2021 JACS指南：肺癌手术患者术前肺功能评估

Abstract

This article translates the guidelines for preoperative pulmonary function assessment in patients with lung cancer who will undergo surgery, established by the Japanese Association of Chest Surgery on May 17, 2021, from Japanese to English. The last version of these guidelines was created on April 5, 2011. Over the past decade, changes in clinical practice have occurred that do not align with the current guidelines, prompting a revision in conjunction with the introduction of new evidence this time. This guideline was developed with reference to the internationally adopted GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system. Extraction of evidence, systematic review, and quality assessment are entrusted to each guideline review committee and the Pulmonary Function Assessment Working Group. Committee members are also responsible for determining the selection of evidence and the extraction period, with a particular emphasis on adopting items considered to be of special importance. The recommended assessment and management is categorized into a general overview, pulmonary function assessment, cardiopulmonary exercise test, pulmonary function assessment for lung cancer with interstitial pneumonia, preoperative smoking cessation, and pulmonary rehabilitation. These are described by the strength of recommendation, the strength of evidence, and the consensus rate.

Keywords Non-small cell lung cancer $\cdot$ Preoperative assessment· Tolerability $\cdot$ Lung resection

Introduction

In the field of lung cancer treatment, novel technologies and pharmaceutical treatments are constantly introduced and immediately applied in daily clinical practice. Advancements in medical practice are significant, and the pace of progress is accelerating. The Japanese Association for Chest Surgery (JACS) released the “Guideline for risk assessment from pulmonary function for lung cancer surgery” in 2011. Since the introduction of the guideline, more than 10years has passed. During this period, minimally invasive surgery has been widely applied, and perioperative management

has progressed. During this period, minimally invasive surgeries have become widely adopted, and there have been advancements in perioperative management as well. Simultaneously, the proportion of elderly patients and those with various comorbidities who undergo surgery has increased. Hence, risk assessment prior to lung cancer surgery has been increasingly important.

To provide guidance in safely implementing the adoption of pulmonary resection in patients with lung cancer, the JACS hereby designed an expert consensus project revising the assessment criteria for preoperative pulmonary function. This guideline is an updated English version based on the revised Japanese guideline published in 2021 [ 1 ].

This guideline was developed based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system [ 2 ]. The members of each guideline review committee and pulmonary function evaluation working group are responsible for evidence extraction, systematic review, and quality evaluation. Further, the

selection of evidence was also assigned to the working group members. Data that are considered important were selected. The consensus rate was calculated based on the votes casted by the working group, comprising seven experts, at the guideline review meeting. The quality of recommendations and evidence used in this guideline was also evaluated according to the GRADE system (Tables 1 and 2 ).

In total, 15 clinical questions (CQs) were stated. The quality of evidence of all statements was C. CQ4 and CQ5 were subdivided into two categories to determine the degree of recommendation. Nine statements had a high consensus at $100\%$ (responders agreed or strongly agreed), and three achieved a consensus between 75 and $90\%$ (responders agreed or strongly agreed). Meanwhile, $<\!75\%$ of responders agreed to two statements (CQ7 and 13) (Table 3 ). However, CQ13, which had the lowest consensus, still reached a $57\%$ agreement level.

Points tonote

The current study aimed to revise and translate the definition of a set of expert consensus-based principles from Japanese into English to assist surgeons in assessing the preoperative pulmonary function of patients with lung cancer. In most

topics, there is lack of evidence, or the evidence has a lowquality level. In this context, expert consensus recommendations are legitimate and can address existing evidence gaps by creating a base knowledge for future research in the field.

I. General remarks (CQ1–3)

CQ1 : Should the indication for surgery in elderly patients with lung cancer be evaluated comprehensively based on not only age but also operative capacity, including the patient’s pulmonary function? Recommendation 1 : Since age alone is not a factor for abandoning curative surgery for lung cancer, it is recommended that comprehensive evaluation and consideration be made after a comprehensive evaluation of the patient’s ability to tolerate surgery. [Degree of recommendation: 1, Quality of evidence: C, Level of agreement: $100\%]$ CQ2 : Is it necessary for a multidisciplinary team including general thoracic surgeons, medical oncologists, radiation oncologists, and respiratory physicians to discuss the treatment strategy for patients with lung cancer, including the indications for surgery?

Table1 Degree of recommendation

|Degree of recommendationDefinition|| |---|---| || 1 Strong recommendation If the guidelines are confident that the desirable effects of the intervention outweigh the undesirable effects (strong recommendation in favor of the intervention) or are less than the undesirable effects (strong recommendation against theintervention) | |2Weekrecommendation| If the desirable effects probably outweigh the undesirable effects (weak recommendation in favor of intervention) or when the undesirable effects probably outweigh the desirable effects (weak recommendation against interven- tion), but considerable uncertainty exists. * | |Norecommendation|When believed that we should not make a recommendation for or against a particular treatment strategy and con-| || clude that even a recommendation to limit the use of an intervention to research is not appropriate * Conditional: a recommendation that is conditional on the patient's values, inaccessible resources, or setting * Optional: any recommendation based on the patient's or physician’s opinion | || * Conditional: a recommendation that is conditional on the patient's values, inaccessible resources, or setting * Optional: any recommendation based on the patient's or physician’s opinion * Limited: A recommendation that is limited by how the issues that infuence the decision are described |

Table2 Quality of Evidence

|Quality of evidenceDefinition|| |---|---| |AHigh|We have great confidence that the results of the intervention are close to the true effect estimates| |B Moderate|There is a moderate degree of confidence in the results of the intervention relative to the true effect estimates. In other| || words, the true effect is considered close to the effect estimate. However, the possibility of a large difference cannot be ruled out | |CLow|There is limited confidence in the effect estimates of interventions. The true effects may differ significantly from the effect| |D Very low| We have minimal confidence in the estimated effect of the intervention. We believe that the true effects are extremely dif- ferent from the effect estimates |

Table3 Final statements

|Statements| Degree of recommendation Quality of Level of|evidence| agreement % | |---|---|---|---| |. General remarks|. General remarks|. General remarks|. General remarks| | CQ1: Should the indication for surgery in elderly patients with lung cancer be evalu- ated comprehensively based on not only age but also operative capacity, including the patient's pulmonary function? |||| | Recommendation l: Since age alone is not a factor for abandoning curative surgery for lung cancer, t is recommended that comprehensive evaluation and consideration be ||C|¥100| | made after a comprehensive evaluation of the patient's ability to tolerate surgery|||| | CQ2: Is it necessary for a multidisciplinary team including general thoracic surgeons, medical oncologists, radiation oncologists, and respiratory physicians to discuss the treatment strategy for patients with lung cancer, including the indications for surgery? |||| | Recommendation 2: Lung cancer treatment should be conducted by a multidisciplinary team to shorten the time required for diagnosis and treatment decision-making, and to contribute to decision-making regarding an appropriate treatment stratey |||| ||||| | CQ3: Is it necessary to assess the risk of perioperative cardiovascular complications in patients with lung cancer who will undergo surgery? |||| | Recommendation 3: Since patients with lung cancer are at high risk of developing atherosclerotic cardiovascular complications associated with smoking, a proactive preoperative assessment of the risk of cardiovascular event is recommended in patients ||C|100| | with lung cancer. Furthermore, based on the disease pathophysiology, preoperative and intraoperative handling must be discussed with the cooperation of cardiology and |||| |cardio-surgery to reduce perioperative risks|||| |1. Pulmonary function Assessment|||| | CQ4: Is it necessary to perform the diffusing capacity for carbon monoxide (DLCO) test, in addition to the general pulmonary function test (spirometry), to assess the risk of |||| | Recommendation 4: The general pulmonary function test (spirometry) is strongly recom- mended on all patients with lung cancer who will undergo surgery. In addition, the diffusing capacity for carbon monoxide (DLCO) test should be performed. In addition to the general pulmonary function test (spirometry), DLCO test is weakly recom- mended for patients with shortness of breath on exertion, diffuse interstitial changes on imaging, smoking history, chronic obstructive pulmonary disease (COPD), or other | Spirometry: 1 DLCO:2* ||100| ||||| | CQ5: Is it necessary to calculate the predicted postoperative (PPO) pulmonary function from the pulmonary function tests (spirometry) and the diffusing capacity for carbon monoxide (DLCO) test to determine the indication for surgery and to determine the |||| | Recommendation 5: PPO FEV1 should be calculated as a predicted postoperative volume F| PPO FEV1: 1||| | in one second in all patients with lung cancer who will undergo surgery. In addition, the predicted postoperative diffusing capacity for carbon monoxide (PPO DLCO) |PPO DLCO: 2**||100| ||||| ||||| | CQ6: In patients with a PPO FEV1 of>60% and PPO DLCO of>60%, can the periop- erative risk be considered average risk? |||| | Recommendation 6: If the patient has no comorbidities and meets the abovementioned criteria, he or she may have an average risk and can undergo lung resection without additional exercise testing |||100| ||||| |CQ7: In patients with a PPO FEV1 of||||

