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Yasuhisa Ohde
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MA06 - Challenges in the Treatment of Early Stage NSCLC (ID 124)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Now Available
- Moderators:Florentino Hernando-Trancho, Ayten Kayi Cangir
- Coordinates: 9/08/2019, 13:30 - 15:00, Colorado Springs (1994)
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MA06.06 - A Phase III Study of Adjuvant Chemotherapy in Patients with Completely Resected, Node-Negative Non-Small Cell Lung Cancer (Now Available) (ID 285)
13:30 - 15:00 | Author(s): Yasuhisa Ohde
- Abstract
- Presentation
Background
Post-operative UFT (tegafur/uracil) has been shown to prolong survival of Japanese patients with completely resected, p-stage I (T1> 2 cm) non-small cell lung cancer (NSCLC). This trial, the Japan Clinical Oncology Group (JCOG) 0707, aimed at estimating the efficacy of S-1 (tegafur/gimeracil/oteracil) compared to UFT as adjuvant therapy in this population.
Method
Eligible patients had received complete resection with lymph node dissection for p-stage I (T1-2N0M0, T1> 2 cm, by 5thEdition UICC TNM) NSCLC, within 56 days of enrollment. Patients were randomized to receive: oral UFT 250mg/m2/day for 2 years (Arm A), or oral S-1 80mg/m2/day for 2 weeks and 1 week rest, for 1 year (Arm B). The initial primary endpoint was overall survival (OS). Based upon the monitoring in Jun. 2013, which showed the combined OS of the 2 arms better than expected (4-year OS of 91.6% vs. presumed 5-year OS of 70-76.5%), it was judged to be underpowered. The study protocol was amended so that the primary endpoint is relapse-free survival (RFS). With the calculated sample size of 960, this study would detect the superiority of Arm B over Arm A with power 80% and one-sided type I error of 0.05, assuming the 5-year RFS of 75% in Arm A and the hazard ratio of 0.75.
Result
From Nov. 2008 to Dec. 2013, 963 patients were enrolled (Arm A : 482, Arm B : 481): median age 66 (range: 33 to 80), male 58%, adenocarcinoma 80%, p-T1/T2 46%/54%. Only 2 received pneumonectomy. >Grade 3 toxicities (hematologic/nonhematologic) were observed in 15.9 (1.5/14.7) % in Arm A, and in 14.9 (3.6/12.1) % in Arm B, respectively. 60.0% of the patients in Arm A and 54.7% of them in Arm B completed the protocol treatment (p=0.10). There were 4 cases of deaths during protocol treatment, probably of cardio-vascular origin, with 1 in Arm A and 3 in Arm B. At the data cut-off of Dec. 2018, the hazard ratio (HR, Arm B vs. Arm A) of RFS was 1.06 (95% confidence interval (C.I.): 0.82-1.36), showing no superiority of S-1 over UFT. The HR of OS was 1.10 (95% C.I.: 0.81-1.50). The 5-year RFS/OS rates were 79.4%/88.8% in Arm A and 79.5%/89.7% in Arm B, respectively. Pre-specified subset analyses for gender, age, smoking, stage, tumor side, lymph node dissection area, pleural invasion and histology revealed no remarkable results; S-1 arm was not superior to UFT arm in each analysis. Of the 77 and 85 OS events for Arm A/Arm B, 45 each (58%/53%, respectively) were due to the NSCLC. During the follow-up period, secondary malignancy was observed in 85 (17.8%) and 84 (17.8%) in Arm A and Arm B, respectively.
Conclusion
Post-operative adjuvant therapy with oral S-1 was not superior to that with UFT in stage I (T>2 cm) NSCLC after complete resection. UFT remains standard in this population. Future investigation should incorporate identification of high-risk population for recurrence, since survival of each arm was so good with substantial number of OS events due to other causes of deaths in this trial.
