THORACIC: LUNG CANCER: CLINICAL TRIAL

A single-arm study of sublobar resection for ground-glass

opacity dominant peripheral lung cancer
Kenji Suzuki, MD,a Shun-ichi Watanabe, MD,b Masashi Wakabayashi, MD,c Hisashi Saji, MD, PhD,d
Keiju Aokage, MD,e Yasumitsu Moriya, MD,f Ichiro Yoshino, MD,g Masahiro Tsuboi, MD,e
Shinichiro Nakamura, ME,h Kenichi Nakamura, MD,c Tetsuya Mitsudomi, MD,i and Hisao Asamura, MD,j
on behalf of the West Japan Oncology Group and Japan Clinical Oncology Group

ABSTRACT CTR
0 0.25 0.5 0.75 1.0
Background: The optimal mode of surgery for ground-glass opacity dominant pe-
Wedge or Sementectomy or
Wedge or
ripheral lung cancer defined with thoracic thin-section computed tomography re- 1.0 cm SEG
SEG
lobectomy
JCOG0804/ JCOG0802/

Tumor size
mains unknown. WJOG4507L
JCOG1211
WJOG4607L
2.0 cm

Methods: We conducted a single-arm confirmatory trial to evaluate the efficacy Segmentectomy

JCOG1211
Lobectomy

and safety of sublobar resection for ground-glass opacity dominant peripheral 3.0 cm
Lobectomy
lung cancer. Lung cancer with maximum tumor diameter 2.0 cm or less and with
consolidation tumor ratio 0.25 or less based on thin-section computed tomography CTR = consolidation/tumor ratio

were registered. The primary end point was 5-year relapse-free survival. The
planned sample size was 330 with the expected 5-year relapse-free survival of
98%, threshold of 95%, 1-sided a of 5%, and power of 90%. The trial is registered
with University Hospital Medical Information Network Clinical Trials Registry, num-
ber University Hospital Medical Information Network 000002008.
Results: Between May 2009 and April 2011, 333 patients were enrolled from 51 in-
stitutions. Median age was 62 years (interquartile range, 56-68), and 109 were
smokers. Median maximum tumor diameter was 1.20 cm (1.00-1.54). Median
maximum tumor diameter of consolidation was 0 (0.00-0.20). The primary end
point, 5-year relapse-free survival, was estimated on 314 patients who underwent
sublobar resection. Operative modes were 258 wide wedge resections and 56 seg-
mentectomies. Median pathological surgical margin was 15 mm (0-55). The 5-year
relapse-free survival was 99.7% (90% confidence interval, 98.3-99.9), which met
the primary end point. There was no local relapse. Grade 3 or higher postoperative
complications based on Common Terminology Criteria for Adverse Effect v3.0
were observed in 17 patients (5.4%), without any grade 4 or 5.
Conclusions: Sublobar resection with enough surgical margin offered sufficient
local control and relapse-free survival for lung cancer clinically resectable N0 staged
by computed tomography with 3 or fewer peripheral lesions 2.0 cm or less
amenable to sublobar resection and with a consolidation tumor ratio of 0.25 or
less. (J Thorac Cardiovasc Surg 2022;163:289-301)
THOR
Current JCOG strategy for stage I lung cancer: The
strategy is decided by considering the maximum tu-
mor dimension and CTR. JCOG0804/WJOG4607L
is a 1-arm study with sublobar resection for radio-
logic noninvasive lung cancer based on the criteria
of JCOG0201, which defined radiologic noninvasive
lung cancer as tumor 2.0 cm or less in size with CTR
0.25 or less. JCOG0802/WJOG4607L is a random-
ized trial comparing lobectomy and segmentec-
tomy for invasive lung cancer, for which the
morbidity results were published in 2019.
JCOG1211 is a study of segmentectomy for larger
radiologic noninvasive lung cancer, which will be
presented in the future.
CENTRAL MESSAGE
Sublobar resection with an
adequate surgical margin offered
sufficient local control and RFS
for GGO-dominant lung cancer.
PERSPECTIVE
Since 1960, even small-sized lung cancers have
required major lung resection with lobectomy.
According to the results of JCOG0804/
WJOG4507L, small and less-invasive lung cancers
were curable with sublobar resection instead of
lobectomy. This study leads to the next step,
such as a follow-up study of lung cancer.

See Commentaries on pages 302, 303, and 305.

Lung cancer is a leading cause of death in the world.1 Sur-

Scanning this QR code will
gical resection remains the gold standard for lung cancer
take you to the table of con-
treatment, and the mode of surgery has been lobectomy
tents to access supplementary
since 1960.2 This is confirmed by the results of a random-
information.
ized trial comparing lobectomy and sublobar resection for
pathological stage I lung cancer conducted by the North

