Prognostic ability of new T1 descriptors in the tumour, node and metastasis classification of surgically treated non-small-cell lung cancer

Prognostic ability of new T1 descriptors in the tumour, node and metastasis classification of... Abstract OBJECTIVES In the tumour, node and metastasis (TNM) classification (8th edition) of non-small-cell lung cancer, T (tumour size) is determined solely according to the size of the solid component determined using computed tomography (CT). However, it is unclear whether tumours of equal size but with differing solid and part-solid components should be similarly treated. Herein, we assessed the prognostic significance of the newly proposed T1 descriptors with respect to the size of the solid component. METHODS We analysed overall survival (OS) and disease-free survival (DFS) between groups of patients (n = 255) with solid or part-solid tumours using propensity score matching. The new staging system was used for classification and comparison of survival. RESULTS Chest CT detected 7 non-solid tumours, 123 part-solid tumours and 125 solid tumours. The 5-year OS and DFS rates differed significantly between the solid tumour (OS 71.2%; DFS 65.4%) and part-solid tumour (OS 83.2%; DFS 78.2%) groups. However, among 81 propensity score matching pairs (including those matched according to the size of the solid component), OS and DFS did not significantly differ between groups. The 5-year OS rates according to disease stage were as follows: cIA1 88.0%; cIA2 79.4% and cIA3 67.6%. CONCLUSIONS Propensity score matching of solid tumour and part-solid tumour groups did not reveal a significant difference in survival as a function of the size of the solid component. A study of a larger cohort is required to validate this result. Non-small-cell lung cancer , Tumour, Node and metastasis staging , Surgical resection , Prognosis INTRODUCTION With approximately 1.61 million new cases each year, lung cancer continues as the most common cancer [1]. Widespread screening using low-dose helical computed tomography (CT) has led to a higher early detection rate of small lung cancers [2]. Since the 1970s, tumour size has served as a primary descriptor and as a significant prognostic factor of lung cancer, which is included in the tumour, node and metastasis (TNM) classification of the staging system of the Union for International Cancer Control [3]. Tumour size, which represents an important tumour descriptor, reflects cancer progression, significantly correlates with prognosis and is easy to measure. According to the new classification (8th edition), which was revised in 2017, T classifications from T1 to a portion of T4 are classified according to tumour size. Thus, only the size of the solid component determined using CT or the size of the invasive component determined on pathological examination is considered, because the size of the solid, invasive component determines prognosis [4]. Studies of the correlations between radiological and pathological characteristics of lung cancer associated with its malignant phenotype reveal that radiologically detected non-solid or part-solid lung adenocarcinomas with components exhibiting ground-glass opacity (GGO) indicate good prognosis and that the pathological features of most cases indicate minimal invasion [5–8]. However, radiologically detected solid lung cancers are considered highly malignant. For example, postoperative nodal involvement occurs in 15–20% of patients, including those with small lung cancers [9, 10]. Therefore, radiologically determined solid lung cancers are considered more malignant when compared with non-solid or part-solid tumours. Moreover, it is unclear whether patients with solid tumours should be treated similar to those with part-solid tumours with solid components of equal size. In this study, we assessed the prognostic value of the newly proposed T1 descriptors according to the size of the solid component of patients with non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS Patients We analysed 255 consecutive patients diagnosed with clinical Stage IA NSCLC, according to the TNM classification (7th edition), who underwent lobectomies at our institution between January 2005 and December 2010. All patients underwent lobectomies, dissection of hilar lymph nodes and specific mediastinal lymph node stations depending on the lobar location of the primary tumour (Stations 2R and 4R for the right upper lobe; Stations 4L, 5L and 6L for the left upper lobe; Stations 2R, 4R, 7, 8 and 9 for the right middle lobe and lower lobe and 4L, 5L, 6L, 7, 8 and 9 for the left lower lobe). Each patient was granted written informed consent to use her or his medical records. The institutional review board approved this study. Perioperative examination Clinical staging was determined according to findings of chest and upper abdomen CT; brain CT or magnetic resonance imaging (MRI) and radionuclide bone scans or positron emission tomography with fluorine-18 fluorodeoxyglucose (FDG-PET), or both. Follow-up examinations were usually conducted every 2–3 months for the first 2 years and every 3–6 months thereafter. Routine follow-up procedures included a physical examination, haematological examination and chest radiography. Chest and abdominal CTs were performed at least once each year. If recurrent disease was suspected, further evaluations, such as MRI and FDG-PET, were performed. Recurrent NSCLC was diagnosed according to physical examinations and diagnostic imaging consistent with recurrent disease. When clinically feasible, diagnoses were histologically confirmed. The date of recurrence was defined as when recurrence was histologically proved or in cases that were diagnosed using clinical evidence, the date when recurrent disease was recognized by the attending physician. Radiological evaluation of primary tumours Contrast-enhanced CT scans of the entire lung were routinely performed during each preoperative examination. Images were viewed in standard lung windows (level −500 to −700 HU; width 1500–2000 HU). The sizes of the whole tumour and the solid component size indicate the maximum diameter of the tumour and the solid part of the tumour, respectively. Tumours were divided into non-solid tumours, part-solid tumours or solid tumours, according to the ratios of the maximum consolidation diameter to maximum tumour diameter (CTR) in thin-section CT images (non-solid, CTR = 0; part solid, 0< CTR <1; solid, CTR = 1). Data collection and extraction Demographic, clinical and treatment data were acquired from an institutional database that included all patients who underwent thoracic surgery. TNM staging was determined according to the 7th edition of the TNM classification [11] and reclassified according to the 8th edition [4], using the maximum consolidation diameter of each case. Statistical analysis Comparisons of continuous and dichotomous variables between groups were performed using the Student’s t-test and the χ2 test, respectively. The probability of survival was estimated using the Kaplan–Meier method. The significance of differences in survival was evaluated using log-rank tests. Univariable and multivariable analyses of all patients were performed to identify significant prognostic factors of overall survival (OS). Variables for survival analyses included age, sex, histology, pathological nodal status and sizes