 291 (54.9%) | 174 (49.3%) | 117 (66.1%) | |
| Segmentectomy | 239 (45.1%) | 179 (50.7%) | 60 (33.9%) |
CTR, consolidation-to-tumor ratio; GGO, ground-glass opacity;IQR, interquartile range; SD, standard deviation;SUVmax, maximum standardized uptake value.
Note: Unless otherwise indicated, data are the number of patients.
Percentages may not sum to 100 because of rounding.
Independent t-test.
Pearson’s χ2 test.
Mann–Whitney U-test.
The longest diameter among the axial, coronal, and sagittal planes.
183 (51.8%) patients in the GGO group and 62 (35.0%) in the solid group had missing values.
Validation of criteria for curative sublobar resection
Of the 353 patients in the GGO group, 97 patients were in the category with CTR ≤0.50 and size ≤3.0 cm. Among these 97 patients, 23 were in the category of CTR ≤0.25 and size ≤2.0 cm. The median follow-up time of the 97 patients for TTR was 47.2 months in these patients (range, 7.0–117.4). None of the 23 patients in the category of CTR ≤0.25 and size ≤2.0 cm experienced tumor recurrence, whereas 2 of 97 patients (2.1%) in the category of CTR ≤0.50 and size ≤3.0 cm experienced tumor recurrence (one local recurrence and one regional recurrence; Figure 2). The 2- year recurrence rate in these patients was 2.1%. Both LVI and pathological nodal metastasis were negative in all 97 patients.
Figure 2.
A 63-year-old male with local recurrence after sublobar resection of primary adenocarcinoma of the lung. (a) The axial CT image with a lung window setting shows a 22 mm part-solid nodule in the right lower lobe. The size of its solid component (arrowheads) was measured to be 6 mm and thus the consolidation-to-tumor ratio was 0.27. The patient underwent segmentectomy and the tumor was confirmed to be an adenocarcinoma without lymphovascular invasion on pathology. On post-operative follow-up CT at 13 months after surgery (b), the axial CT image with a lung window setting shows a tiny new nodule (arrow) developing adjacent to the interlobar fissure and the surgical materials in the right middle lobe. After a further 8 months and at 21 months after surgery, (b, c) axial and coronal CT images with a lung window setting show that the nodule (arrow) has increased in size and appears to be part-solid; it was considered to be a local recurrence. The patient was treated with stereotactic radiotherapy and continued follow-up.
Of the 177 patients in the solid group, 100 had a tumor size of ≤2.0 cm, and 26 of these (26.0%) experienced tumor recurrence within a median follow-up time of 34.2 months (range, 0.6–79.0). In the 100 patients with a tumor size of ≤2.0 cm, VDT was analyzable in 31, and the median interval between the two CT scans was 234 days (range, 47–1918 days). The median VDT was 292 days (range, 51–1776 days) and 11 patients had a VDT ≥400 days. Among the patients who had two thin-slice CT scans but showed no tumor growth, an additional four patients were classified as having a VDT ≥400 days, assuming the lesion to be a sphere and a minimum change of 2 mm in diameter between the two CT scans. Among the 15 patients with VDT ≥400 days, one (6.7%) experienced tumor recurrence (distant metastasis) within a median follow-up time of 38.0 months (range, 6.8–64.4 months). Since the only recurrence occurred at 35.2 months after surgery, the 2-year recurrence rate in these patients was 0.0%.
65 patients with a tumor size of ≤2.0 cm but without available VDT data were excluded from the analysis. Their median follow-up time was 32.2 months, and 17 of them (26.2%) experienced tumor recurrence.
Risk factors for recurrence in GGO-group patients considered not suitable for curative sublobar resection
In the GGO group, 256 patients in the category of CTR >0.50 or size >3.0 cm were considered to have undergone non-curative sublobar resection. In these patients, the median follow-up time for TTR was 38.6 months (range, 0.4–126.2) and tumor recurrence occurred in 21/256 (8.2%; seven local recurrences, six regional recurrences, and eight distant metastasis), with 19 (7.4%) showing occurrence within 2 years after surgery. The 2-year recurrence rate in these patients was 7.7%, which was higher than in the GGO-group patients with criteria for curative intent (2.1%, p = 0.054; Supplementary Figure 1).
