- Email: [email protected]
Impact of Lepidic Component Occupancy on Effects of Adjuvant Chemotherapy for Lung Adenocarcinoma
Impact of Lepidic Component Occupancy on Effects of Adjuvant Chemotherapy for Lung Adenocarcinoma Shinsuke Sasada, MD, PhD, Yoshihiro Miyata, MD, PhD, Takahiro Mimae, MD, PhD, Takeshi Mimura, MD, PhD, and Morihito Okada, MD, PhD Department of Surgical Oncology, Hiroshima University, Hiroshima, Japan
Background. The prognosis of lepidic predominant lung adenocarcinoma is favorable. We postulated that lepidic predominant tumors might not require postoperative adjuvant chemotherapy. The present study aims to determine whether lepidic component occupancy affects overall survival after postoperative adjuvant chemotherapy for lung adenocarcinoma. Methods. Clinical and pathologic data were collected from a database and from the medical records of 964 patients with completely resected lung adenocarcinoma. We assessed the influence of lepidic component occupancy in the tumor on the outcomes of adjuvant chemotherapy. Results. Among the patients, 270 received adjuvant chemotherapy and 694 did not, and 415 and 549 had lepidic predominant and non-lepidic predominant tumors, respectively. Adjuvant chemotherapy contributed to better overall survival compared with observation in non-lepidic predominant tumors (p [ 0.025).
Multivariate analyses revealed age, sex, stage, lepidic component occupancy, and adjuvant chemotherapy as independent prognostic factors for overall survival. The overall survival was significantly longer for patients with non-lepidic predominant tumors at stages IA, IB, and II-III under adjuvant chemotherapy compared with observation (p [ 0.040, p [ 0.007, and p [ 0.012, respectively), whereas survival rates were similar for patients with all stages of lepidic predominant tumors even after propensity score matching study. Conclusions. Lepidic component occupancy reflected the effect of adjuvant chemotherapy for lung adenocarcinoma. Adjuvant chemotherapy did not have much impact for lepidic predominant tumors and could be considered for non-lepidic predominant tumors even at stage IA.
L
lepidic predominant disease has a favorable survival [8]. More effective agents and additional predictive factors are needed to develop effective adjuvant chemotherapy. The International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) has established a multidisciplinary classification of lung adenocarcinoma [8], which is heterogeneous in nature and has several subtypes [9, 10]. The growth of adenocarcinoma is usually classified as lepidic, acinar, papillary, micropapillary, and solid. The prognosis is favorable for lepidic predominant tumors including adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic predominant invasive adenocarcinoma (LPA) [8, 11]. We postulated that lepidic predominant lung adenocarcinoma might not require postoperative adjuvant chemotherapy, whereas non-lepidic predominant tumors might need chemotherapy even during the early stage. Therefore, we retrospectively investigated the relevance between the lepidic component occupancy of the tumor and adjuvant chemotherapy.
ung cancer is the most common cause of cancer death worldwide and adenocarcinoma is the most frequent subtype, accounting for almost half of all lung cancers [1, 2]. The 5-year overall survival rate is 61.4% in the Japanese Lung Cancer Registry study of 13,010 patients with resected lung cancer [3]. Postoperative adjuvant chemotherapy has been investigated in efforts to improve the survival. During the past decade, some large phase III randomized trials of cisplatin-based chemotherapy showed that adjuvant chemotherapy improved 5-year overall survival (OS) rates by 4.1% to 15% [4–6]. However, the effects of adjuvant chemotherapy in stage I tumors could not be confirmed. A pooled analysis of postoperative cisplatin-based chemotherapy similarly showed a survival benefit for stage II and III non-small cell lung cancers [7]. Nonetheless, the benefits of adjuvant chemotherapy are not so large and this requires improvement. It was reported that the histologic subtypes of lung adenocarcinoma related to the prognosis and the Accepted for publication May 26, 2015. Address correspondence to Dr Okada, Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Hiroshima City, Hiroshima 734-8551, Japan; e-mail: [email protected].
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2015;-:-–-) Ó 2015 by The Society of Thoracic Surgeons
Patients and Methods We assessed 1,207 patients with lung adenocarcinoma who underwent surgery between January 1993 and 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.05.102
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Abbreviations and Acronyms AIS = adenocarcinoma in situ CT = computed tomography LPA = lepidic predominant invasive adenocarcinoma MIA = minimally invasive adenocarcinoma OS = overall survival
December 2011. Patients whose tumors were not completely resected, or who had undergone preoperative therapy, postoperative radiation therapy, or who had insufficient data were excluded and we finally analyzed data from 964 patients. The application of adjuvant chemotherapy has changed over the years; therapy was platinum-based for node-positive disease before 1994 and for stage II-III tumors after 1995. Since 2004, tegafur-uracil has been applied to treat stage I (especially T2) tumors. All patients in the present study were reclassified according to the TNM Classification of Malignant Tumors, 7th edition [12]. We defined lepidic predominant tumors as AIS, MIA, and LPA and non-lepidic predominant tumors as other invasive adenocarcinomas. Sublobar resection was considered for clinical stage IA tumors, which could be completely removed with ample surgical margins. No lymph node metastasis was intraoperatively confirmed from rapidly frozen sections of enlarged lymph nodes. Apparent or doubtful nodal metastasis was addressed by lobectomy instead. Systematic lymphadenectomy including hilar and mediastinal node dissection can proceed during segmentectomy, but not during wedge resection. Thus, wedge resection was applied to tumors that consisted mainly of a ground-glass opacity component on high-resolution computed tomography (CT) images. The Institutional Review Board of Hiroshima University Hospital approved the study.