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P1.17 - Treatment of Early Stage/Localized Disease (ID 188)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 3
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.17-04 - Multicenter Observational Study of Node-Negative Non-Small Cell Lung Cancer Patients Who Are Excluded from a Clinical Trial (ID 678)
09:45 - 18:00 | Author(s): Yasuhisa Ohde
- Abstract
Background
The Japan Clinical Oncology Group (JCOG) conducted a randomized phase III trial (JCOG0707), which compared the survival benefit of tegafur/uracil (UFT) and tegafur/gimeracil/oteracil (S-1) for completely resected pathological stage I (T1>2 cm and T2 in the 6th TNM classification) non-small cell lung cancer (NSCLC). A total of 963 patients were enrolled. Recently, there is a growing concern that those who participated in clinical trials are highly selected and do not represent the “real-world” population. Hereby, we conducted a multicenter observational study of patients excluded from JCOG0707 trial during the study period.
Method
Patients with completely resected pathological stage I NSCLC, eligible for, but excluded from the JCOG0707 trial during the enrollment period (Nov. 2008– Dec. 2013) were eligible for this study. Physicians from institutions that participated in the JCOG0707 retrospectively assessed the medical records of each patient. The final survival data were collected as of Dec. 2018.
Result
Of the 48 institutions participating in JCOG0707, 34 participated in this observational study. They had enrolled 917 (“JCOG” cohort) to JCOG0707. To this study, 5004 patients (“All” cohort), or 85% of those initially considered for JCOG0707 at the 34 institutions, were enrolled. Among them, 2388 (47.7%) were ineligible for the trial and 2616 (52.3%) had not been enrolled to JCOG0707 despite being eligible (“Eligible” cohort). Of the 5004 patients, 1659 (33.2%) received adjuvant chemotherapy, mainly UFT (1550 of 1659, or 93.4% of those received any adjuvant chemotherapy).
The 5-year survival rates (5yOS) for All and Eligible cohorts were 83.9% and 89.1%, respectively, versus 89.2% in the JCOG cohort. The 5yOS with UFT adjuvant were 89.4% in Eligible and 88.9% in JCOG cohorts, respectively.
UFT administration was a significant prognostic factor in All (adjusted HR=0.66, p<0.0001), but not in Eligible cohort (adjusted HR=0.88, p=0.28). The patients were classified into 3 subgroups, those with tumors without GGA (ground-glass area, non-invasive component; GGA-), with GGA (GGA+) and tumor size < 3 cm, and GGA+ with tumor size > 3cm. 5yOS of 744 patients in the Eligible cohort with GGA+ and tumor size < 3cm were excellent, 96.9%/96.4% with/without UFT. For 416 patients with GGA+ tumor sized > 3cm in Eligible cohort, invasive tumor size in the pathological specimen was prognostic but not predictive for UFT effect. When the invasive tumor size was >3 cm, 5yOS with/without UFT were 90.0/87.8%, whereas when it was <3 cm, 5yOS with/without UFT were 96.2/96.2%. UFT tended to be associated with better prognosis in 1389 patients with GGA- tumor when the tumor size was >3 cm, (5yOS 83.8% vs 77.4%, adjusted HR=0.82, p=0.27), but not when it was <3 cm (5yOS 88.1% vs 88.1%, adjusted HR=0.97, p=0.87).
Conclusion
Our “real-world” data reproduced the survival outcome of JCOG0707, especially in Eligible cohort. Invasive tumor size was a prognostic factor in GGA+ tumors, suggesting validity of the 8th IASLC TNM classification. GGA+ tumor with invasive tumor size of <3 cm would not require any adjuvant therapy. UFT effect appears to be limited to large GGA- tumor.