Table3 (continued)

|Statements|Degree of recommendation Quality of Level of|evidence| agreement % | |---|---|---|---| |II1. Cardiopulmonary exercise test|||| | CQ9: If a patient with lung cancer who is eligible for surgery is not at average risk based solely on the usual assessment of pulmonary function, is further evaluation with a simple exercise test, such as the cardiopulmonary exercise test (CPET), shuttle walking |||| ||||| |test (SWT), stair climbing test (SCT), and 6-min walk test (6MWT), useful?|||86| | Recommendation 9: If the patient is in borderline where it is difficult to determine the tolerability for surgery based on conventional pulmonary function evaluation, further evaluation with a simple exercise test, such as CPET, SWT, SCT, and 6MWT, can be |||| |CQ10: Should a patient undergoing a shuttle walk of||||

CQ clinical question

\* Degree of recommendation is “1” in patients with shortness of breath on exertion, diffuse interstitial changes on imaging, smoking history, chronic obstructive pulmonary disease (COPD), and other respiratory comorbidities \*\* Degree of recommendation is “1” in patients with shortness of breath on exertion, diffuse interstitial changes on imaging, smoking history, chronic obstructive pulmonary disease (COPD), other respiratory comorbidities DLco carbon monoxide diffusing capacity; FEV forced expiratory volume; PPO predicted postoperative; NSCLC non-small cell lung cancer

Recommendation 2 : Lung cancer treatment should be conducted by a multidisciplinary team to shorten the time required for diagnosis and treatment decision-making, and to contribute to decision-making regarding an appropriate treatment strategy [Degree of recommendation: 1, Quality of evidence: C, Level of agreement: $71\%$ ]

CQ1 & CQ2 : Lung resection plays a major role for the treatment of lung cancer, and preoperative risk assessment is important. However, the risk assessment of lung cancer surgery is complex, and the perioperative complications of lung resection, surgical-related mortality, and long-term function must be considered. The preoperative physical characteristics of patients can affect surgical risk, particularly pulmonary function [ 3 ]. This is because patients with abnormal pulmonary functions due to smoking often develop lung cancer, and these patients are at an increased risk of longterm functional decline, in addition to early postoperative complications [ 4 , 5 ]. Further, smoking causes atherosclerotic cardiovascular complications, which further increase surgical risk [ 5 ]. Therefore, not only the evaluation of pulmonary function including pulmonary diffusing capacity but also the risk assessment of the cardiovascular system should be actively performed according to the criteria described below [ 5 , 6 ].

Previous studies have reported that age alone is not a factor for disregarding radical lung cancer surgery [ 5 , 7 ]. However, preoperative comorbidities, which increase with age, are a risk factor for not only operative mortality and major postoperative complications [ 8 – 10 ] but also low long-term postoperative survival rates after surgery for lung cancer due to increased noncancer-related mortality [ 9 , 11 , 12 ]. Therefore, the indications for lung cancer surgery among elderly individuals should be evaluated comprehensively after a detailed preoperative evaluation, including the assessment of pulmonary function [ 5 ].

In 2001, the overall risk of postoperative mortality in lung cancer cases in the United States was $5.2\%$ , and the risks of lobectomy and pneumonectomy were $4.5\%$ and $8.5\%$ , respectively [ 13 ]. In Japan, according to the 1996 data from the JACS, the overall postoperative mortality rate was $1.1\%$ , and the postoperative mortality rates of lobectomy and pneumonectomy were $0.9\%$ and $2.6\%$ , respectively [ 14 ]. Meanwhile, based on the 2016 data from the National Clinical Database (NCD), the overall postoperative mortality rate was $0.4\%$ , and the postoperative mortality rates of lobectomy and pneumonectomy were $0.4\%$ and $2.3\%$ , respectively [ 15 ]. Thus, the risk of lung cancer surgery has been decreasing, in part, due to advancements in perioperative management, including the use of anesthesia, and the widespread use of minimally invasive surgery [ 5 ]. However, preoperative physiological examination is important for predicting the risk of mortality and morbidity from preoperative cardiopulmonary

complications after lobectomy or pneumonectomy as these complications are still common [ 5 ].

It is recommended that lung cancer treatment be performed by a multidisciplinary team including experienced general thoracic surgeons, medical oncologists, radiation oncologists, and respiratory physicians as it shortens the time required for diagnosis and treatment decisions and contributes to the determination of an appropriate treatment strategy [ 5 ]. In addition, the postoperative mortality rate of lung cancer surgery performed by specialists at their own facilities is lower [ 16 – 19 ]. Therefore, similar to the American College of Chest Physicians (ACCP) [ 5 ] and the European Respiratory Society (ERS) and European Society of Thoracic Surgery (ESTS) guidelines [ 20 ], our guideline recommends that lung cancer surgery should be performed in these settings whenever possible. Induction chemo-radiotherapy for locally advanced lung cancer, which improves resectability and survival, may decrease lung diffusion capacity [ 21 – 23 ] and, thus, increase postoperative complications [ 22 , 24 ]. Therefore, the assessment of preoperative pulmonary function, including pulmonary diffusion capacity, should be performed again after administering induction therapy [ 5 ].

CQ3 : Patients with lung cancer are at high risk of developing atherosclerotic cardiovascular complications associated with smoking. Thus, preoperative cardiovascular risk assessment should be performed before lung cancer surgery, even if the surgery involves limited resections [ 5 ]. The American Heart Association (AHA) has proposed guidelines for the perioperative assessment and management of perioperative cardiovascular risks in noncardiology-related surgery [ 6 , 25 ]. Thus, based on this guideline, the risk assessment of perioperative cardiovascular complications (such as myocardial infarction, pulmonary edema, ventricular fibrillation, complete atrioventricular block, and cardiac-related mortality) should be conducted. The AHA guideline suggests a multistage, multifaceted evaluation in the area of practical science. The following is a brief description of the procedure.

Step 1 : When the noncardiac surgeries (lung cancer surgery) are considered urgent, they are performed under appropriate monitoring, management, and treatment according to existing cardiovascular complications.

Step 2 : In nonurgent surgery, the selection is based on the presence or absence of active cardiac dysfunction. In active cardiac dysfunction, cardiac dysfunction must be treated first. Active cardiac dysfunctions include acute coronary artery syndrome, uncompensated heart failure, severe arrhythmias, and severe valvular disease. For details, please refer to the AHA guidelines [ 6 , 25 ].

