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D. Waller
Moderator of
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OA15 - Sublobar Resections for Early Stage NSCLC (ID 396)
- Event: WCLC 2016
- Type: Oral Session
- Track: Surgery
- Presentations: 8
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OA15.01 - Limited Resection Trial for Pulmonary Sub-solid Nodules: Case Selection Based on High Resolution CT: Outcome at Median Follow-up of 105 Months (ID 4454)
16:00 - 16:10 | Author(s): J. Yoshida, G. Ishii, K. Nagai, T. Hishida, K. Aokage, M. Tsuboi, H. Ito, T. Yokose, H. Nakayama, K. Yamada
- Abstract
- Presentation
Background:
The objective of this study is to confirm limited resection efficacy as radical surgery in patients with minimally invasive lung cancer as indicated by high-resolution (HR) computed tomography (CT), and to confirm intraoperative cytology as a negative margin indicator and reliable margin non-recurrence predictor.
Methods:
Enrollment required patients with a tumor ≤ 2 cm in diameter, diagnosed or suspected as a clinical T1N0M0 carcinoma in the lung periphery based on a CT scan. They had to have a HRCT scan indicating a sub-solid nodule with tumor disappearance ratio; TDR ≥ 0.5. (TDR = 1- DM/DL; DM: maximum tumor diameter on mediastinal settings, DL: maximum tumor diameter on lung settings). Patients unfit for lobectomy and systematic lymph node dissection were excluded. We performed a wedge or segmental resection. The used stapling cartridges were washed with saline, which was cytologically evaluated. If cytology was cancer positive, additional margin was resected, and cytologic examination repeated. If the second exam was positive, a routine lobectomy and systematic lymph node dissection was performed. We aimed at enrolling 100 patients. The primary endpoint is 10-year local recurrence free survival rate.
Results:
This prospective study started in November 2003, and 101 patients were enrolled in 6 years. Of them, 99 were eligible for analysis. The mean age was 62 years (range: 30-75), and 60 were women. There were 11 Noguchi type A tumors, 54 type B tumors, 26 type C tumors, one type D tumor, one malignant lymphoma, 3 hyperplastic lesions, and 3 inflammatory fibroses. None of the 93 malignant nodules showed any vessel invasion. Although no positive cytology results were obtained, pathologically positive margin was reported after surgery in one type C patient. He later underwent a routine lobectomy and systematic lymph node dissection. There was no clear correlation between tumor size, TDR, and Noguchi subtype. No mortality occurred, but one patient developed postoperative pneumothorax and pneumonia, and another hemorrhagic gastric ulcer. With a median follow-up period of 105 months (range: 72−129) as of June 2016, there have been no recurrences, but one patient died for unspecified cause.
Conclusion:
We have repeatedly warned that delayed cut-end recurrence is possible following limited resection even for small sub-solid lung cancers. So far, however, HRCT scans appear to predict non- or minimally invasive sub-solid lung cancers with high reliability, warranting limited resection as curative surgery in this cohort. Intraoperative cytology reliably indicated negative margins and seems to predict freedom from local recurrence.
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OA15.02 - Survival Outcomes in Sublobar Resection for Clinical T1N0M0 Non-Small Cell Lung Cancer: Wedge Resection or Segmentectomy (ID 4710)
16:10 - 16:20 | Author(s): A.K. Kobayashi, R. Ishikawa, M. Takao, A. Shimamoto, A. Ito, H. Shimpo
- Abstract
- Presentation
Background:
Lobectomy remains the standard treatment for early-stage non-small cell lung cancer (NSCLC).In practice, however, sublobar resection has been selectively offered for patients with clinical Stage IA NSCLC as curative treatment. To seek optimal surgical procedure for early stage lung cancer, we carried out retrospective analyses of 2122 patients who had undergone limited resection for c-T1N0M0 NSCLC from 26 institutions of Japanese association for chest surgery.
