A prospective 5-year follow-up study after limited resection for lung cancer with ground-glass opacity

A prospective 5-year follow-up study after limited resection for lung cancer with ground-glass... Abstract OBJECTIVES The incidence of small-sized pulmonary adenocarcinomas with ground-glass opacity (GGO) has recently increased, with excellent postoperative prognosis. The limited resection of such cancers has been deemed to be acceptable based on retrospective studies. We conducted a prospective multi-institutional study evaluating the validity of limited resection for small-sized pulmonary adenocarcinoma with GGO. METHODS The inclusion criteria were 25–80 years of age, no prior treatment, a maximum tumour diameter of 8–20 mm, a GGO ratio of ≥ 80%, clinical T1N0M0, lower 18F-fluorodeoxyglucose accumulation than the mediastinum, resectable by sublobar resection, pulmonary lobectomy tolerable and an intraoperative pathological diagnosis of bronchiloalveolar carcinoma. Wedge resection was preferred, but segmentectomy was permitted. Disease-specific survival and overall survival were analysed. RESULTS From November 2006 to April 2012, 73 patients were enrolled from 13 institutions. One patient was ineligible, and the remaining 72 patients were preregistered. The tumours of 3 and 14 patients were intraoperatively diagnosed as benign lesions and adenocarcinomas with mixed subtype, respectively. Intraoperative cytological/histological examination of surgical margin was not performed in 2 patients, and the remaining 53 patients were ultimately eligible for this study. The mean tumour size was 14.0 mm and the mean GGO ratio was 95.9%. Thirty-nine and 14 patients underwent wedge resection and segmentectomy, respectively. Although all tumours were intraoperatively diagnosed as bronchioloalveolar carcinomas, 6 were ultimately diagnosed as adenocarcinoma with a mixed subtype. No completion lobectomy was performed. As of 1 May 2017, no recurrence of the original lung cancer was observed during 60.0–126.3 months after surgery. Two patients died from other diseases. The 5-year disease-specific and overall survival rates were 100% and 98.1%, respectively. The reduction in the pulmonary function after limited resection was minimal. CONCLUSIONS With these criteria, limited resection was performed safely without any recurrence, and the postoperative pulmonary function was well preserved. The outcomes of limited resection for small-sized lung cancer with GGOs that met the criteria of this study were satisfactory. Lung cancer, Adenocarcinoma, Ground-glass opacity, Limited resection, Prospective study INTRODUCTION Lung cancer screening using low-dose thoracic computed tomography (CT) has been performed since the 1990s and has gradually spread globally [1, 2]. Recently, the National Lung Screening Trial reported the efficacy of CT screening for lung cancer in heavy smokers [3], and several other studies on the efficacy of CT screening are being conducted. With CT screening, many small-sized lung cancers with ground-glass opacity (GGO) are detected, some of which have been reported to have an excellent postoperative prognosis [4, 5]. In 1995, Noguchi et al. [6] reported a new classification system for small-sized adenocarcinomas, and the 5-year postoperative survival rate of patients with resected Noguchi’s Type A (localized bronchioloalveolar carcinoma) and Type B (localized bronchioloalveolar carcinoma with foci of structural collapse of alveoli) adenocarcinomas was 100%. Noguchi’s Type A/B adenocarcinomas were almost equal to bronchioloalveolar carcinomas in the third edition of histological typing published by the World Health Organization. The radiological findings of these adenocarcinomas revealed small-sized lung tumours with GGO as a dominant part. In Japan, many lung tumours with GGO suspected of being bronchioloalveolar carcinomas have been detected on thoracic CT screening [1, 4–6]. Generally, the standard surgical procedure for lung cancer, even for small-sized lung cancer, is pulmonary lobectomy with hilar and mediastinal nodal dissection, based on the results of a randomized controlled trial in which the patients treated with limited resection for cT1N0M0 peripheral lung cancer had a worse prognosis than those treated with pulmonary lobectomy and nodal dissection [7]. However, bronchioloalveolar carcinomas have a low invasive potential [6], and patients with such carcinomas might be candidates for limited pulmonary resection. Since the pathological diagnosis of bronchioloalveolar carcinoma is based on the histological findings of formalin-fixed paraffin-embedded specimen, selecting appropriate candidates preoperatively is not easy. Even lung cancers with GGO occasionally include invasive adenocarcinomas, and chest CT findings alone cannot distinguish the invasive carcinomas from the non-invasive ones [8, 9]. Positron emission tomography imaging with 18F-fluorodeoxyglucose (FDG-PET) provides metabolic information on pulmonary nodules [10, 11]. FDG-PET findings are helpful for the discrimination of non-invasive carcinomas from the invasive ones [11, 12]. Several investigators including us reported that FDG accumulation related invasive ability of pulmonary adenocarcinomas [12–15]. If a combination of chest CT and FDG-PET findings enables the selection of more biologically inactive cancers, then wedge resection might be an appropriate treatment for such tumours. We previously reported a pilot study on wedge resection for small-sized pulmonary adenocarcinomas, in which the criteria for limited resection candidacy were determined [16]. To elucidate the validity of limited pulmonary resection for small-sized pulmonary adenocarcinomas with GGO, we started a multi-institutional prospective study in 2006 (JNETS 0601). As the follow-up periods of all the registered cases in the study reached 60 months, we evaluated the validity of this therapeutic strategy. PATIENTS AND METHODS Setting This study was a single-arm multi-institutional prospective trial. For this trial, preregistration was required before surgical resection. This protocol was approved by the Institutional Review Board in Kanazawa Medical University in 2006 and registered in the University Hospital Medical Information Network Clinical Trial Registration System, Japan (registration number: UMIN000005908). The details are available at https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi? recptno=R000006980. Mandatory examination High-resolution CT (HR-CT) of the chest field and FDG-PET were mandatory. The maximum diameters of the GGO and the consolidation were measured on the axial lung window image on HR-CT. The GGO ratio was calculated using the following equation: GGO ratio = [(maximum diameter of the tumour) – (maximum diameter of consolidation)]/(maximum diameter of the tumour). The FDG accumulation was classified into 3 grades based on a visual evaluation: Grade 2 was equivalent to the accumulation in the mediastinum, while Grade 1 was lower accumulation and Grade 3 higher accumulation. Other examinations required for pulmonary lobectomy, such as pulmonary function, electrocardiogram and ordinary blood tests, were also performed. Preregistration The inclusion criteria for preregistration were determined as follows from the results of our previous study [16]: 25–80 years of age Adenocarcinoma or suspected adenocarcinoma No prior treatment Maximum diameter of 8–20 mm GGO ratio of ≥80% Clinical T1N0M0 (UICC TNM classification, sixth edition) Grade 1 of FDG accumulation Complete resection of the tumour possible with sublobar resection Pulmonary lobectomy tolerable for the patient Given written informed consent The exclusion criteria for preregistration were as follows: Patients with any other cancer within the past 5 years Patients with severe complications Transthoracic CT-guided needle biopsy was not mandatory because of the possibility of pleural dissemination of cancer cells. After informed consent was obtained, a case report form for preregistration was faxed to the central registration centre. At the central registration centre, the inclusion/exclusion criteria were checked, and a preregistration number was faxed to the local hospital. Surgical resection, registration and post-surgical therapy At the local hospital, surgical resection was performed after receiving a fax of the preregistration number. Video-assisted thoracic surgery was preferred but was not mandatory, as maintaining a wide margin (at least 10 mm) with the tumour was considered more important. For pulmonary resection, wedge resection was basically performed, but segmentectomy was accepted when the margin was not wide enough. After wedge resection/segmentectomy, an intraoperative pathological examination with frozen sections was performed. Only cases diagnosed as bronchioloalveolar carcinomas on this intraoperative pathological examination were eligible, and others, such as benign diseases, non-adenocarcinomas or adenocarcinomas with mixed subtype, were considered ineligible. An intraoperative cytological/histological examination of the surgical margin was also performed. When the cytology/histology of the surgical margin was positive, then an additional wedge resection or segmentectomy was performed. If the re-evaluation of the surgical margin was