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Kazuhiko Shien
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P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.13-13 - Potent Anti-Tumor Effect of Ganetespib in Acquired EGFR-TKI Resistance NSCLC Cells (ID 12652)
16:45 - 18:00 | Author(s): Kazuhiko Shien
- Abstract
Background
Non-small cell lung cancer (NCSLC) harboring epidermal growth factor receptor (EGFR) mutation shows favorable response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, almost all these patients eventually acquire resistance to EGFR-TKIs, and novel therapeutic strategies to overcome the acquired resistance have been required. The 90-kDa heat shock protein (HSP90) is a chaperon protein expressed at high levels in cancer cells and involved in folding or stabilization of client proteins essential for cancer cell growth and survival. Ganetespib (STA-9090) is one of the second-generation HSP90 inhibitors with potent anti-tumor effect on NSCLC cells. In this study, we evaluated the anti-tumor effect of ganetespib in EGFR-TKI sensitive and acquired resistance NSCLC cell lines.
a9ded1e5ce5d75814730bb4caaf49419 Method
We treated 4 EGFR-mutant NSCLC cell lines (HCC827, HCC4006, HCC4011 and PC-9), and 5 experimentally established EGFR-TKI (gefitinib) resistance cell lines with ganetespib. The EGFR-TKI resistant mechanism consisted of EGFR T790M second mutation, MET amplification, epithelial-to-mesenchymal transition (EMT) and cancer stem cell-like properties. We determined cell proliferation by MTS assay and calculated the IC50 values. We also performed Western blotting to investigate downstream signaling pathway alterations.
4c3880bb027f159e801041b1021e88e8 Result
The IC50 values in parental NSCLC cell lines ranged from 1.3nM to 15nM, and those in acquired EGFR-TKI resistance NSCLC cell lines ranged from 0.87nM to 25nM, which suggests potent anti-tumor effect of ganetespib. In addition, this effect was observed regardless of the resistant mechanisms, including EMT. Ganetespib effectively suppressed the expression of downstream pathway molecules in all examined cell lines including acquired EGFR-TKI resistance NSCLC cell lines. Also, ganetespib effectively induced apoptosis in parental and acquired EGFR-TKI resistance NSCLC cell lines with EGFR T790M mutation or MET amplification.
8eea62084ca7e541d918e823422bd82e Conclusion
Ganetespib exhibited potent anti-tumor effect in acquired EGFR-TKI resistance NSCLC cell lines regardless of the resistant mechanisms, suggesting that ganetespib could be a promising therapeutic option in the treatment of NSCLC with acquired EGFR-TKI resistance.
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P1.14 - Thymoma/Other Thoracic Malignancies (Not CME Accredited Session) (ID 946)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.14-29 - Surgical Treatment for Metastatic Lung Tumors from Various Sarcomas (ID 12551)
16:45 - 18:00 | Author(s): Kazuhiko Shien
- Abstract
Background
Sarcomas are known to be one of the aggressive malignant tumors. They often develop multiple pulmonary metastasis, and thus systemic therapy is a treatment of choice for metastatic lung tumors. However, effective chemotherapeutic treatments have not yet been established. Surgical resection for metastatic lung tumors is a therapeutic option to control the disease, although it is not a curative therapy.
a9ded1e5ce5d75814730bb4caaf49419 Method
Between January 2006 and April 2018, 396 pulmonary resections were performed for 219 sarcoma patients with metastatic lung tumors in Okayama University Hospital. Among them, 129 sarcoma patients who underwent pulmonary metastasectomy between January 2006 and December 2014 were retrospectively reviewed. In total, 229 pulmonary resections were performed. We analyzed the following factors: age, sex, site of primary lesion, histology, operative procedures, size of the largest lesions resected, maximum number of the resected tumors, postoperative complications, and survival rate.
4c3880bb027f159e801041b1021e88e8 Result
In total, 939 metastatic nodules were resected. Average number of tumors per intervention was 4.1 (range 1-19). These sarcoma patients consisted of 31 males and 98 females, and their average age was 53.6 years (range 14-80 years). Leiomyosarcoma was the most common histological subtype (n = 72, 55.8%) and uterus was the most common location of the primary disease (n = 55, 42.6%). Operative procedures were composed of 173 partial resections, 31 segmentectomies with or without partial resections, 24 lobectomies with or without partial resections, and 1 basal segmental auto-transplantation after pneumonectomy. The postoperative complications were limited, showing that pulmonary metastasectomies for sarcomas are acceptable. Overall 3-year survival after the first pulmonary metastasectomy was 49.5%, and multivariate analysis revealed that the survival was significantly better for the group with disease-free interval of more than 2 years or the size of the largest resected lesion less than 30 mm.