Methods:
A total of 1963 patients with lobectomy tolerance were eligible for survival analysis. We retrospectively categorized patients of these nodules on numbers of criteria for CT findings; scores were added according to the dominance of ground glass appearance (GGA); >75% = 0, <75% =1, and size of tumor; T1a =0, T1b =1. Statistical analyses were carried out using propensity-matching and Kaplan-Myer with log-rank testing.
Results:
We analyzed 1:1 matched 731 patients for segmentectomy and wedge resection with propensity matching.The overall survival (OS) for score 0 group was 90.2% in segmentectomy (n=419) and 94.7% in wedge resection (n=451) (p=0.0351). The disease free survival (DFS) for score 0 group was 90.2% in segmentectomy and 92.7% in wedge resection (p=0.0645). The OS for score 1 group was 93.6% in segmentectomy (n=278) and 80.4% in wedge resection (n=246)(P<0.001)(Fig. 1). The DFS for score 1 group is 94.1% in segmentectomy and 75.3% in wedge resection (P<0.001). The OS for scores 2 was 79.1% in segmentectomy (n=34) and 69.2% in wedge resection (n=34) (p=0.109). The DFS for score 2 group was 87.0% in segmentectomy and 58.1% in wedge resection (p=0.581). Figure 1
Conclusion:
This study showed that GGA dominant T1a may be treated by wedge resection where possible. The consolidation dominant T1b did not benefit from sublobar resection. In patients with GGA dominant T1b or consolidation dominant T1a, anatomical segmentectomy with curative intension may provide better prognosis.
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OA15.03 - Comparison of Prognosis between Lobectomy and Sublobar Resection for Clinical Stage I Non-Small Cell Lung Cancer with Interstitial Lung Disease (ID 4063)
16:20 - 16:30 | Author(s): Y. Tsutani, T. Mimura, Y. Kai, M. Ito, Y. Handa, N. Tsubokawa, K. Misumi, H. Hanaki, Y. Miyata, M. Okada
- Abstract
- Presentation
Background:
The prognosis after standard lobectomy for non-small cell lung cancer (NSCLC) with interstitial lung disease (ILD) is poor. This study aimed to compare the prognosis after lobectomy and sublobar resection for early NSCLC with ILD.
Methods:
Among 794 consecutive patients with clinical stage I NSCLC who underwent complete resection, 107 patients with ILD on high-resolution computed tomography (HRCT), which was defined according to the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association classification, were identified.
Results:
Overall survival (OS) was significantly worse for patients with possible usual interstitial pneumonia (UIP) or UIP pattern than those with inconsistent with UIP pattern (3-year OS, 64.5% vs. 82.1%, respectively; P = 0.031). No significant difference existed in OS between lobectomy and sublobar resection for all patients with ILD (3-year OS, 67.1% vs. 81.9%, respectively; P = 0.14). Although in patients with inconsistent with UIP pattern, OS was similar between lobectomy and sublobar resection groups (3-year OS, 81.1% vs. 83.6%, respectively; P = 0.87), OS was better for patients who underwent sublobar resection than lobectomy in patients with possible UIP or UIP patterns (3-year OS, 81.0% vs. 50.5%, respectively; P = 0.069). Multivariate Cox analysis demonstrated that preoperative diffusing capacity of the lung for carbon monoxide (P = 0.018), not the surgical procedure (P = 0.14), was an independent prognostic factor for OS.
Conclusion:
Sublobar resection can be an alternative choice for clinical stage I NSCLC with ILD especially for UIP or possible UIP patterns on HRCT.