Step 3 : If the patient is in a stable condition, the risk of major cardiovascular complications is assessed based on clinical characteristics of the patients and surgical procedure. The assessment is performed using the risk calculator of the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) ( http:// www.riskcalculator.facs.org ) or the Revised Cardiac Risk Index (RCRI) [ 26 ], which can predict the risk of developing cardiovascular disease during noncardiac surgical procedures. However, the Thoracic RCRI (ThRCRI) [ 27 ], which was modified for patients with lung cancer undergoing pulmonary resections, is more suitable for predicting the incidence of cardiovascular complications. Moreover, the ACCP guidelines recommend the use of this index [ 5 ]. If the risk of developing cardiovascular complications is low $(<1\%)$ , the surgery is considered feasible (Step 4). However, if the risk is higher, the procedure should proceed to Step 5. The ACS NSQIP risk calculator is superior in terms of ease of use and can assess the risk of lung cancer surgery based on approaches (thoracoscopic or open thoracotomy), and extent of lung resection. However, it does not include a history of ischemic or cerebrovascular disease, which are important predictors of postoperative complications. Therefore, the complication rate, including postoperative cardiovascular complications, in lung cancer cases can be underestimated [ 28 ]. Therefore, RCRI or ThRCRI is more suitable for the risk assessment of patients with a history of ischemic or cerebrovascular disease. In such a case, the risk of developing cardiovascular complications in both cases exceeds $1\%$ [ 26 , 27 ]. Further, based on the ThRCRI, the risk of developing cardiovascular complications after lobectomy even in the absence of these comorbidities is $1.5\%$ [ 27 ]. Therefore, if a patient with lung cancer has a history of ischemic or cerebrovascular disease and is scheduled to undergo lobectomy or greater surgical procedures, it is necessary to proceed from Step 2 to Step 5.

Step 5: In this step, the patient’s exercise capacity is assessed, and surgery is performed if the exercise capacity is over 4 metabolic equivalents (MET). The benchmark for 4 METs include climb at least one flight of stairs, walk on level ground at a speed of $\geq5.6\ \mathrm{km}$ per hour (6-min

walk, $\geq660\;\mathrm{m})$ ), perform general housework or yard work, and play table tennis or golf without using a cart [ 29 ].

Step 6 : If the patient cannot perform the equivalent of 4 MET, the treatment strategy for lung cancer or cardiovascular disease is determined via further examinations, including the drug tolerance test (Step 7).

The above-mentioned information is an overview of the cardiovascular assessment according to the AHA guidelines. For further details, please refer to the original articles [ 6 , 25 ].

II. Pulmonary function assessment (CQ4–8)

CQ4 : Is it necessary to perform the diffusing capacity for carbon monoxide (DLco) test, in addition to the general pulmonary func tion test (spirometry), to assess the risk of lung cancer surgery? Recommendation 4 : The general pulmonary function test (spirom etry) is strongly recommended on all patients with lung cancer who will undergo surgery. In addition, the diffusing capacity for carbon monoxide (DLCO) test is weakly recommended. In addition to the general pulmonary function test (spirometry), DLCO test is recom mended for patients with shortness of breath on exertion, diffuse interstitial changes on imaging, smoking history, chronic obstruc tive pulmonary disease (COPD), or other coexisting respiratory diseases ・ Spirometry: all patients with lung cancer who will undergo surgery [Degree of recommendation: 1, Quality of evidence: C, Level of agreement: $100\%$ ] ・ DLCO: all patients with lung cancer who will undergo surgery [Degree of recommendation: 2, Quality of evidence: C, Level of agreement: $100\%$ ] ・ DLCO: patients with shortness of breath on exertion, diffuse inter stitial changes on imaging, smoking history, chronic obstructive pulmonary disease [Degree of recommendation: 1, Quality of evidence: C, Level of agreement: $100\%]$

CQ4 : A general pulmonary function test (spirometry) is strongly recommended to assess the risk of lung cancer surgery. Several retrospective studies have reported that various measurements obtained using spirometry are associated with the risk of lung cancer surgery. In particular, low values of both or either forced expiratory volume in one second (FEV1) and percentage FEV1 (%FEV1) are associated with increased postoperative complications and perioperative mortality rate [ 30 – 34 ]. A previous study conducted on 1000 patients in the United States found that for every $10\%$ decrease in %FEV1, the incidence of postoperative respiratory and cardiovascular complications increased significantly by 1.1- and 1.13-fold, respectively [ 33 ].

In a risk assessment study on lung cancer surgery using data from the Japanese NCD database, %vital capacity (VC) was found to be significantly correlated with perioperative mortality ( ${\cal P}\!<\!0.001$ , $10\%$ decrease $[100–50\%]$ , odds ratio

[OR]: 1.380 $[95\%$ confidence interval, CI: 1.277–1.491]) and perioperative complications $(P\!<\!0.~001$ , $10\%$ decrease $[100–50\%]$ , OR: 1.148 $[95\%$ CI: 1.108–1.188]) [ 35 ].

After spirometry, the pulmonary diffusion capacity (DLCO), which is measured and obtained as diffusing capacity for carbon monoxide, is also a useful index for evaluating the risk of surgery. After assessing the usefulness of the DLCO test for pulmonary function examination to predict the postoperative risk in patients with lung cancer in 1988, DLCO measurement is recommended to patients with shortness of breath on exertion, diffuse interstitial changes on imaging, smoking history, chronic obstructive pulmonary disease (COPD), and other respiratory comorbidities [ 36 , 37 ].

The need to perform both spirometry and the DLCO test is discussed below. Based on two large studies examining the correlation between spirometry and the DLCO test, the correlation coefficient between FEV1 and DLCO was 0.38, and the correlation coefficient between %FEV1 and %DLco was 0.238. These results did not indicate a strong correlation between them [ 38 , 39 ]. In patients without COPD or those with normal spirometry, $\%$ DLCO is correlated with the incidence of postoperative respiratory complications [ 40 ]. Table 4 shows the high-risk criteria for lobectomy used in the Z4032 trial of the American College of Surgeons Oncology Group (ACOSOG) in the United States [ 41 ]. DLCO test and spirometry are also important in determining the indication for surgery and the surgical procedure. Although the basis for setting this criteria was not provided, it is assumed to have been endorsed in the community of thoracic surgeons because this study began in 2005 in the United States and Canada. Based on these statements, the ACCP Guidelines in 2013 recommend the DLCO test to all patients scheduled for surgery, including those with a normal FEV1 [ 5 ].

In Japan, unlike in Europe and the United States, the DLCO test is not recommended to all patients who will undergo pulmonary surgery. In the 7th project of the Japanese Joint Committee of Lung Cancer Registry for patients undergoing lung resection in 2010, only $27\%$ of all patients had data regarding DLCO values [ 42 ]. In addition, in a nationwide survey conducted by the Guidelines Committee of the JACS in 2018 (valid responses: 643), 250 $(39\%)$ respondents answered “Yes, I always include the DLCO test” to the question “Do you include DLco in the preoperative pulmonary function tests?” Considering that $84.7\%$ of thoracic surgeons in the United States always perform the DLCO test before lung resection [ 43 ], these numbers are low. In light of this situation, the recommendation level for the DLCO test in this guideline was set at 2. Hence, it is weakly recommended. However, in patients with shortness of breath on exertion, diffuse interstitial changes on imaging, smoking history, COPD, and other respiratory comorbidities, the risk assessment of

pulmonary surgery via spirometry alone is not sufficient. Hence, in such cases, the importance of the DLCO test should be strongly recognized.