of the whole tumour and its solid component. Age, size of the whole tumour and the size of the solid component were analysed as continuous variables. Variables that were significantly associated with OS in univariable analyses were subjected to multivariable analyses using a Cox proportional hazards regression model. Propensity score matching (PSM) was added as an exploratory analysis of survival among patients with solid tumours and part-solid tumours to balance the size of the solid. Propensity scores were calculated using logistic regression analysis that included the preoperative variables age, sex and solid component size. Matching was performed at a 1:1 ratio and caliper distance = 0.20. All analyses were conducted using the JMP software package (version 11, SAS Institute Inc.). P-value <0.05 was considered significant. RESULTS The characteristics of the 255 patients are summarized in Table 1. Preoperative chest CT detected 7 non-solid tumours, 123 part-solid tumours and 125 solid tumours. All patients underwent pulmonary lobectomy and lymph node dissection. The median follow-up after surgical resection was 60 (range 1–123) months. Mean tumour measurements were as follows: whole tumour 20 (range 0–30) mm, solid component 17 (0–30) mm and CTR 0.84 (0–1.0) (Table 1). Clinical stages (TNM, 8th edition) were as follows: Stage 0, n = 7 (3%); Stage IA1, n = 44 (17%); Stage IA2, n = 125 (49%) and Stage IA3, n = 79 (31%). Table 1: Patient characteristics and sizes of the whole tumour and solid components Variables n = 255 Age (years), mean (range) 66 (23–88) Sex, n (%)  Male 129 (51)  Female 126 (49) Pack-year smoking, n (%)  <20 142 (56)  ≥20 113 (44) Computed tomography findings, n (%)  Non-solid 7 (3)  Part-solid 123 (48)  Solid 125 (49) Histology, n (%)  Adenocarcinoma 219 (86)  Squamous cell carcinoma 28 (11)  Others 8 (3) Whole tumour size (mm), mean (range) 20 (7–30) Solid component size (mm), mean (range) 17 (0–30) CTR, mean (range) 0.84 (0–1) cT descriptor, 8th edition, n (%)  Tis 7 (3)  T1mi 7 (3)  T1a 37 (15)  T1b 125 (49)  T1c 79 (31) cTNM stage, 8th edition, n (%)  0 7 (3)  IA1 44 (17)  IA2 125 (49)  IA3 79 (31) Pathological nodal status, n (%)  N0 221 (87)  N1 16 (6)  N2 18 (7) Variables n = 255 Age (years), mean (range) 66 (23–88) Sex, n (%)  Male 129 (51)  Female 126 (49) Pack-year smoking, n (%)  <20 142 (56)  ≥20 113 (44) Computed tomography findings, n (%)  Non-solid 7 (3)  Part-solid 123 (48)  Solid 125 (49) Histology, n (%)  Adenocarcinoma 219 (86)  Squamous cell carcinoma 28 (11)  Others 8 (3) Whole tumour size (mm), mean (range) 20 (7–30) Solid component size (mm), mean (range) 17 (0–30) CTR, mean (range) 0.84 (0–1) cT descriptor, 8th edition, n (%)  Tis 7 (3)  T1mi 7 (3)  T1a 37 (15)  T1b 125 (49)  T1c 79 (31) cTNM stage, 8th edition, n (%)  0 7 (3)  IA1 44 (17)  IA2 125 (49)  IA3 79 (31) Pathological nodal status, n (%)  N0 221 (87)  N1 16 (6)  N2 18 (7) CTR: ratio of the maximum diameter of consolidation to the maximum tumour diameter. Table 1: Patient characteristics and sizes of the whole tumour and solid components Variables n = 255 Age (years), mean (range) 66 (23–88) Sex, n (%)  Male 129 (51)  Female 126 (49) Pack-year smoking, n (%)  <20 142 (56)  ≥20 113 (44) Computed tomography findings, n (%)  Non-solid 7 (3)  Part-solid 123 (48)  Solid 125 (49) Histology, n (%)  Adenocarcinoma 219 (86)  Squamous cell carcinoma 28 (11)  Others 8 (3) Whole tumour size (mm), mean (range) 20 (7–30) Solid component size (mm), mean (range) 17 (0–30) CTR, mean (range) 0.84 (0–1) cT descriptor, 8th edition, n (%)  Tis 7 (3)  T1mi 7 (3)  T1a 37 (15)  T1b 125 (49)  T1c 79 (31) cTNM stage, 8th edition, n (%)  0 7 (3)  IA1 44 (17)  IA2 125 (49)  IA3 79 (31) Pathological nodal status, n (%)  N0 221 (87)  N1 16 (6)  N2 18 (7) Variables n = 255 Age (years), mean (range) 66 (23–88) Sex, n (%)  Male 129 (51)  Female 126 (49) Pack-year smoking, n (%)  <20 142 (56)  ≥20 113 (44) Computed tomography findings, n (%)  Non-solid 7 (3)  Part-solid 123 (48)  Solid 125 (49) Histology, n (%)  Adenocarcinoma 219 (86)  Squamous cell carcinoma 28 (11)  Others 8 (3) Whole tumour size (mm), mean (range) 20 (7–30) Solid component size (mm), mean (range) 17 (0–30) CTR, mean (range) 0.84 (0–1) cT descriptor, 8th edition, n (%)  Tis 7 (3)  T1mi 7 (3)  T1a 37 (15)  T1b 125 (49)  T1c 79 (31) cTNM stage, 8th edition, n (%)  0 7 (3)  IA1 44 (17)  IA2 125 (49)  IA3 79 (31) Pathological nodal status, n (%)  N0 221 (87)  N1 16 (6)  N2 18 (7) CTR: ratio of the maximum diameter of consolidation to the maximum tumour diameter. The 5-year OS and disease-free survival (DFS) rates were 77.2% and 72.1%, respectively (Fig. 1). The Kaplan–Meier analyses of the solid tumour and part-solid tumour groups (excluding 7 patients with non-solid tumours) are shown in Fig. 2. There were significant differences between groups as follows: 5-year OS, the solid tumour group = 71.2% vs the part-solid group = 83.2% and 5-year DFS, the solid tumour group = 65.4% vs the part-solid group = 78.2% (P = 0.019 and P = 0.011, respectively). The results of PSM of the size of the solid component and the characteristics of solid and part-solid tumour pairs are shown in Table 2. Comparison of long-term survival between the 2 groups using PSM is shown in Fig. 3. Patient pairs (n = 81) were matched in each group. Their 5-year survival rates did not significantly differ as follows: 5-year OS, the solid tumour group = 75.1% vs the part-solid group = 79.6% (P = 0.39) and 5-year DFS, the solid tumour group = 68.2% vs the part-solid group = 71.9% (P = 0.37). The PSM pairs, which were determined according to the size of the solid component, did not significantly differ as a function of OS [hazard ratio (HR) 1.30, 95% confidence interval (CI) 0.71–2.44] or DFS (HR 1.29, 95% CI 0.75–2.24) between the solid tumour and part-solid tumour groups. Multivariable analyses determined that age (P < 0.001), size of the solid component (P = 0.03) and pathological nodal status (P = 0.009) influenced OS (Table 3). Table 2: Propensity score matched comparison of clinical and pathological factors between patients with solid tumours and those with part-solid tumours Variables Part-solid (n = 81) Solid (n = 81) P-value Age (years), mean ± SD 66.7 ± 10.0 67.0 ± 11.6 0.87 Sex, n (%)  Male 40 (49) 42 (52) 0.75  Female 41 (51) 39 (48) PET scan, n (%)  None 63 (78) 54 (67) 0.11  Done 18 (22) 27 (33) Histology, n (%)  Adenocarcinoma 77 (95) 60 (74) <0.001  Squamous cell carcinoma 4 (5) 17 (21)  Other 0 4 (5) Number of resected LN stations, median (range) 6 (2–7) 6 (2–9) 0.21 Number of resected LNs, median (range) 21 (6–89) 24 (2–62) 0.15 Pathological nodal status, n (%)  N0 74 (91) 59 (73) 0.004  N1 3 (4) 15 (18)  N2 4 (5) 7 (9) Solid component size 18.2 ± 6.1 18.1 ± 5.4 0.99 Variables Part-solid (n = 81) Solid (n = 81) P-value Age (years), mean ± SD 66.7 ± 10.0 67.0 ± 11.6 0.87 Sex, n (%)  Male 40 (49) 42 (52) 0.75  Female 41 (51) 39 (48) PET scan, n (%)  None 63 (78) 54 (67) 0.11  Done 18 (22) 27 (33) Histology, n (%)  Adenocarcinoma 77 (95) 60 (74) <0.001  Squamous cell carcinoma 4 (5) 17 (21)  Other 0 4 (5) Number of resected LN stations, median (range) 6 (2–7) 6 (2–9) 0.21 Number of resected LNs, median (range) 21 (6–89) 24 (2–62) 0.15 Pathological nodal status, n (%)  N0 74 (91) 59 (73) 0.004  N1 3 (4) 15 (18)  N2 4 (5) 7 (9) Solid component size 18.2 ± 6.1 18.1 ± 5.4 0.99 LN: lymph node; PET: positron emission tomography; SD: standard deviation. Table 2: Propensity score matched comparison of clinical and pathological factors between patients with solid tumours and those with part-solid tumours Variables Part-solid (n = 81) Solid (n = 81) P-value Age (years), mean ± SD 66.7 ± 10.0 67.0 ± 11.6 0.87 Sex, n (%)  Male 40 (49) 42 (52) 0.75  Female 41 (51) 39 (48) PET scan, n (%)  None 63 (78) 54 (67) 0.11  Done 18 (22) 27 (33) Histology, n (%)  Adenocarcinoma 77 (95) 60 (74) <0.001  Squamous cell carcinoma 4 (5) 17 (21)  Other 0 4 (5) Number of resected LN stations, median (range) 6 (2–7) 6 (2–9) 0.21 Number of resected LNs, median (range) 21 (6–89) 24 (2–62) 0.15 Pathological nodal status, n (%)  N0 74 (91) 59 (73) 0.004  N1 3 (4) 15 (18)  N2 4 (5) 7 (9) Solid component size 18.2 ± 6.1 18.1 ± 5.4 0.99 Variables Part-solid (n = 81) Solid (n = 81) P-value Age (years), mean ± SD 66.7 ± 10.0 67.0 ± 11.6 0.87 Sex, n (%)  Male 40 (49) 42 (52) 0.75  Female 41 (51) 39 (48) PET scan, n (%)  None 63 (78) 54 (67) 0.11  Done 18 (22) 27 (33) Histology, n (%)  Adenocarcinoma 77 (95) 60 (74) <0.001  Squamous cell carcinoma 4 (5) 17 (21)  Other 0 4 (5) Number of resected LN stations, median (range) 6 (2–7) 6 (2–9) 0.21 Number of resected LNs, median (range) 21 (6–89) 24 (2–62) 0.15 Pathological nodal status, n (%)  N0 74 (91) 59 (73) 0.004  N1 3 (4) 15 (18)  N2 4 (5) 7 (9) Solid component size 18.2 ± 6.1 18.1 ± 5.4 0.99 LN: lymph node; PET: positron emission tomography; SD: standard deviation. Table 3: Univariable and multivariable analyses of overall survival Variables Univariable Multivariable HR (95% CI) P-value HR (95% CI) P-value Agea (years) 1.049 (1.022–1.078) <0.001 1.052 (1.024–1.082) <0.001 Males 1.235 (0.750–2.045) 0.40 Histology (adenocarcinoma) 0.624 (0.344–1.228) 0.16 Whole tumour sizea 1.028 (0.985–1.074) 0.20 Solid component sizea 1.057 (1.017–1.099) 0.004 1.044 (1.004–1.086) 0.03 Pathological nodal positive 2.419 (1.328–4.181) 0.005 2.322 (1.255–4.095) 0.009 Variables Univariable Multivariable HR (95% CI) P-value HR (95% CI) P-value Agea (years) 1.049 (1.022–1.078) <0.001 1.052 (1.024–1.082) <0.001 Males 1.235 (0.750–2.045) 0.40 Histology (adenocarcinoma) 0.624 (0.344–1.228) 0.16 Whole tumour sizea 1.028 (0.985–1.074) 0.20 Solid component sizea 1.057 (1.017–1.099) 0.004 1.044 (1.004–1.086) 0.03 Pathological nodal positive 2.419 (1.328–4.181) 0.005 2.322 (1.255–4.095) 0.009 a Age, whole tumour size and solid component size were analysed as continuous variables. CI: confidence interval; HR: hazard ratio. Table 3: Univariable and multivariable analyses of overall survival Variables Univariable Multivariable HR (95% CI) P-value HR (95% CI) P-value Agea (years) 1.049 (1.022–1.078) <0.001 1.052 (1.024–1.082) <0.001 Males 1.235 (0.750–2.045) 0.40 Histology (adenocarcinoma) 0.624 (0.344–1.228) 0.16 Whole tumour sizea 1.028 (0.985–1.074) 0.20 Solid component sizea 1.057 (1.017–1.099) 0.004 1.044 (1.004–1.086) 0.03 Pathological nodal positive 2.419 (1.328–4.181) 0.005 2.322 (1.255–4.095) 0.009 Variables Univariable Multivariable HR (95% CI) P-value HR (95% CI) P-value Agea (years) 1.049 (1.022–1.078) <0.001 1.052 (1.024–1.082) <0.001 Males 1.235 (0.750–2.045) 0.40 Histology (adenocarcinoma) 0.624 (0.344–1.228) 0.16 Whole tumour sizea 1.028 (0.985–1.074) 0.20 Solid component sizea 1.057 (1.017–1.099) 0.004 1.044 (1.004–1.086) 0.03 Pathological nodal positive 2.419 (1.328–4.181) 0.005 2.322 (1.255–4.095) 0.009 a Age, whole tumour size and solid component size were analysed as continuous variables. CI: confidence interval; HR: hazard ratio. Figure 1: View largeDownload slide The Kaplan–Meier analysis of OS (A) and DFS (B). DFS: disease-free survival; OS: overall survival. Figure 1: View largeDownload slide The Kaplan–Meier analysis of OS (A) and DFS (B). DFS: disease-free survival; OS: overall survival. Figure 2: View largeDownload slide The Kaplan–Meier analysis of OS (A) and DFS (B) of patients with solid tumours (blue line) and those with part-solid tumours (red line). DFS: disease-free survival; OS: overall survival. Figure 2: View largeDownload slide The Kaplan–Meier analysis of OS (A) and DFS (B) of patients with solid tumours (blue line) and those with part-solid tumours (red line). DFS: disease-free survival; OS: overall survival. Figure 3: View largeDownload slide The Kaplan–Meier analysis of OS (A) and DFS (B) of patients with solid tumours (blue line) and those with part-solid tumours (red line) according to the results of propensity score matching. DFS: disease-free survival; OS: overall survival. Figure 3: View largeDownload slide The Kaplan–Meier analysis of OS (A) and DFS (B) of patients with solid tumours (blue line) and those with part-solid tumours (red line) according to the results of propensity score matching. DFS: disease-free survival; OS: overall survival. The respective 5-year OS and DFS rates according to clinical stage (TNM classification, 8th edition) were as follows: Stage IA1, 88.3% and 88.0%; Stage IA2, 79.4% and 75.1% and Stage IA3, 67.6% and 57.6% (Fig. 4). Figure 4: View largeDownload slide The Kaplan–Meier analysis of OS (A) and DFS (B) according to the cTNM staging (the TNM classification, 8th edition, UICC): cIA1 (red line), cIA2 (green line) and cIA3 (blue line). DFS: disease-free survival; OS: overall survival; TNM: tumour, node, and metastasis; UICC: union for international cancer control. Figure 4: View largeDownload slide The Kaplan–Meier analysis of OS (A) and DFS (B) according to the cTNM staging (the TNM classification, 8th edition, UICC): cIA1 (red line), cIA2 (green line) and cIA3 (blue line). DFS: disease-free survival; OS: overall survival; TNM: tumour, node, and metastasis; UICC: union for international cancer control. DISCUSSION The stratification of patients with early-stage NSCLC according to their predicted outcomes is particularly important for determining appropriate treatment strategies such as limited resection and adjuvant therapy [12, 13]. The International Association for the Study of Lung Cancer Staging and Prognostic Factor Committee created a database to analyse prognoses for revising the 7th edition of the TNM classification of lung cancer [14]. The survival analyses focused on clinical and pathological T descriptors for lung cancer by incorporating the size of the whole tumour [14]. The new (8th edition, effective 2017) T classifications, from T1 to a portion of T4, are based specifically on the size of the solid component detected using CT or the size of the invasive component on pathological examination, because the size of the solid, invasive component determines prognosis [4]. However, there is controversy concerning whether patients with solid tumours should be treated similar to patients with part-solid tumours with a solid component of equal size. For example, some studies show that the diameter of the solid tumour without ground-glass opacities, as indicated using high-resolution CT, is a more accurate measurement of tumour nodules for predicting the prognosis of patients with NSCLC [15–21]. Furthermore, the size of the solid tumour determined using high-resolution CT more accurately predicts high-grade malignancy and prognosis of patients with clinical Stage IA lung adenocarcinoma [17–19]. CTR and the consolidation size are important for predicting invasion and for diagnosing