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OA15.04 - Discussant for OA15.01, OA15.02, OA15.03 (ID 7090)
16:30 - 16:45 | Author(s): S.B. Watzka
- Abstract
- Presentation
Abstract not provided
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OA15.05 - Anatomical Pulmonary Segmentectomy and Sub-Sebmentectomy for Lung Cancer Using the Novel Fluorescence Technique with Vitamin B2 (ID 5305)
16:45 - 16:55 | Author(s): R. Waseda, Y. Tatsuzawa, I. Matsumoto, H. Takemura
- Abstract
- Presentation
Background:
The identification of an accurate segment is essential for successful anatomic pulmonary segmentectomy. We have previously developed a new fluorescence technique using a PDD endoscope system[TM] and vitamin B2 for identification of pulmonary segments in animal experiments. In this study, we applied this technique clinically to examine the efficacy and safety in anatomical pulmonary segmentectomy and sub-segmentectomy for pulmonary malignancies.
Methods:
Our technique requires two key instruments, a PDD endoscope system[TM](KARL STORZ GmbH and Co., Tuttlingen, Germany) as a fluorescence sensing device and vitamin B2 solution as a fluorescent substance. 17 patients with small lung nodules were enrolled in this study. Regarding our surgical technique, after identification of the target segmental or sub-segmental bronchus, vitaminB2 solution is injected via the bronchus. The target segment is identified as a fluorescent segment with the PDD endoscope system[TM]. The identified segment is resected with an electric cautery, stapling devices, or combination of them. In case patient’s lung has severe abnormal change such as emphysema or fibrosis, another technique is indicated. After ligation of the target segmental or sub-segmental artery, vitaminB2 solution is systemically administrated with intravenous injection. The target segment is identified as a defect of fluorescence with the PDD endoscope system[TM]. Following outcomes were collected; success rate of identifying the pulmonary segments, pathological evaluation of dissection margin, duration of chest drainage, and perioperative complications.
Results:
A total of 18 procedures were performed using this technique. Performed segmentectomy or sub-segmentectomy were as follows; Right S1, S2, S3, S2a+3b, S6, S9, Left S1+2, S3, S4+5, S6, S8a+9b, S9+10. Resected nodules were 14 primary lung cancers, 1 MALT-lymphoma, 1 metastatic lung cancer, and 2 benign lung nodules. Histology of primary lung cancer was adenocarcinoma in all 14 cases. Pathological stage of lung cancer was 12 stageIA (pT1a; 10, pT1b; 2), 1 stageIIA (pT1aN1), and 1 stageIIIA (pT1aN2). The success rate of identifying pulmonary segments was 100%. Dissection of segmental border was performed with only electric cautery in 12 procedures, and with both of electric cautery and stapling device in 6 procedures. In all cases, no cancer cells were found on the resection margin pathologically. Mean drainage time was 1.7 days (1-4 days). Regarding perioperative complications, veno-vagal reflex was occurred after systemic injection of vitaminB2 in one case, and 1 delayed pneumothorax was found in one case.
Conclusion:
Our novel fluorescence technique involving a PDD endoscope system[TM] and vitaminB2 allowed performing accurate and safe pulmonary segmentectomy and sub-segmentectomy.
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- Abstract
- Presentation
Background:
Although the confirmation of an appropriate resection margin from the tumor is crucial for reducing the risk of local recurrence after lung segmentectomy for pulmonary malignancies, there has been no method of measurement. We established a novel approach for performing segmentectomy by using an infrared thoracoscopy with transbronchial instillation of indocianine green (ICG), and improved this method by adding an advanced computer technology via lung volume analyzer for obtaining an appropriate resection margin.
Methods:
Preoperatively, each patient underwent multislice enhanced computed tomography (CT) using 320-slice scanners for pulmonary angiography and virtual bronchoscopy, and to create several virtual segmentectomies by using Volume Analyzer Synapse VINCENT (Fujifilm co., Tokyo, Japan). We measured the shortest distance from the tumor to the resection margin in each simulated segmentectomy and selected the most appropriate area of sublobar resection based on the adequate resection margin of approximately 2 cm from the tumor. We prospectively performed segmentectomy in 17 patients and compared between simulated distance and actual distance measured from the specimen.