Follow-Up Evaluation All patients were followed up from the day of surgery. Postoperative follow-up procedures comprised physical examinations and chest roentgenogram every 3 months and chest and abdominal CT imaging every 6 months for the first 2 years. Thereafter, the patients were followed up by physical examinations and chest x-rays every 6 months and annual CT assessments.
Statistical Analysis Summarized data are presented as numbers or means standard deviation unless otherwise stated. Frequencies were compared using the c2 test for categoric variables. Continuous variables were compared using the unpaired t test. Survival was analyzed using the Kaplan-Meier method and assessed using the log-rank test. Predictive and prognostic factors were assessed by univariate and multivariate analyses using the Cox proportional hazards model. We applied 1:1 propensity score matching to balance the assignment of patients with lepidic predominant tumors and the variables were age, sex, stages, and
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pleural, lymphatic, and vascular invasion. A p value less than 0.05 was considered statistically significant. Data were statistically analyzed using EZR which is a graphic user interface for R version 2.13.0 (The R Foundation for Statistical Computing, Vienna, Austria).
Results Among 964 patients with tumors that had been treated by complete resection, 270 (28.0%) received adjuvant chemotherapy and 694 (72.0%) did not. Chemotherapy comprised platinum-based regimens, oral fluoropyrimidine, as well as other and unknown regimens (n ¼ 84 (31.1%), n ¼ 170 (63.0%), n ¼ 15 (5.6%), n ¼ 1 (0.3%), respectively). The median follow-up period was 57 months. Table 1 shows the clinicopathologic characteristics of all patients in this study. The group given adjuvant chemotherapy contained younger patients, more males, larger tumors, lobectomy, higher stage diseases, nonlepidic predominant tumors and those with more pleural, lymphatic, and vascular invasion than the group that was under observation. The 5-year OS rates of all patients were similar between both groups (observation; 80.6% and adjuvant chemotherapy; 79.1%, p ¼ 0.705; Fig 1A). The prognosis was better for the patients with non-lepidic predominant tumors under adjuvant chemotherapy than those who were not, whereas that for lepidic predominant tumors was the opposite (5-year OS: Table 1. Patients’ Background
Characteristic Age (years) Sex Male Female Tumor size (cm) CEA (ng/mL) Procedure Lobectomy Sublobar resection Stage IA IB II III Lepidic predominance Lepidic Non-lepidic Pleural invasion Positive Lymphatic invasion Positive Vascular invasion Positive
No Adjuvant Adjuvant Chemotherapy Chemotherapy (n ¼ 694) (n ¼ 270) p Value 66.5 9.8
64.3 9.6
353 (50.9) 341 (49.1) 2.4 1.5 6.5 21.9
168 (62.2) 102 (37.8) 3.4 1.4 9.9 31.4
422 (60.8) 272 (39.2)
256 (94.8) 14 (5.2)
0.002 0.002
<0.001 0.075 <0.001
<0.001 459 124 63 48
(66.1) (17.9) (9.1) (6.9)
59 97 62 52
(21.9) (35.9) (23.0) (19.3) <0.001
344 (49.6) 350 (50.4)
71 (26.3) 199 (73.7)
136 (19.6)
94 (34.8)
148 (26.1)
111 (45.5)
121 (20.9)
95 (38.2)
<0.001 <0.001 <0.001
CEA ¼ carcinoembryonic antigen.
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78.0% vs 67.9%, p ¼ 0.025; 82.1% vs 92.9%, p ¼ 0.043, respectively, Figs 1B and 1C). The frequency of recurrence was 150 (21.6%) and 96 (35.6%) in the observed and treated groups and the type of recurrence was similar (data not shown). The results of univariate analysis of the effects of adjuvant chemotherapy shown in Figure 2 indicated that adjuvant chemotherapy is beneficial for treating stage IBIII tumors, non-lepidic predominant tumors, and positive pleural, lymphatic, and vascular invasion, but not for lepidic predominant tumors, which become worse. Multivariate Cox hazards analysis revealed that advanced age, male sex, higher stage, non-lepidic predominant tumors, and the absence of adjuvant chemotherapy were significant factors for a poor prognosis (Table 2). Figure 3 shows overall survival according to the predominance of a lepidic component at each stage. The 5-year OS of patients with lepidic predominant tumors did not significantly differ between the observed and treated groups (stage IA: 97.0% vs 92.3%, p ¼ 0.758; stage IB: 81.1% vs 90.1%, p ¼ 0.406; stage II-III; 52.1% vs 56.7%, p ¼ 0.524, respectively) (Figs 3A–3C). In contrast, the 5-year OS rate for those with non-lepidic predominant tumors was better for the treated than the observed group at all stages (IA: 95.0% vs 81.1%, p ¼ 0.040, IB; 89.1% vs 67.6%, p ¼ 0.007; II-III; 64.1% vs 44.2%, p ¼ 0.012) (Figs 3D–3F). Among patients with lepidic and non-lepidic predominant tumors, the group given adjuvant chemotherapy had features of higher stage and more invasive disease (Table 3). Only 34 patients with stage IIIII disease had lepidic predominant tumors. After propensity score matching by age, sex, stages, and pleural, lymphatic, and vascular invasion, the both pairs of 132 patients (66 patients each) with lepidic predominant tumors were well matched excluding surgical procedure (Table 4). The 5-year OS of matched patients with lepidic predominant tumors did not significantly differ between the observed and treated groups (76.4% vs 83.5%, p ¼ 0.229) (Fig 4). We also performed a propensity score matching analysis in patients treated with oral fluoropyrimidines after 2004 to reduce the bias and the results did not change in the matched patients with lepidic and non-lepidic predominant tumors (lepidic; 87.5% vs 87.0%, p ¼ 0.963 and non-lepidic; 66.8% vs 91.1%, p < 0.001).