The Journal of Thoracic and Cardiovascular Surgery c Volume 163, Number 1 289
 Thoracic: Lung Cancer: Clinical Trial
Abbreviations and Acronyms
CI ¼ confidence interval
CT ¼ computed tomography
CTR ¼ consolidation tumor ratio
FEV1 ¼ forced expiratory volume in 1 second
FVC ¼ forced vital capacity
GGO ¼ ground-glass opacity
JCOG ¼ Japan Clinical Oncology Group
MIA ¼ minimally invasive adenocarcinoma
RFS ¼ relapse-free survival
WJOG ¼ West Japan Oncology Group
American Lung Cancer Study Group.3 Sublobar resection
for lung cancer has been indicated only for lung cancer in
a compromised host. On the other hand, recent established
evidence of screening for lung cancer and advances in diag-
THOR
nostic modality such as thoracic thin-section computed to-
mography (CT) have resulted in the increase in early
detection of small lung tumors. The indications for sublobar
resection are now extended for small-sized early lung can-
cer and multiple lung cancers.4 Intentional sublobar resec-
tion can be approved for patients who can tolerate
lobectomy if, at least, no nodal involvement is ensured.
To select lung cancer that has no nodal involvement or lym-
phovascular invasion, the Japan Clinical Oncology Group
(JCOG) conducted JCOG0201 study.5,6 The study defined
radiologic noninvasive lung cancer as lung cancer 2 cm or
less in size having a consolidation tumor ratio (CTR) 0.25
or less, that is, a large area of ground-glass opacity
(GGO), and confirmed an excellent prognosis. On the basis
of the results, JCOG and West Japan Oncology Group
(WJOG) conducted 2 prospective intergroup studies to
investigate the optimal mode of surgery for peripherally
located small-sized lung cancer.6 JCOG0802/WJOG4607L
was a randomized, controlled noninferiority design
trial comparing segmentectomy and lobectomy for radio-
logically invasive lung cancer defined by JCOG0201 and
JCOG0804/WJOG4507L single phase II trial for radiolog-
ically noninvasive lung cancer defined by JCOG0201
From the aDepartment of General Thoracic Surgery, Juntendo University School of
Medicine, Tokyo, Japan; bDivision of Thoracic Surgery, National Cancer Center
Hospital, Tokyo, Japan; cJapan Clinical Oncology Group Data Center/Operations
Office, National Cancer Center Hospital, Tokyo, Japan; dDepartment of General
Thoracic Surgery, St Marianna University School of Medicine, Kanagawa, Japan;
e The individual group member names are listed at the end of the article.
Division of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan;
f Received for publication Sept 10, 2019; revisions received Sept 15, 2020; accepted for
Department of Thoracic Surgery, Chiba Rosai Hospital, Chiba, Japan; gDepartment
of General Thoracic Surgery, Graduate School of Medicine, Chiba University,
Chiba, Japan; hWest Japan Oncology Group Data Center, Osaka, Japan; iFaculty
of Medicine, Department of Surgery, Kindai University, Osaka, Japan; and jDivi-
sion of Thoracic Surgery, Keio University School of Medicine, Tokyo, Japan, on
behalf of West Japan Oncology Group and Japan Clinical Oncology Group.
This study is supported in part by the National Cancer Center Research and Develop-
ment Fund, a Grants-in-Aid for Cancer Research from the Ministry of Health, La-
bour and Welfare of Japan and by AMED under Grant Number
JP15ck0106051h0002.
290 The Journal of Thoracic and Cardiovascular Surgery c January 2022
Suzuki et al
(Central Image). After confirming the results of both
studies, the standard mode of surgery for peripherally
located small-sized lung cancer will be decided. The final
results of JCOG0802/WJOG4506L will be confirmed in
2021.
The aim of this study is to confirm the feasibility of sub-
lobar resection for GGO-dominant peripheral lung cancer to
establish the standard mode of surgery.
MATERIALS AND METHODS
Study Design and Patients
Eligibility criteria at registration included age 20 to 79 years, an Eastern
Cooperative Oncology Group performance status of 0 or 1, and a tumor of a
clinically resectable N0 lung cancer suspected lesion. All of the following
conditions are required at the contrast-enhanced chest CT within 56 days
before registration: (1) radiologically suspicious lung cancer; (2) bilateral
or unilateral 3 or less number of lesions; (3) center of the tumor located in
the outer third of the lung field; and (4) no sign of nodal involvement. Thin-
section CT was mandatory and should fulfill both of the following condi-
tions: (1) maximum tumor diameter of 2.0 cm or less and (2) tumor with
CTR 0.25 or less. CTR was defined as a ratio of the maximum dimension
of consolidation to the maximum tumor dimension (see Figure 3.5.2 in the
Online Data Supplement).5 CTR was investigated in the prospective multi-
institutional study JCOG0201, and “radiologic noninvasive carcinoma” is
defined as lung carcinoma with a CTR 0.25 or less. Preoperative histologic
or cytologic diagnosis is not mandatory; however, if available, the diag-
nosis should be adenocarcinoma and not invasive. It is judged that lobec-
tomy is possible based on CT and the patient’s tolerability to lobectomy.
Sufficient organ function and written informed consent were needed.
Anatomic definition, clinical staging, and pathological classification in
the trial are based on TNM staging system 6th edition.7 After the second
revision, data are collected on the basis of the TNM 7th edition,8 and
description in the trial is based on TNM 6th edition. Thin-section CT
was evaluated within 56 days before registration for TNM staging. The pri-
mary tumor is evaluated with thin-section CT scan.
The study protocol was approved by the Protocol Review Committee in
JCOG and WJOG and the institutional review board of each participating
hospital before initiation of the study. This study was conducted in accor-
dance with the Declaration of Helsinki and the Japanese Ethical Guidelines
for Clinical Research.
Procedures
Protocol treatment, surgical resection, should be performed within
14 days after registration. Pulmonary resection can be performed with
video assistance or as an open procedure (Video 1). Factors related to
inability to perform sublobar resections should be investigated, and if so,
This trial is registered with the University Hospital Medical Information Network-
CTR (UMIN000002008). Institutional Review Board Number: Juntendo 21-37,
May 29, 2009.
Presented at: the American Society of Clinical Oncology, Chicago, Illinois, June 2-6,
2017.
publication Sept 19, 2020; available ahead of print Nov 12, 2020.
Address for reprints: Kenji Suzuki, MD, General Thoracic Surgery, Juntendo Univer-
sity School of Medicine, 1-3 Hongo 3 chome, Bunkyoku, Tokyo 113-8431, Japan
(E-mail: kjsuzuki@juntendo.ac.jp).
0022-5223/$36.00
Copyright Ó 2020 Published by Elsevier Inc. on behalf of The American Association
for Thoracic Surgery
https://doi.org/10.1016/j.jtcvs.2020.09.146
Suzuki et al Thoracic: Lung Cancer: Clinical Trial

than adenocarcinoma with intraoperative needle biopsy, if available; (3)

VIDEO 1. Robot-assisted segmentectomy for lung adenocarcinoma
located in the superior segment of the left lower lobe is shown. Frozen-
section and final diagnosis confirmed the tumor as MIA. Console time
was 45 minutes with 3 mL blood loss. Video available at: https://www.
macroscopic or microscopic nodal involvement; and (4) insufficient surgi-
cal margin in case of sublobar resection. After confirming those factors,
wide wedge resection is planned and performed (Figure 1). However, if
the surgeon noticed that the preceding wedge might result in insufficient
margin, segmentectomy could be selected for the surgical procedure
from the beginning. The resected specimen should be sent to the patholo-
gist intraoperatively for evaluation of the surgical margin and histology of
the primary tumor by frozen-section diagnosis, either pathology or
cytology. The protocol should be terminated if frozen-section diagnosis re-
sults in other histology than adenocarcinoma. After diagnosis of invasive
adenocarcinoma by frozen-section, the mode of surgery needs to be
decided: wide wedge resection or segmentectomy. Nodal dissection was
not mandatory for hilar and mediastinal region when performing wedge
resection. However, macroscopic swollen nodes, which are apparently
diagnosed to be positive for tumor cells, require terminating the protocol.
Otherwise, suspected nodes should be sent for frozen diagnosis, pathology,
or cytology. The macroscopic surgical margin should be 5 mm or more,
which is confirmed by evaluating the distance between the tumor and the
parenchyma staple or cut line. Macroscopic positive margin or surgical
margin less than 5 mm needs frozen-section diagnosis. Positive margin

jtcvs.org/article/S0022-5223(20)33043-9/fulltext.
the study protocol is terminated (Figure 1). Treatment after termination of
the protocol is not restricted. Intraoperative unresectable factors are (1) ma-
lignant effusion or pleural dissemination; (2) histologic diagnosis rather
THOR
by frozen-section needs conversion to segmentectomy or lobectomy to
maintain enough surgical margin, and if not, the protocol should be termi-
nated. Simultaneous resection is mandatory for ipsilateral multiple lung
cancers at registration, and staged operation is not allowed. When multiple
tumors are detected that are suspected to be lung cancer on thin-section CT,

333 registered patients

JCOG 248 / WJOG 85 Non-eligible (N = 8)
Past history of chemotherapy (N = 2)
No thin section CT preoperatively (N = 1)
Active cancers (N = 3)
All eligible (N = 325) Radiologically invasive cancer (N = 2)

No lung resection (N = 0)

All surgical patients (N = 325)

MacroscopicaIly incomplete resection (N = 0)

Conversion to lobectomy (N = 11)

Macroscopically complete resection (N = 325)
Wedge-segmentectomy-lobectomy (N = 1)
Wedge-lobectomy (N = 6)
Segmentectomy-lobectomy (N = 3)
All sublobar resections (N = 314) Lobectomy (N = 1)
(Population for primary analysis)

MacroscopicaIly incomplete resection (N = 0)

Non-cancerous lesion (N = 9)

Pathological complete resection (N = 305)

Pathological non-adenocarcinoma (N = 15)*

All completed sublobar resection (N = 290) * For patients with more than one lesions, at least one lesion which
diagnosed to be adenocarcinoma made the patients categorize to “all
completed sublobar resection.”
FIGURE 1. Consort diagram of JCOG0804/WJOG4507L study. JCOG0804/WJOG4607L is a 1-arm study with wide wedge resection for GGO-dominant
lung cancer based on the criteria of JCOG0201, which defined radiologic noninvasive lung cancer as tumor 2.0 cm or less in size with CTR 0.25 or less. After
wedge resection, factors related to ineligibility for sublobar resections should be investigated, and surgical procedures according to the study protocol is
terminated if an unresectable factor is found intraoperatively. JCOG, Japan Clinical Oncology Group; WJOG, West Japan Oncology Group; CT, computed
tomography.