Results:
The average number of created patterns of virtual segmentectomy in each case was 4.1 ± 1.0. The mean distance of resection margin in selected virtual segmentectomy was 19.3 ± 9.7 mm. On the other hand, actual shortest distance in resected specimen was 25.4 ± 8.1 mm, which was significantly longer than simulated distance (p=0.027). There was no tumor recurrence in all patients.
Conclusion:
Lung volume analyzer was an excellent tool for selecting an ideal area of sublobar resection with an appropriate resection margin.
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- Abstract
- Presentation
Background:
The standard surgical treatment of stage I non-small cell lung cancer is anatomical lobectomy. However, in some cases, small peripheral lung cancer (≤2cm) is treated by sublobar resection. The purpose of this study was to define the necessity of completion lobectomy when the tumor was revealed as non-small cell lung cancer with pleural invasion or lymphovascular invasion after sublobar resection.
Methods:
We retrospectively reviewed 271 consecutive patients who underwent curative resection for stage I non–small cell lung cancer of 2 cm or less. We analyzed clinicopathological findings and survival between two groups with either invasion-positive tumor (tumor with visceral pleural invasion or lymphovascular invasion) or invasion-negative tumor (tumor without visceral pleural invasion and lymphovascular invasion): sublobar resection group and lobectomy group.
Results:
Except for age and pulmonary function, there were no differences in clinocopathological characteristics between sublobar resection group and lobectomy group with invasion-positive tumor or invasion-negative tumor. There was no difference in the 5-year recurrence-free survival rate between two groups in the invasion-positive tumor and invasion-negative tumor (78.9% vs 79.8%; p=0.928, 80.2% vs 85.4%; p=0.505). In the multivariate analysis, only number of dissected lymph nodes was a significant recurrence-related factor of stage I invasive-positive non-small cell lung cancer (hazard ratio 0.914, 95% confidence interval 0.845-0.988, p=0.023). Sublobar resection was not a risk factor for recurrence.
Conclusion:
The survival between sublobar resection group and lobectomy group in small (≤2cm) non-small cell lung cancer with visceral pleural invasion or lymphovascular invasion were not different. Completion lobectomy is not necessary in small lung cancer after sublobar resection whether the tumor has visceral pleural invasion or lymphovascular invasion.
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OA15.08 - Discussant for OA15.05, OA15.06, OA15.07 (ID 7091)
17:15 - 17:30 | Author(s): W. Zhong
- Abstract
- Presentation
Abstract not provided
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Author of
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MTE15 - Lymph Node Mapping in Lung Cancer (Ticketed Session) (ID 309)
- Event: WCLC 2016
- Type: Meet the Expert Session (Ticketed Session)
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 07:30 - 08:30, Strauss 1
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MTE15.02 - Lymph Node Mapping in Lung Cancer (ID 6567)
08:00 - 08:30 | Author(s): D. Waller
- Abstract
- Presentation
Abstract:
LYMPH NODE MAPPING IN LUNG CANCER Kenji Suzuki (Japan), David Waller (UK) The How and Why ? The Aim will be to outline the various methods to map the extent of lymph node metastasis from a primary NSCLC and to assess the clinical application and implications of each intervention. The Aim will also be to highlight the following areas of clinical debate and controversial issues 1.Preoperative Non-invasive – Lymph node mapping may start with simple Ultrasound guided cervical node aspiration cytology [1] . Can this be all that is needed in some advanced cases? c Can computed tomography/ positron emission tomography (CTPET) be relied upon to obviate the need for invasive nodal mapping ? Can newer techniques including CT lymphography [2] improve the accuracy of mapping ? Does magnetic resonance imaging (MRI) have a role in preoperative lymph node mapping. Invasive – We will consider in detail the debate between endobronchial and endoluminal ultrasound (EBUS/EUS) and surgical lymph node mapping. What role, if any, does cervical mediastinoscopy have in addition to EBUS/EUS [3] ? Does the increased sensitivity of more invasive surgical mediastinal procedures like VAMLA [4] and TEMLA contribute significantly to preoperative mapping ? We will discuss why these investigations should influence primary therapy and which patients should undergo induction therapy and which should have primary resection. Evidence from the latest TNM revision suggest that mediastinal nodal disease needs more accurate mapping than previously appreciated. We will consider how many of these stages of mapping are required before making a decision to operate and will propose a controversial algorithm for surgical treatment of N2 disease [5]. 