Comment We investigated the relationship between the lepidic component occupancy of lung adenocarcinoma tumors Fig 1. Kaplan-Meier survival curves of patients after surgery who were treated with or without adjuvant chemotherapy. (A) Five-year overall survival (OS) of all patients were similar between both groups (observation, 80.6%; adjuvant chemotherapy, 79.1%; p ¼ 0.705). (B) Five-year OS is better for patients with lepidic predominant tumors under observation than under adjuvant chemotherapy (92.9% vs 82.1%, p ¼ 0.043). (C) Five-year OS is better for patients with nonlepidic predominant tumors under adjuvant chemotherapy than observation (78.0% vs 67.9%, p ¼ 0.025).
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Fig 2. Forest plot of effects of adjuvant chemotherapy according to various factors. (CI ¼ confidence interval; HR ¼ hazard ratio.)
Table 2. Multivariate Cox Proportional Hazard Analysis of Overall Survival Variable
HR (95% CI)
Age (65 vs <65 years) Sex (male vs female) CEA (>5 vs 5 ng/mL) Procedure Lobectomy Sublobar resection Stage IA IB II III Lepidic predominance (non-lepidic vs lepidic) Pleural invasion (yes vs no) Lymphatic invasion (yes vs no) Vascular invasion (yes vs no) Adjuvant chemotherapy (yes vs no) CEA ¼ carcinoembryonic antigen; hazard ratio.
1.63 (1.17–2.28) 1.74 (1.24–2.46) 1.10 (0.78–1.56) 1 0.90 (0.59–1.39)
p Value 0.004 0.002 0.578 0.650 –
1.98 3.07 5.00 1.60
1 (1.16–3.36) (1.77–5.31) (2.75–9.12) (1.01–2.52)
– 0.012 <0.001 <0.001 0.045
0.88 1.48 1.39 0.52
(0.60–1.29) (0.96–2.28) (0.94–2.07) (0.36–0.75)
0.503 0.077 0.104 <0.001
CI ¼ confidence interval;
HR ¼
and the effects of postoperative adjuvant chemotherapy on the basis of the hypothesis that lepidic predominant tumors might not require postoperative adjuvant chemotherapy. Lepidic component occupancy reflected the effect of adjuvant chemotherapy for stage I-III lung adenocarcinoma. Previous large randomized phase III trials and a metaanalysis have confirmed that cisplatin-based adjuvant chemotherapy confers a significant 5-year OS advantage of about 5% compared with observation [4–7]. However, these studies did not find a benefit of adjuvant chemotherapy for patients with stage I disease. A randomized trial indicated an advantage of carboplatin plus paclitaxel against larger (4 cm) stage IB tumors [13] and Japanese studies have shown that tegafur-uracil was useful against stage I tumors [14, 15]. The present indication for adjuvant chemotherapy is determined based only on pathologic stage and T status, but lung cancer is extremely heterogeneous. A sub-analysis of the data of the Adjuvant Navelbine International Trialist Association (ANITA) trial suggested that adjuvant cisplatin plus vinorelbine is effective against adenocarcinoma compared with nonadenocarcinoma [16]. Adenocarcinoma is most common and particularly heterogeneous among histologic types,
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Fig 3. Kaplan-Meier survival curves according to lepidic component predominance in each stage. (A)–(C). Patients with lepidic predominant lung adenocarcinoma under observation and adjuvant chemotherapy do not significantly differ (5-year overall survival [OS]: IA, 97.0% vs 92.3%, p ¼ 0.758; IB, 81.1% vs 90.1%, p ¼ 0.406; II-III, 52.1% vs 56.7%, p ¼ 0.524, respectively). (D)–(F). Five-year OS was better for patients with non-lepidic predominant tumors under adjuvant chemotherapy than observation (IA, 95.0% vs 81.1%, p ¼ 0.040; IB, 89.1% vs 67.6%, p ¼ 0.007; II-III, 64.1% vs 44.2%, p ¼ 0.012, respectively). (A) and (D), stage IA; (B) and (E), stage IB; (C) and (F), stage II-III.