Thus, spirometry and the pulmonary diffusion capacity test can provide important information for predicting the postoperative clinical course. Therefore, it is important to confirm that the tests are performed using standard measurement methods. Moreover, one must consider that the measured values may vary based on the patient’s condition.

CQ5 : Is it necessary to calculate the predicted postoperative (PPO) pulmonary function from the pulmonary function tests (spirometry) and the diffusing capacity for carbon monoxide (DLCO) test to determine the indication for surgery and to determine the surgical procedure? Recommendation 5 : PPO FEV1 should be calculated as a predicted postoperative volume in one second in all patients with lung cancer who will undergo surgery. In addition, the predicted postoperative diffusing capacity for carbon monoxide (PPO DLco) should be calculated on patients with shortness of breath on exertion, diffuse interstitial changes on imaging, smoking history, chronic obstruc tive pulmonary disease (COPD), or other coexisting respiratory diseases ・ PPO FEV1: all patients with lung cancer who will undergo surgery [Degree of recommendation: 1, Quality of evidence: C, Level of agreement: $100\%]$ ・ PPO DLco: all patients with lung cancer who will undergo surgery [Degree of recommendation: 2, Quality of evidence: C, Level of agreement: $100\%]$ ・ PPO DLco: patients with shortness of breath on exertion, diffuse interstitial changes on imaging, smoking history, chronic obstruc tive pulmonary disease [Degree of recommendation: 1, Quality of evidence: C, Level of agreement: 100%]

Table4 High-risk criteria for lobectomy in the ACOSOG Z4032 trial

Major criteria

1. FEV1 of $\leq\!50\%$ predicted 2. DLco of $\leq\!50\%$ predicted

Minor criteria

1. Age $\geq75$ years 2. FEV1 of $>\!50\%–60\%$ predicted 3. DLco of $>50\%–60\%$ predicted 4. Pulmonary hypertension (defined as pulmonary artery systolic pressure of $>\!40\:\mathrm{mmHg}$ ) as estimated on echocardiography or right heart catheterization 5. Poor left ventricular function (defined as an ejection fraction of $\leq\!40\%$ ) 6. Resting or exercise arterial PO2 of $\leq\!55\;\mathrm{mmHg}$ or SpO2 of $\leq\!88\%$ 7. PCO2 of>45mmHg 8. Modified Medical Research Council Dyspnea Scale score of $\geq3$

DLCO carbon monoxide diffusing capacity; FEV1 forced expiratory volume in 1s; PCO2 carbon dioxide partial pressure; SpO2 saturation of percutaneous oxygen

\* High-risk for lobectomy was determined if a patient met one of the major criteria or two of the minor criteria

CQ5 : If lobectomy or greater resection is performed, the predicted postoperative pulmonary function is calculated as follows:

Pneumonectomy [ 44 , 45 ]

a significant predictor of cardiopulmonary complications and surgery-related mortality after open or thoracoscopic lobectomy. Based on these findings, the predicted postoperative pulmonary function should be calculated [ 51 ]. In

( PPO ) FEV 1 = preoperative FEV 1 × ( 1 − fraction of total perfusion for the resected lung ) .

(1)

Lobectomy or pneumonectomy [ 46 , 47 ]:

$$(P P O)\,F E V1=p r e o p e r a t i v e\,F E V1\times(1-Y/z).$$ (2)

Use the value obtained by measuring FEV1 with bronchodilators if necessary.

\*y: Number of functional (unobstructed) lung segments that should be resected

$^{*}\mathbf{Z}$ : Sum of the left and right segments (usually 9 on the left and 10 on the right)

The same formula, similar to the abovementioned one, may be used for the DLCO value to calculate the PPO DLCO [ 48 ].

In addition, by calculating the proportionality to the standard values, these values are often used as %PPO FEV1 and %PPO DLCO.

The following information presents the predicted postoperative pulmonary function. To predict postoperative complications, a factorial analysis of pulmonary function test parameters (such as %FEV1, %PPO FEV1, $\%$ DLCO, and %PPO DLCO) in 906 patients undergoing lung resections was conducted. Results showed that %PPO FEV1 and %PPO DLCO were independent factors. [ 49 ]. In an analysis of $>1400$ patients who underwent lung resections, the risk of respiratory complications increased with decreased %PPO FEV1 and %PPO DLCO. In particular, the risk of complications increased by $10\%$ for every $5\%$ decrease in predicted postoperative values [ 50 ]. In patients with a normal FEV1, a decrease in PPO DLCO $(<40\%)$ was a risk factor for postoperative pulmonary complications ( $P\!=\!0.004$ , OR: 3 $[95\%$ CI: 1.4–6.3]) [ 38 ]. In patients without COPD, PPO FEV1 was a risk factor for respiratory complications and perioperative mortality ( $(P\!<\!0.001$ , $10\%$ increase, OR: 0.783 $[95\%$ CI: 0.704–0.872]) [ 39 ]. Thus, since PPO FEV1 and PPO DLCO were predictors of perioperative complications and mortality, the 2013 ACCP guidelines recommend that the predicted postoperative pulmonary function of all patients who will undergo pulmonary resection should be calculated. Furthermore, in 2014, a previous study performed an analysis using data from the Society of Thoracic Surgeons General Thoracic database (2009–2011, a large US database). Results showed that %PPO FEV1 was a significant risk factor of perioperative cardiopulmonary complications after open or thoracoscopic lobectomy and perioperative mortality after surgery via open thoracotomy. Further, %PPO DLCO was

previous research in Japan, %PPO DLCO was found to be correlated with the incidence of respiratory complications after thoracoscopic lobectomy [ 52 ].

Therefore, this guideline recommended that PPO FEV1 should be calculated as a predicted postoperative pulmonary function in all patients scheduled for pulmonary surgery. To calculate PPO DLCO, this guideline had recommendation 2 (weakly recommended) due to the same reasons outlined in the previous section. Further, it was assigned with a recommendation of 1 in patients with shortness of breath on exertion, diffuse interstitial changes on imaging, smoking history, COPD, or other respiratory comorbidities.

In patients who will undergo pneumonectomy, prediction using Eq. 2 , as described above, may yield inaccurate results because local airway obstruction and impaired pulmonary blood flow are not rare. In such cases, pulmonary ventilation and pulmonary blood-flow scintigraphy should be conducted, and Eq. 1 must be used, as described above [ 53 ].

The abovementioned formulas are for lobectomy and larger lung resections, and there is no report with sufficient evidence for predicting postoperative pulmonary function in patients undergoing limited resections (segmentectomy or wedge resection). Previous reports have revealed that decreased pulmonary function due to segmentectomy is correlated with the number of segments and is smaller than that due to lobectomy. However, it is more likely to be lower than the predicted value calculated using Eq. 2 . Further, it varies based on resection site [ 54 – 57 ]. Patients who undergo wedge resection of the lungs present with a decrease of approximately $5\%$ in FEV1 [ 58 ].

CQ6 : In patients with a PPO FEV1 of

and PPO DLCO

of

, can the perioperative risk be considered average risk?