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P1.17-12 - Osteogenic and Brain Metastases After Resection of NSCLC: Implications for the Use of FDG-PET and Brain MRI in Postoperative Surveillance (Now Available) (ID 973)
09:45 - 18:00 | Author(s): Yasuhisa Ohde
- Abstract
Background
In several guidelines for lung cancer treatment, routine use of FDG-PET and brain MRI have not been recommend due to their insufficient evidence of survival benefits for resected NSCLC. In clinical practice, not a small portion of patients experience metastases in osteogenic and/or brain at the initial recurrence after surgery, which routine chest CT hardly diagnose them. In this retrospective study, we aimed to propose the candidates for surveillance using FDG-PET and brain MRI to diagnose OM/BM.
Method
We retrospectively enrolled 1099 patients who underwent pulmonary resections of lobectomy or more for NSCLC between 2002 and 2013. From medical records, clinicopathological data were collected and reviewed. Surveillance by using FDG-PET and brain MRI were basically performed at patients’ complaint of symptoms and/or detection of other metastatic disease. Clinicopathological factors associated with osteogenic metastases (OM) and/ or brain metastases (BM) were investigated by univariate and multivariate analyses.
Result
We included 1055 patients with lobectomies and 44 patients with pneumonectomies. Nine hundred thirty-three patients (88.4%) received mediastinal and hilar lymphnodes dissection. Seven hundred twenty-one patients had adenocarcinoma histology, 274 had squamous cell carcinoma histology. The prevalence of pStage was as following; pIA: 265 (25.1%), pIB: 348(33.0%), pIIA: 185(17.5%), pIIB: 105 (10.0%), pIIIA: 193 (18.3%), pIIIB: 3 (0.3%) (TNM 7th edition). Postoperative recurrence were identified in 344 patients (32.6%), OM or/and BM were observed in 115 patients (10.9%) as the initial recurrence. OM were diagnosed in 56 patients (5.6%). In the initial year after resection, 41.1% of OM were diagnosed, and 82% in the 2 years. BM were identified as the initial recurrence in 72 patients (6.6%). In the initial year, 44.1% of BM were diagnosed, and 78.9% in the 2 years. Multivariate analyses following univariate analyses revealed higher preoperative serum CEA level than 5ng/ml and presence of pathological nodal metastases were significantly associated with both postoperative OM and BM (p=0.011,<0.001 in OM, p=0.044, <0.001 in BM). Prevalence of OM and/or BM was 24.6% in patients with high serum CEA and nodal metastases. Postrecurrence survival of asymptomatic patients were better than those of symptomatic patients in both OM and BM groups (p=0.009 and 0.29, respectively)
Conclusion
Preoperative high serum CEA level and pathological nodal spread were closely associated with OM and BM after resection of NSCLC. Most of those events developed in 2 years after resections. Under the patient selections, efficacies of the use of FDG-PET and brain MRI are worthy to be evaluate in respect to earlier detections, maintenance of QOL and survival outcomes.
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P1.17-36 - Analyses of Segmental and Intrapulmonary Lymph Node Metastases of Small-Sized Peripheral Solid Predominant Non-Small Cell Lung Cancer (NSCLC) (ID 1571)
09:45 - 18:00 | Author(s): Yasuhisa Ohde
- Abstract
Background
Currently, randomized clinical trials to evaluate segmentectomy compared with lobectomy for peripheral small size non-small cell lung cancer (NSCLC) are ongoing, and the results are expected. The extent of lymph node dissection in intentional segmentectomy has not been clarified. The purpose of this study was to retrospectively investigate the pattern of segmental and intrapulmonary metastasis in intentional segmentectomy.
Method
We reviewed the records of patients who underwent lobectomies and systematic lymph node dissections for small(≦2cm) peripheral solid-predominant and clinical/surgical N0 NSCLC from 2002 to 2018. Among them, a total of 239 patients whose primary nodules was located in the outer third peripheral lung field and consolidation-tumor ratio (CTR) >0.5 on thin-section computed tomography (TSCT); who could be candidates for intentional segmentectomy were enrolled in this study. We analyzed the clinical and radiological factors, which may predict nodal metastases, and the distribution patterns of lymph node metastases.