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Table 3. Characteristics of Patients According to Lepidic Component Predominance Lepidic Predominant Characteristic
No Adjuvant (n ¼ 344)
Adjuvant (n ¼ 71)
65.6 9.8
65.3 9.2
139 (40.4) 205 (59.6) 2.1 1.6 2.9 2.8
42 (59.2) 29 (40.8) 3.4 1.3 3.9 3.2
175 (50.9) 169 (49.1)
67 (94.4) 4 (5.6)
286 42 11 5
22 31 14 4
Age (years) Sex Male Female Tumor size (cm) CEA (ng/mL) Procedure Lobectomy Sublobar resection Stage IA IB II III Pleural invasion Positive Lymphatic invasion Positive Vascular invasion Positive
Non-Lepidic Predominant p Value 0.828 0.006
<0.001 0.015 <0.001
No Adjuvant (n ¼ 350)
Adjuvant (n ¼ 199)
67.4 9.7
64.0 9.7
214 (61.1) 136 (38.9) 2.6 1.3 9.8 29.8
126 (63.3) 73 (36.7) 3.3 1.4 11.9 36.2
247 (70.6) 103 (29.4)
189 (95.0) 10 (5.0)
<0.001 (83.1) (12.2) (3.2) (1.5)
(31.0) (43.7) (19.7) (5.6)
10 (14.1)
14 (5.1)
11 (16.4)
11 (4.0)
8 (11.9)
<0.001 0.648
<0.001 0.469 <0.001
<0.001 173 82 52 43
(49.4) (23.4) (14.9) (12.3)
37 66 48 48
(18.6) (33.2) (24.1) (24.1)
0.016 18 (5.2)
p Value
0.053 118 (33.7)
84 (42.2)
134 (45.3)
100 (56.5)
110 (36.5)
87 (47.8)
0.004
0.022
0.017
0.017
CEA ¼ carcinoembryonic antigen.
and the IASLC/ATS/ERS proposed a new classification for the diagnosis and treatment of lung adenocarcinoma that requires a multidisciplinary approach [8]. The prognosis of lepidic predominant tumors, such as AIS, MIA, and LPA, is usually favorable [8, 11, 17]. Yoshizawa and colleagues [11] classified LPA as being of intermediate grade; however, the 5-year disease-free survival rate of patients with LPA was 90%, which was relatively good. In contrast, others have considered aggressive adjunctive therapy for solid or micropapillary predominant diseases because their prognosis is distressing [11, 17–19]. However, the relationship between adenocarcinoma subtypes and the effect of adjuvant chemotherapy has not been directly evaluated. The present study suggested that adjuvant chemotherapy prolonged the survival of patients with nonlepidic, but not of those with lepidic predominant tumors in stage I-III adenocarcinoma. Propensity score matched analysis of patients with lepidic predominant tumors supported the result. The effects of anti-cancer agents upon lepidic predominant tumors could be small, or a difference in OS might be undetectable because of a favorable prognosis, especially of stage I tumors. Among 415 patients with lepidic predominant tumors, only 19 (4.6%) had nodal metastasis and to refer these 19 patients for adjuvant chemotherapy would have been premature. Adjuvant chemotherapy is effective against non-lepidic predominant tumors at all disease stages; however,
Table 4. Characteristics of Propensity Score Matched Patients With Lepidic Predominant Tumors
Characteristic Age (years) Sex Male Female Tumor size (cm) CEA (ng/mL) Procedure Lobectomy Sublobar resection Stage IA IB II III Pleural invasion Positive Lymphatic invasion Positive Vascular invasion Positive
No Adjuvant Adjuvant Chemotherapy Chemotherapy (n ¼ 66) (n ¼ 66) p Value 68.0 9.7
65.8 9.1
41 (62.1) 25 (37.9) 3.2 2.7 4.2 5.9
38 (57.6) 29 (42.4) 3.4 1.3 3.8 3.2
41 (62.1) 25 (37.9)
62 (93.9) 4 (6.1)
30 26 7 3
19 31 12 4
0.179 0.723
0.465 0.555 <0.001
0.230 (45.5) (39.4) (10.6) (4.5)
(28.8) (47.0) (18.2) (6.1) 1
8 (12.1)
8 (12.1)
8 (12.1)
11 (16.7)
9 (13.6)
8 (12.1)
0.621 1
CEA ¼ carcinoembryonic antigen.
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chemotherapy regimens have not been unified over the years. To reflect Japanese clinical trials, 134 (85.9%) patients with stage I disease were treated with oral fluoropyrimidines. In conclusion, lepidic component occupancy reflected the effect of adjuvant chemotherapy for lung adenocarcinoma. Adjuvant chemotherapy could not demonstrate much therapeutic impact for lepidic predominant tumors within the limitations of retrospective subgroup analysis, but should be considered for non-lepidic predominant tumors even at earlier stages. This issue requires further investigation including subtype data.
References
Fig 4. Kaplan-Meier survival curves of propensity score matched patients with lepidic predominant tumors. Five-year overall survival (OS) did not significantly differ between the observed and treated groups (76.4% vs. 83.5%, p ¼ 0.229).