negative, then the case was regarded as eligible. If lobectomy was needed, the cases were considered ineligible. Since the eligibility evaluation and registration of this study was completed intraoperatively, even if a tumour was diagnosed as invasive adenocarcinoma with mixed subtype at the ultimate pathological diagnosis, the case was not excluded from the study. In cases where the ultimate diagnosis was adenocarcinoma with mixed subtype, despite an intraoperative diagnosis of bronchioloalveolar carcinoma, the option of completion lobectomy was permitted if the patient needed this surgery. Other post-surgical therapies were not permitted until recurrence was confirmed pathologically or radiologically. Pulmonary function The vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and FEV1/FVC (FEV1%) were basically evaluated 3 times: preoperatively, early postoperatively (within 3 months after surgery) and late postoperatively (approximately 1 year after surgery). The postoperative changing rates (CRs) were calculated with the following formulae: Early postoperative-CR-VC = (Early postoperative-VC/ Preoperative-VC), Late postoperative-CR-VC = (Late postoperative-VC/ Preoperative-VC). For the FEV1 and FEV1%, the early postoperative-CR and late postoperative-CR were calculated similarly. Follow-up and recurrence Follow-up was performed at least once a year at the local hospital. In cases where a subsequent tumour was detected during the follow-up period, it could be difficult to determine whether the subsequent neoplasm was a recurrence of the original tumour or a second primary lung cancer. In the protocol of this study, second primary lung cancer was basically defined in accordance with the definition by Cortese et al. [17] when (i) the subsequent tumour had a different histological type from the original cancer or (ii) the subsequent tumour had a similar histological type to the original cancer but was a solitary tumour without any extrathoracic metastases and no carcinoma was found in the lymphatics at common to both cancers. Otherwise, the subsequent tumour was considered to be recurrence of the original cancer. End points and statistical analyses The main objective of this study was to prospectively investigate the validity of limited resection for patients having lung cancer with GGO in terms of the 5-year disease-specific survival. The secondary end points were the overall survival, the disease-free survival, the mode of recurrence and the change in the pulmonary function. The survival was calculated from the day of pulmonary resection to the day of event. The survival analyses were planned to be conducted 60 months after pulmonary resection in all eligible patients. The sample size was calculated as follows. The disease-specific 5-year survival rates of the patients who underwent pulmonary lobectomy among those who met the criteria of this study were assumed to be 98%. Because the postoperative pulmonary function of the patients who underwent limited resection was assumed to be better than that in those who underwent pulmonary lobectomy, the non-inferiority margin at 5 years was set at 8%. With an alpha error of 0.05 and a power of 0.80, and with some dropout cases expected, 53 registered cases were needed for this study. The survival rates were calculated by the Kaplan–Meier method. Paired t-test was used to compare the pulmonary function. All statistical analyses were calculated with the EZR software program on R commander [18]. A P-value of <0.05 was regarded as statistically significant. RESULTS Preregistration and registration From November 2006 to April 2012, a total of 73 patients were prospectively enrolled from 13 institutions (Fig. 1). One patient was ineligible for preregistration criteria, and the remaining 72 patients were preregistered. Figure 1: View largeDownload slide Flow chart of the patients in this study. FDG: 18F-fluorodeoxyglucose. Figure 1: View largeDownload slide Flow chart of the patients in this study. FDG: 18F-fluorodeoxyglucose. All 72 patients underwent sublobar pulmonary resection. The tumours of 3 patients were intraoperatively diagnosed as benign lesions, and the tumours of 14 patients were diagnosed as adenocarcinomas with mixed subtype. Intraoperative cytological/histological examination of surgical margin was not performed in 2 patients, so they were regarded as ineligible. Of the remaining 53 patients, intraoperative examination of surgical margin in 1 patient was positive for cancer cells. After another wedge resection in the patient, a re-evaluation of the surgical margin was found to be negative for cancer cells, and therefore the patient was considered eligible. These 53 patients were ultimately regarded as eligible. Of the 19 ineligible patients, 16 underwent pulmonary resection of lung cancer (2 cases of wedge resection without an intraoperative evaluation of surgical margin, 9 cases of adenocarcinomas with mixed subtype after wedge resections and 5 cases of adenocarcinomas with mixed subtype after lobectomy conversion). They were also followed up and additionally analysed. Patient characteristics The patient characteristics are listed in Table 1. There were 25 men and 28 women, and the mean age was 61.7 years. The mean tumour size was 14.0 mm, and the mean GGO ratio was 95.9%. Over 90% of cases underwent pulmonary resection under video-assisted thoracic surgery. Thirty-nine and 14 patients underwent wedge resections and segmentectomies, respectively. Table 1: Characteristics of the eligible patients (n = 53)   Number of patients  Gender     Male  25   Female  28  Age (years)     30–39  2   40–49  5   50–59  15   60–69  19   70–79  12  Maximum diameter (mm)     8–10  9   11–15  25   16–20  19  Ground-glass opacity ratio (%)     80–89  12   90–99  2   100  39  Approach     Video-assisted thoracic surgery  48   Open thoracotomy  5  Surgical procedure     Wedge resection  39   Segmentectomy  14  Re-resection     Done  1   Not done  52  Postoperative diagnosis     Bronchioloalveolar carcinoma  47   Adenocarcinoma with mixed subtype  6    Number of patients  Gender     Male  25   Female  28  Age (years)     30–39  2   40–49  5   50–59  15   60–69  19   70–79  12  Maximum diameter (mm)     8–10  9   11–15  25   16–20  19  Ground-glass opacity ratio (%)     80–89  12   90–99  2   100  39  Approach     Video-assisted thoracic surgery  48   Open thoracotomy  5  Surgical procedure     Wedge resection  39   Segmentectomy  14  Re-resection     Done  1   Not done  52  Postoperative diagnosis     Bronchioloalveolar carcinoma  47   Adenocarcinoma with mixed subtype  6  Pathological diagnoses The intraoperative pathological diagnoses of all tumours were bronchioloalveolar carcinomas (16 Noguchi’s Type A adenocarcinomas and 37 Type B). The ultimate diagnoses of the tumours were bronchioloalveolar carcinomas in 47 patients and adenocarcinomas with a mixed subtype in 6 patients (Table 1). All patients were staged as pathological T1N0M0, Stage IA. For all 6 cases of resected adenocarcinomas with mixed subtype, the patients and surgeons in charge discussed completion lobectomy, and all of them decided not to undergo additional surgery. Changes in pulmonary function Preoperative and early postoperative pulmonary function tests were performed in all 53 eligible patients, but 9 patients refused the late postoperative test. The changes in the pulmonary function were compared in the remaining 44 cases. The VC, FEV1, FEV1% and postoperative CR are listed in Table 2. Although both the early postoperative and the late postoperative VC and FEV1 were significantly smaller than the preoperative VC and FEV1, the average late postoperative CRs of both VC and FEV1 were 0.96, and the reduction was only 4%. FEV1% was similar, regardless of the period examined. Table 2: Changes in the pulmonary function (n = 44)   Average value (range)  Paired t-test  Average postoperative changing rate (range)  Preoperative VC (ml)  3351 (1800–5500)*      Early postoperative VC (ml)  2830 (1510–4910)  P < 0.001 compared to *  0.86 (0.41–1.01)  Late postoperative VC (ml)  3178 (1740–5450)  P = 0.002 compared to *  0.96 (0.66–1.14)  Preoperative FEV1 (ml)  2547 (1300–4440)**      Early postoperative FEV1 (ml)  2144 (1110–4050)  P < 0.001 compared to **  0.86 (0.38–1.17)  Late postoperative FEV1 (ml)  2417 (1360–4390)  P = 0.011 compared to **  0.96 (0.72–1.58)  Preoperative FEV1% (%)  76.6 (61.9–91.0)***      Early postoperative FEV1% (%)  75.9 (60.1–91.0)  P = 0.459 compared to ***  0.99 (0.73–1.23)  Late postoperative FEV1% (%)  76.5 (60.1–95.6)  P = 0.929 compared to ***  1.00 (0.79–1.33)    Average value (range)  Paired t-test  Average postoperative changing rate (range)  Preoperative VC (ml)  3351 (1800–5500)*      Early postoperative VC (ml)  2830 (1510–4910)  P < 0.001 compared to *  0.86 (0.41–1.01)  Late postoperative VC (ml)  3178 (1740–5450)  P = 0.002 compared to *  0.96 (0.66–1.14)  Preoperative FEV1 (ml)  2547 (1300–4440)**      Early postoperative FEV1 (ml)  2144 (1110–4050)  P < 0.001 compared to **  0.86 (0.38–1.17)  Late postoperative FEV1 (ml)  2417 (1360–4390)  P = 0.011 compared to **  0.96 (0.72–1.58)  Preoperative FEV1% (%)  76.6 (61.9–91.0)***      Early postoperative FEV1% (%)  75.9 (60.1–91.0)  P = 0.459 compared to ***  0.99 (0.73–1.23)  Late postoperative