Result
Of all patients, 33 (14%) had lymph node metastases (pN1:15, pN2:18). Segmental lymph node metastases (# 13) were observed in 4 cases(1.7%), and there were no metastasis of #13 in adjacent segment. #12 lymph node metastases were in 18 cases (7.5%), and # 11 lymph node metastases in 12 cases (5.0%), respectively. Skip N2 metastases were in 7 cases (2.9%), and all were in the range of regional lymphatic resection.
Conclusion
Solid-predominant NSCLC may have 14% lymph node metastasisa even with clinical and surgical N0. It may not be necessary to examined outside tumor-bearing segmental lymph nodes. However, there should be adequate lymph node sampling and intraoperative frozen section. In particular, intraoperative sampling of # 11 and # 12 is useful for selection of lobectomy convert cases.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-41 - Clinical and Immunological Factors Associated with Mutation Burden in Non-Small Cell Lung Cancer (ID 1313)
10:15 - 18:15 | Author(s): Yasuhisa Ohde
- Abstract
Background
It is unclear whether factors including clinical and immune microenvironment (IME) are associated with tumor mutation burden (TMB) in patients with non-small cell lung cancer (NSCLC). We aimed to develop a prediction model to identify the association between these factors and TMB in patients with NSCLC.
Method
We assessed somatic mutation burden in surgical tumor specimens with whole exome sequencing (WES) using an ion torrent proton platform (Thermo Fisher Scientific). The IME profiles including PD-L1 tumor proportion score (TPS), stromal CD8 tumor infiltrating T cell (TIL) density, and stromal Foxp3 TIL were quantified by digital pathology using a machine learning algorithm. To detect factors associated with TMB, factors including clinical and IME were assessed using a multipul regression model. Two hundred NSCLC patients, for whom both WES and clinical data from Project HOPE (High-Tech-Omics-based Patient Evaluation) were available, excluding those with low tumor purity (less than 20%), were assessed in this study.
Result
Out of 250 NSCLC patients with tumors surgically resected between September 2014 and September 2015, we analyzed tumors from 200 patients. Patient background: median age (range) 70 (39-87), male 37.5%, smoker 27.5%, pathological stage (p-stage) (I/ II/ III) 63.5/22.5/14.0% respectively, histological type (Ad/Sq) 77.0/23.0%, primary tumor location (upper/lower) 58.5/41.5%, median standardized uptake value (SUV) 7.5 (0.86-29.8), median serum CEA level (range) 3.4 ng/ml (0.5-144.3), median serum CYFRA 21-1 level 1.2 ng/ml (1.0-38.0), median TMB 2.19/ Mb (0.12-64.38), median PD-L1 TPS 15.1% (0.09-77.4), median stromal CD8 TIL 582.1/mm2 (120.0-4967.6), and median stromal Foxp3 TIL 183.7/mm2 (6.3-544.0).
In simple regression analysis, gender (male/female), smoking status (yes/no), p-stage (I/II,III,IV), age (< 70, ≥70), primary tumor location (lower/upper), serum CEA level (low [< 5.0ng/ml], high [≥ 5.0 ng/ml]), serum CYFRA level (low [< 3.5ng/ml], high [≥3.5 ng/ml]), and actionable mutation status (Mt+/Mt-) were favorable prognostic factors (p < .0001, p = .0001, p = .072, p = .027, p = .045, p = .002, p = .009, and p = .069 respectively).
Multiple regression analysis identified five factors [smoking status: smoker, age: less than 70, primary tumor location: lower, serum CEA level (greater than 5ng/ml), and serum CYFRA level (greater than 3.5ng/ml)] associated with higher TMB (p = .002, p = .045, p = .03, p = .046 and p = .016 respectively).
Conclusion
IME factors did not associate with tumor mutation burden. However, along with smoking, lower primary location, elevated CEA and CYFRA level may be independent predictors of high TMB.