LVI, VPI, and pathological nodal metastasis were more frequent in patients with recurrence than in patients without recurrence (Table 2). As fibrosis was extremely rare (3/256) and none of the patients with fibrosis had recurrence, it was excluded from the analysis. Univariable analysis revealed that 2-year TTR was associated with tumor size (p = 0.01), solid portion size (p = 0.002), LVI (p < 0.001), VPI (p = 0.03), pN category (p = 0.01), SUVmax (p = 0.04), and spiculation (p = 0.02) (Table 3). SUVmax was excluded from the multivariable analysis because of a large number of missing values (127/256). In the multivariable analysis, solid portion size (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.00–1.15; p = 0.04), pN category (HR, 6.63; 95% CI, 1.44–30.64; p = 0.02), LVI (HR, 3.28; 95% CI, 1.13–9.50; p = 0.03), and spiculation (HR, 4.49; 95% CI, 1.26–16.02; p = 0.02) were independent risk factors for 2 year TTR (Figure 3). Given the minimum number of events per predictor parameter, areas under the receiver operating characteristics curves (AUC) were obtained by combining two out of four predictors. As a result, pN category and LVI showed the highest AUC of 0.664 (Supplementary materials). Kaplan–Meier curves for 2-year TTR stratified by LVI and pN category are shown in Figure 4.
Table 2.
Comparisons between those with and without tumor recurrence in GGO-group patients who underwent non-curative sublobar resection (n = 256)
| No recurrence (n = 234) | Recurrence (n = 22) | p-value | |
|---|---|---|---|
| Age | 63.3 ± 10.3 | 67.4 ± 12.5 | 0.08 a |
| Sex | 0.07 b | ||
| Female | 143 (61.1%) | 9 (40.9%) | |
| Male | 91 (38.9%) | 13 (59.1%) | |
| Tumor size (mm) | 19 ± 7 | 23 ± 10 | 0.04 a |
| Solid portion size (mm) | 15 ± 6 | 19 ± 9 | 0.008 a |
| CTR | 0.78 ± 0.14 | 0.83 ± 0.14 | 0.12 a |
| Smoking status | 0.08 b | ||
| Non-smoker | 169 (72.2%) | 12 (54.5%) | |
| Ex/current smoker | 65 (27.8%) | 10 (45.5%) | |
| Smoking amount (pack-years) | 7.3 ± 15.8 | 13.0 ± 19.9 | 0.11 b |
| Surgical method | 0.45 b | ||
| Wedge resection | 108 (46.2%) | 12 (54.5%) | |
| Segmentectomy | 126 (53.8%) | 10 (45.5%) | |
| pN category | 0.03 b | ||
| N0 or Nx | 230 (98.3%) | 20 (90.9%) | |
| N1/2 | 4 (1.7%) | 2 (9.1%) | |
| Lymphovascular invasion | 11 (4.7%) | 5 (22.7%) | 0.001 b |
| Visceral pleural invasion | 10 (4.3%) | 3 (13.6%) | 0.06 b |
| Resection margin distance (cm) | 1.3 ± 1.1 | 1.2 ± 1.2 | 0.44a |
| SUVmax c | 2.6 ± 1.4 | 3.2 ± 2.1 | 0.16 a |
| Air-bronchogram/bubble lucency | 127 (54.3%) | 8 (36.4%) | 0.11 b |
| Spiculation | 123 (52.6%) | 18 (81.8%) | 0.008 b |
| Pleural/fissure retraction | 148 (63.2%) | 16 (72.7%) | 0.38 b |
| Emphysema | 30 (12.8%) | 6 (27.3%) | 0.06 b |
| Fibrosis | 3 (1.3%) | 0 (0.0%) | 0.59 b |
CTR = consolidation-to-tumor ratio, GGO = ground-glass opacity, SUVmax = maximum standardized uptake value.