The Journal of Thoracic and Cardiovascular Surgery c Volume 163, Number 1 291
 Thoracic: Lung Cancer: Clinical Trial Suzuki et al

the primary lesion is defined as the tumor with the largest dimension of TABLE 1. Patients’ characteristics at registration
consolidation. Completion of protocol treatment is defined as macroscopic
Characteristics Number (n ¼ 333)
complete resection and confirmation by pathological diagnosis of all the
following: (1) histologic typing of adenocarcinoma; (2) complete resec- Age (y)
tion; (3) no nodal involvement; and (4) sublobar resection performed. Median 62
The day of protocol treatment completion is the day of operation. IQR 56-68
Postoperative pathological findings are determined according to the Sex
World Health Organization histologic classification published in 1999.9
Women 223 (67.0%)
Noguchi’s classification, which evaluates degree of pathological invasion
Men 110 (33.0%)
by the presence of active fibroblast, was only evaluated in adenocarci-
noma.10 According to Noguchi’s classification, type A is adenocarcinoma No. of lesions
in situ, type B is minimally invasive adenocarcinoma (MIA), type C is MIA 1 lesion 317 (95.2%)
or invasive adenocarcinoma with lepidic growth, and type D, E, F is inva- 2 lesions 15 (4.5%)
sive adenocarcinoma without lepidic growth. Microscopically, the surgical 3 lesions 1 (0.3%)
margin between the tumor and the resection line was measured by the min-
Radiologic maximum tumor
imum diameter between the tumor margin and the stapler line margin or
resection margin without pleura. dimension on thin-section
Routine examinations every 6 months for 5 years after surgery and every CT (cm)
1 year for additional 5 years are necessary for chest x-ray and tumor marker Median 1.20
of carcinoembryonic antigen. Patients with noncancerous lesion do not IQR 1.00-1.54
require follow-up. When the CT revealed multiple lung lesions, thin-
THOR

Eastern Cooperative Oncology

section CT was added. Routine chest CT is mandatory every 1 year for Group Performance status at
10 years.
registration
0 328 (98.5%)
Outcome 1 5 (1.5%)
Evaluation of the efficacy and safety of sublobar resection for GGO-
dominant lung cancer 2 cm or less in size was the purpose of the study. Smoking history
The primary end point was relapse-free survival (RFS) in patients who None 224 (67.3%)
completed their surgery with sublobar resection. RFS was defined as the Present 109 (32.7%)
time from registration to relapse or death from any cause or to last date Duration of smoking (y)
of contact with the surviving patient. The secondary end points were over- Median 25.5
all survival, frequency of local recurrence, postoperative respiratory func- IQR 15-37
tion, forced expiratory volume in 1 second (FEV1), forced vital capacity
Unknown 5
(FVC), proportion of completion of sublobar resection, and adverse events.
Overall survival was defined as the time from registration to death from any Mean smoking per day (No. of
cause or to the last date of contact with the surviving patient. Spirometry is cigarettes)
performed at 6 months and 12 months after surgery. Postoperative early Median 20
complication was defined as a complication occurring within 30 days IQR 15-30
from surgery. Complications were evaluated with the Common Terminol- Unknown 4
ogy Criteria for Adverse Events version 3.0.
Preoperative diagnosis
None 322 (96.7%)
Statistical Analysis Present 11 (3.3%)
The primary analysis was performed at 5-year RFS. Required sample
size was 311, assuming an expected 5-year RFS of 98%, a threshold Preoperative diagnosis if
5-year RFS of 95%, the 1-sided alpha of 5%, and a power of more than available
90%. Planned sample size was set at 330 patients to account for ineligible Adenocarcinoma 9
patients. RFS and overall survival were calculated by using the Kaplan– Non–small cell 1
Meier method, and the confidence intervals (CIs) of the time point estima- Preinvasive lesion 1
tion were estimated by the Greenwood formula. If the lower limit of 90% Clinical TNM and stage at
CI of 5-year RFS for patients with sublobar resection was more than 95%,
registration
the primary end point was met. The proportion of completion of sublobar
T1aN0M0 333 (100%)
resection and its CI were estimated by the exact binomial method. Expert
clinician input was used to decide the CI. This study was designed to inves- Stage IA 333 (100%)
tigate whether the 5-year RFS of the group of all sublobar resections was Location of the tumor
comparable to or better than that of historical control of the group of all Right upper lobe 111 (33.3%)
sublobar resections. Safety analysis was performed for all operated pa- Right middle lobe 12 (3.6%)
tients. As a sensitivity analysis, the primary and secondary end points Right lower lobe 86 (25.8%)
were analyzed to all registered patients. All statistical analyses were per-
Left upper lobe 77 (23.1%)
formed by using SAS software, release 9.4 (SAS Institute, Inc, Cary,
Left lower lobe 47 (14.1%)
IQR, Interquartile range; CT, computed tomography.

292 The Journal of Thoracic and Cardiovascular Surgery c January 2022

Suzuki et al Thoracic: Lung Cancer: Clinical Trial

TABLE 2. Preoperative factors per lesion

Lesion 1 Lesion 2 Lesion 3 All lesions
Parameters (n ¼ 333) (n ¼ 16) (n ¼ 1) (n ¼ 350)
Radiologic maximum tumor dimension on lung window setting of thin-section CT (cm)
Median 1.20 0.80 0.60 1.20
IQR 1.00-1.54 0.65-0.95 0.60-0.60 0.96-1.50
Radiologic maximum consolidation dimension on lung window setting of thin-section CT (cm)
Median 0.00 0.00 0.00 0.00
IQR 0.00-0.20 0.00-0.00 0.00-0.00 0.00-0.20
CTR
Median 0.00 0.00 0.00 0.00
IQR 0.00-0.20 0.00-0.00 0.00-0.00 0.00-0.20
Pleural indentation
Absent 276 15 1 292
Present 57 1 0 58
Air bronchogram within the lesion
Absent 247 13 1 261

THOR
Present 86 3 0 89
Radiologic maximum tumor dimension on mediastinal window setting of thin-section CT (cm)
Median 0.00
Range 0.00-0.00
CT, Computed tomography; IQR, interquartile range; CTR, consolidation tumor ratio.

NC). This trial is registered with the University Hospital Medical Informa-
tion Network-CTR, number UMIN000002008.
Role of the Funding Sources
The funders had no role in the study design, data collection, data anal-
ysis, data interpretation, or writing of the report. The corresponding author
had full access to all the data in the study and the final responsibility for
deciding on the submission of the report for publication.
RESULTS
Between May 6, 2009, and April 26, 2011, 333 patients
were enrolled from 51 institutions (JCOG 31, WJOG 20).
Eight patients were ineligible, and 325 patients were
eligible (Figure 1). No patients underwent positron emis-
sion tomography, endobronchial ultrasound-guided biopsy,
or mediastinoscopy. No unresectable factors were noted.
Among 325 patients who underwent pulmonary resection,
conversion to lobectomy was necessary in 11 patients,
and sublobar resection was performed in 314 patients.
Among them, no macroscopic incomplete resection and 9
noncancer lesions were found, and pathological complete
resection was performed in 305 patients with cancer. A total
of 15 patients had other histology than adenocarcinoma, and