2.Intraoperative We will discuss the arguments surrounding the necessary extent of intraoperative lymph node dissection. We will consider the relative merits of the methods for intraoperative sentinel node identification including Near Infrared thoracoscopy and radiolabelling [6,7]. We will ask whether the investment in technology and time is beneficial for the patient. Is the added information about metastases of clinical value ? We will evaluate the argument between nodal sampling vs systematic nodal dissection [8] and attempt to formulate an intraoperative mapping algorithm. Intraoperative nodal mapping has been proposed as a prerequisite to direct the extent of lung resection. We will examine how the findings of nodal disease have been used to discriminate between lobectomy vs pneumonectomy or between lobectomy vs segmentectomy. We will consider the argument that nodal metastatic disease is not a justification for more extensive sacrifice of functioning lung tissue. Is there any role for intraoperative nodal analysis in determining the extent of resection? How reliable is this method of nodal mapping. 3.Postoperative Once the pathologist has the resected lymph nodes we will attempt to rationalize how they should be analysed, asking the question : “ What are the minimum sampling requirements ?”. We will also analyse whether the more detailed nodal mapping of micrometastatic disease by immunohistochemistry significantly influences patient management or outcome [10] ? Finally we will discuss how these pathological results could influence the use of adjuvant chemotherapy/ radiotherapy or more interestingly targeted therapies. We intend the session to be interactive between presenters and delegates with a free exchange of ideas and experience. We hope to stimulate delegates to re-evaluate their own approach to lung cancer staging. References 1. Chang DB, Yang PC, Yu CJ, Kuo SH, Lee YC, Luh KT.Ultrasonography and ultrasonographically guided fine-needle aspiration biopsy of impalpable cervical lymph nodes in patients with non-small cell lung cancer.Cancer. 1992 Sep 1;70(5):1111-4 2. Suga K, Yuan Y, Ueda K, Kaneda Y, Kawakami Y, Zaki M, Matsunaga N Computed tomography lymphography with intrapulmonary injection of iopamidol for sentinel lymph node localization. Invest Radiol. 2004 Jun;39(6):313-24. 3. Annema JT, van Meerbeeck JP, Rintoul RC, Dooms C, Deschepper E, Dekkers OM, De Leyn P, Braun J, Carroll NR, Praet M, de Ryck F, Vansteenkiste J, Vermassen F, Versteegh MI, Veseliç M, Nicholson AG, Rabe KF, Tournoy KG. Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial .JAMA. 2010 Nov 24;304(20):2245-52 4. Witte B, Hürtgen M.Video-assisted mediastinoscopic lymphadenectomy (VAMLA).J Thorac Oncol. 2007 Apr;2(4):367-9 5. De Leyn P, Dooms C, Kuzdzal J, Lardinois D, Passlick B, Rami-Porta R, Turna A, Van Schil P, Venuta F, Waller D, Weder W, Zielinski M. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg. 2014 May;45(5):787-98 6. Hachey KJ, Colson YL. Current innovations in sentinel lymph node mapping for the staging and treatment of resectable lung cancer. Semin Thorac Cardiovasc Surg. 2014 Autumn;26(3):201-9 7. Tomoshige K, Tsuchiya T, Otsubo R, Oikawa M, Yamasaki N, Matsumoto K, Miyazaki T, Hayashi T, Kinoshita N, Nanashima A, Nagayasu T.Intraoperative diagnosis of lymph node metastasis in non-small-cell lung cancer by a semi-dry dot-blot method.Eur J Cardiothorac Surg. 2016 Feb;49(2):617-22 8. Darling GE, Allen MS, Decker PA, Ballman K, Malthaner RA, Inculet RI, Jones DR, McKenna RJ, Landreneau RJ, Rusch VW, Putnam JB Jr. Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 Trial . J Thorac Cardiovasc Surg. 2011 Mar;141(3):662-70 9. Nomori H, Cong Y, Sugimura H. Utility and pitfalls of sentinel node identification using indocyanine green during segmentectomy for cT1N0M0 non-small cell lung cancer. Surg Today. 2016 Aug;46(8):908-13 10. Deng XF, Jiang L, Liu QX, Zhou D, Hou B, Cui K, Min JX, Dai JG Lymph node micrometastases are associated with disease recurrence and poor survival for early-stage non-small cell lung cancer patients: a meta-analysis. J Cardiothorac Surg. 2016 Feb 16;11:28.