Note: Unless otherwise indicated, data are the number of patients.
Percentages may not sum to 100 because of rounding.
Independent t-test.
Pearson’s χ2 test.
†127 missing values were replaced with the median.
Table 3.
Univariable and multivariable Cox proportional hazards model analysis of 2-year time to recurrence in GGO-group patients not suitable for curative sublobar resection (n = 256)
| Variables | Univariable analysis | Multivariable analysis | ||
|---|---|---|---|---|
| HR (95% CI) | p-value | HR (95% CI) | p-value | |
| Age | 1.05 (1.00, 1.10) | 0.07 | ||
| Sex | ||||
| Female | Reference | |||
| Male | 1.77 (0.74, 4.28) | 0.20 | ||
| Tumor size | 1.06 (1.01, 1.12) | a0.01 | ||
| Solid portion size | 1.10 (1.03, 1.16) | a0.002 | 1.07 (1.00, 1.15) | a0.04 |
| CTR (unit = 0.1) | 1.29 (0.94, 1.79) | 0.12 | ||
| Smoking status | ||||
| Non-smoker | Reference | |||
| Ex/current smoker | 1.62 (0.66, 3.97) | 0.29 | ||
| Smoking amount (pack-year) | 1.01 (0.99, 1.03) | 0.36 | ||
| Surgical method | ||||
| Wedge resection | Reference | |||
| Segmentectomy | 0.71 (0.30, 1.72) | 0.45 | ||
| pN category | ||||
| N0 or Nx | Reference | Reference | ||
| N1/2 | 6.67 (1.55, 28.77) | a0.01 | 6.63 (1.44, 30.64) | a0.02 |
| Lymphovascular invasion | 6.79 (2.44, 18.87) | a<0.001 | 3.28 (1.13, 9.50) | a0.03 |
| Visceral pleural invasion | 4.06 (1.19, 13.89) | a0.03 | . | |
| Resection margin distance | 0.79 (0.49, 1.28) | 0.35 | ||
| SUVmaxb | 1.21 (1.00, 1.45) | a0.04 | ||
| Air-bronchogram/bubble lucency | 0.47 (0.19, 1.18) | 0.11 | ||
| Spiculation | 4.75 (1.39, 16.20) | a0.02 | 4.49 (1.26, 16.02) | a0.02 |
| Pleural/fissure retraction | 1.38 (0.53, 3.60) | 0.51 | . | |
| Emphysema | 1.50 (0.50, 4.50) | 0.47 | ||
CI, confidence interval; CTR, consolidation-to-tumor ratio HR, hazard ratio;GGO, ground-glass opacity; SUVmax, maximum standardized uptake value.
A significant difference at p < .05.
127 missing values were be replaced with median.
Figure 3.
A 50-year-old female with ipsilateral lung metastases after sublobar resection of primary adenocarcinoma of the lung. (a, b) Axial and coronal CT images with a lung window setting show a 21 mm part-solid nodule with spiculation (arrows) in the left lower lobe. The size of its solid component (arrowheads) was measured as 14 mm, and therefore the consolidation-to-tumor ratio was 0.67. The patient underwent wedge resection and the tumor was confirmed to be an adenocarcinoma without lymphovascular invasion on pathology. On post-operative follow-up CT at 15 months after surgery, (c) axial CT images with a lung window setting show multiple tiny new nodules in the left upper lobe (arrow) and left lower lobe (not shown). After a further 15 months and 30 months after surgery, (d) the size and number of the part-solid nodules had increased (arrows) and they patient was considered to have ipsilateral lung metastasis. The patient is being closely followed for signs of progression and is considering chemotherapy.
Figure 4.
Kaplan–Meier curves showing estimated time to recurrence in the 256 patients with CTR >0.50 or size >3.0 cm in the GGO group stratified by LVI (a) and pN category (b), and in the 97 patients with tumor size >2.0 cm or VDT <400 days in the solid group stratified by LVI (c) and fibrosis (d). CTR, consolidation-to-tumor ratio; GGO, ground-glass opacity; LVI, lymphovascular invasion; VDT, volume doubling time.