FEV1% (%)  76.5 (60.1–95.6)  P = 0.929 compared to ***  1.00 (0.79–1.33)  *Refers to the comparison to preoperative VC. **Refers to the comparison to preoperative FEV1. ***Refers to the comparison to preoperative FEV1%. VC: vital capacity; FEV1: forced expiratory volume in 1 s; FEV1%: forced expiratory volume in 1 s/forced vital capacity. Of the 9 patients who refused the late postoperative test, the average early postoperative CRs of VC, FEV1 and FEV1% were 0.89, 0.87 and 1.00, respectively, which were similar to those of the other patients. Recurrence, multiple cancers and the survival As on 1 May 2017, no patients were lost to follow-up and no recurrence of previously resected pulmonary adenocarcinomas was observed. However, 5 metachronous multiple cancers were diagnosed (Supplementary material, Table S1). One patient died 37 months after pulmonary resection due to bladder cancer. Another patient was diagnosed with bladder cancer 23 months after surgery but was alive and showed no recurrence of lung cancer at 72 months after the first surgery. The other 3 patients suffered from another lung cancer, which was diagnosed as metachronous primary lung cancer according to the criteria of the protocol of this study [17]. Two of them had contralateral solitary pulmonary adenocarcinoma with no nodal involvement, and these patients underwent pulmonary resection again. The third patient had squamous cell carcinoma but did not undergo further surgical treatment and was still alive 76 months after pulmonary resection. During the follow-up period, 2 patients died. One died due to bladder cancer 37 months after surgery as described above, and the other died due to ileus 69 months after pulmonary surgery. Neither of the 2 patients had recurrence of lung cancer. The follow-up period of the living patients ranged from 60.0 to 126.3 (average 72.8) months. The 5-year disease-specific survival rate of all 53 eligible patients was 100%. Because there were no events during the observation period, neither the standard error nor the 95% confidence interval could be calculated. Both the 5-year overall and disease-free survival rates were 98.1% (Fig. 2). Figure 2: View largeDownload slide Survival curves of the patients in this study. DFS: disease-free survival; DSS: disease-specific survival; OS: overall survival. Figure 2: View largeDownload slide Survival curves of the patients in this study. DFS: disease-free survival; DSS: disease-specific survival; OS: overall survival. For the 6 patients treated by wedge resection, who had been intraoperatively diagnosed as bronchioloalveolar carcinoma but were ultimately diagnosed as adenocarcinoma with mixed subtype, neither recurrence nor death was observed at 62.1–99.7 months after wedge resection. In addition, we performed survival analyses of the 16 ineligible patients with resected lung cancer. During the observed follow-up period (61.2–97.5 months), neither recurrence nor death was observed, and the 5-year disease-specific, overall and disease-free survival were all 100%. DISCUSSION In Japan, many small-sized lung cancers with GGO have been detected by low-dose thoracic CT screening [1, 4–6]. Some of them had no stromal, vascular or pleural invasion and also had markedly longer doubling times than typical pulmonary adenocarcinomas [6, 19]. Those cancers were suggested as potential candidates for limited pulmonary resection because of their low invasiveness. However, a previous randomized trial clearly demonstrated that limited resection was not appropriate, even for cT1N0M0 tumours [7]. Therefore, consideration regarding candidacy for limited resection should be performed carefully. An intraoperative pathological diagnosis of having very small invasion would not be completely accurate [8, 20, 21], due to the difficulties of examining the deepest part of the invasion with limited condition of specimen processing. We had expected that several tumours in the eligible patients would be ultimately diagnosed as invasive adenocarcinomas, and we, therefore, had developed this protocol of the present study to include these misdiagnoses. Indeed, 6 of the 53 eligible patients were ultimately diagnosed as having adenocarcinoma with mixed subtype. Although our protocol permitted additional completion lobectomy when the ultimate pathological diagnosis was invasive adenocarcinoma, no patients in this study underwent additional surgery. Even without additional surgery, no recurrence was observed in these 6 patients during the observed period. Although HR-CT findings have a good correlation with the tumour invasiveness, some reports have shown that a non-negligible number of invasive cancers can slip through this check, even in pure GGO cases [8, 9, 22]. As described earlier, an intraoperative pathological examination of small invasion was not completely accurate [8, 20, 21]. Because the survival rate of the patients having lung cancer with GGO would be expected to be very high after lobectomy, we tried to decrease the risk of recurrence in this trial as much as possible. In the previous studies, FDG-PET provides metabolic information on pulmonary lesions. Due to this property, FDG-PET findings of bronchioloalveolar carcinoma have many false-negative results for the diagnosis of the malignancy. However, when limited to the cancer cases, the FDG accumulation correlated well with invasive ability even in small-sized adenocarcinomas [12–15]. Therefore, we set these strict criteria, including a GGO ratio ≥80%, a Grade 1 FDG accumulation and an intraoperative pathological diagnosis of bronchioloalveolar carcinoma. We considered the tumours that met these criteria to be largely non-invasive cancers that could be expected not to recur after complete resection, even by wedge resection. However, such tumours are rare, and thus we were unable to collect a sufficient number of cases for a randomized trial, even as a multi-institutional study. We therefore conducted this trial as a single-arm prospective trial. The average postoperative CRs of both VC and FEV1 in the early postoperative phase were 0.86, and those in the late postoperative phase were 0.96, which indicated that the reduction of pulmonary function by limited resection was minimal. The 5-year disease specific and overall survival rates were 100% and 98.1%, respectively. Because of the lack of any events during the observation period, neither the standard error nor the 95% confidence interval could be calculated. With the censored cases, the 10-year disease-specific survival was also 100%. There have already been several articles reporting good prognoses of the patients who underwent limited resection for lung cancers with GGO [8, 21–23]. However, most of the previous reports were not prospective studies but retrospective analyses of case series. Even compared with these reports, the prognoses of our patients were excellent. Moreover, the follow-up periods of all patients in our study were 5 years or more, whereas that of some patients in all of the previous reports did not reach 5 years. Our results were more definite than the previous ones and indicate that the patients who meet the criteria of the protocol do not need pulmonary lobectomy, and limited resection, mainly wedge resection, is sufficient. There are several issues to be discussed. First, a 3-point visual grading system was used to interpret the FDG uptake within the primary lesions, and the standard uptake value (SUV) threshold was not used. The SUV is affected by many factors [24, 25], and there have been some reports that a visual scale was as accurate as using an SUV threshold [26]. It is well known that the SUV value of a tumour measured by a PET camera is different from the SUV value of the same tumour measured by another PET camera. Because many kinds of PET cameras were used in different hospitals for this study, a visual scale was found to be more adequate. Second, to exclude invasive cancers from this study as much as possible, the criteria used in this study were very strict. Although a non-negligible number of invasive cancers slipped through HR-CT in the previous reports [8, 9, 22], more appropriate criteria of interpretation of HR-CT findings should be established [27]. The intraoperative pathological diagnosis and the interpretation of FDG-PET findings should also be investigated. Third, on the other hand, pulmonary adenocarcinoma with minimal invasion can be a suitable target for the subsequent studies of pulmonary wedge resection [28]. Indeed, by the additional survival analyses of 14 ineligible patients in this study, who underwent pulmonary resection (9 wedge only and 5 lobectomy) for adenocarcinoma with mixed subtype, were also excellent, even though some cases received only wedge resection. The number of patients in this study was very limited, and further studies with more patients will be required. Fourth, the follow-up period of all patients were 60 months or over, which indicated that the results within 60 months after surgery were definite. However, there have been some reports of recurrence beyond 60 months [29], due to long doubling time of such tumours, and we should follow these patients with caution. Judging from our one patient who needed another wedge resection even with 1 cm margin of visual evaluation, intraoperative