invasive adenocarcinoma in part-solid tumours [20]. Moreover, the volume of the solid component of NSCLC is more strongly associated with prognosis when compared with tumour size, whole tumour volume and CTR [21]. In contrast, the size of the solid component is not a prognostic factor of part-solid lung cancer, suggesting that the size of the solid component is only significant when applied to solid lung cancers [10]. In this study, we focused on the size of the solid component and investigated its possible use as a prognostic factor of clinical Stage IA NSCLC, according to the 8th edition of the TNM classification. To eliminate the influence of surgery or a patient’s condition on prognosis, we limited our study population to patients who underwent lobectomies. First, when we compared OS and DFS of the solid tumour and part-solid tumour groups, we found that their 5-year OS and DFS rates were significantly different. However, when members of the 2 groups were analysed using PSM according to the sizes of the solid components of their tumours, lymph-node-positive cases were much more frequent in the solid tumour group than in the part-solid tumour group. On the other hand, there were no significant differences among OS and DFS between the 2 groups. We conclude, therefore, that stratifying patients with solid and part-solid tumours according to the size of the solid component is reasonable and appropriate. The discrepancy between lymph node status and OS or DFS of 2 groups may be referred from small sample size. Otherwise, adjuvant chemotherapy or treatments for recurrence might reduce the extent of the OS or DFS between the solid tumour group and part-solid tumour group. Furthermore, OS and DFS plotted according to clinical stage (defined according to the 8th edition of the TNM classification) were well balanced in this cohort. Although this stratification efficiently predicted the prognosis of patients with early-stage lung cancer, problems remain. First, previous data published before the 8th edition of the TNM classification are of limited use if they lack data for solid component sizes, which may influence ongoing or future studies using earlier records. Second, this limitation may influence current treatment strategies such as limited resection, adjuvant therapy and follow-up. Numerous patients with early-stage NSCLC undergo limited resections such as segmentectomy and wedge resection. Thus, a Phase III study was conducted in Japan on patients with small peripheral NSCLC to evaluate the non-inferiority of segmentectomy in comparison with lobectomy [12]; thus, segmentectomy may become a standard therapy for low-grade lung cancer. Furthermore, Japanese treatment guidelines recommend postoperative oral tegafur–uracil therapy for patients with completely resected p-Stage 1b-T2N0M0 NSCLC (recommendation Grade B) [13]. These treatments are administered according to the size of the whole primary tumour [12, 13]. Therefore, the size of the whole tumour, including ground-glass and lepidic components, detected using radiology and histopathology should be recorded separately in the new TNM classification. Limitations The limitations of this study include its retrospective observational design using data acquired from the database of a single institution, and we enrolled only patients who had undergone surgical resection. Furthermore, patients included in this study were limited to those who underwent lobectomies for lesions ≤3 cm in diameter nor did we include patients who underwent limited resection or had part-solid tumours >3 cm with a solid component of ≤3 cm. Despite these limitations, this study indicates that combined stratification comprising patients with solid tumours and part-solid tumours according to the size of the solid component is clinically reasonable and appropriate. CONCLUSION In conclusion, PSM did not detect a significant difference in survival between the groups with solid tumours and those with part-solid tumours when matched according to the size of the solid component. The new T descriptors included in the 8th edition of the TNM classification provide a detailed classification of patients with NSCLC ≤3 cm in diameter. A large-cohort validation study is required to identify optimum treatment strategies to improve the outcomes of patients with early-stage NSCLC. Conflict of interest: none declared. REFERENCES 1 Population Division, Population Estimates and Projections Section, Department of Economics and Social Affairs, United Nations. 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A phase III randomized trial of lobectomy versus limited resection for small-sized peripheral non-small cell lung cancer (JCOG0802/WJOG4607L) . Jpn J Clin Oncol 2010 ; 40 : 271 – 4 . Google Scholar CrossRef Search ADS PubMed 13 The Japan Lung cancer Society. Clinical Practice Guideline for Lung Cancer. http://www.haigan.gr.jp/modules/guideline/index.php? content_id=3 (18 July 2017, date last accessed). 14 Rami-Porta R , Bolejack V , Crowley J , Ball D , Kim J , Lyons G et al. The IASLC Lung Cancer Staging Project: proposals for the Revisions of the T Descriptors in the forthcoming Eighth Edition of the TNM Classification for Lung Cancer . J Thorac Oncol 2015 ; 10 : 990 – 1003 . Google Scholar CrossRef Search ADS PubMed 15 Maeyashiki T , Suzuki K , Hattori A , Matsunaga T , Takamochi K , Oh S. The size of consolidation on thin-section computed tomography is a better predictor of survival than the maximum tumour dimension in resectable lung cancer . 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Solid tumor size on high-resolution computed tomography and maximum standardized uptake on positron emission tomography for new clinical T descriptors with T1 lung adenocarcinoma . Ann Oncol 2013 ; 24 : 2376 – 81 . Google Scholar CrossRef Search ADS PubMed 19 Tsutani Y , Miyata Y , Yamanaka T , Nakayama H , Okumura S , Adachi S et al. Solid tumors versus mixed tumors with a ground-glass opacity component in patients with clinical stage IA lung adenocarcinoma: prognostic comparison using high-resolution computed tomography findings . J Thorac Cardiovasc Surg 2013 ; 146 : 17 – 23 . Google Scholar CrossRef Search ADS PubMed 20 Kudo Y , Matsubayashi J , Saji H , Akata S , Shimada Y , Kato Y et al. Association between high-resolution computed tomography findings and the IASLC/ATS/ERS classification of small lung adenocarcinomas in Japanese patients . Lung Cancer 2015 ; 90 : 47 – 54 . Google Scholar CrossRef Search ADS PubMed 21 Takenaka T , Yamazaki K , Miura N , Takeo S. The prognostic impact of tumor volume in patients with clinical stage IA non-small cell lung cancer . J Thorac Oncol 2016 ; 11 : 1074 – 80 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Interactive CardioVascular and Thoracic Surgery Oxford University Press

Prognostic ability of new T1 descriptors in the tumour, node and metastasis classification of surgically treated non-small-cell lung cancer

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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1569-9293
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1569-9285
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10.1093/icvts/ivy164
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Abstract