TABLE 3. Surgical factors per lesion

Lesion 1 Lesion 2 Lesion 3 All lesions
Parameters (n ¼ 333) (n ¼ 23) (n ¼ 2) (n ¼ 358)
Mode of surgery in detail
Wide wedge resection 264 18 2 284
Wedge converted to 5 0 0 5
segmentectomy
Wedge converted to 1 0 0 1
lobectomy by way of
segmentectomy
Wedge converted to 6 0 0 6
lobectomy
Segmentectomy 53 4 0 57
Segmentectomy converted 3 0 0 3
to lobectomy
Lobectomy 1 1 0 2
Exploratory thoracotomy 0 0 0 0
Resected segments in wedge or segmentectomy (multiple selections allowed)
Right side
(Continued)

The Journal of Thoracic and Cardiovascular Surgery c Volume 163, Number 1 293
 Thoracic: Lung Cancer: Clinical Trial Suzuki et al

TABLE 3. Continued
Lesion 1 Lesion 2 Lesion 3 All lesions
Parameters (n ¼ 333) (n ¼ 23) (n ¼ 2) (n ¼ 358)
S1 46 5 1 52
S2 35 1 1 37
S3 29 2 0 31
S4 10 0 0 10
S5 3 0 0 3
S6 36 5 0 41
S7 1 0 0 1
S8 22 4 0 26
S9 19 0 0 19
S10 8 0 0 8
Left side
S1þ2 42 2 0 44
S3 18 1 0 19
S4 13 1 0 14
S5 4 0 0 4
THOR

S6 13 1 0 14
S8 9 0 0 9
S9 14 0 0 14
S10 11 1 0 12
Reasons for conversion to segmentectomy (multiple selections allowed)
Insufficient surgical margin 45 2 0 47
Positive surgical margin 1 0 0 1
Nodal involvement by 0 0 0 0
cancer
Pathological invasiveness of 3 1 0 4
lung cancer
Unable to identify the tumor 9 1 0 10
by intraoperative
palpation
Other reasons 0 0 0 0
Resected lobe for lobectomy case
Right upper 5 1 0 6
Right middle 0 0 0 0
Right lower 5 0 0 5
Left upper 0 0 0 0
Left lower 1 0 0 1
Reasons for conversion to lobectomy (multiple selection allowed)
Insufficient surgical margin 2 1 0 3
Positive surgical margin 1 0 0 1
Nodal involvement by 0 0 0 0
cancer
Pathological diagnosis other 1 0 0 1
than adenocarcinoma
Pathological invasiveness of 7 0 0 7
lung cancer
Other reasons 0 0 0 0
Macroscopic distance between tumor and the stapler margin (mm)
5 10 (3.0%) - - -
5 and 10 90 (27.2%) - - -
>10 233 (69.8%) - - -
Nodal dissection
No dissection - - - 251
Hilar dissection - - - 44
Mediastinal dissection - - 21

294 The Journal of Thoracic and Cardiovascular Surgery c January 2022

Suzuki et al Thoracic: Lung Cancer: Clinical Trial

TABLE 4. Pathological factors per lesion

Lesion 1 Lesion 2 Lesion 3 All lesions
(n ¼ 333) (n ¼ 36) (n ¼ 6) (n ¼ 375)
Histology
Preinvasive lesion 16 9 4 29
Adenocarcinoma 307 23 1 331
Squamous cell carcinoma 0 0 0 0
Other cancer histologies 0 0 0 0
Noncancerous lesion 10 4 1 15
Differentiation in cancer
Well 293 31 5 329
Moderate 11 0 0 11
Poor 1 0 0 1
Unknown 18 1 0 19
Noguchi’s classification*
A 109 11 1 121
B 98 10 0 108
C 86 2 0 88

THOR
D 1 0 0 1
E 0 0 0 0
F 6 0 0 6
Unknown 7 0 0 7
Pathological maximum tumor dimension (cm, noncancerous lesion excluded)
Median 1.00 0.40 0.20 1.00
IQR 0.80-1.40 0.25-0.65 0.20-0.30 0.80-1.30
Pathological distance between tumor and the stapler margin (mm, noncancerous lesion excluded)
5 26 (8.1%) - - -
5 and 10 88 (27.2%) - - -
>10 209 (64.7%) - - -
IQR, Interquartile range. *According to Noguchi’s classification, type A is adenocarcinoma in situ, type B is MIA, type C is MIA or invasive adenocarcinoma with lepidic growth,
and type D, E, F is invasive adenocarcinoma without lepidic growth.

290 patients (87.0%) completed the protocol treatment.
The majority of patients were female (67.0%). The protocol
permitted up to 3 lesions, and 16 patients had 2 or more le-
sions preoperatively (Table 1). For the primary lesions,
radiologic maximum tumor dimension on lung window
setting was 1.2 cm in median, and radiologic maximum
consolidation dimension on lung window was 0 in median.
This meant that more than half of lesions in the registered
patients were pure GGO (Table 2). A total of 23 patients
had multiple lesions intraoperatively (Table E1). All second
or third lesions were resected with sublobar resection
except in 1 patient (Table 3). Pathological investigation re-
vealed multiple lung lesions in 36 patients: 13 with atypical
adenomatous hyperplasia, 24 with adenocarcinoma, and 5
with noncancerous lesions (Table 4). The discrepancy
between those were pathologically proven multiple lung
tumors. Approximately 67% of patients had no history of
smoking.
For the surgical margin, the median macroscopic dis-
tance between tumor and surgical stump was 15 mm (inter-
quartile range, 10-20) (Table 3). The median pathological
surgical margin was 15 mm (10-20) (Table 4). Wide wedge
resection was performed in 264 patients (79.3%), and con-
version to segmentectomy was indicated in 5 patients
(1.5%). Segmentectomy from the beginning was performed
in 53 patients (15.9%). Sublobar resection was completed
in 322 (96.7%) of 333 patients. Eight patients were ineli-
gible, and all sublobar resections included 314 (96.6%;
95% CI, 94.0-98.3) of 325 patients who underwent surgical
resection for lung cancer. Reasons for conversion to lobec-
tomy were as follows: insufficient margin in 2 patients,
other histology than adenocarcinoma in 1 patient, and path-
ological invasiveness in 7 patients (Table 3). Two reopera-
tions of lobectomy after wide wedge resection were
performed: 1 video-assisted middle lobectomy performed
for insufficient surgical margin of macroscopic 3 mm and
pathologically 0 mm, and 1 video assisted left lower lobec-
tomy performed for pathological invasive nature, Noguchi
type F (ie, true papillary adenocarcinoma). Histologic diag-
nosis was not confirmed preoperatively in 322 patients
(96.7%). All histologic diagnoses of the primary lesions
were adenocarcinoma or atypical adenomatous hyperplasia

The Journal of Thoracic and Cardiovascular Surgery c Volume 163, Number 1 295
 Thoracic: Lung Cancer: Clinical Trial Suzuki et al

TABLE 5. Postoperative complications (n ¼ 333)

Early complications (n ¼ 333) Late-onset complications* (n ¼ 323)
CTCAE Grade 1 Grade 2 Grade 3 Grade 4 Grade 1 Grade 2 Grade 3 Grade 4
Supraventricular arrhythmia
Atrial fibrillation 3 1 0 0 - - - -
Atrial tachycardia/ 0 1 0 0 - - - -
paroxysmal atrial
tachycardia
Ventricular extrasystole 1 0 0 0 - - - -
Cardiac ischemia/infarction 0 0 0 0 - - - -
Hypotension 1 1 0 0 - - - -
Fever 20 2 0 0 - - - -
Fatigue 10 0 0 0 - - - -
Insomnia 12 1 0 0 - - - -
Diarrhea 2 0 1 0 - - - -
Constipation 10 2 0 0 - - - -
THOR