mixed acinar-, papillary-, solid-, and micropapillarypredominant invasive adenocarcinomas cannot be subtyped due to the absence of comparative data. A detailed investigation that includes subtype information is required. There are the literatures which have suggested that the invasive component size and the maximum standardized uptake value on F-18-fluorodeoxyglucose positron emission tomography and computed tomography can be candidates for adjuvant chemotherapy [20, 21], but subtyping was not considered. More adequate predictive factors are required to maximize the benefit of adjuvant chemotherapy because the current survival benefit is insufficient and chemotherapy has the potential for latestage harm [22]. This concept is important, as well as the surgical invasiveness and the postoperative pulmonary function [23–25]. This study has some limitations. Only lepidic component predominance was analyzed and comprehensive subtype information is unavailable. Such information is essential because the nature and prognosis of acinar-, papillary-, solid-, and micropapillary-predominant invasive types of adenocarcinoma differ, and we are presently in the process of collecting these data. Bias is an inherent limitation of the retrospective study design. Although more patients in the observation group were performed sublobar resection even after matching, previous studies reported that sublobar resection could achieve a similar prognosis with lobectomy in the selective patients [26, 27] and the multivariate analysis of this study showed that surgical procedure was not an independent prognostic factor. Indications for adjuvant chemotherapy have not only been changing, they are also at the discretion of each physician, and thus
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Background. The prognosis of lepidic predominant lung adenocarcinoma is favorable. We postulated that lepidic predominant tumors might not require postoperative adjuvant chemotherapy. The present study aims to determine whether lepidic component occupancy affects overall survival after postoperative adjuvant chemotherapy for lung adenocarcinoma. Methods. Clinical and pathologic data were collected from a database and from the medical records of 964 patients with completely resected lung adenocarcinoma. We assessed the influence of lepidic component occupancy in the tumor on the outcomes of adjuvant chemotherapy. Results. Among the patients, 270 received adjuvant chemotherapy and 694 did not, and 415 and 549 had lepidic predominant and non-lepidic predominant tumors, respectively. Adjuvant chemotherapy contributed to better overall survival compared with observation in non-lepidic predominant tumors (p [ 0.025).
Multivariate analyses revealed age, sex, stage, lepidic component occupancy, and adjuvant chemotherapy as independent prognostic factors for overall survival. The overall survival was significantly longer for patients with non-lepidic predominant tumors at stages IA, IB, and II-III under adjuvant chemotherapy compared with observation (p [ 0.040, p [ 0.007, and p [ 0.012, respectively), whereas survival rates were similar for patients with all stages of lepidic predominant tumors even after propensity score matching study. Conclusions. Lepidic component occupancy reflected the effect of adjuvant chemotherapy for lung adenocarcinoma. Adjuvant chemotherapy did not have much impact for lepidic predominant tumors and could be considered for non-lepidic predominant tumors even at stage IA.
L
lepidic predominant disease has a favorable survival [8]. More effective agents and additional predictive factors are needed to develop effective adjuvant chemotherapy. The International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) has established a multidisciplinary classification of lung adenocarcinoma [8], which is heterogeneous in nature and has several subtypes [9, 10]. The growth of adenocarcinoma is usually classified as lepidic, acinar, papillary, micropapillary, and solid. The prognosis is favorable for lepidic predominant tumors including adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic predominant invasive adenocarcinoma (LPA) [8, 11]. We postulated that lepidic predominant lung adenocarcinoma might not require postoperative adjuvant chemotherapy, whereas non-lepidic predominant tumors might need chemotherapy even during the early stage. Therefore, we retrospectively investigated the relevance between the lepidic component occupancy of the tumor and adjuvant chemotherapy.
ung cancer is the most common cause of cancer death worldwide and adenocarcinoma is the most frequent subtype, accounting for almost half of all lung cancers [1, 2]. The 5-year overall survival rate is 61.4% in the Japanese Lung Cancer Registry study of 13,010 patients with resected lung cancer [3]. Postoperative adjuvant chemotherapy has been investigated in efforts to improve the survival. During the past decade, some large phase III randomized trials of cisplatin-based chemotherapy showed that adjuvant chemotherapy improved 5-year overall survival (OS) rates by 4.1% to 15% [4–6]. However, the effects of adjuvant chemotherapy in stage I tumors could not be confirmed. A pooled analysis of postoperative cisplatin-based chemotherapy similarly showed a survival benefit for stage II and III non-small cell lung cancers [7]. Nonetheless, the benefits of adjuvant chemotherapy are not so large and this requires improvement. It was reported that the histologic subtypes of lung adenocarcinoma related to the prognosis and the Accepted for publication May 26, 2015. Address correspondence to Dr Okada, Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Hiroshima City, Hiroshima 734-8551, Japan; e-mail: [email protected].
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2015;-:-–-) Ó 2015 by The Society of Thoracic Surgeons
Patients and Methods We assessed 1,207 patients with lung adenocarcinoma who underwent surgery between January 1993 and 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.05.102
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Abbreviations and Acronyms AIS = adenocarcinoma in situ CT = computed tomography LPA = lepidic predominant invasive adenocarcinoma MIA = minimally invasive adenocarcinoma OS = overall survival
December 2011. Patients whose tumors were not completely resected, or who had undergone preoperative therapy, postoperative radiation therapy, or who had insufficient data were excluded and we finally analyzed data from 964 patients. The application of adjuvant chemotherapy has changed over the years; therapy was platinum-based for node-positive disease before 1994 and for stage II-III tumors after 1995. Since 2004, tegafur-uracil has been applied to treat stage I (especially T2) tumors. All patients in the present study were reclassified according to the TNM Classification of Malignant Tumors, 7th edition [12]. We defined lepidic predominant tumors as AIS, MIA, and LPA and non-lepidic predominant tumors as other invasive adenocarcinomas. Sublobar resection was considered for clinical stage IA tumors, which could be completely removed with ample surgical margins. No lymph node metastasis was intraoperatively confirmed from rapidly frozen sections of enlarged lymph nodes. Apparent or doubtful nodal metastasis was addressed by lobectomy instead. Systematic lymphadenectomy including hilar and mediastinal node dissection can proceed during segmentectomy, but not during wedge resection. Thus, wedge resection was applied to tumors that consisted mainly of a ground-glass opacity component on high-resolution computed tomography (CT) images. The Institutional Review Board of Hiroshima University Hospital approved the study.