Recommendation 6 : If the patient has no comorbidities and meets the abovementioned criteria, he or she may have an average risk and

can undergo lung resection without additional exercise testing [Degree of recommendation: 2, Quality of evidence: C, Level of

agreement:

CQ6 : Various parameters (such as %FEV1, %PPO FEV1, %DLCO, and %PPO DLCO) obtained from pulmonary function tests are correlated with perioperative risk in lobectomy or greater lung resection. However, there is a lack of clear evidence regarding the threshold for a high perioperative

risk. The 2013 ACCP guidelines states that no additional testing is recommended in patients with a PPO FEV1 of $\dot{>}60\%$ and a PPO DLCO of $\cdot\,{<}\,60\%$ . In addition, the threshold has been increased from 40 to $60\%$ since the 2007 ACCP Guidelines [ 5 , 36 ]. Although the reason for the change is not stated, a related statement in the guideline showed that preoperative (rather than predicted postoperative) %FEV1 and $\%$ DLCO of $\geq60\%$ in patients undergoing lobectomy resulted in respiratory complications, with an incidence rate of $12\%$ [ 34 ]. Moreover, an %FEV1 of $60\%$ was the best cutoff for the risk of respiratory complications according to the ROC analysis of the predicted cutoff value of postoperative respiratory complications using the preoperative %FEV1. [ 32 ]. These details cannot sufficiently explain this clinical question due to the predicted postoperative values. However, since the criteria of the ACCP Guidelines in 2013 are widely accepted worldwide and no clear refutation has been published in the literature, these criteria have been followed in this guideline.

CQ7 : In patients with a PPO FEV1 of $<\!60\%$ or PPO DLCO of $<\!60\%$ , is there a possibility of a high perioperative risk? Recommendation 7 : Patients may have a high perioperative risk, and a simple exercise tolerance test should be considered [Degree of recommendation: 1, Quality of evidence: C, Level of agreement: $71\%$ ] CQ8 : In patients with a PPO FEV1 of $<30\%$ or PPO DLCO of $<30\%$ , is there a possibility of a very high perioperative risk? Recommendation 8 : The perioperative risk can be very high, and cau tious determination of surgical indications using a simple exercise or cardiopulmonary stress test is suggested [Degree of recommendation: 2, Quality of evidence: C, Level of agreement: $100\%$ ]

CQ7 & CQ8 : In the 2013 ACCP guidelines, the recommendation for patients who do not meet the conditions described in CQ6 is divided into two categories. PPO FEV1 of $<60\%$ or PPO DLCO of $<\!60\%$ but both are $>30\%$ , and PPO FEV1 of $<30\%$ or PPO DLCO of $<30\%$ . In these patients, different exercise stress tests are recommended [ 5 ].

More details on exercise testing are provided in the section of Cardiopulmonary exercise test.

A previous study evaluated the association between predicted postoperative pulmonary function and perioperative complications or perioperative mortality using data from a large database from the United States described above. Results showed the incidence of postoperative complications and perioperative mortality in patients with a PPO FEV1 and PPO DLCO of $<60\%$ and $<30\%$ , respectively, for open and thoracoscopic lobectomy (Table 5 ) [ 51 ]. Patients with a PPO FEV1 of $<60\%$ or PPO DLCO of $<60\%$ had higher complication and perioperative mortality rates compared with other patients in the whole cohort. However, these values are within the fully acceptable risk range.

In another report, 50 patients with a significantly low pulmonary function (PPO DLCO of $<40\%$ ) underwent lobectomy without perioperative mortality, and 35 $(70\%)$ patients were discharged at a median of 5days after surgery without complications. Therefore, along with additional tests and appropriate patient selection, lobectomy can be safely performed such patients with low pulmonary function [ 59 ]. In a Spanish multicenter prospective study of patients with a low pulmonary function, either PPO FEV1 or PPO DLCO can be $<\!40\%$ or both can be between 30 and $40\%$ . Therefore, additional tests were performed to select patients who can undergo surgery. Results showed that patients with low pulmonary function had a higher perioperative risk than those with good pulmonary function. Further, they had a better long-term prognosis than patients who did not undergo surgery [ 60 ].

In view of the abovementioned information, patients with a PPO FEV1 of $<\!60\%$ or a PPO DLCO of $<\!60\%$ who will undergo lobectomy or greater lung resection may be at high perioperative risk. Therefore, in such patients, a simple exercise test should be considered. Patients with a PPO FEV1 of $<30\%$ or a PPO DLCO of $<30\%$ have an even higher incidence of perioperative complications and perioperative mortality, which can be considered a very

Table5 Post-operative complication and mortality rates according to operative approaches in the ACOSOG Z4032 trial

||Open||VATS|VATS| |---|---|---|---|---| || Post-operative complication | Post-operative mortality | Post-operative complication | Post- operative mortality | |Overall|13.1%|2.1%|7.5%|0.8%| |PPO %FEV1 of|||||

PPO predicted postoperative; FEV1 forced expiratory volume in 1 s; DLco carbon monoxide diffusing capacity; VATS video-assisted thoracoscopic surgery

major risk. Therefore, a simple exercise test or a cardiopulmonary exercise test can be used to cautiously determine the indications for surgery. If surgery is required, the following measures should be considered to preserve pulmonary function.

When performing surgery on patients with low pulmonary function, the following points should be considered: Thoracoscopic surgery suppresses postoperative decline in pulmonary function compared with open thoracotomy. Hence, it is beneficial in lung resection for patients with low pulmonary function [ 61 ]. Thoracoscopic surgery had a significantly lower incidence of perioperative events after lobectomy than open thoracic surgery (Table 5 ) [ 51 ]. In another analysis using a large database from the United States, thoracoscopic surgery was associated with a significantly lower incidence of respiratory complications compared with open thoracotomy in patients with reduced %FEV1 [ 62 ]. From the perspective of preserving postoperative pulmonary function, the selection of limited resection is also beneficial in terms of perioperative outcomes. In the ACOSOGZ4032 prospective clinical trial of patients at high risk for lobectomy who are undergoing wedge resection, the incidence rates of 30-day mortality and complications were low at $1.4\%$ and $28.0\%$ , respectively [ 41 ]. The local recurrence rate was $7.7\%$ , and the 3-year survival rate was $71\%$ . These outcomes are considered good in patients with low pulmonary function undergoing lung resection [ 63 ]. Nonsurgical local therapy can also be an option. The third is the volume reduction effect observed in patients with COPD, particularly if the lung lobes with significant emphysema are resected. Patients with COPD after lobectomy are more likely to present with preserved pulmonary function than patients without COPD. This effect is particularly observed after upper lobectomy [ 64 – 67 ].

III. Cardiopulmonary exercise test (CQ9–11)

CQ9 : If a patient with lung cancer who is eligible for surgery is not at average risk based solely on the usual assessment of pulmonary function, is further evaluation with a simple exercise test, such as cardiopulmonary exercise test (CPET), shuttle walking test (SWT), stair climbing test (SCT), and 6-min walk test (6MWT), useful? Recommendation 9 : If the patient is in borderline where it is difficult to determine the tolerability for surgery based on conventional pulmonary function evaluation, further evaluation with a simple exercise test, such as CPET, SWT, SCT, and 6MWT, can be useful and recommended [Degree of recommendation: 1, Quality of evidence: C, Level of agreement: $86\%$ ] CQ10 : Should a patient undergoing a shuttle walk of $<\!25$ shuttles or ${<}400\,\mathrm{m}$ , or those who climb stairs of $<22~\mathrm{m}$ receive the meas urement of maximal oxygen uptake (VO2max) with a cardiopulmo nary stress test (CPET)? Recommendation 10 : If the patient with a shuttle walking test of $\cdot\!<\!25$ shuttles or ${<}400\,\mathrm{m}$ or a stair climbing test of $\cdot\!<\!22~\mathrm{m}$ will undergo surgery, the maximum oxygen uptake (VO2max) could be meas ured with a pulmonary stress test (CPET) [Degree of recommendation: 2, Quality of evidence: C, Level of agreement: $100\%$ ] CQ11 : If a VO2max of $\cdot\,{<}\,10\,\,\mathrm{mL/kg/min}$ or a predicted postoperative value of $\cdot\,{<}\,35\%$ are detected in patients who will undergo surgery, should minimally invasive surgery, limited resection, or nonsurgical treatment be considered? Recommendation 11 : In patients who will undergo surgery, if the maximal oxygen uptake (VO2max) is $<10\,\mathrm{mL/kg/min}$ or the pre dicted postoperative maximal oxygen uptake (VO2max) is $<35\%$ , minimally invasive surgery, limited resection, or nonsurgical treat ment should be considered [Degree of recommendation: 1, Quality of evidence: C, Level of agreement: $86\%]$