8eea62084ca7e541d918e823422bd82e Conclusion
Surgical resections for metastatic lung tumors from various sarcomas were performed without major complications, indicating the acceptable feasibility. If disease-free interval is more than 2 years and the size of the largest resected lesion is less than 30 mm, patients may maximally benefit from surgical resection.
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P1.14-30 - Prognostic Factors for Sarcoma Patients with Lung Metastasis Who Underwent Extended Pulmonary Resection (ID 12710)
16:45 - 18:00 | Author(s): Kazuhiko Shien
- Abstract
Background
Since the effects of chemotherapy and molecular targeting agents for sarcoma with lung metastasis are limited, pulmonary metastasectomy can become one of the treatment options for the control of disease. Partial resection is the first choice of surgical procedure for lung metastasis to preserve pulmonary function. As for the tumors which occur at hilum or are too large for partial resection, the extended resection such as segmentectomy or lobectomy is occasionally required while the clinical impact of these procedures is unknown. In this study, we examined preoperative prognostic factors of sarcoma patients who underwent segmentectomy or lobectomy for lung metastasis.
a9ded1e5ce5d75814730bb4caaf49419 Method
During January 2006 to December 2014, a total of 129 patients underwent pulmonary resection for lung metastasis of sarcoma at Okayama University Hospital. Among them, 40 patients (31%) underwent segmentectomy or lobectomy. The 3-year survival rate was evaluated by univariate (Kaplan‑Meier method) and multivariate (Cox proportional hazard model) analyses with log-rank test.
4c3880bb027f159e801041b1021e88e8 Result
Among 40 patients, the median age was 55 years old (range, 17 to 76). Thirty-five patients (88%) were female. Thirty patients (75%) harbored two or more distant metastatic lesions at initial diagnosis and 21 patients (52.5%) suffered from bilateral lung metastasis at the first lung metastasectomy. Median maximum diameter of the maximum lung tumor and median number of the lung metastasis was 30 mm (range, 8 to 110) and 3 (range, 1 to 19), respectively. Eight patients (20%) had two years or more disease-free interval at the first lung resection. The 3-year survival rate was 36.8% in the entire cohort. The univariate analyses revealed that the 3-year survival rate was significantly better in the patients with smaller size of lung metastasis (50.5% in the tumors with maximum diameter ≤ 30mm vs 20.7% in those > 30mm, P < 0.01), unilateral lung metastasis (45.6% vs 29.5% for bilateral, P < 0.05), and the absence of metastatic lesion at initial diagnosis (50.9% vs 28.1% for the presence, P < 0.05). Smaller numbers of lung metastasis and longer disease-free interval showed favorable prognosis with marginal significance (P < 0.1). The multivariate analysis with the above five factors revealed that unilateral lung metastasis at the first pulmonary metasetasectomy was an independent favorable prognostic factor (HR 2.41, 95%CI 1.09 to 5.32, P < 0.05).
8eea62084ca7e541d918e823422bd82e Conclusion
Extended pulmonary resection such as segmentectomy or lobectomy may be considered for the patients with sarcoma lung metastasis especially when the tumors are unilateral.
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P1.17 - Treatment of Locoregional Disease - NSCLC (Not CME Accredited Session) (ID 949)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.17-15 - Perioperative Prognostic Nutrition Index for Induction Chemoradiotherapy Followed by Surgery in Locally Advanced Non-Small Lung Cancers (ID 13055)
16:45 - 18:00 | Author(s): Kazuhiko Shien
- Abstract
Background
The perioperative nutritional and immunological statuses significantly associated the clinical outcome of the surgery, especially for the extended surgery. Induction chemoradiotherapy (iCRT) followed by surgery is one of treatment options for locally advanced (LA) non-small cell lung cancers (NSCLCs) although there is a risk for increasing postoperative complications. A prognostic nutritional index (PNI), calculated using serum albumin levels and peripheral lymphocyte count, has been used to predict the clinical outcome of various cancers including early stage NSCLCs but not LA-NSCLC after iCRT. In this study, we investigated the impact of PNI on clinical outcome of iCRT followed by surgery in the patients with LA-NSCLCs.
a9ded1e5ce5d75814730bb4caaf49419 Method
During 1999 to 2016, 173 patients underwent iCRT followed by surgery in Okayama University Hospital. Among them, 128 patients who matched to inclusion criteria were studied. We retrospectively calculated the PNI at (1) pre-iCRT (median 5 days before administration), (2) pre-operation (Ope) (median 5 day before surgery), and (3) post-Ope (median 30 days after surgery) and reviewed the medical records.