Risk factors for recurrence in solid-group patients considered not suitable for curative sublobar resection
In the solid group, 77 patients with tumor size >2.0 cm, and 20 patients with tumor size ≤2.0 cm but with VDT <400 days, were considered to have undergone non-curative sublobar resection. In these 97 patients, the median follow-up time for TTR was 31.6 months (range, 0.4–102.0), and tumor recurrence occurred in 28.9% (28/97, 5 local recurrences, 10 regional recurrences, and 13 distant metastasis), with 26 recurrences (26.8%) occurring within 2 years after surgery. The 2-year recurrence rate in these patients was 28.6%, which was worse than in the solid-group patients with criteria for curative intent (0.0%, p = 0.03; Supplementary Figure 1).
LVI, VPI, and pathological nodal metastasis were more frequent in patients with recurrence that in patients without recurrence (Table 4). Fibrosis was present in 21.6% (21/97), of whom 42.9% (9/21) had recurrence. Univariable analysis revealed that 2-year TTR was associated with LVI (p < 0.001), VPI (p = 0.03), pN category (p = 0.01), and fibrosis (p = 0.02; Table 5). In the multivariable analysis, LVI (HR, 4.37; 95% CI, 1.97–9.72; p < 0.001) and fibrosis (HR, 3.18, 95% CI, 1.39–7.28; p = 0.006) were independent risk factors for 2-year TTR (Figures 4 and 5).
Table 4.
Comparisons between patients with and without tumor recurrence in solid-group patients who underwent non-curative sublobar resection (n = 97)
| No recurrence (n = 69) | Recurrence (n = 28) |
p-value | |
|---|---|---|---|
| Age | 68.2 ± 8.9 | 69.9 ± 7.4 | 0.39 a |
| Sex | 0.01 b | ||
| Female | 13 (18.8%) | 5 (17.9%) | |
| Male | 56 (81.2%) | 23 (82.1%) | |
| Tumor size (mm) | 28 ± 9 | 26 ± 11 | 0.40 a |
| Smoking status | 0.67 b | ||
| Non-smoker | 15 (21.7%) | 5 (17.9%) | |
| Ex/current smoker | 54 (78.3%) | 23 (82.1%) | |
| Smoking amount (pack-years) | 32.2 ± 25.9 | 26.9 ± 21.8 | 0.34 a |
| Surgical method | 0.68 b | ||
| Wedge resection | 45 (65.2%) | 17 (60.7%) | |
| Segmentectomy | 24 (34.8%) | 11 (39.3%) | |
| pN category | 0.17 b | ||
| N0 or Nx | 65 (94.2%) | 23 (82.1%) | |
| N1/2 | 4 (5.8%) | 5 (17.9%) | |
| Lymphovascular invasion | 11 (15.9%) | 16 (57.1%) | <0.001 b |
| Visceral pleural invasion | 14 (20.3%) | 12 (42.9%) | 0.02 b |
| Resection margin distance (cm) | 1.3 ± 1.3 | 1.3 ± 1.2 | 0.93 a |
| SUVmax c | 7.6 ± 3.8 | 8.8 ± 4.1 | 0.15 a |
| Air-bronchogram/bubble lucency | 15 (21.7%) | 6 (21.4%) | 0.001 b |
| Spiculation | 54 (78.3%) | 16 (57.1%) | 0.04 b |
| Pleural/fissure retraction | 40 (58.0%) | 15 (53.6%) | 0.69 b |
| Emphysema | 41 (59.4%) | 16 (57.1%) | 0.04 b |
| Fibrosis | 12 (17.4%) | 9 (32.1%) | 0.11 b |
CTR = consolidation-to-tumor ratio, SUVmax = maximum standardized uptake value.
Note: Unless otherwise indicated, data are the number of patients.
Percentages may not sum to 100 because of rounding.
Independent t-test
Pearson’s χ2 test.
31 missing values were replaced with median.
Table 5.