Follow-Up Evaluation All patients were followed up from the day of surgery. Postoperative follow-up procedures comprised physical examinations and chest roentgenogram every 3 months and chest and abdominal CT imaging every 6 months for the first 2 years. Thereafter, the patients were followed up by physical examinations and chest x-rays every 6 months and annual CT assessments.
Statistical Analysis Summarized data are presented as numbers or means standard deviation unless otherwise stated. Frequencies were compared using the c2 test for categoric variables. Continuous variables were compared using the unpaired t test. Survival was analyzed using the Kaplan-Meier method and assessed using the log-rank test. Predictive and prognostic factors were assessed by univariate and multivariate analyses using the Cox proportional hazards model. We applied 1:1 propensity score matching to balance the assignment of patients with lepidic predominant tumors and the variables were age, sex, stages, and
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pleural, lymphatic, and vascular invasion. A p value less than 0.05 was considered statistically significant. Data were statistically analyzed using EZR which is a graphic user interface for R version 2.13.0 (The R Foundation for Statistical Computing, Vienna, Austria).
Results Among 964 patients with tumors that had been treated by complete resection, 270 (28.0%) received adjuvant chemotherapy and 694 (72.0%) did not. Chemotherapy comprised platinum-based regimens, oral fluoropyrimidine, as well as other and unknown regimens (n ¼ 84 (31.1%), n ¼ 170 (63.0%), n ¼ 15 (5.6%), n ¼ 1 (0.3%), respectively). The median follow-up period was 57 months. Table 1 shows the clinicopathologic characteristics of all patients in this study. The group given adjuvant chemotherapy contained younger patients, more males, larger tumors, lobectomy, higher stage diseases, nonlepidic predominant tumors and those with more pleural, lymphatic, and vascular invasion than the group that was under observation. The 5-year OS rates of all patients were similar between both groups (observation; 80.6% and adjuvant chemotherapy; 79.1%, p ¼ 0.705; Fig 1A). The prognosis was better for the patients with non-lepidic predominant tumors under adjuvant chemotherapy than those who were not, whereas that for lepidic predominant tumors was the opposite (5-year OS: Table 1. Patients’ Background
Characteristic Age (years) Sex Male Female Tumor size (cm) CEA (ng/mL) Procedure Lobectomy Sublobar resection Stage IA IB II III Lepidic predominance Lepidic Non-lepidic Pleural invasion Positive Lymphatic invasion Positive Vascular invasion Positive
No Adjuvant Adjuvant Chemotherapy Chemotherapy (n ¼ 694) (n ¼ 270) p Value 66.5 9.8
64.3 9.6
353 (50.9) 341 (49.1) 2.4 1.5 6.5 21.9
168 (62.2) 102 (37.8) 3.4 1.4 9.9 31.4
422 (60.8) 272 (39.2)
256 (94.8) 14 (5.2)
0.002 0.002
<0.001 0.075 <0.001
<0.001 459 124 63 48
(66.1) (17.9) (9.1) (6.9)
59 97 62 52
(21.9) (35.9) (23.0) (19.3) <0.001
344 (49.6) 350 (50.4)
71 (26.3) 199 (73.7)
136 (19.6)
94 (34.8)
148 (26.1)
111 (45.5)
121 (20.9)
95 (38.2)
<0.001 <0.001 <0.001
CEA ¼ carcinoembryonic antigen.
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78.0% vs 67.9%, p ¼ 0.025; 82.1% vs 92.9%, p ¼ 0.043, respectively, Figs 1B and 1C). The frequency of recurrence was 150 (21.6%) and 96 (35.6%) in the observed and treated groups and the type of recurrence was similar (data not shown). The results of univariate analysis of the effects of adjuvant chemotherapy shown in Figure 2 indicated that adjuvant chemotherapy is beneficial for treating stage IBIII tumors, non-lepidic predominant tumors, and positive pleural, lymphatic, and vascular invasion, but not for lepidic predominant tumors, which become worse. Multivariate Cox hazards analysis revealed that advanced age, male sex, higher stage, non-lepidic predominant tumors, and the absence of adjuvant chemotherapy were significant factors for a poor prognosis (Table 2). Figure 3 shows overall survival according to the predominance of a lepidic component at each stage. The 5-year OS of patients with lepidic predominant tumors did not significantly differ between the observed and treated groups (stage IA: 97.0% vs 92.3%, p ¼ 0.758; stage IB: 81.1% vs 90.1%, p ¼ 0.406; stage II-III; 52.1% vs 56.7%, p ¼ 0.524, respectively) (Figs 3A–3C). In contrast, the 5-year OS rate for those with non-lepidic predominant tumors was better for the treated than the observed group at all stages (IA: 95.0% vs 81.1%, p ¼ 0.040, IB; 89.1% vs 67.6%, p ¼ 0.007; II-III; 64.1% vs 44.2%, p ¼ 0.012) (Figs 3D–3F). Among patients with lepidic and non-lepidic predominant tumors, the group given adjuvant chemotherapy had features of higher stage and more invasive disease (Table 3). Only 34 patients with stage IIIII disease had lepidic predominant tumors. After propensity score matching by age, sex, stages, and pleural, lymphatic, and vascular invasion, the both pairs of 132 patients (66 patients each) with lepidic predominant tumors were well matched excluding surgical procedure (Table 4). The 5-year OS of matched patients with lepidic predominant tumors did not significantly differ between the observed and treated groups (76.4% vs 83.5%, p ¼ 0.229) (Fig 4). We also performed a propensity score matching analysis in patients treated with oral fluoropyrimidines after 2004 to reduce the bias and the results did not change in the matched patients with lepidic and non-lepidic predominant tumors (lepidic; 87.5% vs 87.0%, p ¼ 0.963 and non-lepidic; 66.8% vs 91.1%, p < 0.001).