$C Q9–C Q I I$ : The general pulmonary function test (spirometry) and DLCO test results are strongly associated with postoperative complications and mortality. Further, they are useful indices in determining the appropriateness of surgery [ 5 ]. However, they are not always accurate predictors of postoperative outcomes because they evaluate pulmonary function at rest and assess the surface of pulmonary function only. These indices are particularly challenging to determine in patients whose tolerance is in the borderline area of operative tolerability. Therefore, the exercise stress test can facilitate evaluation of the function of the whole physical function, including cardiopulmonary functions. Further, it is advantageous as it can allow a more accurate evaluation of tolerance to physical stress caused by lung resection. Due to this reason, the exercise stress test has long been recommended by European and American guidelines as an index for evaluating tolerance in borderline patients who will undergo functional surgery [ 5 , 20 , 68 ].

The cardiopulmonary exercise test (CPET), a formal exercise test performed before pulmonary resection, analyzes expiratory gasses during exercise. This test is described in several texts and guidelines and is a sophisticated physiological test technique that measures values, such as rate response, minute ventilation, minute oxygen uptake, and oxygen uptake during stress electrocardiography and exercise. The maximal oxygen uptake (VO2max) is measured by exercise testing and is recommended in various guidelines as the next step after pulmonary function testing in the preoperative risk assessment of patients with poor pulmonary function [ 5 , 20 , 68 ]. The European guidelines emphasize the role of CPET in preoperative testing, and the 2013 ACCP guidelines recommend that CPET can be performed on all patients with a FEV1 or DLCO that is $<30\%$ of the predictive value [ 5 ]. If the VO2max is>20mL/kg/min or $>75\%$ of the

predicted value, a planned lung resection (up to pneumonectomy) can be performed with an average risk without further testing. However, patients with a VO2max of $<20~\mathrm{mL/kg/}$ min should be considered at high surgical risk. By contrast, if the VO2max is<10mL/kg/min or $<35\%$ of the predicted value, the postoperative mortality rate is extremely high, and there are scattered reports indicating that lobectomy should not be indicated [ 69 – 72 ]. However, research reports on these data are limited because the number of cases examined is not large. By contrast, a meta-analysis has examined the role of VO2max in assessing the risk of postoperative complications in patients undergoing surgical treatment. Benzo etal. analyzed data from 14 studies examining VO2max in 955 patients. Results showed that patients with postoperative complications had a VO2max that is $3~\mathrm{mL/kg/min}$ lower than that of patients without postoperative complications. Therefore, CPET is useful for risk assessment before lung resection [ 73 ]. Loewen etal. reviewed a large study that investigated CPET for functional indications for lung resection [ 74 ]. Patients with impaired function had a significantly lower VO2max compared with healthy patients. Moreover, previous studies had similar results. Several studies have shown that patients with a VO2max of $10{-}15~\mathrm{mL/kg/min}$ or $35\%–75\%$ predicted value have a higher postoperative mortality rate [ 69 – 74 ]. However, any lung resection, including pneumonectomy, can be safely performed on patients with a VO2max of $>20\:\mathrm{mL/kg/min}$ . Brunelli etal. assessed 200 patients who were assessed preoperatively using CPET before anatomical lung resection. This study showed no postoperative mortality, and the complication rate was only $7\%$ in the group with a VO2max of>20mL/kg/min [ 75 ].

The correlation between CPET and postoperative complications, and the standard tests values considered for safe surgery has been reported for several years. Moreover, this can provide information on preoperative risk assessment and the evaluation of indications for surgery. However, the number of cases evaluated in each report was not necessarily large, and it is challenging to establish a clear absolute threshold for the suitability of the procedure. Furthermore, CPET is not a test that can be easily performed in each facility, and it is not considered essential. Therefore, we set the recommendation level for the implementation of CPET testing at 2. Due to this reason, the algorithm in this guideline (Fig. 1 ) does not include CPET as a mandatory test. If CPET cannot be performed at a facility, the evaluation should be made prior to CPET. In patients with a PPO FEV1 of $<30\%$ or those with a PPO DLCO of $<30\%$ , a simple exercise stress test should be performed to cautiously determine the surgical indications.

Historically, simple walking tests have been performed as an alternative or preliminary test to the CPET, which is not easily performed. These include the Shuttle Walk Test

(SWT), the 6-Minute Walk Test (6MWT), and the Stair Climbing Test (SCT).

The SWT is generally performed by walking between two points at $10\;\mathrm{m}$ apart with a voice signal and gradually increasing the walking speed according to the voice guidance. The test ends when the patient can no longer walk at the guidance speed, and the score is the total distance walked. The SWT result is associated with postoperative complication rates and VO2max. Individuals who can walk 25 round trips or 400 m often have a VO2max of $\mathrm{\Sigma\,}$ $\mathrm{kg/min}$ on CPET and can safely undergo surgery. In contrast, those who cannot walk 25 round trips nor 400 m are more likely to have a VO2max of<10 mL/kg/min [ 76 – 81 ]. However, the number of reports on this correlation is limited. The 6MWT is a test in which participants can walk as long as possible in a straight line within a specified time. Further, it is unique as it emphasizes self-paced walking. However, the number of reports is small, and it is not recommended in the European guidelines [ 20 ]. In addition, it is difficult to assume that the testing and evaluation method is standardized [ 82 ].

Similar to the SWT, the SCT measures maximal stair climbing. Moreover, the SCT result is associated with postoperative complication rates and VO2max on CPET [ 83 – 90 ]. Brunelli etal. found that $50\%$ of patients who walked $<12~\mathrm{m}$ in the SCT had moderate or severe cardiopulmonary complications. Meanwhile, only $6.5\%$ of patients who could ascend or descend more than $14\textrm{m}$ in the SCT had such complications [ 85 ]. Brunelli etal. performed another study with a larger number of patients $(n\!=\!640)$ ). Results showed that the postoperative complication rates of patients who walked $<12~\mathrm{m}$ in the SCT were 2.5–13 times higher than that in patients who walked $\geq22$ m in the SCT. The postoperative mortality rate of patients with an SCT of $\leq12\,\mathrm{~m~}$ was $13\%$ [ 86 ]. Furthermore, the postoperative mortality rate of patients who could ascend or descend $>22~\mathrm{m}$ in the SCT was $20\%$ . However, patients with a PPO FEV1 or PPO DLco of $<40\%$ who could ascend or descend $>22~\mathrm{m}$ in the SCT did not present with postoperative complications. Hence, spirometry, PPO FEV1, and PPO DLCO values alone are not sufficient for facilitating an appropriate evaluation. Moreover, a comprehensive evaluation is required. In another study by Brunelli etal., the positive predictive value of a CPET VO2max of $\geq15\,\mathrm{\mL/kg/min}$ was $86\%$ in patients who could ascend or descend $>22~\mathrm{m}$ . Hence, individuals who can ascend or descend $>22~\mathrm{m}$ have nearly normal pulmonary function and can undergo surgery without further exercise testing. Moreover, they have an average surgical risk [ 87 ]. Therefore, based on these study results, several guidelines have set the threshold for SCT at $22\textrm{m}$ [ 5 ]. Although the height of stairs in hospitals is challenging to measure, in general, the exercise tolerance of people

 Fig.1 Pulmonary function assessment algorithm

who can climb more than 3 flights of stairs (54 stairs at $18.5~\mathrm{cm}$ per stair) often has a VO2max $\mathrm{of}\,{\geq}\,15~\mathrm{mL}/\mathrm{kg}/$ min. By contrast, those who cannot climb 1 flight of stairs (18 stairs) commonly present with a VO2max of $>10\:\mathrm{mL}/$ $\mathrm{kg/min}$ [ 88 ]. Therefore, in institutions where CPET testing is not available, minimally invasive surgery, limited resection, or nonsurgical treatment should be considered in such patients who are assumed to have high risk for surgery. People who cannot climb stairs due to preoperative comorbidities are also at high risk for perioperative mortality [ 89 , 90 ]. Based on the abovementioned details, the ability to climb to the 3rd and 5th floors is considered the threshold for lobectomy and pneumonectomy, respectively. Although SCT is performed more frequently than SWT and there are several reports on the use of SCT in preoperative functional assessment, there is an issue regarding the height of the stairs that should be ascended and descended and the number of stairs. That is, they are not uniform.