Univariable and multivariable Cox proportional hazards model analysis of 2-year time to recurrence in solid-group patients not suitable for curative sublobar resection (n = 97)
| Variables | Univariable analysis | Multivariable analysis | ||
|---|---|---|---|---|
| HR (95% CI) | p-value | HR (95% CI) | p-value | |
| Age | 1.02 (0.98, 1.07) | 0.37 | ||
| Sex | ||||
| Female | reference | |||
| Male | 1.44 (0.50, 4.18) | 0.50 | ||
| Tumor size | 1.00 (0.96, 1.04) | 0.79 | ||
| Smoking status | ||||
| Non-smoker | reference | |||
| Ex/current smoker | 1.68 (0.58, 4.86) | 0.34 | ||
| Smoking amount (pack-years) | 1.00 (0.98, 1.01) | 0.57 | ||
| Surgical method | ||||
| Wedge resection | reference | |||
| Segmentectomy | 0.82 (0.36, 1.83) | 0.62 | ||
| pN category | ||||
| N0 or Nx | reference | |||
| N1/2 | 3.61 (1.34, 9.76) | a0.01 | ||
| Lymphovascular invasion | 4.50 (2.06, 9.85) | a<0.001 | 4.37 (1.97, 9.72) | a<0.001 |
| Visceral pleural invasion | 2.36 (1.08, 5.14) | a0.03 | . | |
| Resection margin distance | 0.96 (0.71, 1.31) | 0.81 | ||
| SUVmaxb | 1.07 (0.98, 1.17) | 0.14 | ||
| Air-bronchogram/bubble lucency | 0.83 (0.31, 2.20) | 0.70 | ||
| Spiculation | 0.58 (0.26, 1.27) | 0.17 | . | |
| Pleural/fissure retraction | 0.91 (0.42, 1.97) | 0.82 | ||
| Emphysema | 0.97 (0.45, 2.12) | 0.94 | ||
| Fibrosis | 2.59 (1.15, 5.83) | a0.02 | 3.18 (1.39, 7.28) | a0.006 |
CI, confidence interval; HR, hazard ratio;SUVmax, maximum standardized uptake value.
A significant difference at p < .05.
31 missing values were replaced with median.
Figure 5.
A 65-year-old male with pleural metastases after sublobar resection of primary large cell neuroendocrine carcinoma of the lung. (a) The axial CT scan of the initial study shows a small round solid nodule in the right lower lobe and background lung with honeycombing cysts, indicating end-stage lung fibrosis. The volume of the tumor was calculated as 0.39 ml. (b) In the axial CT scan after 8 months, the lesion is slightly enlarged and its volume has increased to 0.85 ml. The volume doubling time was 224.2 days. The patient underwent wedge resection considering the small lesion size and their poor lung function. The tumor was confirmed to be a large cell neuroendocrine carcinoma with lymphovascular invasion on pathology. On the first post-operative follow-up CT at 5 months after surgery, (c) the axial CT image with a lung window setting shows several new nodules at the right interlobar fissure (arrowheads). On the next follow-up CT at 11 months after surgery, (d) fissural nodules were markedly enlarged (arrowheads) indicating pleural metastasis. The patient continued follow-up while receiving chemotherapy.
Discussion
Despite the increasing use of sublobar resection, it is unclear whether patients selected according to criteria based on tumor size, CTR, and VDT on CT have a low risk of recurrence after surgery. In addition, the risk factors for recurrence have not been investigated in patients considered not suitable for curative sublobar resection according to the selection criteria. In our study, patients who met the criteria for curative sublobar resection showed a low 2-year recurrence rate (2.1% in GGO group and 0.0% in solid group). Risk factors for 2-year TTR in patients who underwent non-curative sublobar resection were pN category (HR, 6.63; p = 0.02) and LVI (HR, 3.28; p = 0.03) in the GGO group and LVI (HR, 4.37; p < 0.001) and fibrosis (HR, 3.18; p = 0.006) in the solid group.