4c3880bb027f159e801041b1021e88e8 Result
The median age was 62 years old (range 31 – 79) and 100 patients were male. Seventy patients were adenocarcinomas and 46 were squamous cell carcinomas. Clinical stages were IIA / IIB (n = 15), IIIA (n = 87), IIIB (n = 25), and IV (n = 1). Main regimen of iCRT was CDDP / DOC with concurrent radiotherapy (46 gray). Treatment responses were CR/PR (n = 99), SD (n = 27), and PD (n = 2). Lung resections were lobectomy (n = 109), bi-lobectomy (n = 14), and pneumonectomy (n = 5) and additional procedures were performed in 93 patients. Based on the invasiveness of surgery, we categorized into three groups: 1) highly invasive group (n = 60), 2) intermediate group (n = 33), and 3) standard group (n = 35). Pathological complete responses were present in 37 patients. The PNI were significantly decreased during treatment course [49 (24 – 71) in pre-ICRT, 44 (30 – 58) in pre-Ope, and 41 (22 – 58) in post-Ope]. Among the entire cohort, the perioperative PNI values showed some effect on overall survival. However, among the highly invasive group, the poor preoperative PNI values significantly correlated with worse overall survival.
8eea62084ca7e541d918e823422bd82e Conclusion
Peri-treatment nutritional evaluation using PNI is important to predict clinical outcome of the patients who received the iCRT followed by surgery with LA-NSCLCs especially when highly invasive surgery is required.
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P1.17-17 - The Impact of Induction Chemoradiotherapy Followed by Surgery for N1 Involved Non-Small Cell Lung Cancer (ID 12046)
16:45 - 18:00 | Author(s): Kazuhiko Shien
- Abstract
Background
Induction chemoradiotherapy (iCRT) followed by surgery is usually selected for locally advanced non-small cell lung cancer (NSCLC) patients with mediastinal lymph node (LN) metastasis or invasion to adjacent organs, whereas it is occasionally performed for clinical N1 (cN1) NSCLC patients harboring such as a centrally located primary tumor or a bulky LN to improve local control rate and secure a cancer-free surgical margin. However, the survival benefit of iCRT followed by surgery for NSCLC patients with N1 LN involvement remains controversial. Furthermore, the accuracy of the radiological examination for N1 metastasis is unsatisfactory. In this study, we investigated the clinical outcomes of surgery with or without iCRT based on the estimation of the pretreatment LN metastatic status from fibrotic or necrotic changes of resected LNs in the cN1 NSCLC patients.
a9ded1e5ce5d75814730bb4caaf49419 Method
cN1 NSCLC patients who underwent complete resection with or without iCRT at our institution between January 1999 and December 2016 were subjected. We divided the enrolled patients into two groups as the primary surgery (PS) group and the iCRT followed by surgery (IC) group. As for IC group, we determined the pretreatment LN metastatic status based on the pathological features of resected LNs. We compared the clinical outcomes of pretreatment N1 involved patients with or without iCRT.
4c3880bb027f159e801041b1021e88e8 Result
Among 127 cN1 NSCLC patients, 40 patients were considered as pretreatment N1 involvement, consisting of 26 and 14 patients in the PS and IC groups, respectively. The central type tumor and the continuous type of LN, which frequently required the extended surgical procedures, were significantly more frequent in the IC group than in the PS group (P < 0.01). Although there was no significant difference in the recurrence pattern between the two groups, none of patients developed local recurrence in the IC group. Regarding the patients with a centrally located tumor or a bulky LN (> 2.0cm), the 5-year recurrence-free survival was significantly better in the IC group than in the PS group (74.1% vs, 36.4%; P =0.03).
8eea62084ca7e541d918e823422bd82e Conclusion
Our study demonstrated that iCRT followed by surgery could suppress the disease recurrence in the N1-involved NSCLC patients especially for the patients harboring a centrally located tumor or bulky LNs at N1 level, suggesting that these patients may be good candidates for iCRT followed by surgery to avoid extended resections and to suppress the local recurrence.