cytological/histological assessment of surgical margin might be useful, especially with approximate 1 cm margin. Fifth, the pulmonary adenocarcinomas with GGO sometimes have very long doubling time, and there are some possibilities of overdiagnosis [30]. In our 53 patients, the tumours of the 47 patients were bronchioloalveolar carcinomas without invasion, which were ‘adenocarcinomas in situ’ in the fourth edition of histological typing published by the World Health Organization. It has not been elucidated as to what kind of adenocarcinomas in situ would develop to a life-threatening cancer, and some of our cases might be an overdiagnosis. However, of the 72 preregistered patients in this study, who were eligible by preoperative information only, 20 patients (6 of 53 eligible patients and 14 of 16 ineligible patients) had adenocarcinomas with mixed subtype, and they were rarely overdiagnosed. The maximum diameter of some invasive tumours was only 9 mm. At present, we cannot distinguish these invasive cancers from adenocarcinomas in situ preoperatively. Further studies are required about overdiagnosis of such tumours. CONCLUSION This report described the results of a multi-institutional prospective study on limited resection of lung cancer with GGO using HR-CT, PET findings and intraoperative pathological examination. Although the number of patients in this study was limited, the results were informative. With these criteria, limited resection was performed safely without any recurrence, and the postoperative pulmonary function was well preserved. The outcomes of limited resection for small-sized lung cancer with GGOs that met the criteria of this study were satisfactory. Further studies are awaited to increase the number of eligible candidates for wedge resection. SUPPLEMENTARY MATERIAL Supplementary material is available at EJCTS online. ACKNOWLEDGEMENTS We are grateful to Yuko Ito for her assistance and to Keisuke Fukui (biostatistician) of the Department of Cancer Epidemiology and Prevention, Osaka International Cancer Institute, Japan, for his advice concerning the statistical analyses. We are also grateful to Mitsunori Yamakawa, Yuko Hashimoto, Kazuyuki Ishida, Yoshimasa Nakazato, Naoki Yanagawa, Ikuro Sato, Hiroyoshi Suzuki, Hidekachi Kurotaki for their contribution to the pathological assessment. Funding This research was partially supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan [17H04125]. Conflict of interest: none declared. REFERENCES 1 Kaneko M, Eguchi K, Ohmatsu H, Kakinuma R, Naruke T, Suemasu K et al.   Peripheral lung cancer: screening and detection with low-dose spiral CT versus radiography. Radiology  1996; 201: 798– 802. Google Scholar CrossRef Search ADS PubMed  2 Henschke CI, Yankelevitz DF, Libby DM, Pasmantier MW, Smith JP, Miettinen OS. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med  2006; 355: 1763– 71. Google Scholar CrossRef Search ADS PubMed  3 The National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med  2011; 365: 395– 409. CrossRef Search ADS PubMed  4 Asamura H, Suzuki K, Watanabe S, Matsuno Y, Maeshima A, Tsuchiya R. A clinicopathological study of resected subcentimeter lung cancers: a favorable prognosis for ground glass opacity lesions. Ann Thorac Surg  2003; 76: 1016– 22. Google Scholar CrossRef Search ADS PubMed  5 Sakurai H, Dobashi Y, Mizutani E, Matsubara H, Suzuki S, Takano K et al.   Bronchioloalveolar carcinoma of the lung 3 centimeters or less in diameter: a prognostic assessment. Ann Thorac Surg  2004; 78: 1728– 33. Google Scholar CrossRef Search ADS PubMed  6 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. Google Scholar CrossRef Search ADS PubMed  7 Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1N0 non-small cell lung cancer. Ann Thorac Surg  1995; 60: 615– 23. Google Scholar CrossRef Search ADS PubMed  8 Ohtaka K, Hida Y, Kaga K, Kato T, Muto J, Nakada-Kubota R et al.   Limited resection and two-staged lobectomy for non-small cell lung cancer with ground-glass opacity. J Cardiothorac Surg  2013; 8: 111. Google Scholar CrossRef Search ADS PubMed  9 Si MJ, Xiao-Feng Tao XF, Du GY, Cai LL, Han HX, Liang XZ et al.   Thin-section computed tomography-histopathologic comparisons of pulmonary focal interstitial fibrosis, atypical adenomatoushyperplasia, adenocarcinoma in situ, and minimally invasive adenocarcinoma with pure ground-glass opacity. Eur J Radiol  2016; 85: 1708– 15. Google Scholar CrossRef Search ADS PubMed  10 Vesselle H, Schmidt RA, Pugsley JM, Li M, Kohlmyer SG, Vallires E et al.   Lung cancer proliferation correlates with [F-18]fluorodeoxyglucose uptake by positron emission tomography. Clin Cancer Res  2000; 6: 3837– 44. Google Scholar PubMed  11 Higashi K, Ueda Y, Yagishita M, Arisaka Y, Sakurai A, Oguchi M et al.   FDG PET measurement of the proliferative potential on non-small cell lung cancer. J Nucl Med  2000; 41: 85– 92. Google Scholar PubMed  12 Higashi K, Ueda Y, Seki H, Yuasa K, Oguchi M, Noguchi T et al.   Fluorine-18-FDG PET imaging is negative in bronchioloalveolar lung carcinoma. J Nucl Med  1998; 39: 1016– 20. Google Scholar PubMed  13 Sagawa M, Higashi K, Sugita M, Ueda Y, Maeda S, Toga H et al.   Fluorodeoxyglucose uptake correlates with the growth pattern of small pripheral pulmonary adenocarcinoma. Surg Today  2006; 36: 230– 4. Google Scholar CrossRef Search ADS PubMed  14 Maeda R, Isowa N, Onuma H, Miura H, Harada T, Touge H et al.   The maximum standardized uptake values on positron emission tomography to predict the Noguchi classification and invasiveness in clinical stage IA adenocarcinoma measuring 2 cm or less in size. Interact CardioVasc Thorac Surg  2009; 9: 70– 3. Google Scholar CrossRef Search ADS PubMed  15 Tsunezuka Y, Shimizu Y, Tanaka N, Takayanagi T, Kawano M. Positron emission tomography in relation to Noguchi’s classification for diagnosis of peripheral non-small-cell lung cancer 2 cm or less in size. World J Surg  2007; 31: 314– 7. Google Scholar CrossRef Search ADS PubMed  16 Sagawa M, Higashi K, Usuda K, Aikawa H, Machida Y, Tanaka M et al.   Curative wedge resection for non-invasive bronchioloalveolar carcinoma. Tohoku J Exp Med  2009; 217: 133– 7. Google Scholar CrossRef Search ADS PubMed  17 Cortese DA, Pairolero PC, Bergstralh EJ, Woolner LB, Uhlenhopp MA, Piehler JM et al.   Roentgenographically occult lung cancer. a ten-year experience. J Thorac Cardiovasc Surg  1983; 86: 373– 80. Google Scholar PubMed  18 Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant  2013; 48: 452– 8. Google Scholar CrossRef Search ADS PubMed  19 Aoki T, Nakata H, Watanabe H, Nakamura K, Kasai T, Hashimoto H et al.   Evolution of peripheral lung adenocarcinomas: CT findings correlated with histology and tumor doubling time. AJR Am J Roentgenol  2000; 174: 763– 8. Google Scholar CrossRef Search ADS PubMed  20 He P, Yao G, Guan Y, Lin Y, He J. Diagnosis of lung adenocarcinoma in situ and minimally invasive adenocarcinoma from intraoperative frozen sections: an analysis of 136 cases. J Clin Pathol  2016; 69: 1076– 80. Google Scholar CrossRef Search ADS PubMed  21 Koike T, Togashi K, Shirato T, Sato S, Hirahara H, Sugawara M et al.   Limited resection for noninvasive bronchioloalveolar carcinoma diagnosed by intraoperative pathologic examination. Ann Thorac Surg  2009; 88: 1106– 11. Google Scholar CrossRef Search ADS PubMed  22 Nakata M, Sawada S, Saeki H, Takashima S, Mogami H, Teramoto N et al.   Prospective study of thoracoscopic limited resection for ground-glass opacity selected by computed tomography. Ann Thorac Surg  2003; 75: 1601-6. Google Scholar CrossRef Search ADS   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. Google Scholar CrossRef Search ADS PubMed  24 Keyes J. SUV: standard uptake or silly useless value? J Nucl Med  1995; 36: 1836– 9. Google Scholar PubMed  25 Chin BB, Lyengar S, Sabundayo BP, Schwartz D. Standardized uptake values in 2-deoxy-2-[18F]Fluoro-d-glucose with positron emission tomography. Mol Imaging Biol  2002; 4: 294– 300. Google Scholar CrossRef Search ADS PubMed  26 Vansteenkiste JF, Stroobants SG, De Leyn PR, Dupont PJ, Bogaert J, Maes A et al.   Lymph node staging in non-small-cell lung cancer with FDG-PET scan: a prospective study on 690 lymph node stations from 68 patients. J Clin Oncol  1998; 16: 2142– 9. Google Scholar CrossRef Search ADS PubMed  27 Suzuki K, Koike T, Asakawa T, Kusumoto M, Asamura H, Nagai K et al.   A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer: JCOG0201. J Thorac Oncol  2011; 6: 751– 6. Google Scholar CrossRef Search ADS PubMed  28 Yoshida J, Ishii G, Hishida T, Aokage K, Tsuboi M, Ito H et al.   Limited resection trial for pulmonary ground-glass opacity nodules: case selection based on high-resolution computed tomography—interim results. JJCO  2015; 45: 677– 81. Google Scholar PubMed  29 Nakao M, Yoshida J, Goto K, Ishii G, Kawase A, Aokage K et al.   Long-term outcomes of 50 cases of limited-resection trial for pulmonary ground-glass opacity nodules. J Thorac Oncol  2012; 7: 1563– 6. Google Scholar CrossRef Search ADS PubMed  30 Marcus PM, Prorok PC, Miller AB, DeVoto EJ, Kramer BS. Conceptualizing overdiagnosis in cancer screening. J Natl Cancer Inst  2015; 107: djv014. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Cardio-Thoracic Surgery Oxford University Press