Generally, sublobar resection for lung cancer is not considered a curative option, but can have a curative effect for selected lung cancers. For lung cancers including GGO, JCOG proposed criteria of CTR ≤0.50 and size ≤3.0 cm. In our study, only 2 of 97 patients in these criteria experienced tumor recurrence. In 15 patients with solid lung cancers classified according to the NCCN-proposed selection criteria (tumor size of <2.0 cm and VDT ≥ 400 days), only one patient experienced tumor recurrence (at 35.2 months after surgery). Although VDT could only be analyzed in a limited number of patients (31 of 100 patients with tumor size of ≤2.0 cm), it demonstrated the ability to discriminate tumors with a low risk of recurrence. Given that VDT is the only criterion other than tumor size in solid lung cancer, VDT may need to be used more in clinical practice. On the basis of our results, the current criteria for sublobar resection candidates can be considered to be satisfactory. Further investigations on the verification of our observations in a large population are warranted.
Of note, sublobar resection in patients who underwent non-curative sublobar resection also achieved good outcomes (2-year recurrence rate, 7.7%) in the GGO group. The risk factors for 2-year TTR after non-curative sublobar resection were pN category and LVI. Pathological nodal metastasis was positive in only 2.3% (6/256) of patients in the GGO group and one-third of patients with pathological nodal metastasis (33.3% [2/6]) experienced recurrence. Our results correspond with those of a previous study in patients who underwent lobectomy or pneumonectomy for NSCLC, 28 which showed that GGO was a favorable predictor of survival only in patients of pN0 category (adjusted HR, 0.47 for 5-year overall survival; p = .002), not in those of pN1/2. Therefore, the appropriate extent of lymph node dissection may be necessary in sublobar resection for tumors with GGO.
Contrary to the results in the GGO group, the recurrence rate of non-curative sublobar resection in the solid group was higher than that of curative resection (2-year recurrence rate, 28.6% vs 0.0%; p = 0.03). The higher recurrence rate of sublobar resection should be considered when deciding on surgical methods for patients not suitable according to current criteria. In our analysis, fibrosis was identified as an independent predictor of recurrence. As a previous study 29 reported that the median VDT of lung cancers in idiopathic interstitial pneumonia (78.2 days) was significantly shorter than in chronic obstructive pulmonary disease (126.1 days; p = 0.004), fibrosis might be associated with rapid tumor growth and aggressiveness. Considering that fibrosis is recognizable on pre-operative CT, analysis of fibrosis on CT should be helpful for determination of surgical resection method and prediction of surgical outcome.
LVI was the only risk factor common to both GGO and solid groups. Even though LVI is not included in the descriptors of the current lung cancer staging system, many previous studies have consistently shown it to be a negative prognostic factor in Stage I NSCLC, 30–32 and a few studies have suggested the use of adjuvant chemotherapy in Stage I patients with LVI. 33,34 Our results also support its prognostic importance, particularly after sublobar resection. LVI discovered after surgery may indicate a requirement for close surveillance or adjuvant treatment.
Our study has several limitations. First, our study was a retrospective study. Second, VDT could not be calculated in most of the patients in the solid group (69/100) because VDT requires two or more CT scans at least 30 days apart to capture tumor growth. Therefore, there will be limitations to the widespread application of VDT as an ideal parameter for selecting candidates for curative sublobar resection. Third, not all tumor recurrences were pathologically confirmed, and some were partly diagnosed by a clinical–radiological consensus.
In conclusion, the existing criteria for identifying patients suitable for curative-intent sublobar resection were found to be satisfactory, with such patients having a significantly lower rate of recurrence than those undergoing non-curative resection. LVI and a pN category in tumors with GGO components, and LVI and fibrosis in solid tumors, were risk factors for recurrence after non-curative sublobar resection.
Contributor Information
Sohee Park, Email: sohee706@gmail.com.
Sang Min Lee, Email: sangmin.lee.md@gmail.com.
Jooae Choe, Email: jooae23@gmail.com.
Sehoon Choi, Email: choishn@gmail.com.
Sehee Kim, Email: seheek2050@gmail.com.
Kyung-Hyun Do, Email: dokh@amc.seoul.kr.
Joon Beom Seo, Email: seojb@amc.seoul.kr.
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