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P3.03 - Poster Session with Presenters Present (ID 473)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.03-005 - Inhibition of PRMT5 is Synthetic Lethal in Mesotheliomas Harboring MTAP Loss (ID 6078)
14:30 - 14:30 | Author(s): D. Waller
- Abstract
Background:
Mesothelioma remains an incurable cancer with limited therapy. Genetically targeted personalised treatment strategies are currently lacking. Mesotheliomas harbor frequent loss of chromosome 9p21.3 locus encoding for CDKN2A and frequently encompassing methyladenosine phosphoryl transferase (MTAP). Loss of MTAP has recently been shown to be associated with dependency on the symmetrical demethylation of arginine-4 on histone H4 methyltransferase PRMT5. We sought to determine whether mesothelioma cells with MTAP HD would be vulnerable to inhibition of PRMT5, and to explore the pharmacodynamics associated with its suppression.
Methods:
Genome-wide copy number variation (CNV) analysis was undertaken in 94 patients. CNVs were determined using the array based platform, Affymetrix Oncoscan v3. Multiregional whole exome sequencing was also performed on samples from 6 patients. The expression of MTAP and the effect of the drugs tested on H4R3Me2s was evaluated by western blot. Cell growth was analysed by clonogenic assay after focused RNAi targeting MTAP and/or PRMT5, or treatment with a PRMT5 inhibitor
Results:
Oncoscan analysis identified homozygous loss of CDKN2A in 50%, and heterozygous loss in 20.2% of patients. Homozygous loss of MTAP was seen in 39.3% and heterozygous loss in 28.7%, 76.6% of patients had concurrent loss of CDKN2A and MTAP. Homozygous MTAP deletion was found to be present in all regions of tumour ie a truncal deletion, in 3 out of 6 patients. In 65 patients treated with surgery only, homozygous loss of CDKN2A or MTAP was prognostic for progression free survival (CDKN2A: 7.5 vs. 32.9 months, HR 4.536 95%CI 1.765-11.659, p=0.002; MTAP: 7.5 vs. 18.4 months, HR 3.289 95%CI 1.314-8.237, p=0.007). To determine the dependency of MTAP negative cells on PRMT5, we used either siRNA targeting PRMT5 or a PRMT5 inhibitor. PRMT5 silencing did not induce measurable apoptosis however a significant suppression of clonogenic activity was observed after 10 days in MTAP negative cells(H2591). The same effect was observed after concurrent silencing of PRMT5 and MTAP in MTAP positive mesothelioma cells(MPP89). We then utilised a PRMT5 small molecule inhibitor, EPZ015666, to recapitulate RNAi knockdown. Although a clear suppression of H4R3Me2s was observed after 96 hours treatment, the relative potency on clonogenic assay was less than RNAi.
Conclusion:
Homozygous deletion of MTAP is a common genetic event in mesothelioma. Suppression of PRMT5 represents a novel potential approach for targeting mesotheliomas with 9p21.3 loss. The discrepancy between small molecule inhibitors and RNAi, suggests that PRMT5 dependence may require functions that extend beyond its methyltransferase function.