Loading next page...
 
/lp/ou_press/a-prospective-5-year-follow-up-study-after-limited-resection-for-lung-0vd0Hz10es
Publisher
Oxford University Press
ISSN
1010-7940
eISSN
1873-734X
D.O.I.
10.1093/ejcts/ezx418
Publisher site
See Article on Publisher Site

Abstract

Abstract OBJECTIVES The incidence of small-sized pulmonary adenocarcinomas with ground-glass opacity (GGO) has recently increased, with excellent postoperative prognosis. The limited resection of such cancers has been deemed to be acceptable based on retrospective studies. We conducted a prospective multi-institutional study evaluating the validity of limited resection for small-sized pulmonary adenocarcinoma with GGO. METHODS The inclusion criteria were 25–80 years of age, no prior treatment, a maximum tumour diameter of 8–20 mm, a GGO ratio of ≥ 80%, clinical T1N0M0, lower 18F-fluorodeoxyglucose accumulation than the mediastinum, resectable by sublobar resection, pulmonary lobectomy tolerable and an intraoperative pathological diagnosis of bronchiloalveolar carcinoma. Wedge resection was preferred, but segmentectomy was permitted. Disease-specific survival and overall survival were analysed. RESULTS From November 2006 to April 2012, 73 patients were enrolled from 13 institutions. One patient was ineligible, and the remaining 72 patients were preregistered. The tumours of 3 and 14 patients were intraoperatively diagnosed as benign lesions and adenocarcinomas with mixed subtype, respectively. Intraoperative cytological/histological examination of surgical margin was not performed in 2 patients, and the remaining 53 patients were ultimately eligible for this study. The mean tumour size was 14.0 mm and the mean GGO ratio was 95.9%. Thirty-nine and 14 patients underwent wedge resection and segmentectomy, respectively. Although all tumours were intraoperatively diagnosed as bronchioloalveolar carcinomas, 6 were ultimately diagnosed as adenocarcinoma with a mixed subtype. No completion lobectomy was performed. As of 1 May 2017, no recurrence of the original lung cancer was observed during 60.0–126.3 months after surgery. Two patients died from other diseases. The 5-year disease-specific and overall survival rates were 100% and 98.1%, respectively. The reduction in the pulmonary function after limited resection was minimal. CONCLUSIONS With these criteria, limited resection was performed safely without any recurrence, and the postoperative pulmonary function was well preserved. The outcomes of limited resection for small-sized lung cancer with GGOs that met the criteria of this study were satisfactory. Lung cancer, Adenocarcinoma, Ground-glass opacity, Limited resection, Prospective study INTRODUCTION Lung cancer screening using low-dose thoracic computed tomography (CT) has been performed since the 1990s and has gradually spread globally [1, 2]. Recently, the National Lung Screening Trial reported the efficacy of CT screening for lung cancer in heavy smokers [3], and several other studies on the efficacy of CT screening are being conducted. With CT screening, many small-sized lung cancers with ground-glass opacity (GGO) are detected, some of which have been reported to have an excellent postoperative prognosis [4, 5]. In 1995, Noguchi et al. [6] reported a new classification system for small-sized adenocarcinomas, and the 5-year postoperative survival rate of patients with resected Noguchi’s Type A (localized bronchioloalveolar carcinoma) and Type B (localized bronchioloalveolar carcinoma with foci of structural collapse of alveoli) adenocarcinomas was 100%. Noguchi’s Type A/B adenocarcinomas were almost equal to bronchioloalveolar carcinomas in the third edition of histological typing published by the World Health Organization. The radiological findings of these adenocarcinomas revealed small-sized lung tumours with GGO as a dominant part. In Japan, many lung tumours with GGO suspected of being bronchioloalveolar carcinomas have been detected on thoracic CT screening [1, 4–6]. Generally, the standard surgical procedure for lung cancer, even for small-sized lung cancer, is pulmonary lobectomy with hilar and mediastinal nodal dissection, based on the results of a randomized controlled trial in which the patients treated with limited resection for cT1N0M0 peripheral lung cancer had a worse prognosis than those treated with pulmonary lobectomy and nodal dissection [7]. However, bronchioloalveolar carcinomas have a low invasive potential [6], and patients with such carcinomas might be candidates for limited pulmonary resection. Since the pathological diagnosis of bronchioloalveolar carcinoma is based on the histological findings of formalin-fixed paraffin-embedded specimen, selecting appropriate candidates preoperatively is not easy. Even lung cancers with GGO occasionally include invasive adenocarcinomas, and chest CT findings alone cannot distinguish the invasive carcinomas from the non-invasive ones [8, 9]. Positron emission tomography imaging with 18F-fluorodeoxyglucose (FDG-PET) provides metabolic information on pulmonary nodules [10, 11]. FDG-PET findings are helpful for the discrimination of non-invasive carcinomas from the invasive ones [11, 12]. Several investigators including us reported that FDG accumulation related invasive ability of pulmonary adenocarcinomas [12–15]. If a combination of chest CT and FDG-PET findings enables the selection of more biologically inactive cancers, then wedge resection might be an appropriate treatment for such tumours. We previously reported a pilot study on wedge resection for small-sized pulmonary adenocarcinomas, in which the criteria for limited resection candidacy were determined [16]. To elucidate the validity of limited pulmonary resection for small-sized pulmonary adenocarcinomas with GGO, we started a multi-institutional prospective study in 2006 (JNETS 0601). As the follow-up periods of all the registered cases in the study reached 60 months, we evaluated the validity of this therapeutic strategy. PATIENTS AND METHODS Setting This study was a single-arm multi-institutional prospective trial. For this trial, preregistration was required before surgical resection. This protocol was approved by the Institutional Review Board in Kanazawa Medical University in 2006 and registered in the University Hospital Medical Information Network Clinical Trial Registration System, Japan (registration number: UMIN000005908). The details are available at https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi? recptno=R000006980. Mandatory examination High-resolution CT (HR-CT) of the chest field and FDG-PET were mandatory. The maximum diameters of the GGO and the consolidation were measured on the axial lung window image on HR-CT. The GGO ratio was calculated using the following equation: GGO ratio = [(maximum diameter of the tumour) – (maximum diameter of consolidation)]/(maximum diameter of the tumour). The FDG accumulation was classified into 3 grades based on a visual evaluation: Grade 2 was equivalent to the accumulation in the mediastinum, while Grade 1 was lower accumulation and Grade 3 higher accumulation. Other examinations required for pulmonary lobectomy, such as pulmonary function, electrocardiogram and ordinary blood tests, were also performed. Preregistration The inclusion criteria for preregistration were determined as follows from the results of our previous study [16]: 25–80 years of age Adenocarcinoma or suspected adenocarcinoma No prior treatment Maximum diameter of 8–20 mm GGO ratio of ≥80% Clinical T1N0M0 (UICC TNM classification, sixth edition) Grade 1 of FDG accumulation Complete resection of the tumour possible with sublobar resection Pulmonary lobectomy tolerable for the patient Given written informed consent The exclusion criteria for preregistration were as follows: Patients with any other cancer within the past 5 years Patients with severe complications Transthoracic CT-guided needle biopsy was not mandatory because of the possibility of pleural dissemination of cancer cells. After informed consent was obtained, a case report form for preregistration was faxed to the central registration centre. At the central registration centre, the inclusion/exclusion criteria were checked, and a preregistration number was faxed to the local hospital. Surgical resection, registration and post-surgical therapy At the local hospital, surgical resection was performed after receiving a fax of the preregistration number. Video-assisted thoracic surgery was preferred but was not mandatory, as maintaining a wide margin (at least 10 mm) with the tumour was considered more important. For pulmonary resection, wedge resection was basically performed, but segmentectomy was accepted when the margin was not wide enough. After wedge resection/segmentectomy, an intraoperative pathological examination with frozen sections was performed. Only cases diagnosed as bronchioloalveolar carcinomas on this intraoperative pathological examination were eligible, and others, such as benign diseases, non-adenocarcinomas or adenocarcinomas with mixed subtype, were considered ineligible. An intraoperative cytological/histological examination of the surgical margin was also performed. When the cytology/histology of the surgical margin was positive, then an additional wedge resection or segmentectomy was performed. If the re-evaluation of the surgical margin was negative, then the case was regarded as eligible. If lobectomy was needed, the cases were considered ineligible. Since the eligibility evaluation and registration of this study was completed intraoperatively, even if a tumour was diagnosed as