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P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.01-71 - Clinical Outcome of Induction Chemoradiotherapy Followed by Surgery for the Patients with cN2 Non-Small Cell Lung Cancer (ID 13091)
16:45 - 18:00 | Author(s): Kazuhiko Shien
- Abstract
Background
The treatment strategy for clinical N2 (cN2) non-small cell lung cancer (NSCLC) is still controversial, because its clinical outcome is unsatisfactory and cN2 NSCLC harbors various conditions. In this study, we investigated the clinical outcome of induction chemoradiotherapy (iCRT) followed by surgery in the patients with cN2 NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
During 1999 to 2016, 92 patients with cN2 NSCLC were surgically treated after iCRT in our hospital. Overall survival (OS) and relapse-free survival (RFS) were evaluated by the Kaplan-Meier method with log-rank test (univariate analyses) and by the cox proportional hazard model (multivariate analyses).
4c3880bb027f159e801041b1021e88e8 Result
Median follow-up was 49.3 months (range 3.0 - 216). Median age was 62 (21 - 79). Sixty-nine patients (75%) were male. Fifty-four and 38 patients were cStageIIIA and IIIB, respectively. Forty-six (50%) patients were adenocarcinoma. As for iCRT, the CDDP plus DTX regimen was applied for most of patients (96.7%), and the median radiation dose was 46Gy (36 - 60). Complete/major/minor pathological responses were exhibited in 29/36/27 patients, respectively. pCR was observed in 22 patients. The 5-year rates of OS and RFS were 64.1% and 48.1%, respectively. The patients with lower-lobe origin, cStage IIIA (UICC8th), poor radiological response (progressive or stable disease), minor pathological response, re-operation within 30days after surgery, or recurrence showed significantly worse OS than the others. In addition, the patients with lower lobe origin, cStageIIIA, multi-station N2, poor radiological response, or minor pathological response showed significantly worse RFS. The multivariate analysis revealed that the patients with lower-lobe origin tumors and multi-station N2 showed significantly worse OS [Hazard Ratio (HR) 2.55, 95% confidence interval (CI) 1.11 - 5.71, P= 0.028] and RFS (HR 2.45, 95%CI 1.34 - 4.69, P= 0.003), respectively. Adenocarcinoma, lower-lobe origin, multi-station N2, cStageIIIA, poor radiological response, and minor pathological response significantly correlated to recurrence. Among them, adenocarcinoma (odds ratio (OR) 3.27, 95%CI 1.21 – 8.89, P= 0.02), lower-lobe origin (OR 5.22, 95%CI 1.48 – 18.40, P= 0.01), and multi-station N2 (OR 3.63, 95%CI 1.32 – 9.88, P= 0.012) independently correlated to recurrence.
8eea62084ca7e541d918e823422bd82e Conclusion
iCRT followed by surgery may be one of the feasible treatment options for the patients with cN2-NSCLCs, especially for those which harbor non-lower lobe origin and multi-station N2 .
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P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.01-72 - Pulmonary Resection in a Prone Position for Lung Cancer Invading the Spine: Two Cases Report (ID 12700)
12:00 - 13:30 | Author(s): Kazuhiko Shien
- Abstract
Background
The prone position is usually not selected for pulmonary resection. The intraoperative body position is an important issue in surgery for non-small cell lung cancer (NSCLC) invading the spine because the standard intraoperative body position for vertebrectomy is a prone position, while that for pulmonary resection is a lateral decubitus position. Intraoperative changes in body position are correlated with disadvantages such as the risks of infection and nerve injury.
We have previously reported significantly favorable clinical outcome of induction chemoradiotherapy (iCRT) followed by surgery among patients with clinical T3 or T4 locally advanced NSCLC, compared with initial surgery. iCRT can prevent cancer cell microresidues at local sites and to eradicate micrometastatic disease at distant sites.
a9ded1e5ce5d75814730bb4caaf49419 Method
Case 1: A 60-year-old man was found to have squamous cell carcinoma of the left lung with invasion of the adjacent chest wall and vertebral bodies from Th3 to Th5 and his clinical stage (UICC 7th edition) was diagnosed as c-stage IIIA (cT4N0M0).