Comment We investigated the relationship between the lepidic component occupancy of lung adenocarcinoma tumors Fig 1. Kaplan-Meier survival curves of patients after surgery who were treated with or without adjuvant chemotherapy. (A) Five-year overall survival (OS) of all patients were similar between both groups (observation, 80.6%; adjuvant chemotherapy, 79.1%; p ¼ 0.705). (B) Five-year OS is better for patients with lepidic predominant tumors under observation than under adjuvant chemotherapy (92.9% vs 82.1%, p ¼ 0.043). (C) Five-year OS is better for patients with nonlepidic predominant tumors under adjuvant chemotherapy than observation (78.0% vs 67.9%, p ¼ 0.025).
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Fig 2. Forest plot of effects of adjuvant chemotherapy according to various factors. (CI ¼ confidence interval; HR ¼ hazard ratio.)
Table 2. Multivariate Cox Proportional Hazard Analysis of Overall Survival Variable
HR (95% CI)
Age (65 vs <65 years) Sex (male vs female) CEA (>5 vs 5 ng/mL) Procedure Lobectomy Sublobar resection Stage IA IB II III Lepidic predominance (non-lepidic vs lepidic) Pleural invasion (yes vs no) Lymphatic invasion (yes vs no) Vascular invasion (yes vs no) Adjuvant chemotherapy (yes vs no) CEA ¼ carcinoembryonic antigen; hazard ratio.
1.63 (1.17–2.28) 1.74 (1.24–2.46) 1.10 (0.78–1.56) 1 0.90 (0.59–1.39)
p Value 0.004 0.002 0.578 0.650 –
1.98 3.07 5.00 1.60
1 (1.16–3.36) (1.77–5.31) (2.75–9.12) (1.01–2.52)
– 0.012 <0.001 <0.001 0.045
0.88 1.48 1.39 0.52
(0.60–1.29) (0.96–2.28) (0.94–2.07) (0.36–0.75)
0.503 0.077 0.104 <0.001
CI ¼ confidence interval;
HR ¼
and the effects of postoperative adjuvant chemotherapy on the basis of the hypothesis that lepidic predominant tumors might not require postoperative adjuvant chemotherapy. Lepidic component occupancy reflected the effect of adjuvant chemotherapy for stage I-III lung adenocarcinoma. Previous large randomized phase III trials and a metaanalysis have confirmed that cisplatin-based adjuvant chemotherapy confers a significant 5-year OS advantage of about 5% compared with observation [4–7]. However, these studies did not find a benefit of adjuvant chemotherapy for patients with stage I disease. A randomized trial indicated an advantage of carboplatin plus paclitaxel against larger (4 cm) stage IB tumors [13] and Japanese studies have shown that tegafur-uracil was useful against stage I tumors [14, 15]. The present indication for adjuvant chemotherapy is determined based only on pathologic stage and T status, but lung cancer is extremely heterogeneous. A sub-analysis of the data of the Adjuvant Navelbine International Trialist Association (ANITA) trial suggested that adjuvant cisplatin plus vinorelbine is effective against adenocarcinoma compared with nonadenocarcinoma [16]. Adenocarcinoma is most common and particularly heterogeneous among histologic types,
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Fig 3. Kaplan-Meier survival curves according to lepidic component predominance in each stage. (A)–(C). Patients with lepidic predominant lung adenocarcinoma under observation and adjuvant chemotherapy do not significantly differ (5-year overall survival [OS]: IA, 97.0% vs 92.3%, p ¼ 0.758; IB, 81.1% vs 90.1%, p ¼ 0.406; II-III, 52.1% vs 56.7%, p ¼ 0.524, respectively). (D)–(F). Five-year OS was better for patients with non-lepidic predominant tumors under adjuvant chemotherapy than observation (IA, 95.0% vs 81.1%, p ¼ 0.040; IB, 89.1% vs 67.6%, p ¼ 0.007; II-III, 64.1% vs 44.2%, p ¼ 0.012, respectively). (A) and (D), stage IA; (B) and (E), stage IB; (C) and (F), stage II-III.
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Table 3. Characteristics of Patients According to Lepidic Component Predominance Lepidic Predominant Characteristic
No Adjuvant (n ¼ 344)
Adjuvant (n ¼ 71)
65.6 9.8
65.3 9.2
139 (40.4) 205 (59.6) 2.1 1.6 2.9 2.8
42 (59.2) 29 (40.8) 3.4 1.3 3.9 3.2
175 (50.9) 169 (49.1)
67 (94.4) 4 (5.6)
286 42 11 5
22 31 14 4
Age (years) Sex Male Female Tumor size (cm) CEA (ng/mL) Procedure Lobectomy Sublobar resection Stage IA IB II III Pleural invasion Positive Lymphatic invasion Positive Vascular invasion Positive
Non-Lepidic Predominant p Value 0.828 0.006
<0.001 0.015 <0.001
No Adjuvant (n ¼ 350)
Adjuvant (n ¼ 199)
67.4 9.7
64.0 9.7
214 (61.1) 136 (38.9) 2.6 1.3 9.8 29.8
126 (63.3) 73 (36.7) 3.3 1.4 11.9 36.2
247 (70.6) 103 (29.4)
189 (95.0) 10 (5.0)
<0.001 (83.1) (12.2) (3.2) (1.5)
(31.0) (43.7) (19.7) (5.6)
10 (14.1)
14 (5.1)
11 (16.4)
11 (4.0)
8 (11.9)
<0.001 0.648
<0.001 0.469 <0.001
<0.001 173 82 52 43
(49.4) (23.4) (14.9) (12.3)
37 66 48 48
(18.6) (33.2) (24.1) (24.1)
0.016 18 (5.2)
p Value
0.053 118 (33.7)
84 (42.2)
134 (45.3)
100 (56.5)
110 (36.5)
87 (47.8)
0.004
0.022
0.017
0.017
CEA ¼ carcinoembryonic antigen.