invasive adenocarcinoma with mixed subtype at the ultimate pathological diagnosis, the case was not excluded from the study. In cases where the ultimate diagnosis was adenocarcinoma with mixed subtype, despite an intraoperative diagnosis of bronchioloalveolar carcinoma, the option of completion lobectomy was permitted if the patient needed this surgery. Other post-surgical therapies were not permitted until recurrence was confirmed pathologically or radiologically. Pulmonary function The vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and FEV1/FVC (FEV1%) were basically evaluated 3 times: preoperatively, early postoperatively (within 3 months after surgery) and late postoperatively (approximately 1 year after surgery). The postoperative changing rates (CRs) were calculated with the following formulae: Early postoperative-CR-VC = (Early postoperative-VC/ Preoperative-VC), Late postoperative-CR-VC = (Late postoperative-VC/ Preoperative-VC). For the FEV1 and FEV1%, the early postoperative-CR and late postoperative-CR were calculated similarly. Follow-up and recurrence Follow-up was performed at least once a year at the local hospital. In cases where a subsequent tumour was detected during the follow-up period, it could be difficult to determine whether the subsequent neoplasm was a recurrence of the original tumour or a second primary lung cancer. In the protocol of this study, second primary lung cancer was basically defined in accordance with the definition by Cortese et al. [17] when (i) the subsequent tumour had a different histological type from the original cancer or (ii) the subsequent tumour had a similar histological type to the original cancer but was a solitary tumour without any extrathoracic metastases and no carcinoma was found in the lymphatics at common to both cancers. Otherwise, the subsequent tumour was considered to be recurrence of the original cancer. End points and statistical analyses The main objective of this study was to prospectively investigate the validity of limited resection for patients having lung cancer with GGO in terms of the 5-year disease-specific survival. The secondary end points were the overall survival, the disease-free survival, the mode of recurrence and the change in the pulmonary function. The survival was calculated from the day of pulmonary resection to the day of event. The survival analyses were planned to be conducted 60 months after pulmonary resection in all eligible patients. The sample size was calculated as follows. The disease-specific 5-year survival rates of the patients who underwent pulmonary lobectomy among those who met the criteria of this study were assumed to be 98%. Because the postoperative pulmonary function of the patients who underwent limited resection was assumed to be better than that in those who underwent pulmonary lobectomy, the non-inferiority margin at 5 years was set at 8%. With an alpha error of 0.05 and a power of 0.80, and with some dropout cases expected, 53 registered cases were needed for this study. The survival rates were calculated by the Kaplan–Meier method. Paired t-test was used to compare the pulmonary function. All statistical analyses were calculated with the EZR software program on R commander [18]. A P-value of <0.05 was regarded as statistically significant. RESULTS Preregistration and registration From November 2006 to April 2012, a total of 73 patients were prospectively enrolled from 13 institutions (Fig. 1). One patient was ineligible for preregistration criteria, and the remaining 72 patients were preregistered. Figure 1: View largeDownload slide Flow chart of the patients in this study. FDG: 18F-fluorodeoxyglucose. Figure 1: View largeDownload slide Flow chart of the patients in this study. FDG: 18F-fluorodeoxyglucose. All 72 patients underwent sublobar pulmonary resection. The tumours of 3 patients were intraoperatively diagnosed as benign lesions, and the tumours of 14 patients were diagnosed as adenocarcinomas with mixed subtype. Intraoperative cytological/histological examination of surgical margin was not performed in 2 patients, so they were regarded as ineligible. Of the remaining 53 patients, intraoperative examination of surgical margin in 1 patient was positive for cancer cells. After another wedge resection in the patient, a re-evaluation of the surgical margin was found to be negative for cancer cells, and therefore the patient was considered eligible. These 53 patients were ultimately regarded as eligible. Of the 19 ineligible patients, 16 underwent pulmonary resection of lung cancer (2 cases of wedge resection without an intraoperative evaluation of surgical margin, 9 cases of adenocarcinomas with mixed subtype after wedge resections and 5 cases of adenocarcinomas with mixed subtype after lobectomy conversion). They were also followed up and additionally analysed. Patient characteristics The patient characteristics are listed in Table 1. There were 25 men and 28 women, and the mean age was 61.7 years. The mean tumour size was 14.0 mm, and the mean GGO ratio was 95.9%. Over 90% of cases underwent pulmonary resection under video-assisted thoracic surgery. Thirty-nine and 14 patients underwent wedge resections and segmentectomies, respectively. Table 1: Characteristics of the eligible patients (n = 53)   Number of patients  Gender     Male  25   Female  28  Age (years)     30–39  2   40–49  5   50–59  15   60–69  19   70–79  12  Maximum diameter (mm)     8–10  9   11–15  25   16–20  19  Ground-glass opacity ratio (%)     80–89  12   90–99  2   100  39  Approach     Video-assisted thoracic surgery  48   Open thoracotomy  5  Surgical procedure     Wedge resection  39   Segmentectomy  14  Re-resection     Done  1   Not done  52  Postoperative diagnosis     Bronchioloalveolar carcinoma  47   Adenocarcinoma with mixed subtype  6    Number of patients  Gender     Male  25   Female  28  Age (years)     30–39  2   40–49  5   50–59  15   60–69  19   70–79  12  Maximum diameter (mm)     8–10  9   11–15  25   16–20  19  Ground-glass opacity ratio (%)     80–89  12   90–99  2   100  39  Approach     Video-assisted thoracic surgery  48   Open thoracotomy  5  Surgical procedure     Wedge resection  39   Segmentectomy  14  Re-resection     Done  1   Not done  52  Postoperative diagnosis     Bronchioloalveolar carcinoma  47   Adenocarcinoma with mixed subtype  6  Pathological diagnoses The intraoperative pathological diagnoses of all tumours were bronchioloalveolar carcinomas (16 Noguchi’s Type A adenocarcinomas and 37 Type B). The ultimate diagnoses of the tumours were bronchioloalveolar carcinomas in 47 patients and adenocarcinomas with a mixed subtype in 6 patients (Table 1). All patients were staged as pathological T1N0M0, Stage IA. For all 6 cases of resected adenocarcinomas with mixed subtype, the patients and surgeons in charge discussed completion lobectomy, and all of them decided not to undergo additional surgery. Changes in pulmonary function Preoperative and early postoperative pulmonary function tests were performed in all 53 eligible patients, but 9 patients refused the late postoperative test. The changes in the pulmonary function were compared in the remaining 44 cases. The VC, FEV1, FEV1% and postoperative CR are listed in Table 2. Although both the early postoperative and the late postoperative VC and FEV1 were significantly smaller than the preoperative VC and FEV1, the average late postoperative CRs of both VC and FEV1 were 0.96, and the reduction was only 4%. FEV1% was similar, regardless of the period examined. Table 2: Changes in the pulmonary function (n = 44)   Average value (range)  Paired t-test  Average postoperative changing rate (range)  Preoperative VC (ml)  3351 (1800–5500)*      Early postoperative VC (ml)  2830 (1510–4910)  P < 0.001 compared to *  0.86 (0.41–1.01)  Late postoperative VC (ml)  3178 (1740–5450)  P = 0.002 compared to *  0.96 (0.66–1.14)  Preoperative FEV1 (ml)  2547 (1300–4440)**      Early postoperative FEV1 (ml)  2144 (1110–4050)  P < 0.001 compared to **  0.86 (0.38–1.17)  Late postoperative FEV1 (ml)  2417 (1360–4390)  P = 0.011 compared to **  0.96 (0.72–1.58)  Preoperative FEV1% (%)  76.6 (61.9–91.0)***      Early postoperative FEV1% (%)  75.9 (60.1–91.0)  P = 0.459 compared to ***  0.99 (0.73–1.23)  Late postoperative FEV1% (%)  76.5 (60.1–95.6)  P = 0.929 compared to ***  1.00 (0.79–1.33)    Average value (range)  Paired t-test  Average postoperative changing rate (range)  Preoperative VC (ml)  3351 (1800–5500)*      Early postoperative VC (ml)  2830 (1510–4910)  P < 0.001 compared to *  0.86 (0.41–1.01)  Late postoperative VC (ml)  3178 (1740–5450)  P = 0.002 compared to *  0.96 (0.66–1.14)  Preoperative FEV1 (ml)  2547 (1300–4440)**      Early postoperative FEV1 (ml)  2144 (1110–4050)  P < 0.001 compared to **  0.86 (0.38–1.17)  Late postoperative FEV1 (ml)  2417 (1360–4390)  P = 0.011 compared to **  0.96 (0.72–1.58)  Preoperative FEV1% (%)  76.6 (61.9–91.0)***      Early postoperative FEV1% (%)  75.9 (60.1–91.0)  P = 0.459 compared to ***  0.99 (0.73–1.23)  Late postoperative FEV1% (%)  76.5 (60.1–95.6)  P = 0.929 compared to ***  1.00 (0.79–1.33)  *Refers to the comparison to preoperative VC. **Refers to the comparison to preoperative FEV1. ***Refers to the comparison to preoperative FEV1%. VC: vital capacity; FEV1: forced expiratory volume in 1 s; FEV1%: forced expiratory volume in 1 s/forced vital capacity. Of the 9 patients who refused the late postoperative test, the average early postoperative CRs of VC, FEV1 and FEV1% were 0.89, 0.87 and 1.00, respectively, which were similar to those of the other