Case 2: A 63-year-old man was found to have adenocarcinoma of the right lung with invasion of the adjacent chest wall and Th3 and Th4 vertebral bodies and was diagnosed as c-stage IIIA (cT4N1M0).
They were treated with iCRT consisting of two cycles of cisplatin plus docetaxel with concurrent radiotherapy of total 46 Gy.
4c3880bb027f159e801041b1021e88e8 Result
They obtained a moderate decrease in tumor size after iCRT (restaging ycT4N0M0: Case 1, ycT4N0M0: Case 2).
The surgery was started in the prone position. After partial vertebrectomy and chest wall resection were performed using an O-arm with a navigation system, upper lobectomy with systemic lymph node dissection (sLND) was performed through the chest wall defect via the posterior approach. Firstly, all pulmonary arterial branches to upper lobe were divided. Next, after division of the posterior and anterior interlobar fissure, the upper lobe bronchus was transected. Finally, the upper pulmonary vein was divided, and sLND was performed under an excellent view.
Pathologic examination confirmed complete resection of squamous cell carcinoma invading the vertebral bodies and a diagnosis of Ef3 and ypN0 in Case 1, and complete resection of adenocarcinoma adjacent to the vertebral bodies, which had not been infiltrated, and a diagnosis of Ef2 and ypN0 in Case 2.
8eea62084ca7e541d918e823422bd82e Conclusion
Lobectomy with systemic LND in the prone position, especially after wide resection of the bony thorax, can be performed via the posterior approach without any significant difficulties in the patients with NSCLC invading the spine.
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P3.CR - Case Reports (Not CME Accredited Session) (ID 984)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.CR-07 - Comprehensive Genomic Profiles for a Mediastinal Tumor Suspected of Synovial Sarcoma: A Case Report (ID 12832)
12:00 - 13:30 | Author(s): Kazuhiko Shien
- Abstract
Background
Synovial sarcoma (SS) is an aggressive malignant tumor and accounts for 5 to 10% of all types of soft tissue sarcomas. SS commonly occurs in the deep tissue adjacent to the joints or tendons in the limbs while SS rarely occurs in the mediastinum. Most of SS harbor t(X;18)(p11.2;q11.2), which leads to chimeric fusion of SYT with one of the SSX genes. Furthermore, somatic mutations of cancer-related genes such as PIKC3A, TERT, CDH1, and PTEN have also been reported in the SS even though the frequencies of these genetic alterations were not high. Recently, the comprehensive genomic profile (CGP) using the next-generation sequencing (NGS) is widely used for better understanding of tumorigenesis and it can also provide clinically actionable information to guide treatment decisions for patients.
a9ded1e5ce5d75814730bb4caaf49419 Method
In this study, the clinical and histological records of an anterior mediastinal tumor suspected of SS were reviewed, and a reverse transcript polymerase chain reaction (RT-PCR) assay and NGS using a high sensitivity amplicon-based targeted sequencing method incorporating molecular barcodes (a panel designed for hotspots of 47 cancer-related genes) were performed to identify the genetic alterations.
4c3880bb027f159e801041b1021e88e8 Result
A 78 years old woman was referred to our hospital because of approximately 9 cm anterior mediastinal tumor. A positron emission tomography showed the high fluorine-18-fluorodeoxyglucose uptake. The patient underwent median sternotomy and resection of the tumor combined with wedge resection of the left upper lobe of lung. Histological examination revealed a monomorphic spindle cell growth and immunohistochemical stains (AE1/AE3, CAM5.2, CD34, CD99, Desmin, Nestin, a-SMA, CDK4, CD56, c-kit, EMA, and S-100) were negative, so the tumor was suspected of SS. We performed a RT-PCR assay for SYT-SXX fusion, however, it was not detected. NGS analysis revealed the presence of hotspot mutations in 4 cancer-related genes (PIK3CA, CDKN2A, PTEN, and MAP2K4). Because the tumor was completely resected, an adjuvant therapy had not been planned and the scheduled medical checkup has been performed. Fortunately, the patient is alive without any recurrence for 5 years.
8eea62084ca7e541d918e823422bd82e Conclusion
The genetic features of a mediastinal tumor suspected of SS, without SYT-SSX fusion, were evaluated by CGP analysis. In case of the rare tumor especially when it occurs in the unusual location and the histological and molecular assessments are not conclusive, a CGP assay may be helpful to reveal the genetic feature of the tumor and to determine the effective targeted drugs.
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