Vomiting 12 3 0 0 - - - -
Hematoma 4 1 0 0 - - - -
Infection with G0-2 decreased ANC
Wound infection - 1 1 0 - 2 1 0
Pneumonia - 1 2 0 - 3 1 0
Pleural infection - 1 0 0 - 1 1 0
Fistula-lung 9 7 0 0 0 1 0 0
Fistula-bronchus 0 0 0 0 0 0 0 0
Atelectasis 1 1 0 0 0 0 0 0
Chylothorax 2 0 0 0 - - - -
Cough 7 2 0 - 7 2 0 -
Pneumothorax 0 2 0 0 2 0 0 0
Thrombosis - 0 1 0 - 0 0 0
Pain
Chest/thorax, NOS 67 20 0 0 - - - -
CNS ischemia - 0 0 0 - 0 0 0
Delirium 1 1 2 0 - - - -
Recurrent laryngeal nerve 0 0 0 0 - - - -
palsy
Phrenic nerve dysfunction 0 0 0 0 - - - -
CTCAE, Common Terminology Criteria for Adverse Events; ANC, absolute neutrophil count; NOS, not otherwise specified; CNS, central nervous system. *Late-onset compli-
cation developed 30 days after operation. Ten patients with noncancerous lesion were excluded because no follow-up was required.

except in 10 patients (Table 4). For Noguchi’s classification,
type A and B, equivalent to adenocarcinoma in situ or MIA,
were found in 207 patients (62.2%) and type C, D, E, and F
were found in 86 patients (25.8%), 1 patient (0.3%), 0 pa-
tients (0%), and 6 patients (1.8%), respectively.
Mode of surgery included 264 (79.3%) wide wedge
resections, 58 (17.4%) segmentectomies, and 11 (3.3%)
lobectomies. Postoperative early complications of grade 2
or more was found in 124 patients (37.2%), grade 3 or
more was found in 17 patients (5.1%), and grade 4 or
more was found in 0 patients (0.0%). Early complications
were mainly minor, such as postoperative febrile state
or thoracic pain after surgery (Table 5). If there were com-
plications, grade 2 or more was found in 128 patients
(38.4%), grade 3 or more was found in 17 patients
(5.1%), and grade 4 or more was found in 0 (0.0%) of
333 patients. There were 10 censored cases for noncan-
cerous lesions. One patient died of another disease. The

296 The Journal of Thoracic and Cardiovascular Surgery c January 2022

Suzuki et al Thoracic: Lung Cancer: Clinical Trial

JCOG0804/WJOG4507L Study showed excellent survival after sublobar resection for peripherally located
Ground Glass dominant lung tumor

Sublobar resection

100%

Proportion relapse-free surviving

90%
80%
70%
60%
50%
40%
30%
N = 314 20%
0% < CTR < 25%
10%

THOR
0%
0 1 2 3 4 5 6 7 8
Years after enrollment
No. at Risk
314 304 304 304 304 303 88 0
Sublobar resection is enough for Ground Glass dominant
peripherally located lung cancer
FIGURE 2. The 5-year relapse free survival for all patients except benign lesions and atypical adenomatous hyperplasia with sublobar resection was 99.7%
(90% CI, 97.6-99.9). CTR, Consolidation tumor ratio.

5-year RFS for all patients with sublobar resection was 97.6-99.9, Figure 3). Of 333 patients, 2 died of other causes,
99.7% (90% CI, 98.3-99.9), which met the primary end and the 5-year overall survival was 99.4% (95% CI, 97.5-
point (Figure 2). The 5-year RFS for all patients except 99.8). Median follow-up time for patients alive was
for those with benign lesions and atypical adenomatous hy- 5.5 years. There were no differences in survival by mode
perplasia with sublobar resection was 99.7% (90% CI, of surgery (wedge vs segmentectomy, Figure E1) and by

100%
Proportion relapse-free surviving

90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
0 1 2 3 4 5 6 7 8
Years after enrollment
No. at Risk
290 289 289 289 289 288 82 0
FIGURE 3. Sublobar resection, mainly wide wedge resection, with enough surgical margin offered sufficient local control and RFS for GGO-dominant
lung cancer.