These simple exercise tolerance tests are advantageous. That is, they can easily reproduce the patient’s daily activities during exertion and can comprehensively evaluate the cause of exercise limitation and exercise tolerance. However, there are relatively few tests related to postoperative complications, and another issue is that there is no standardization of parameters used in various inspection methods, which include the height and the width of stairs, speed of stair climbing, and number of stairs between floors. However, the use of simple exercise test, as a substitute for CPET or a preliminary evaluation to CPET, is very useful when CPET cannot be easily performed. Therefore, the recommendation level was set at 1.

IV. Evaluation ofpulmonary function forlung cancer complicated byinterstitial pneumonia (CQ12, 13)

Recommendation 13 The diffusion capacity for carbon monoxide (DLCO), resting arterial oxygen partial pressure (PaO2), and oxygen saturation (SpO2) after a 6-min walk test are important prognostic factors in patients with interstitial pneumonia. Thus, testing of these parameters could be performed on patients with lung cancer accompanied by interstitial pneumonia who will undergo surgery. [Degree of recommendation: 2, Quality of evidence: C, Level of agreement: $100\%]$

CQ12 & CQ13 : Although the 2013 ACCP guideline recommend the measurement of DLCO in diffuse parenchymal lung disease [ 5 ], the guideline does not specifically address the need for or the value of specific pulmonary function in lung cancer accompanied with interstitial pneumonia. The ACCP 2012 and Society of Thoracic Surgeons (STS) 2012 Consensus Statement for the treatment of patients with stage I NSCLC who presented with low pulmonary function [ 91 ] also focus on COPD as a prognostic predictor and comorbidity. However, postoperative mortality and morbidity of patients with interstitial pneumonitis were not mentioned. Only two Japanese reports are cited in these statements. Their results have shown that patients with interstitial pneumonia have higher postoperative mortality and morbidity rates [ 92 , 93 ]. However, pulmonary function and low DLCO are indicators of postoperative complications in all patients with lung cancer as already mentioned in this guideline. Further, there is no doubt that many of these patients will present with comorbidity particularly interstitial pneumonia.

There are several reports on the correlation between postoperative acute exacerbation of interstitial pneumonia or acute respiratory distress syndrome (ARDS), which are major postoperative complications [ 94 – 98 ], and pulmonary function (VC and $\%\mathbf{V}\mathbf{C}$ ) in patients with lung cancer who present with interstitial pneumonia. Only Kumar etal. performed an evaluation on 24 patients using the composite physiologic index (CPI) [ 99 ]: 91.0—{ $0.65~\mathrm{{x}}$ %predicted DLCO}—{0.53 x %predicted FVC}+%predicted $\mathrm{FVC}+0.34\mathrm{~x~}\%$ predicted FEV1). Results showed a correlation between CPI and DLCO [ 100 ]. In a nationwide survey performed by Sato etal. from the JACS [ 98 ], $\%$ DLCO was recorded in 1128 of 1763 patients. However, no correlation was found between $\%$ DLCO, as well as FEV1, and postoperative acute exacerbation. There are only few comprehensive reports focusing on other pulmonary complications. However, the prospective JACS-led multicenter study of patients with lung cancer accompanied with interstitial pneumonia who underwent surgery, which completed its enrollment ( $\lceil n\!=\!1257\rceil$ ) in 2019, provided data on grade 3 or higher complications. This then provided a high level of evidence for the evaluation of pulmonary function using DLCO.

Honma etal. reported that the median durations of overall survival were 57, 29, 19, and 9 months in patients with a $\%\mathbf{V}\mathbf{C}$ of $\ge80\%$ , $60–80\%$ , $40–60\%$ , and $\leq40\%$ ,

respectively [ 101 ]. $\%\mathbf{V}\mathbf{C}$ and $\%$ DLCO are used to evaluate pulmonary function in the GAP score comprising sex, age, and pulmonary function tests proposed by Ley etal. [ 102 ]. In the GAP score modified for Japanese patients based on the results of the Hokkaido Study, $\%\mathbf{V}\mathbf{C}$ is composed of three groups $(\geq80\%$ , $65{-}80\%$ , and $\leq\!65\%$ ). Moreover, $\%$ DLCO comprises three groups $(\ge65\%$ , $45{-}65\%$ , and $\leq\!45\%$ ), and the 2-year mortality rate after surgery in patients with 2 or higher severity is approximately $43.1\%$ .

Greater than $50\%$ of patients with a resting arterial oxygen partial pressure of $\ge80$ Torr (severity 1) developed desaturation (SpO2 of $<90\%$ ) after the 6MWT. Hence, these patients have a significantly worse prognosis than those without desaturation. Then, in the Japanese classification of disease severity staging system for idiopathic pulmonary fibrosis, as revised in 2017, such patients were considered to have stage 2 disease (3-year mortality rate: $31.4\%$ vs. $14.1\%$ and median survival: 50.5 vs. 99.3 months) [ 103 ]. Notably, patients with a resting PaO2 of 70–79 Torr of desaturation after 6MWT presented with stage 3 disease, and the 3-year mortality rate for them was $46.5\%$ .

The prognostic impact of %PPO DLCO and %PPO VC predicted before lung cancer resection is unknown. However, since $\%$ DLCO is correlated with the severity and prognosis of idiopathic interstitial pneumonia, as described above, we proposed that the preoperative evaluation of PPO DLCO, which decreases in postoperative severity, should also be considered.

V. Preoperative smoking cessation and pulmonary rehabilitation (CQ14, 15)

CQ14 : Should smoking cessation be recommended to preoperative and postoperative patients with NSCLC? Recommendation 14 : Smoking cessation is recommended for preoperative and postoperative patients with NSCLC [Degree of recommendation: 1, Quality of evidence: C, Level of agreement: $100\%$ ]

CQ14 : Several studies have consistently shown the effects of smoking, including an increased risk of developing lung cancer [ 104 ] and increased mortality [ 105 ]. In terms of perioperative effects, smoking is associated with an increased risk of infection and delayed wound healing [ 106 ]. In a prospective observational study of 1008 patients, smokers and ex-smokers had a significantly higher volume of intraoperative sputum than never-smokers (OR: 2.1, $95\%$ CI: 1.5–3.1, $P\!=\!0.0001$ ) [ 107 ].

Several reports on the association between smoking and the postoperative respiratory complications in patients with lung cancer have been published [ 4 , 5 , 108 – 111 ]. In an analysis of a prospective observational study of 300 patients, smokers/ex-smokers had significantly higher rates of respiratory complications than never-smokers ( $23\%$ vs. $8\%$ , $P\!=\!0.03$ ) [ 108 ]. In an analysis of approximately 7990 individuals from the United States database, smokers/exsmokers had a higher perioperative mortality rate than never-smokers ( $.1.5\%$ vs. $0.39\%$ ) [ 109 ]. Similar reports have been made elsewhere [ 4 , 110 , 111 ], and smoking is considered a risk factor of postoperative respiratory complications and perioperative mortality in lung cancer.