Abstract OBJECTIVES In the tumour, node and metastasis (TNM) classification (8th edition) of non-small-cell lung cancer, T (tumour size) is determined solely according to the size of the solid component determined using computed tomography (CT). However, it is unclear whether tumours of equal size but with differing solid and part-solid components should be similarly treated. Herein, we assessed the prognostic significance of the newly proposed T1 descriptors with respect to the size of the solid component. METHODS We analysed overall survival (OS) and disease-free survival (DFS) between groups of patients (n = 255) with solid or part-solid tumours using propensity score matching. The new staging system was used for classification and comparison of survival. RESULTS Chest CT detected 7 non-solid tumours, 123 part-solid tumours and 125 solid tumours. The 5-year OS and DFS rates differed significantly between the solid tumour (OS 71.2%; DFS 65.4%) and part-solid tumour (OS 83.2%; DFS 78.2%) groups. However, among 81 propensity score matching pairs (including those matched according to the size of the solid component), OS and DFS did not significantly differ between groups. The 5-year OS rates according to disease stage were as follows: cIA1 88.0%; cIA2 79.4% and cIA3 67.6%. CONCLUSIONS Propensity score matching of solid tumour and part-solid tumour groups did not reveal a significant difference in survival as a function of the size of the solid component. A study of a larger cohort is required to validate this result. Non-small-cell lung cancer , Tumour, Node and metastasis staging , Surgical resection , Prognosis INTRODUCTION With approximately 1.61 million new cases each year, lung cancer continues as the most common cancer [1]. Widespread screening using low-dose helical computed tomography (CT) has led to a higher early detection rate of small lung cancers [2]. Since the 1970s, tumour size has served as a primary descriptor and as a significant prognostic factor of lung cancer, which is included in the tumour, node and metastasis (TNM) classification of the staging system of the Union for International Cancer Control [3]. Tumour size, which represents an important tumour descriptor, reflects cancer progression, significantly correlates with prognosis and is easy to measure. According to the new classification (8th edition), which was revised in 2017, T classifications from T1 to a portion of T4 are classified according to tumour size. Thus, only the size of the solid component determined using CT or the size of the invasive component determined on pathological examination is considered, because the size of the solid, invasive component determines prognosis [4]. Studies of the correlations between radiological and pathological characteristics of lung cancer associated with its malignant phenotype reveal that radiologically detected non-solid or part-solid lung adenocarcinomas with components exhibiting ground-glass opacity (GGO) indicate good prognosis and that the pathological features of most cases indicate minimal invasion [5–8]. However, radiologically detected solid lung cancers are considered highly malignant. For example, postoperative nodal involvement occurs in 15–20% of patients, including those with small lung cancers [9, 10]. Therefore, radiologically determined solid lung cancers are considered more malignant when compared with non-solid or part-solid tumours. Moreover, it is unclear whether patients with solid tumours should be treated similar to those with part-solid tumours with solid components of equal size. In this study, we assessed the prognostic value of the newly proposed T1 descriptors according to the size of the solid component of patients with non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS Patients We analysed 255 consecutive patients diagnosed with clinical Stage IA NSCLC, according to the TNM classification (7th edition), who underwent lobectomies at our institution between January 2005 and December 2010. All patients underwent lobectomies, dissection of hilar lymph nodes and specific mediastinal lymph node stations depending on the lobar location of the primary tumour (Stations 2R and 4R for the right upper lobe; Stations 4L, 5L and 6L for the left upper lobe; Stations 2R, 4R, 7, 8 and 9 for the right middle lobe and lower lobe and 4L, 5L, 6L, 7, 8 and 9 for the left lower lobe). Each patient was granted written informed consent to use her or his medical records. The institutional review board approved this study. Perioperative examination Clinical staging was determined according to findings of chest and upper abdomen CT; brain CT or magnetic resonance imaging (MRI) and radionuclide bone scans or positron emission tomography with fluorine-18 fluorodeoxyglucose (FDG-PET), or both. Follow-up examinations were usually conducted every 2–3 months for the first 2 years and every 3–6 months thereafter. Routine follow-up procedures included a physical examination, haematological examination and chest radiography. Chest and abdominal CTs were performed at least once each year. If recurrent disease was suspected, further evaluations, such as MRI and FDG-PET, were performed. Recurrent NSCLC was diagnosed according to physical examinations and diagnostic imaging consistent with recurrent disease. When clinically feasible, diagnoses were histologically confirmed. The date of recurrence was defined as when recurrence was histologically proved or in cases that were diagnosed using clinical evidence, the date when recurrent disease was recognized by the attending physician. Radiological evaluation of primary tumours Contrast-enhanced CT scans of the entire lung were routinely performed during each preoperative examination. Images were viewed in standard lung windows (level −500 to −700 HU; width 1500–2000 HU). The sizes of the whole tumour and the solid component size indicate the maximum diameter of the tumour and the solid part of the tumour, respectively. Tumours were divided into non-solid tumours, part-solid tumours or solid tumours, according to the ratios of the maximum consolidation diameter to maximum tumour diameter (CTR) in thin-section CT images (non-solid, CTR = 0; part solid, 0< CTR <1; solid, CTR = 1). Data collection and extraction Demographic, clinical and treatment data were acquired from an institutional database that included all patients who underwent thoracic surgery. TNM staging was determined according to the 7th edition of the TNM classification [11] and reclassified according to the 8th edition [4], using the maximum consolidation diameter of each case. Statistical analysis Comparisons of continuous and dichotomous variables between groups were performed using the Student’s t-test and the χ2 test, respectively. The probability of survival was estimated using the Kaplan–Meier method. The significance of differences in survival was evaluated using log-rank tests. Univariable and multivariable analyses of all patients were performed to identify significant prognostic factors of overall survival (OS). Variables for survival analyses included age, sex, histology, pathological nodal status and sizes of the whole tumour and its solid component. Age, size of the whole tumour and the size of the solid component were analysed as continuous variables. Variables that were significantly associated with OS in univariable analyses were subjected to multivariable analyses using a Cox proportional hazards regression model. Propensity score matching (PSM) was added as an exploratory analysis of survival among patients with solid tumours and part-solid tumours to balance the size of the solid. Propensity scores were calculated using logistic regression analysis that included the preoperative variables age, sex and solid component size. Matching was performed at a 1:1 ratio and caliper distance = 0.20. All analyses were conducted using the JMP software package (version 11, SAS Institute Inc.). P-value <0.05 was considered significant. RESULTS The characteristics of the 255 patients are summarized in Table 1. Preoperative chest CT detected 7 non-solid tumours, 123 part-solid tumours and 125 solid tumours. All patients underwent pulmonary lobectomy and lymph node dissection. The median follow-up after surgical resection was 60 (range 1–123) months. Mean tumour measurements were as follows: whole tumour 20 (range 0–30) mm, solid component 17 (0–30) mm and CTR 0.84 (0–1.0) (Table 1). Clinical stages (TNM, 8th edition) were as follows: Stage 0, n = 7 (3%); Stage IA1, n = 44 (17%); Stage IA2, n = 125 (49%) and Stage IA3, n = 79 (31%). Table 1: Patient characteristics and sizes of the whole tumour and solid components Variables n = 255 Age (years), mean (range) 66 (23–88) Sex, n (%)  Male 129 (51)  Female 126 (49) Pack-year smoking, n (%)  <20 142 (56)  ≥20 113 (44) Computed tomography findings, n (%)  Non-solid 7 (3)  Part-solid 123 (48)  Solid 125 (49) Histology, n (%)  Adenocarcinoma 219 (86)  Squamous cell carcinoma 28 (11)  Others 8 (3) Whole tumour size (mm), mean (range) 20 (7–30) Solid component size (mm), mean (range) 17 (0–30) CTR, mean (range) 0.84 (0–1) cT descriptor, 8th edition, n (%)  Tis 7 (3)  T1mi 7 (3)  T1a 37 (15)  T1b 125 (49)  T1c 79 (31) cTNM stage, 8th edition, n (%)  0 7 (3)  IA1 44 (17)  IA2 125 (49)  IA3 79 (31) Pathological nodal status, n (%)  N0 221 (87)  N1 16 (6)  N2 18 (7) Variables n = 255 Age (years), mean (range) 66 (23–88) Sex, n (%)  Male 129 (51)  Female 126 (49) Pack-year smoking, n (%)  <20 142 (56)  ≥20 113 (44) Computed tomography findings, n (%)  Non-solid 7 (3)  Part-solid 123 (48)  Solid 125 (49) Histology, n (%)  Adenocarcinoma 219 (86)  Squamous cell carcinoma 28 (11)  Others 8 (3) Whole tumour size (mm), mean (range) 20 (7–30) Solid component size (mm), mean (range) 17 (0–30) CTR, mean (range) 0.84 (0–1) cT descriptor, 8th edition, n (%)  Tis 7 (3)  T1mi 7 (3)  T1a 37 (15)  T1b 125 (49)  T1c 79 (31) cTNM stage, 8th edition, n (%)  0 7 (3)  IA1 44 (17)  IA2 125 (49)  IA3 79 (31) Pathological nodal status, n (%)  N0 221 (87)  N1 16 (6)  N2 18 (7) CTR: ratio of the maximum diameter of consolidation to the maximum tumour diameter. Table 1: Patient characteristics and sizes of the whole tumour and solid components Variables n = 255 Age (years), mean (range) 66 (23–88) Sex, n (%)  Male 129 (51)  Female 126 (49) Pack-year smoking, n (%)  <20 142 (56)  ≥20 113 (44) Computed tomography findings, n (%)  Non-solid 7 (3)  Part-solid 123 (48)  Solid 125 (49) Histology, n (%)  Adenocarcinoma 219 (86)  Squamous cell carcinoma 28 (11)  Others 8 (3) Whole tumour size (mm), mean (range) 20 (7–30) Solid component size (mm), mean (range) 17 (0–30) CTR, mean (range) 0.84 (0–1) cT descriptor, 8th edition, n (%)  Tis 7 (3)  T1mi 7 (3)  T1a 37 (15)  T1b 125 (49)  T1c 79 (31) cTNM stage, 8th edition, n (%)  0 7 (3)  IA1 44 (17)  IA2 125 (49)  IA3 79 (31) Pathological nodal status, n (%)  N0 221 (87)  N1 16 (6)  N2 18 (7) Variables n = 255 Age (years), mean (range) 66 (23–88) Sex, n (%)  Male 129 (51)  Female 126 (49) Pack-year smoking, n (%)  <20 142 (56)  ≥20 113 (44) Computed tomography findings, n (%)  Non-solid 7 (3)  Part-solid 123 (48)  Solid 125 (49) Histology, n (%)  Adenocarcinoma 219 (86)  Squamous cell carcinoma 28 (11)  Others 8 (3) Whole tumour size (mm), mean (range) 20 (7–30) Solid component size (mm), mean (range) 17 (0–30) CTR, mean (range) 0.84 (0–1) cT descriptor, 8th edition, n (%)  Tis 7 (3)  T1mi 7 (3)  T1a 37 (15)  T1b 125 (49)  T1c 79 (31) cTNM stage, 8th edition, n (%)  0 7 (3)  IA1 44 (17)  IA2 125 (49)  IA3 79 (31) Pathological nodal status, n (%)  N0 221 (87)  N1 16 (6)  N2 18 (7) CTR: ratio of the maximum diameter of consolidation to the maximum tumour diameter. The 5-year OS and disease-free survival (DFS) rates were 77.2% and 72.1%, respectively (Fig. 1). The Kaplan–Meier analyses of the solid tumour and part-solid tumour groups (excluding 7 patients with non-solid tumours) are shown in Fig. 2. There were significant differences between groups as follows: 5-year OS, the solid tumour group = 71.2% vs the part-solid group = 83.2% and 5-year DFS, the solid tumour group = 65.4% vs the part-solid group = 78.2% (P = 0.019 and P = 0.011, respectively). The results of PSM of the size of the solid component and the characteristics of solid and part-solid tumour pairs are shown in Table 2. Comparison of long-term survival between the 2 groups using PSM is shown in Fig. 3. Patient pairs (n = 81) were matched in each group. Their 5-year survival rates did not significantly differ as follows: 5-year OS, the solid tumour group = 75.1% vs the part-solid group = 79.6% (P = 0.39) and 5-year DFS, the solid tumour group = 68.2% vs the part-solid group = 71.9% (P = 0.37). The PSM pairs, which were determined according to the size of the solid component, did not significantly differ as a function of OS [hazard ratio (HR) 1.30, 95% confidence interval (CI) 0.71–2.44] or DFS (HR 1.29, 95% CI 0.75–2.24) between the solid tumour and part-solid tumour groups. Multivariable analyses determined that age (P < 0.001), size of the solid component (P = 0.03) and pathological nodal status (P = 0.009) influenced OS (Table 3). Table 2: Propensity score matched comparison of clinical and pathological factors between patients with solid tumours and those with part-solid tumours Variables Part-solid (n = 81) Solid (n = 81) P-value Age (years), mean ± SD 66.7 ± 10.0 67.0 ± 11.6 0.87 Sex, n (%)  Male 40 (49) 42 (52) 0.75  Female 41 (51) 39 (48) PET scan, n (%)  None 63 (78) 54 (67) 0.11  Done 18 (22) 27 (33) Histology, n (%)  Adenocarcinoma 77 (95) 60 (74) <0.001  Squamous cell carcinoma 4 (5) 17 (21)  Other 0 4 (5) Number of resected LN stations, median (range) 6 (2–7) 6 (2–9) 0.21 Number of resected LNs, median (range) 21 (6–89) 24 (2–62) 0.15 Pathological nodal status, n (%)  N0 74 (91) 59 (73) 0.004  N1 3 (4) 15 (18)  N2 4 (5) 7 (9) Solid component size 18.2 ± 6.1 18.1 ± 5.4 0.99 Variables Part-solid (n = 81) Solid (n = 81) P-value Age (years), mean ± SD 66.7 ± 10.0 67.0 ± 11.6 0.87 Sex, n (%)  Male 40 (49) 42 (52) 0.75  Female 41 (51) 39 (48) PET scan, n (%)  None 63 (78) 54 (67) 0.11  Done 18 (22) 27 (33) Histology, n (%)  Adenocarcinoma 77 (95) 60 (74) <0.001  Squamous cell carcinoma 4 (5) 17 (21)  Other 0 4 (5) Number of resected LN stations, median (range) 6 (2–7) 6 (2–9) 0.21 Number of resected LNs, median (range) 21 (6–89) 24 (2–62) 0.15 Pathological nodal status, n (%)  N0 74 (91) 59 (73) 0.004  N1 3 (4) 15 (18)  N2 4 (5) 7 (9) Solid component size 18.2 ± 6.1 18.1 ± 5.4 0.99 LN: lymph node; PET: positron emission tomography; SD: standard deviation. Table 2: Propensity score matched comparison of clinical and pathological factors between patients with solid tumours and those with part-solid tumours Variables Part-solid (n = 81) Solid (n = 81) P-value Age (years), mean ± SD 66.7 ± 10.0 67.0 ± 11.6 0.87 Sex, n (%)  Male 40 (49) 42 (52) 0.75  Female 41 (51) 39 (48) PET scan, n (%)  None 63 (78) 54 (67) 0.11  Done 18 (22) 27 (33) Histology, n (%)  Adenocarcinoma 77 (95) 60 (74) <0.001  Squamous cell carcinoma 4 (5) 17 (21)  Other 0 4 (5) Number of resected LN stations, median (range) 6 (2–7) 6 (2–9) 0.21 Number of resected LNs, median (range) 21 (6–89) 24 (2–62) 0.15 Pathological nodal status, n (%)  N0 74 (91) 59 (73) 0.004  N1 3 (4) 15 (18)  N2 4 (5) 7 (9) Solid component size 18.2 ± 6.1 18.1 ± 5.4 0.99 Variables Part-solid (n = 81) Solid (n = 81) P-value Age (years), mean ± SD 66.7 ± 10.0 67.0 ± 11.6 0.87 Sex, n (%)  Male 40 (49) 42 (52) 0.75  Female 41 (51) 39 (48) PET scan, n (%)  None 63 (78) 54 (67) 0.11  Done 18 (22) 27 (33) Histology, n (%)  Adenocarcinoma 77 (95) 60 (74) <0.001  Squamous cell carcinoma 4 (5) 17 (21)  Other 0 4 (5) Number of resected LN stations, median (range) 6 (2–7) 6 (2–9) 0.21 Number of resected LNs, median (range) 21 (6–89) 24 (2–62) 0.15 Pathological nodal status, n (%)  N0 74 (91) 59 (73) 0.004  N1 3 (4) 15 (18)  N2 4 (5) 7 (9) Solid component size 18.2 ± 6.1 18.1 ± 5.4 0.99 LN: lymph node; PET: positron emission tomography; SD: standard deviation. Table 3: Univariable and multivariable analyses of overall survival Variables Univariable Multivariable HR (95% CI) P-value HR (95% CI) P-value Agea (years) 1.049 (1.022–1.078) <0.001 1.052 (1.024–1.082) <0.001 Males 1.235 (0.750–2.045) 0.40 Histology (adenocarcinoma) 0.624 (0.344–1.228) 0.16 Whole tumour sizea 1.028 (0.985–1.074) 0.20 Solid component sizea 1.057 (1.017–1.099) 0.004 1.044 (1.004–1.086) 0.03 Pathological nodal positive 2.419 (1.328–4.181) 0.005 2.322 (1.255–4.095) 0.009 Variables Univariable Multivariable HR (95% CI) P-value HR (95% CI) P-value Agea (years) 1.049 (1.022–1.078) <0.001 1.052 (1.024–1.082) <0.001 Males 1.235 (0.750–2.045) 0.40 Histology (adenocarcinoma) 0.624 (0.344–1.228) 0.16 Whole tumour sizea 1.028 (0.985–1.074) 0.20 Solid component sizea 1.057 (1.017–1.099) 0.004 1.044 (1.004–1.086) 0.03 Pathological nodal positive 2.419 (1.328–4.181) 0.005 2.322 (1.255–4.095) 0.009 a Age, whole tumour size and solid component size were analysed as continuous variables. CI: confidence interval; HR: hazard ratio. Table 3: Univariable and multivariable analyses of overall survival Variables Univariable Multivariable HR (95% CI) P-value HR (95% CI) P-value Agea (years) 1.049 (1.022–1.078) <0.001 1.052 (1.024–1.082) <0.001 Males 1.235 (0.750–2.045) 0.40 Histology (adenocarcinoma) 0.624 (0.344–1.228) 0.16 Whole tumour sizea 1.028 (0.985–1.074) 0.20 Solid component sizea 1.057 (1.017–1.099) 0.004 1.044 (1.004–1.086) 0.03 Pathological nodal positive 2.419 (1.328–4.181) 0.005 2.322 (1.255–4.095) 0.009 Variables Univariable Multivariable HR (95% CI) P-value HR (95% CI) P-value Agea (years) 1.049 (1.022–1.078) <0.001 1.052 (1.024–1.082) <0.001 Males 1.235 (0.750–2.045) 0.40 Histology (adenocarcinoma) 0.624 (0.344–1.228) 0.16 Whole tumour sizea 1.028 (0.985–1.074) 0.20 Solid component sizea 1.057 (1.017–1.099) 0.004 1.044 (1.004–1.086) 0.03 Pathological nodal positive 2.419 (1.328–4.181) 0.005 2.322 (1.255–4.095) 0.009 a Age, whole tumour size and solid component size were analysed as continuous variables. CI: confidence interval; HR: hazard ratio. Figure 1: View largeDownload slide The Kaplan–Meier analysis of OS (A) and DFS (B). DFS: disease-free survival; OS: overall survival. Figure 1: View largeDownload slide The Kaplan–Meier analysis of OS (A) and DFS (B). DFS: disease-free survival; OS: overall survival. Figure 2: View largeDownload slide The Kaplan–Meier analysis of OS (A) and DFS (B) of patients with solid tumours (blue line) and those with part-solid tumours (red line). DFS: disease-free survival; OS: overall survival. Figure 2: View largeDownload slide The Kaplan–Meier analysis of OS (A) and DFS (B) of patients with solid tumours (blue line) and those with part-solid tumours (red line). DFS: disease-free survival; OS: overall survival. Figure 3: View largeDownload slide The Kaplan–Meier analysis of OS (A) and DFS (B) of patients with solid tumours (blue line) and those with part-solid tumours (red line) according to the results of propensity score matching. DFS: disease-free survival; OS: overall survival. Figure 3: View largeDownload slide The Kaplan–Meier analysis of OS (A) and DFS (B) of patients with solid tumours (blue line) and those with part-solid tumours (red line) according to the results of propensity score matching. DFS: disease-free survival; OS: overall survival. The respective 5-year OS and DFS rates according to clinical stage (TNM classification, 8th edition) were as follows: Stage IA1, 88.3% and 88.0%; Stage IA2, 79.4% and 75.1% and Stage IA3, 67.6% and 57.6% (Fig. 4). Figure 4: View largeDownload slide The Kaplan–Meier analysis of OS (A) and DFS (B) according to the cTNM staging (the TNM classification, 8th edition, UICC): cIA1 (red line), cIA2 (green line) and cIA3 (blue line). DFS: disease-free survival; OS: overall survival; TNM: tumour, node, and metastasis; UICC: union for international cancer control. Figure 4: View largeDownload slide The Kaplan–Meier analysis of OS (A) and DFS (B) according to the cTNM staging (the TNM classification, 8th edition, UICC): cIA1 (red line), cIA2 (green line) and cIA3 (blue line). DFS: disease-free survival; OS: overall survival; TNM: tumour, node, and metastasis; UICC: union for international cancer control. DISCUSSION The stratification of patients with early-stage NSCLC according to their predicted outcomes is particularly important for determining appropriate treatment strategies such as limited resection and adjuvant therapy [12, 13]. The International Association for the Study of Lung Cancer Staging and Prognostic Factor Committee created a database to analyse prognoses for revising the 7th edition of the TNM classification of lung cancer [14]. The survival analyses focused on clinical and pathological T descriptors for lung cancer by incorporating the size of the whole tumour [14]. The new (8th edition, effective 2017) T classifications, from T1 to a portion of T4, are based specifically on the size of the solid component detected using CT or the size of the invasive component on pathological examination, because the size of the solid, invasive component determines prognosis [4]. However, there is controversy concerning whether patients with solid tumours should be treated similar to patients with part-solid tumours with a solid component of equal size. For example, some studies show that the diameter of the solid tumour without ground-glass opacities, as indicated using high-resolution CT, is a more accurate measurement of tumour nodules for predicting the prognosis of patients with NSCLC [15–21]. Furthermore, the size of the solid tumour determined using high-resolution CT more accurately predicts high-grade malignancy and prognosis of patients with clinical Stage IA lung adenocarcinoma [17–19]. CTR and the consolidation size are important for predicting invasion and for diagnosing invasive adenocarcinoma in part-solid tumours [20]. Moreover, the volume of the solid component of NSCLC is more strongly associated with prognosis when compared with tumour size, whole tumour volume and CTR [21]. In contrast, the size of the solid component is not a prognostic factor of part-solid lung cancer, suggesting that the size of the solid