The Journal of Thoracic and Cardiovascular Surgery c Volume 163, Number 1 297
 Thoracic: Lung Cancer: Clinical Trial
Noguchi classification (Noguchi type A or B vs the others,
Figure E2). Among 314 patients with sublobar resection,
287 had available spirometry data and postoperative change
of the ratio of FEV1 and FVC at 1 year after operation
ranged from 0.37 to 0.49 with a median of 0.045 and
from 0.47 to 0.40 with a median of 0.026, respectively.
For 247 patients who underwent 1 wide wedge resection,
data were available for 226 and change in the ratio of
FEV1 and FVC at 1 year after operation ranged from
0.25 to 0.49 with a median of 0.036 and ranged from
0.25 to 0.40 with a median of 0.022.
DISCUSSION
The 5-year RFS was 99.7% (90% CI, 98.3-99.9) after
sublobar resection, and this met the primary end point.
There was 1 death from other cause, and no local or
cut-end failure was noted. Sublobar resection offered
THOR
sufficient local control and RFS for radiologic GGO-
dominant lung cancer on thin-section CT, which was
shown with prospective multi-institutional base for the
first time. Although many studies have reported this result,
they were retrospective.11-26 Some authors reported
extremely high stump recurrence, more than 20%, after
wide wedge resection for Noguchi’s type A and B
adenocarcinoma.27,28 According to our results from
JCOG0804/WJOG4507L, sublobar resection for GGO-
dominant peripheral lung cancer was feasible and effec-
tive, and if appropriate, conversion to anatomic resection
was done.
We have set a basic strategy for building the standard
mode of surgery for peripherally located lung cancer under
the framework of JCOG. In 2002, we had started a multi-
institutional prospective study on radiologic-pathological
correlation in peripheral lung cancer, and the result was re-
ported in 2011 in the JCOG0201 study.5,29 The result was
not as we expected because published data have suggested
CTR 0.5 or less was the predictor for pathologically nonin-
vasive cancer, and the criteria for radiologic noninvasive
cancer were tumor with CTR 0.25, not 0.5, or less and a
maximum tumor dimension of 2.0 cm or less in size.
Thus, CTR 0.25 is judged to be safe for selecting radio-
logic noninvasive lung cancer. We had started 2 indepen-
dent prospective studies for establishing standard
treatment of peripheral early lung cancer. One was
JCOG0802/WJOG4607L, which targeted “radiologic
invasive” lung cancer, and the other was JCOG0804/
WJOG4507L, which targeted “radiologic noninvasive”
lung cancer.6 The former, JCOG0802/WJOG4607L, was
a randomized controlled trial to confirm the noninferiority
of segmentectomy to lobectomy for invasive cancer, for
which the morbidity had been reported, and the results of
the final analysis will be reported in the future. We have
discussed the optimal mode of study for the latter
JCOG0804/WJOG4507L, that is, randomized or
298 The Journal of Thoracic and Cardiovascular Surgery c January 2022
Suzuki et al
nonrandomized setting. After discussion, we decided to
perform a single-arm, nonrandomized trial, because few
thoracic surgeons wanted to perform lobectomy for
GGO-dominant lung cancer on thin-section CT. Thus, in
the near future, the basic standard for peripherally located
lung cancer 2.0 cm or less in size is set.
One of the most important issues in sublobar resection is
surgical margin. JCOG0804/WJOG4507L set a sufficient
surgical margin, the shortest distance between the tumor
and the cut-end uncovered by visceral pleura, as 5 mm. In-
traoperative confirmation of the surgical margin was
mandatory in this study. If the surgeon judged the margin
was not sufficient, the surgeon converted the mode of sur-
gery from wide wedge resection to segmentectomy or lo-
bectomy. There was no local relapse in all patients, and a
surgical margin 5 mm or more is considered to be adequate
for GGO-dominant peripheral lung cancer 2.0 cm or less in
size with CTR 0.25 or less.
Wide wedge resection is one of the safest operations for
lung cancer, which was confirmed by this study. There
were no mortality (grade 5). Grade 2 or higher postopera-
tive complications based on Common Terminology
Criteria for Adverse Effect version 3.0 were observed in
119 patients (37.9%), and grade 3 complications were
observed in 17 patients (5.4%), with no grade 4 or 5.
Recent investigation on wedge resection showed 24%
morbidity after this operation.30 In a recent report from
North America, morbidity after wedge resection was
0.6% in 340 patients in the multicenter prospective trial.31
Compared with these recent reports, morbidity for the
wedge resection is low. We confirmed the safety of wedge
resection based on a multi-institutional prospective study
in Japan.
Postoperative lung function at 6 and 12 months showed
less than 5% absolute change in median for FEV1 and
FVC. Wedge resection and segmentectomy are performed
in sublobar resection, and those operative procedures are
completely different in regard to surgical insult. Preserved
pulmonary function after sublobar resection remains
controversial.3 However, lung function after wedge was
remarkably preserved compared with lobectomy, which
was confirmed by this trial. Thus, the indication for wedge
resection, instead of segmentectomy, should be investigated
in the near future.
Study Limitations
A limitation of the study was its nonrandomized fashion.
We had a thorough discussion before starting this trial, and
we abandoned the randomized fashion for the JCOG0804/
WJOG4507L trial because lobectomy was considered to
be too invasive for GGO-dominant lung cancer. If the loca-
tion of the tumor is peripheral enough and allows the
thoracic surgeon to perform a sublobar resection, especially
wedge, lobectomy should not be used. Eligibility criteria
Suzuki et al
requires evaluation with thin-section CT and CTR 0.25 or
less, and the radiologic evaluation was not always objective.
CTR depends on subjective evaluation and should be
refined in the near future. Thus, reproducibility of radio-
logic evaluation of the tumor as to CTR is the second limi-
tation of the trial. The third limitation was missing data on
postoperative pulmonary function. Pulmonary function is
evaluated at 6 and 12 months after the operation, but the
data in 75 and 27 patients were missing at 6 and 12 months,
respectively.
CONCLUSIONS
We conducted a single-arm study of sublobar surgi-
cal resection for GGO-dominant lung cancer defined
with thoracic thin-section CT and concluded that sub-
lobar resection with a sufficient surgical margin was
feasible and effective. This strategy should be the first
choice of mode of operation for patients with GGO-
dominant peripheral lung tumor 2.0 cm or less in
size.
Conflict of Interest Statement
Dr Suzuki reports grants from National Cancer Center,
grants from Ministry of Health, Labour and Welfare of
Japan, during the conduct of the study; grants and personal
fees from Ethicon, grants and personal fees from Med-
tronic, grants and personal fees from Taiho, grants and per-
sonal fees from Eli Lilly, personal fees from Intuitive, grants
from Shoen kai, grants and personal fees from Kyowa Kirin,
grants from Ezai, grants from Shionogi, grants from Ono,
grants and personal fees from Teijin, grants and personal
fees from CSL Behring, personal fees from Daiichi Sankyo,
personal fees from Gunze, personal fees from AstraZeneca,
personal fees from The Chemo-Sero-Therapeutic Research
Institute, outside the submitted work. Dr Watanabe reports
grants from Ministry of Health, Labour and Welfare of
Japan, during the conduct of the study; personal fees from
Ethicon Endo-Surgery Japan, a Johnson & Johnson com-
pany, personal fees from Covidien Japan, personal fees
from CSL Behring, personal fees from Astellas, personal
fees from Stryker, outside the submitted work. Dr Waka-
bayashi reports grants from Ministry of Health, Labour
and Welfare of Japan, grants from National Cancer Center,
during the conduct of the study. Dr Saji reports grants from
Ministry of Health, Labour and Welfare of Japan, grants
from National Cancer Center, during the conduct of the
study; personal fees from Boehringer Ingelheim, personal
fees from AstraZeneca, personal fees from Bristol-Myers
Squibb, personal fees from Nihon Medi-Physics, personal
fees from Pfizer, personal fees from Ethicon, personal
fees from Chugai Pharmaceutical Co, Ltd, personal fees
from TAIHO Pharmaceutical Co, Ltd, personal fees from
FUJIFILM Medical Co, Ltd, outside the submitted work.
The Journal of Thoracic and Cardiovascular Surgery c Volume 163, Number 1
Thoracic: Lung Cancer: Clinical Trial
Dr Aokage reports grants from Ministry of Health, Labour
and Welfare of Japan, during the conduct of the study; per-
sonal fees from Covidien Japan (seminar presentation), per-
sonal fees from Johnson and Johnson (interview on product
development), personal fees from Johnson and Johnson
(video presentation), personal fees from Covidien Japan
(editorial supervise), personal fees from Johnson and John-
son (video presentation), personal fees from TAIHO
PHARMA (writing), personal fees from TEIJIN PHARMA
(seminar presentation), personal fees from CSL Behring
(writing), personal fees from SANO hospital (surgical su-
pervise), personal fees from UCHIO clinic (medical super-
vise), personal fees from Covidien Japan (seminar
presentation), personal fees from Johnson and Johnson
(seminar presentation), personal fees from CSL Behring
(editorial supervise), personal fees from Medela Healthcare
(seminar presentation), personal fees from Yokohama city
THOR
university medical center (seminar presentation), personal
fees from KONICA MINOLTA (medical supervise),
outside the submitted work. Dr Moriya reports grants
from Ministry of Health, Labour and Welfare, Japan, grants
from National Cancer Center Japan, during the conduct of
the study. Dr Yoshino reports grants and personal fees
from Taiho Pharma, grants and personal fees from Pfizer,
personal fees from AstraZeneca, grants from Shionogi,
grants and personal fees from Chugai Pharma, personal
fees from Johnson and Johnson, personal fees from Med-
tronic, personal fees from Boehringer Ingelheim, personal
fees and other from Olympus, outside the submitted work.
Dr Tsuboi reports grants from Ministry of Health, Labour
and Welfare of Japan, during the conduct of the study;
grants from AstraZeneca KK, personal fees from AstraZe-
neca KK, personal fees from Eli Lilly Japan, personal
fees from Boehringer-Ingelheim Japan, personal fees from
Daiichi-Sankyo, personal fees from Chugai Pharmaceutical
Co, Ltd, personal fees from Taiho Pharma, personal fees
from Johnson & Johnson Japan, personal fees from Covi-
dien Japan, personal fees from Teijin Pharma, personal
fees from CSL Behring, personal fees from Bristol-Myers
Squibb Japan, personal fees from MSD Japan, outside the
submitted work. Dr S. Nakamura reports grants from Min-