By contrast, although there is no evidence on the association between the duration of preoperative smoking cessation and postoperative respiratory complications in patients with lung cancer, a retrospective cohort study showed that smoking cessation for $\geq4$ weeks before surgery can be associated with fewer perioperative respiratory complications in patients who underwent lung resection $(n\!=\!288)$ ) [ 110 ]. A retrospective cohort study of 666 patients undergoing lung resection also showed that the incidence of postoperative respiratory complications was significantly lower with longer periods of smoking cessation in the 1-, 3-, 6-, and 12-month preoperative smoking cessation groups [ 4 ]. A meta-analysis including various fields other than lung resection, such as gastroenterology, orthopedics, and cardiovascular surgery, found no significant correlation was observed between the duration of preoperative smoking cessation and the incidence of postoperative complications [ 112 ]. Nevertheless, there are no high-quality evidence-based reports on lung cancer that reached a similar conclusion.

Based on the abovementioned data, at present, it is challenging to uniformly determine the period of smoking cessation required before surgery. However, it is desirable to set an appropriate period of smoking cessation while considering lung cancer progression. In a prospective study on smoking and quality of life in the first year after lung cancer surgery, compared with never smokers and ex-smokers, current smokers had a significantly poorer recovery of physical functions ( $(P\!=\!0.01$ ), greater number of symptoms, such as dyspnea ${\it P}\!=\!0.04)$ ) and chest pain $(P\!=\!0.02)$ ), and lower quality of life at 12 months after surgery for lung cancer [ 113 ]. Regarding smoking and long-term prognosis after surgery for pathological stage I lung cancer, smokers had a significantly poorer 10-year survival rate than neversmokers ( $41.0\%$ vs. $65.0\%$ , $P\!=\!0.001$ ). Moreover, smoking was an independent prognostic factor (OR: 1.99, $95\%$ CI: 1.51–2.62, $P\!<\!0.0001$ ) [ 114 ]. Furthermore, smoking may increase the risk of heterochronic lung cancer [ 115 – 117 ]. Smoking causes health hazards not only to smokers themselves but also to those around them due to passive smoking [ 118 , 119 ]. Therefore, smoking cessation should be

strongly recommended. In addition, there is no scientific evidence showing that noncombustible/heated cigarettes and electronic cigarettes have less negative health effects than conventional cigarettes. The use of conventional cigarettes should be discouraged during the perioperative period. Although limited data are available at present, smoking cessation should be implemented pre- and postoperatively in patients with NSCLC. The strength of evidence is C. Further, based on the overall assessment, smoking cessation is strongly recommended (with a score of 1).

CQ15 : Should preoperative and postoperative patients with NSCLC undergo pulmonary rehabilitation? Recommendation 15 : Pulmonary rehabilitation is recommended for preoperative and postoperative patients with NSCLC, particularly those at high risk [Degree of recommendation: 1, Quality of evidence: C, Level of agreement: $85.7\%]$ ]

CQ15 : At present, there is no solid evidence supporting the recommendation of routine preoperative pulmonary rehabilitation for patients with lung cancer. However, there are increasing reports showing that preoperative pulmonary rehabilitation may be useful [ 120 – 126 ]. There is also a report showing that preoperative pulmonary rehabilitation improved exercise tolerance and quality of life in patients with lung cancer who present with COPD [ 120 ]. In addition, the VO2max increased by $2.8~\mathrm{mL/kg/min}$ $(P\!<\!0.001)$ ) after 4weeks of short-term rehabilitation. However, the pulmonary function test values did not improve [ 121 ]. Furthermore, preoperative pulmonary rehabilitation not only improves exercise tolerance and quality of life but also reduces postoperative respiratory complications [ 122 – 126 ]. A meta-analysis of 404 patients with lung cancer reported that preoperative pulmonary rehabilitation significantly reduced postoperative respiratory complications (OR: 0.44, $95\%$ CI: 0.27–0.71, $P\!<\!0.0001]$ ) and shortened the mean length of postoperative hospital stays by 4.23days [ 126 ].

Post-operative pulmonary rehabilitation after lung resection is beneficial in several cases [ 127 – 131 ]. These reports show that postoperative pulmonary rehabilitation improves exercise tolerance, quality of life, and pulmonary function test values [ 127 , 128 ]. Even if the objective values of pulmonary function tests did not increase, exercise performance can improve [ 129 ]. Furthermore, early postoperative weaning shortened the duration of postoperative oxygen administration [ 130 ]. Moreover, early postoperative pulmonary rehabilitation significantly reduced the frequency of sputum expectoration on bronchoscopy within 72h ( $16\%$ vs. $5.6\%$ , $P\!=\!0.0006$ ) compared to the control group [ 131 ]. By contrast, there is no evidence regarding the duration or program of preoperative and postoperative pulmonary rehabilitation.

It is challenging to quantify and standardize data on preoperative and postoperative pulmonary rehabilitation based

on previous reports. The decision to perform perioperative pulmonary rehabilitation for lung cancer is based on each facility. However, it can be beneficial, particularly in clinically high-risk patients (those exceeding the “average risk” in the risk assessment algorithm). Based on the abovementioned data, the strength of evidence is C, and the overall rating for performing preoperative and postoperative pulmonary rehabilitation is 1.

Acknowledgements This study was supported by The Japanese Association for Chest Surgery, Kyoto, Japan.

Declarations

Conflict of interest The authors have no conflict of interest to declare.

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Authors and Affiliations

YasuhisaOhde 1 · KazuhiroUeda 2 · JiroOkami 3 · HajimeSaito 3 · ToshihikoSato 4 · EijiYatsuyanagi 5 · MasanoriTsuchida 6 · TakahiroMimae 7 · HiroyukiAdachi 8 · TomoyukiHishida 9 · HisashiSaji 10,11 · IchiroYoshino 12,13 · Committee for Guideline Assessment, The Japanese Association for Chest Surgery, Tokyo, Japan

\* Masanori Tsuchida masatsu@med.niigata-u.ac.jp \* Hisashi Saji hisashisaji@gmail.com 1 Division ofThoracic Surgery, Shizuoka Cancer Center, Shizuoka, Japan 2 Department ofGeneral Thoracic Surgery, Kagoshima University Graduate School ofMedical andDental Sciences, Kagoshima, Japan 3 Department ofGeneral Thoracic Surgery, Osaka International Cancer Institute, Osaka, Japan 4 Department ofGeneral Thoracic, Breast andPediatric Surgery, Fukuoka University School ofMedicine, Fukuoka, Japan 5 Department ofGeneral Thoracic Surgery, National Hospital Organization Obihiro Hospital, Hokkaido, Japan 6 Division ofThoracic andCardiovascular Surgery, Niigata University Graduate School ofMedical andDental Sciences, Niigata, Japan 7 Department ofSurgical Oncology, Hiroshima University, Hiroshima, Japan 8 Department ofSurgery, Yokohama City University, Kanagawa, Japan

12 International University ofHealth andWelfare Narita Hospital, Narita, Japan 13 The Japanese Association forChest Surgery, Kyoto, Japan

9 Division ofThoracic Surgery, Department ofSurgery, Keio University School ofMedicine, Tokyo, Japan 10 Department ofChest Surgery, St. Marianna University School ofMedicine, Kanagawa, Japan 11 Committee forGuideline Assessment, The Japanese Association forChest Surgery, Kyoto, Japan