patients. Recurrence, multiple cancers and the survival As on 1 May 2017, no patients were lost to follow-up and no recurrence of previously resected pulmonary adenocarcinomas was observed. However, 5 metachronous multiple cancers were diagnosed (Supplementary material, Table S1). One patient died 37 months after pulmonary resection due to bladder cancer. Another patient was diagnosed with bladder cancer 23 months after surgery but was alive and showed no recurrence of lung cancer at 72 months after the first surgery. The other 3 patients suffered from another lung cancer, which was diagnosed as metachronous primary lung cancer according to the criteria of the protocol of this study [17]. Two of them had contralateral solitary pulmonary adenocarcinoma with no nodal involvement, and these patients underwent pulmonary resection again. The third patient had squamous cell carcinoma but did not undergo further surgical treatment and was still alive 76 months after pulmonary resection. During the follow-up period, 2 patients died. One died due to bladder cancer 37 months after surgery as described above, and the other died due to ileus 69 months after pulmonary surgery. Neither of the 2 patients had recurrence of lung cancer. The follow-up period of the living patients ranged from 60.0 to 126.3 (average 72.8) months. The 5-year disease-specific survival rate of all 53 eligible patients was 100%. Because there were no events during the observation period, neither the standard error nor the 95% confidence interval could be calculated. Both the 5-year overall and disease-free survival rates were 98.1% (Fig. 2). Figure 2: View largeDownload slide Survival curves of the patients in this study. DFS: disease-free survival; DSS: disease-specific survival; OS: overall survival. Figure 2: View largeDownload slide Survival curves of the patients in this study. DFS: disease-free survival; DSS: disease-specific survival; OS: overall survival. For the 6 patients treated by wedge resection, who had been intraoperatively diagnosed as bronchioloalveolar carcinoma but were ultimately diagnosed as adenocarcinoma with mixed subtype, neither recurrence nor death was observed at 62.1–99.7 months after wedge resection. In addition, we performed survival analyses of the 16 ineligible patients with resected lung cancer. During the observed follow-up period (61.2–97.5 months), neither recurrence nor death was observed, and the 5-year disease-specific, overall and disease-free survival were all 100%. DISCUSSION In Japan, many small-sized lung cancers with GGO have been detected by low-dose thoracic CT screening [1, 4–6]. Some of them had no stromal, vascular or pleural invasion and also had markedly longer doubling times than typical pulmonary adenocarcinomas [6, 19]. Those cancers were suggested as potential candidates for limited pulmonary resection because of their low invasiveness. However, a previous randomized trial clearly demonstrated that limited resection was not appropriate, even for cT1N0M0 tumours [7]. Therefore, consideration regarding candidacy for limited resection should be performed carefully. An intraoperative pathological diagnosis of having very small invasion would not be completely accurate [8, 20, 21], due to the difficulties of examining the deepest part of the invasion with limited condition of specimen processing. We had expected that several tumours in the eligible patients would be ultimately diagnosed as invasive adenocarcinomas, and we, therefore, had developed this protocol of the present study to include these misdiagnoses. Indeed, 6 of the 53 eligible patients were ultimately diagnosed as having adenocarcinoma with mixed subtype. Although our protocol permitted additional completion lobectomy when the ultimate pathological diagnosis was invasive adenocarcinoma, no patients in this study underwent additional surgery. Even without additional surgery, no recurrence was observed in these 6 patients during the observed period. Although HR-CT findings have a good correlation with the tumour invasiveness, some reports have shown that a non-negligible number of invasive cancers can slip through this check, even in pure GGO cases [8, 9, 22]. As described earlier, an intraoperative pathological examination of small invasion was not completely accurate [8, 20, 21]. Because the survival rate of the patients having lung cancer with GGO would be expected to be very high after lobectomy, we tried to decrease the risk of recurrence in this trial as much as possible. In the previous studies, FDG-PET provides metabolic information on pulmonary lesions. Due to this property, FDG-PET findings of bronchioloalveolar carcinoma have many false-negative results for the diagnosis of the malignancy. However, when limited to the cancer cases, the FDG accumulation correlated well with invasive ability even in small-sized adenocarcinomas [12–15]. Therefore, we set these strict criteria, including a GGO ratio ≥80%, a Grade 1 FDG accumulation and an intraoperative pathological diagnosis of bronchioloalveolar carcinoma. We considered the tumours that met these criteria to be largely non-invasive cancers that could be expected not to recur after complete resection, even by wedge resection. However, such tumours are rare, and thus we were unable to collect a sufficient number of cases for a randomized trial, even as a multi-institutional study. We therefore conducted this trial as a single-arm prospective trial. The average postoperative CRs of both VC and FEV1 in the early postoperative phase were 0.86, and those in the late postoperative phase were 0.96, which indicated that the reduction of pulmonary function by limited resection was minimal. The 5-year disease specific and overall survival rates were 100% and 98.1%, respectively. Because of the lack of any events during the observation period, neither the standard error nor the 95% confidence interval could be calculated. With the censored cases, the 10-year disease-specific survival was also 100%. There have already been several articles reporting good prognoses of the patients who underwent limited resection for lung cancers with GGO [8, 21–23]. However, most of the previous reports were not prospective studies but retrospective analyses of case series. Even compared with these reports, the prognoses of our patients were excellent. Moreover, the follow-up periods of all patients in our study were 5 years or more, whereas that of some patients in all of the previous reports did not reach 5 years. Our results were more definite than the previous ones and indicate that the patients who meet the criteria of the protocol do not need pulmonary lobectomy, and limited resection, mainly wedge resection, is sufficient. There are several issues to be discussed. First, a 3-point visual grading system was used to interpret the FDG uptake within the primary lesions, and the standard uptake value (SUV) threshold was not used. The SUV is affected by many factors [24, 25], and there have been some reports that a visual scale was as accurate as using an SUV threshold [26]. It is well known that the SUV value of a tumour measured by a PET camera is different from the SUV value of the same tumour measured by another PET camera. Because many kinds of PET cameras were used in different hospitals for this study, a visual scale was found to be more adequate. Second, to exclude invasive cancers from this study as much as possible, the criteria used in this study were very strict. Although a non-negligible number of invasive cancers slipped through HR-CT in the previous reports [8, 9, 22], more appropriate criteria of interpretation of HR-CT findings should be established [27]. The intraoperative pathological diagnosis and the interpretation of FDG-PET findings should also be investigated. Third, on the other hand, pulmonary adenocarcinoma with minimal invasion can be a suitable target for the subsequent studies of pulmonary wedge resection [28]. Indeed, by the additional survival analyses of 14 ineligible patients in this study, who underwent pulmonary resection (9 wedge only and 5 lobectomy) for adenocarcinoma with mixed subtype, were also excellent, even though some cases received only wedge resection. The number of patients in this study was very limited, and further studies with more patients will be required. Fourth, the follow-up period of all patients were 60 months or over, which indicated that the results within 60 months after surgery were definite. However, there have been some reports of recurrence beyond 60 months [29], due to long doubling time of such tumours, and we should follow these patients with caution. Judging from our one patient who needed another wedge resection even with 1 cm margin of visual evaluation, intraoperative cytological/histological assessment of surgical margin might be useful, especially with approximate 1 cm margin. Fifth, the pulmonary adenocarcinomas with GGO sometimes have very long doubling time, and there are some possibilities of overdiagnosis [30]. In our 53 patients, the tumours of the 47 patients were bronchioloalveolar carcinomas without invasion, which were ‘adenocarcinomas in situ’ in the fourth edition of histological typing published by the World Health Organization. It has not been elucidated as to what kind of adenocarcinomas in situ would develop to a life-threatening cancer, and some of our cases might be an overdiagnosis. However, of the 72 preregistered patients in this study, who were eligible by preoperative information only, 20 patients (6 of 53 eligible patients and 14 of 16 ineligible patients) had adenocarcinomas with mixed