istry of Health, Labour and Welfare, Japan, grants from Na-
tional Cancer Center Japan, during the conduct of the study.
Dr K. Nakamura reports personal fees from Taiho, personal
fees from Merck, personal fees from Chugai, personal fees
from Bayer, outside the submitted work. Dr Mitsudomi re-
ports personal fees from AstraZeneca, grants and personal
fees from Pfizer, grants and personal fees from Boehringer
Ingelheim, personal fees from MSD, personal fees from
BMS, grants and personal fees from Ono, grants and per-
sonal fees from Taiho, grants and personal fees from El-
Lilly, grants and personal fees from Chugai, personal fees
from Daiichi-Sankyo, personal fees from Kyowa-Hakko
299
 Thoracic: Lung Cancer: Clinical Trial
Kirin, grants and personal fees from Covidien, personal fees
from Johnson and Johnson, outside the submitted work. Dr
Asamura reports grants from Ministry of Health, Labour
and Welfare of Japan, grants from National Cancer Center,
during the conduct of the study; personal fees from Covi-
dien Japan, personal fees from Johnson and Johnson, per-
sonal fees from Shionogi Pharma, personal fees from
AstraZeneca, personal fees from Novartis, personal fees
from Astellas Pharma, personal fees from Taiho Pharma-
ceutical, personal fees from Kyowa Kirin, personal fees
from Ono Pharma, personal fees from Lilly, personal fees
from Chugai, outside the submitted work.
The Journal policy requires editors and reviewers to
disclose conflicts of interest and to decline handling or re-
viewing manuscripts for which they may have a conflict
of interest. The editors and reviewers of this article have
no conflicts of interest.
THOR
PARTICIPATING INSTITUTIONS (FROM NORTH TO
SOUTH)
Participating institutions (51 institutions: JCOG 31 institutions
from north to south, WJOG 20 institutions)
JAPAN CLINICAL ONCOLOGY GROUP
Ibaraki Prefectural Central Hospital & Cancer Center, Tochigi
Cancer Center, Gunma Prefectural Cancer Center, Saitama Cancer
Center, National Cancer Center Hospital East, Department of Gen-
eral Thoracic Surgery, Chiba University Graduate School of Med-
icine, National Cancer Center Hospital, Kyorin University, School
of Medicine, Tokyo Medical University, Cancer Institute Hospital
of Japanese Foundation for Cancer Research, Juntendo University
Hospital, Kanagawa Cancer Center, Niigata Cancer Center Hospi-
tal, Kanazawa University School of Medicine, Shizuoka Cancer
Center, Aichi Cancer Center Hospital, Nagoya University Grad-
uate School of Medicine, Kyoto University Hospital, Osaka Inter-
national Cancer Institute, Osaka Prefectural Hospital Organization
Osaka Habikino Medical Center, National Hospital Organization
Kinki-Chuo Chest Medical Center, Osaka City General Hospital,
Hyogo Cancer Center, Okayama University Hospital, National
Hospital Organization Kure Medical Center and Chugoku Cancer
Center , Hiroshima University Hospital, National Hospital Organi-
zation Shikoku Cancer Center, National Hospital Organization
Kyushu Cancer Center, Nagasaki University Hospital, Kumamoto
Chuo Hospital, National Hospital Organization, Okinawa National
Hospital
WEST JAPAN ONCOLOGY GROUP
Yamagata Prefectural Central Hospital, Kanagawa Cardiovas-
cular and Respiratory Center, Ishikawa Prefectural Central Hospi-
tal, Gifu Municipal Hospital, Kindai University Nara Hospital,
National Hospital Organization Osaka Toneyama Medical Center,
Kobe City Medical Center General Hospital, Kurashiki Central
Hospital, Kawasaki Medical School Hospital, Hiroshima City Hir-
oshima Citizens Hospital, Hiroshima City Asa Citizens Hospital,
300 The Journal of Thoracic and Cardiovascular Surgery c January 2022
Suzuki et al
Kumamoto University Hospital, Nishiniigata Chuo Hospital, Kyu-
syu University Hospital, Nihonkai General Hospital, Asahikawa
Medical University Hospital, Mie University Hospital, Chiba Can-
cer Center, Japanese Red Cross Nagasaki Genbaku Hospital, and
Oita Prefectural Hospital.
The authors thank the members of the JCOG Data Center/Oper-
ations Office and WJOG Data Center for their support.
References
1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer
incidence and mortality worldwide: sources, methods and major patterns in
GLOBOCAN 2012. Int J Cancer. 2015;136:E359-86.
2. Cahan WG. Radical lobectomy. J Thorac Cardiovasc Surg. 1960;39:555-72.
3. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resec-
tion for T1 N0 non- small cell lung cancer. Lung cancer study group [see com-
ments]. Ann Thorac Surg. 1995;60:615-23.
4. Suzuki K. Whack-a-mole strategy for multifocal ground glass opacities of the
lung. J Thorac Dis. 2017;9(Suppl 3):S201-7.
5. Suzuki K, Koike T, Asakawa T, Kusumoto M, Asamura H, Nagai K, et al. A pro-
spective radiological study of thin-section computed tomography to predict path-
ological non-invasiveness in peripheral clinical IA lung cancer (JCOG0201). J
Thorac Oncol. 2011;6:751-6.
6. Nakamura K, Saji H, Nakajima R, Okada M, Asamura H, Shibata T, et al. A phase
III randomized trial of lobectomy versus limited resection for small-sized periph-
eral non-small cell lung cancer (JCOG0802/WJOG4607L). Jpn J Clin Oncol.
2010;40:271-4.
7. Sobin LH, Wittekind C. International Union Against Cancer: TNM Classifica-
tion of Malignant Tumours. 6th ed. New York: Wiley-Liss; 2002.
8. Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, et al.
The IASLC lung cancer staging project: proposals for the revision of the TNM
stage groupings in the forthcoming (seventh) edition of the TNM classification
of malignant tumours. J Thorac Oncol. 2007;2:706-14.
9. Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilia E. Histological Typing
of Lung Cancer and Pleural Tumors. Berlin, Germany: Springer; 1999.
10. Noguchi M, Morikawa A, Kawasaki M, Matsuno Y, Yamada T, Hirohashi S, et al.
Small adenocarcinoma of the lung. Histologic characteristics and prognosis.
Cancer. 1995;75:2844-52.
11. Aokage K, Yoshida J, Ishii G, Matsumura Y, Haruki T, Hishida T, et al. Identifi-
cation of early t1b lung adenocarcinoma based on thin-section computed tomog-
raphy findings. J Thorac Oncol. 2013;8:1289-94.
12. Aoki T, Tomoda Y, Watanabe H, Nakata H, Kasai T, Hashimoto H, et al. Periph-
eral lung adenocarcinoma: correlation of thin-section CT findings with histologic
prognostic factors and survival. Radiology. 2001;220:803-9.
13. Jang HJ, Lee KS, Kwon OJ, Rhee CH, Shim YM, Han J. Bronchioloalveolar car-
cinoma: focal area of ground-glass attenuation at thin-section CT as an early sign.
Radiology. 1996;199:485-8.
14. Kodama K, Doi O, Higashiyama M, Yokouchi H. Intentional limited resection for
selected patients with T1 N0 M0 non- small-cell lung cancer: a single-institution
study. J Thorac Cardiovasc Surg. 1997;114:347-53.
15. Kodama K, Higashiyama M, Yokouchi H, Takami K, Kuriyama K, Mano M, et al.
Prognostic value of ground-glass opacity found in small lung adenocarcinoma on
high-resolution CT scanning. Lung Cancer. 2001;33:17-25.
16. Koike T, Togashi K, Shirato T, Sato S, Hirahara H, Sugawara M, et al. Limited
resection for noninvasive bronchioloalveolar carcinoma diagnosed by intraoper-
ative pathologic examination. Ann Thorac Surg. 2009;88:1106-11.
17. Nakata M, Sawada S, Saeki H, Takashima S, Mogami H, Teramoto N, et al. Pro-
spective study of thoracoscopic limited resection for ground-glass opacity
selected by computed tomography. Ann Thorac Surg. 2003;75:1601-6.
18. Ohde Y, Nagai K, Yoshida J, Nishimura M, Takahashi K, Suzuki K, et al. The pro-
portion of consolidation to ground-glass opacity on high resolution CT is a good
predictor for distinguishing the population of non-invasive peripheral adenocar-
cinoma. Lung Cancer. 2003;42:303-10.
19. Okada M, Nishio W, Sakamoto T, Uchino K, Tsubota N. Discrepancy of computed
tomographic image between lung and mediastinal windows as a prognostic impli-
cation in small lung adenocarcinoma. Ann Thorac Surg. 2003;76:1828-32.
20. Shimada Y, Yoshida J, Hishida T, Nishimura M, Ishii G, Nagai K. Predictive fac-
tors of pathologically proven noninvasive tumor characteristics in T1aN0M0 pe-
ripheral non-small cell lung cancer. Chest. 2012;141:1003-9.
Suzuki et al
21. Suzuki K, Asamura H, Kusumoto M, Kondo H, Tsuchiya R. “Early” peripheral
lung cancer: prognostic significance of ground glass opacity on thin-section
computed tomographic scan. Ann Thorac Surg. 2002;74:1635-9.
22. Takamochi K, Nagai K, Yoshida J, Suzuki K, Ohde Y, Nishimura M, et al. Path-
ologic N0 status in pulmonary adenocarcinoma is predictable by combining
serum carcinoembryonic antigen level and computed tomographic findings. J
Thorac Cardiovasc Surg. 2001;122:325-30.
23. Watanabe S, Watanabe T, Arai K, Kasai T, Haratake J, Urayama H. Results of
wedge resection for focal bronchioloalveolar carcinoma showing pure ground-
glass attenuation on computed tomography. Ann Thorac Surg. 2002;73:1071-5.
24. Yamato Y, Tsuchida M, Watanabe T, Aoki T, Koizumi N, Umezu H, et al. Early
results of a prospective study of limited resection for bronchioloalveolar adeno-
carcinoma of the lung. Ann Thorac Surg. 2001;71:971-4.
25. Yoshida J, Nagai K, Yokose T, Nishimura M, Kakinuma R, Ohmatsu H, et al.
Limited resection trial for pulmonary ground-glass opacity nodules: fifty-case
experience. J Thorac Cardiovasc Surg. 2005;129:991-6.
26. Suzuki K, Kusumoto M, Watanabe S, Tsuchiya R, Asamura H. Radiologic clas-
sification of small adenocarcinoma of the lung: radiologic-pathologic correlation
and its prognostic impact. Ann Thorac Surg. 2006;81:413-9.
27. Nakao M, Yoshida J, Goto K, Ishii G, Kawase A, Aokage K, et al. Long-term out-
comes of 50 cases of limited-resection trial for pulmonary ground-glass opacity
nodules. J Thorac Oncol. 2012;7:1563-6.
The Journal of Thoracic and Cardiovascular Surgery c Volume 163, Number 1
Thoracic: Lung Cancer: Clinical Trial
28. Yoshida J, Ishii G, Yokose T, Aokage K, Hishida T, Nishimura M, et al. Possible
delayed cut-end recurrence after limited resection for ground-glass opacity
adenocarcinoma, intraoperatively diagnosed as Noguchi type B, in three patients.
J Thorac Oncol. 2010;5:546-50.
29. Suzuki K. JCOG0201 defined “radiological early peripheral lung adenocarci-
noma”. J Thorac Oncol. 2011;6:1452-3.
30. Altorki NK, Kamel MK, Narula N, Ghaly G, Nasar A, Rahouma M, et al.
Anatomical segmentectomy and wedge resections are associated with compara-
ble outcomes for patients with small cT1N0 non-small cell lung cancer. J Thorac
Oncol. 2016;11:1984-92.
31. Altorki NK, Wang X, Wigle D, Gu L, Darling G, Ashrafi AS, et al. Periop-
erative mortality and morbidity after sublobar versus lobar resection for
early-stage non-small-cell lung cancer: post-hoc analysis of an international,
randomised, phase 3 trial (CALGB/Alliance 140503). Lancet Respir Med.
2018;6:915-24.
Key Words: GGO, lung cancer, prognosis, sublobar
resection
THOR
301
 Thoracic: Lung Cancer: Clinical Trial Suzuki et al