and the IASLC/ATS/ERS proposed a new classification for the diagnosis and treatment of lung adenocarcinoma that requires a multidisciplinary approach [8]. The prognosis of lepidic predominant tumors, such as AIS, MIA, and LPA, is usually favorable [8, 11, 17]. Yoshizawa and colleagues [11] classified LPA as being of intermediate grade; however, the 5-year disease-free survival rate of patients with LPA was 90%, which was relatively good. In contrast, others have considered aggressive adjunctive therapy for solid or micropapillary predominant diseases because their prognosis is distressing [11, 17–19]. However, the relationship between adenocarcinoma subtypes and the effect of adjuvant chemotherapy has not been directly evaluated. The present study suggested that adjuvant chemotherapy prolonged the survival of patients with nonlepidic, but not of those with lepidic predominant tumors in stage I-III adenocarcinoma. Propensity score matched analysis of patients with lepidic predominant tumors supported the result. The effects of anti-cancer agents upon lepidic predominant tumors could be small, or a difference in OS might be undetectable because of a favorable prognosis, especially of stage I tumors. Among 415 patients with lepidic predominant tumors, only 19 (4.6%) had nodal metastasis and to refer these 19 patients for adjuvant chemotherapy would have been premature. Adjuvant chemotherapy is effective against non-lepidic predominant tumors at all disease stages; however,
Table 4. Characteristics of Propensity Score Matched Patients With Lepidic Predominant Tumors
Characteristic Age (years) Sex Male Female Tumor size (cm) CEA (ng/mL) Procedure Lobectomy Sublobar resection Stage IA IB II III Pleural invasion Positive Lymphatic invasion Positive Vascular invasion Positive
No Adjuvant Adjuvant Chemotherapy Chemotherapy (n ¼ 66) (n ¼ 66) p Value 68.0 9.7
65.8 9.1
41 (62.1) 25 (37.9) 3.2 2.7 4.2 5.9
38 (57.6) 29 (42.4) 3.4 1.3 3.8 3.2
41 (62.1) 25 (37.9)
62 (93.9) 4 (6.1)
30 26 7 3
19 31 12 4
0.179 0.723
0.465 0.555 <0.001
0.230 (45.5) (39.4) (10.6) (4.5)
(28.8) (47.0) (18.2) (6.1) 1
8 (12.1)
8 (12.1)
8 (12.1)
11 (16.7)
9 (13.6)
8 (12.1)
0.621 1
CEA ¼ carcinoembryonic antigen.
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chemotherapy regimens have not been unified over the years. To reflect Japanese clinical trials, 134 (85.9%) patients with stage I disease were treated with oral fluoropyrimidines. In conclusion, lepidic component occupancy reflected the effect of adjuvant chemotherapy for lung adenocarcinoma. Adjuvant chemotherapy could not demonstrate much therapeutic impact for lepidic predominant tumors within the limitations of retrospective subgroup analysis, but should be considered for non-lepidic predominant tumors even at earlier stages. This issue requires further investigation including subtype data.
References
Fig 4. Kaplan-Meier survival curves of propensity score matched patients with lepidic predominant tumors. Five-year overall survival (OS) did not significantly differ between the observed and treated groups (76.4% vs. 83.5%, p ¼ 0.229).
mixed acinar-, papillary-, solid-, and micropapillarypredominant invasive adenocarcinomas cannot be subtyped due to the absence of comparative data. A detailed investigation that includes subtype information is required. There are the literatures which have suggested that the invasive component size and the maximum standardized uptake value on F-18-fluorodeoxyglucose positron emission tomography and computed tomography can be candidates for adjuvant chemotherapy [20, 21], but subtyping was not considered. More adequate predictive factors are required to maximize the benefit of adjuvant chemotherapy because the current survival benefit is insufficient and chemotherapy has the potential for latestage harm [22]. This concept is important, as well as the surgical invasiveness and the postoperative pulmonary function [23–25]. This study has some limitations. Only lepidic component predominance was analyzed and comprehensive subtype information is unavailable. Such information is essential because the nature and prognosis of acinar-, papillary-, solid-, and micropapillary-predominant invasive types of adenocarcinoma differ, and we are presently in the process of collecting these data. Bias is an inherent limitation of the retrospective study design. Although more patients in the observation group were performed sublobar resection even after matching, previous studies reported that sublobar resection could achieve a similar prognosis with lobectomy in the selective patients [26, 27] and the multivariate analysis of this study showed that surgical procedure was not an independent prognostic factor. Indications for adjuvant chemotherapy have not only been changing, they are also at the discretion of each physician, and thus
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