component is only significant when applied to solid lung cancers [10]. In this study, we focused on the size of the solid component and investigated its possible use as a prognostic factor of clinical Stage IA NSCLC, according to the 8th edition of the TNM classification. To eliminate the influence of surgery or a patient’s condition on prognosis, we limited our study population to patients who underwent lobectomies. First, when we compared OS and DFS of the solid tumour and part-solid tumour groups, we found that their 5-year OS and DFS rates were significantly different. However, when members of the 2 groups were analysed using PSM according to the sizes of the solid components of their tumours, lymph-node-positive cases were much more frequent in the solid tumour group than in the part-solid tumour group. On the other hand, there were no significant differences among OS and DFS between the 2 groups. We conclude, therefore, that stratifying patients with solid and part-solid tumours according to the size of the solid component is reasonable and appropriate. The discrepancy between lymph node status and OS or DFS of 2 groups may be referred from small sample size. Otherwise, adjuvant chemotherapy or treatments for recurrence might reduce the extent of the OS or DFS between the solid tumour group and part-solid tumour group. Furthermore, OS and DFS plotted according to clinical stage (defined according to the 8th edition of the TNM classification) were well balanced in this cohort. Although this stratification efficiently predicted the prognosis of patients with early-stage lung cancer, problems remain. First, previous data published before the 8th edition of the TNM classification are of limited use if they lack data for solid component sizes, which may influence ongoing or future studies using earlier records. Second, this limitation may influence current treatment strategies such as limited resection, adjuvant therapy and follow-up. Numerous patients with early-stage NSCLC undergo limited resections such as segmentectomy and wedge resection. Thus, a Phase III study was conducted in Japan on patients with small peripheral NSCLC to evaluate the non-inferiority of segmentectomy in comparison with lobectomy [12]; thus, segmentectomy may become a standard therapy for low-grade lung cancer. Furthermore, Japanese treatment guidelines recommend postoperative oral tegafur–uracil therapy for patients with completely resected p-Stage 1b-T2N0M0 NSCLC (recommendation Grade B) [13]. These treatments are administered according to the size of the whole primary tumour [12, 13]. Therefore, the size of the whole tumour, including ground-glass and lepidic components, detected using radiology and histopathology should be recorded separately in the new TNM classification. Limitations The limitations of this study include its retrospective observational design using data acquired from the database of a single institution, and we enrolled only patients who had undergone surgical resection. Furthermore, patients included in this study were limited to those who underwent lobectomies for lesions ≤3 cm in diameter nor did we include patients who underwent limited resection or had part-solid tumours >3 cm with a solid component of ≤3 cm. Despite these limitations, this study indicates that combined stratification comprising patients with solid tumours and part-solid tumours according to the size of the solid component is clinically reasonable and appropriate. CONCLUSION In conclusion, PSM did not detect a significant difference in survival between the groups with solid tumours and those with part-solid tumours when matched according to the size of the solid component. The new T descriptors included in the 8th edition of the TNM classification provide a detailed classification of patients with NSCLC ≤3 cm in diameter. A large-cohort validation study is required to identify optimum treatment strategies to improve the outcomes of patients with early-stage NSCLC. Conflict of interest: none declared. REFERENCES 1 Population Division, Population Estimates and Projections Section, Department of Economics and Social Affairs, United Nations. 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A phase III randomized trial of lobectomy versus limited resection for small-sized peripheral non-small cell lung cancer (JCOG0802/WJOG4607L) . Jpn J Clin Oncol 2010 ; 40 : 271 – 4 . Google Scholar CrossRef Search ADS PubMed 13 The Japan Lung cancer Society. Clinical Practice Guideline for Lung Cancer. http://www.haigan.gr.jp/modules/guideline/index.php? content_id=3 (18 July 2017, date last accessed). 14 Rami-Porta R , Bolejack V , Crowley J , Ball D , Kim J , Lyons G et al. The IASLC Lung Cancer Staging Project: proposals for the Revisions of the T Descriptors in the forthcoming Eighth Edition of the TNM Classification for Lung Cancer . J Thorac Oncol 2015 ; 10 : 990 – 1003 . Google Scholar CrossRef Search ADS PubMed 15 Maeyashiki T , Suzuki K , Hattori A , Matsunaga T , Takamochi K , Oh S. The size of consolidation on thin-section computed tomography is a better predictor of survival than the maximum tumour dimension in resectable lung cancer . Eur J Cardiothorac Surg 2013 ; 43 : 915 – 8 . Google Scholar CrossRef Search ADS PubMed 16 Nakamura S , Fukui T , Taniguchi T , Usami N , Kawaguchi K , Ishiguro F et al. Prognostic impact of tumor size eliminating the ground glass opacity component: modified clinical T descriptors of the tumor, node, metastasis classification of lung cancer . J Thorac Oncol 2013 ; 8 : 1551 – 7 . Google Scholar CrossRef Search ADS PubMed 17 Tsutani Y , Miyata Y , Nakayama H , Okumura S , Adachi S , Yoshimura M et al. Prognostic significance of using solid versus whole tumor size on high-resolution computed tomography for predicting pathologic malignant grade of tumors in clinical stage IA lung adenocarcinoma: a multicenter study . J Thorac Cardiovasc Surg 2012 ; 143 : 607 – 12 . Google Scholar CrossRef Search ADS PubMed 18 Tsutani Y , Miyata Y , Nakayama H , Okumura S , Adachi S , Yoshimura M et al. Solid tumor size on high-resolution computed tomography and maximum standardized uptake on positron emission tomography for new clinical T descriptors with T1 lung adenocarcinoma . Ann Oncol 2013 ; 24 : 2376 – 81 . Google Scholar CrossRef Search ADS PubMed 19 Tsutani Y , Miyata Y , Yamanaka T , Nakayama H , Okumura S , Adachi S et al. Solid tumors versus mixed tumors with a ground-glass opacity component in patients with clinical stage IA lung adenocarcinoma: prognostic comparison using high-resolution computed tomography findings . J Thorac Cardiovasc Surg 2013 ; 146 : 17 – 23 . Google Scholar CrossRef Search ADS PubMed 20 Kudo Y , Matsubayashi J , Saji H , Akata S , Shimada Y , Kato Y et al. Association between high-resolution computed tomography findings and the IASLC/ATS/ERS classification of small lung adenocarcinomas in Japanese patients . Lung Cancer 2015 ; 90 : 47 – 54 . Google Scholar CrossRef Search ADS PubMed 21 Takenaka T , Yamazaki K , Miura N , Takeo S. The prognostic impact of tumor volume in patients with clinical stage IA non-small cell lung cancer . J Thorac Oncol 2016 ; 11 : 1074 – 80 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Interactive CardioVascular and Thoracic SurgeryOxford University Press

Published: May 19, 2018

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