1.0

0.8

Overall survival
0.6

0.4

0.2

+ Censored
Logrank two-sided P = .0350
0.0
1 56 55 55 55 55 55 15 0
2 258 249 249 249 249 248 73 0

0 1 2 3 4 5 6 7
THOR

Years after enrollment

N events censored MST 95%LCI 95%UCI
Segmentectomy 56 1 55 Not estimable Not estimable Not estimable
Wedge resection 258 0 258 Not estimable Not estimable Not estimable
1: Segmentectomy 2: Wedge resection
FIGURE E1. The overall survival by Noguchi classification. According to Noguchi’s classification, type A is adenocarcinoma in situ, type B is MIA, type C
is MIA or invasive adenocarcinoma with lepidic growth, and type D, E, and F are invasive adenocarcinoma without lepidic growth. MST, Mean survival time;
LCI, lower confidence interval; UCI, upper confidence interval.

1.0

0.8
Overall survival

0.6

0.4

0.2

+ Censored
0.0 Logrank two-sided P = .1183
AB 200 200 200 200 200 200 58 0
CDEF 82 81 81 81 81 80 24 0

0 1 2 3 4 5 6 7
Years after enrollment
N events censored MST 95%LCI 95%UCI
AB 200 0 200 Not estimable Not estimable Not estimable
CDEF 82 1 81 Not estimable Not estimable Not estimable
AB CDEF
FIGURE E2. The overall survival by mode of surgery: wedge versus segmentectomy. MST, Mean survival time; LCI, lower confidence interval; UCI, upper
confidence interval.

301.e1 The Journal of Thoracic and Cardiovascular Surgery c January 2022

Suzuki et al Thoracic: Lung Cancer: Clinical Trial

TABLE E1. Intraoperative and postoperative factors in overall TABLE E1. Continued
patients Characteristics Number (n ¼ 333)
Characteristics Number (n ¼ 333) Pathological TNMy,z
Operative time (min) pT1 307
Median 88 pT1a 304
IQR 64-119 pT1b 3
Resection of pulmonary parenchyma pT2 or more 0
Yes 333 PN0 323
None 0 pN1 or more 0
Use of thoracoscope Pathological stagey,z
Yes 310 pIA 307
None 23 Pathological complete
No. of lesions resectiony
1 310 Yes 323
2 21 N0 0
3 2 Postoperative treatmenty
Combined resection Yes 323
N0 0

THOR
None 333
Yes 0 IQR, Interquartile range. *Two reoperations of lobectomy after wedge resection were
performed for insufficient surgical margin and invasiveness of adenocarcinoma. yTen
Pleural dissemination cases with noncancerous lesions were excluded. zSixteen atypical adenomatous hy-
None 333 perplasia cases were excluded.
Yes 0
Pleural lavage cytology
Negative 333
Positive 0
Malignant effusion
None 333
Yes 0
Pulmonary metastasis
None 333
Yes 0
Nodal involvement
None 333
Yes 0
Complete resection
Yes 333
N0 0
Intraoperative bleeding (mL)
Median 5
IQR 0-18
Intraoperative or
postoperative transfusion
until the first
postoperative day
None 333
Yes 0
Length of hospital stay since
the surgery day to
discharge (d)
Median 7
IQR 5-10
Reoperation
None 331
Yes 2*
(Continued)

The Journal of Thoracic and Cardiovascular Surgery c Volume 163, Number 1 301.e2