subtype, and they were rarely overdiagnosed. The maximum diameter of some invasive tumours was only 9 mm. At present, we cannot distinguish these invasive cancers from adenocarcinomas in situ preoperatively. Further studies are required about overdiagnosis of such tumours. CONCLUSION This report described the results of a multi-institutional prospective study on limited resection of lung cancer with GGO using HR-CT, PET findings and intraoperative pathological examination. Although the number of patients in this study was limited, the results were informative. With these criteria, limited resection was performed safely without any recurrence, and the postoperative pulmonary function was well preserved. The outcomes of limited resection for small-sized lung cancer with GGOs that met the criteria of this study were satisfactory. Further studies are awaited to increase the number of eligible candidates for wedge resection. SUPPLEMENTARY MATERIAL Supplementary material is available at EJCTS online. ACKNOWLEDGEMENTS We are grateful to Yuko Ito for her assistance and to Keisuke Fukui (biostatistician) of the Department of Cancer Epidemiology and Prevention, Osaka International Cancer Institute, Japan, for his advice concerning the statistical analyses. We are also grateful to Mitsunori Yamakawa, Yuko Hashimoto, Kazuyuki Ishida, Yoshimasa Nakazato, Naoki Yanagawa, Ikuro Sato, Hiroyoshi Suzuki, Hidekachi Kurotaki for their contribution to the pathological assessment. Funding This research was partially supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan [17H04125]. Conflict of interest: none declared. REFERENCES 1 Kaneko M, Eguchi K, Ohmatsu H, Kakinuma R, Naruke T, Suemasu K et al.   Peripheral lung cancer: screening and detection with low-dose spiral CT versus radiography. Radiology  1996; 201: 798– 802. Google Scholar CrossRef Search ADS PubMed  2 Henschke CI, Yankelevitz DF, Libby DM, Pasmantier MW, Smith JP, Miettinen OS. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med  2006; 355: 1763– 71. Google Scholar CrossRef Search ADS PubMed  3 The National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med  2011; 365: 395– 409. CrossRef Search ADS PubMed  4 Asamura H, Suzuki K, Watanabe S, Matsuno Y, Maeshima A, Tsuchiya R. A clinicopathological study of resected subcentimeter lung cancers: a favorable prognosis for ground glass opacity lesions. Ann Thorac Surg  2003; 76: 1016– 22. Google Scholar CrossRef Search ADS PubMed  5 Sakurai H, Dobashi Y, Mizutani E, Matsubara H, Suzuki S, Takano K et al.   Bronchioloalveolar carcinoma of the lung 3 centimeters or less in diameter: a prognostic assessment. Ann Thorac Surg  2004; 78: 1728– 33. Google Scholar CrossRef Search ADS PubMed  6 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. Google Scholar CrossRef Search ADS PubMed  7 Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1N0 non-small cell lung cancer. Ann Thorac Surg  1995; 60: 615– 23. Google Scholar CrossRef Search ADS PubMed  8 Ohtaka K, Hida Y, Kaga K, Kato T, Muto J, Nakada-Kubota R et al.   Limited resection and two-staged lobectomy for non-small cell lung cancer with ground-glass opacity. J Cardiothorac Surg  2013; 8: 111. Google Scholar CrossRef Search ADS PubMed  9 Si MJ, Xiao-Feng Tao XF, Du GY, Cai LL, Han HX, Liang XZ et al.   Thin-section computed tomography-histopathologic comparisons of pulmonary focal interstitial fibrosis, atypical adenomatoushyperplasia, adenocarcinoma in situ, and minimally invasive adenocarcinoma with pure ground-glass opacity. Eur J Radiol  2016; 85: 1708– 15. Google Scholar CrossRef Search ADS PubMed  10 Vesselle H, Schmidt RA, Pugsley JM, Li M, Kohlmyer SG, Vallires E et al.   Lung cancer proliferation correlates with [F-18]fluorodeoxyglucose uptake by positron emission tomography. Clin Cancer Res  2000; 6: 3837– 44. Google Scholar PubMed  11 Higashi K, Ueda Y, Yagishita M, Arisaka Y, Sakurai A, Oguchi M et al.   FDG PET measurement of the proliferative potential on non-small cell lung cancer. J Nucl Med  2000; 41: 85– 92. Google Scholar PubMed  12 Higashi K, Ueda Y, Seki H, Yuasa K, Oguchi M, Noguchi T et al.   Fluorine-18-FDG PET imaging is negative in bronchioloalveolar lung carcinoma. J Nucl Med  1998; 39: 1016– 20. Google Scholar PubMed  13 Sagawa M, Higashi K, Sugita M, Ueda Y, Maeda S, Toga H et al.   Fluorodeoxyglucose uptake correlates with the growth pattern of small pripheral pulmonary adenocarcinoma. Surg Today  2006; 36: 230– 4. Google Scholar CrossRef Search ADS PubMed  14 Maeda R, Isowa N, Onuma H, Miura H, Harada T, Touge H et al.   The maximum standardized uptake values on positron emission tomography to predict the Noguchi classification and invasiveness in clinical stage IA adenocarcinoma measuring 2 cm or less in size. Interact CardioVasc Thorac Surg  2009; 9: 70– 3. Google Scholar CrossRef Search ADS PubMed  15 Tsunezuka Y, Shimizu Y, Tanaka N, Takayanagi T, Kawano M. Positron emission tomography in relation to Noguchi’s classification for diagnosis of peripheral non-small-cell lung cancer 2 cm or less in size. World J Surg  2007; 31: 314– 7. Google Scholar CrossRef Search ADS PubMed  16 Sagawa M, Higashi K, Usuda K, Aikawa H, Machida Y, Tanaka M et al.   Curative wedge resection for non-invasive bronchioloalveolar carcinoma. Tohoku J Exp Med  2009; 217: 133– 7. Google Scholar CrossRef Search ADS PubMed  17 Cortese DA, Pairolero PC, Bergstralh EJ, Woolner LB, Uhlenhopp MA, Piehler JM et al.   Roentgenographically occult lung cancer. a ten-year experience. J Thorac Cardiovasc Surg  1983; 86: 373– 80. Google Scholar PubMed  18 Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant  2013; 48: 452– 8. Google Scholar CrossRef Search ADS PubMed  19 Aoki T, Nakata H, Watanabe H, Nakamura K, Kasai T, Hashimoto H et al.   Evolution of peripheral lung adenocarcinomas: CT findings correlated with histology and tumor doubling time. AJR Am J Roentgenol  2000; 174: 763– 8. Google Scholar CrossRef Search ADS PubMed  20 He P, Yao G, Guan Y, Lin Y, He J. Diagnosis of lung adenocarcinoma in situ and minimally invasive adenocarcinoma from intraoperative frozen sections: an analysis of 136 cases. J Clin Pathol  2016; 69: 1076– 80. Google Scholar CrossRef Search ADS PubMed  21 Koike T, Togashi K, Shirato T, Sato S, Hirahara H, Sugawara M et al.   Limited resection for noninvasive bronchioloalveolar carcinoma diagnosed by intraoperative pathologic examination. Ann Thorac Surg  2009; 88: 1106– 11. Google Scholar CrossRef Search ADS PubMed  22 Nakata M, Sawada S, Saeki H, Takashima S, Mogami H, Teramoto N et al.   Prospective study of thoracoscopic limited resection for ground-glass opacity selected by computed tomography. Ann Thorac Surg  2003; 75: 1601-6. Google Scholar CrossRef Search ADS   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. Google Scholar CrossRef Search ADS PubMed  24 Keyes J. SUV: standard uptake or silly useless value? J Nucl Med  1995; 36: 1836– 9. Google Scholar PubMed  25 Chin BB, Lyengar S, Sabundayo BP, Schwartz D. Standardized uptake values in 2-deoxy-2-[18F]Fluoro-d-glucose with positron emission tomography. Mol Imaging Biol  2002; 4: 294– 300. Google Scholar CrossRef Search ADS PubMed  26 Vansteenkiste JF, Stroobants SG, De Leyn PR, Dupont PJ, Bogaert J, Maes A et al.   Lymph node staging in non-small-cell lung cancer with FDG-PET scan: a prospective study on 690 lymph node stations from 68 patients. J Clin Oncol  1998; 16: 2142– 9. Google Scholar CrossRef Search ADS PubMed  27 Suzuki K, Koike T, Asakawa T, Kusumoto M, Asamura H, Nagai K et al.   A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer: JCOG0201. J Thorac Oncol  2011; 6: 751– 6. Google Scholar CrossRef Search ADS PubMed  28 Yoshida J, Ishii G, Hishida T, Aokage K, Tsuboi M, Ito H et al.   Limited resection trial for pulmonary ground-glass opacity nodules: case selection based on high-resolution computed tomography—interim results. JJCO  2015; 45: 677– 81. Google Scholar PubMed  29 Nakao M, Yoshida J, Goto K, Ishii G, Kawase A, Aokage K et al.   Long-term outcomes of 50 cases of limited-resection trial for pulmonary ground-glass opacity nodules. J Thorac Oncol  2012; 7: 1563– 6. Google Scholar CrossRef Search ADS PubMed  30 Marcus PM, Prorok PC, Miller AB, DeVoto EJ, Kramer BS. Conceptualizing overdiagnosis in cancer screening. J Natl Cancer Inst  2015; 107: djv014. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Journal

European Journal of Cardio-Thoracic SurgeryOxford University Press

Published: Apr 1, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 12 million articles from more than
10,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Unlimited reading

Read as many articles as you need. Full articles with original layout, charts and figures. Read online, from anywhere.

Stay up to date

Keep up with your field with Personalized Recommendations and Follow Journals to get automatic updates.

Organize your research

It’s easy to organize your research with our built-in tools.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

Monthly Plan

  • Read unlimited articles
  • Personalized recommendations
  • No expiration
  • Print 20 pages per month
  • 20% off on PDF purchases
  • Organize your research
  • Get updates on your journals and topic searches

$49/month

Start Free Trial

14-day Free Trial

Best Deal — 39% off

Annual Plan

  • All the features of the Professional Plan, but for 39% off!
  • Billed annually
  • No expiration
  • For the normal price of 10 articles elsewhere, you get one full year of unlimited access to articles.

$588

$360/year

billed annually
Start Free Trial

14-day Free Trial