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H. Onishi

Moderator of

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    O10 - Stereotactic Ablative Body Radiotherapy (ID 104)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 8
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      O10.01 - Exploring the optimal biologically effective dose of stereotactic body radiation therapy for Stage I non-small-cell lung cancer - An update (ID 3030)

      16:15 - 17:45  |  Author(s): J. Wang, B. Li, J. Zhang

      • Abstract
      • Presentation
      • Slides

      Background
      To investigate the relationship between the different levels of biologically effective dose (BED) and the outcome of stereotactic body radiation therapy (SBRT) for Stage I non–small-cell lung cancer (NSCLC).

      Methods
      Eligible studies were identified on Medline, Embase and the Cochrane Library from January 2001 to March 2013. According to the quartile of included studies, BED was divided into four dose groups: low (<100Gy), medium (100–112.3Gy), medium to high (112.3–135Gy), high (>135Gy). To obtain pooled estimates of overall survival (OS), local control rate (LCR), cancer-specific survival(CSS), regional failure rate(RFR), distant failure rate (DFR),data were combined in a random effect model. The difference in pooled estimate among BED groups was assessed with the Pearson chi-squared test. The meta-regression model was used to explore the relationship between the characteristics of the studies and the prognostic index.

      Results
      Fifty-nine observational studies with a total of 5,562 patients were included in the meta-analysis. Pooled estimates of 2-year and 3-year OS in the medium BED (79%, 71%) group were higher than in the low (64%, 57%) or medium to high BED (69%, 57%) or high groups (66%, 56%), respectively (p<0.001, p<0.001, p<0.001,respectively). Pooled estimates of 2-year LCR in the medium BED (89%) group was lower than in medium to high BED (94%)or high groups (94%), respectively (p=0.003,0.009 respectively). While no significant differences were observed between each two of four different levels of BED and the 3-year RFR.

      Conclusion
      Based on the meta-analysis, a statistically significant OS benefit at 2 and 3 years can be demonstrated in the treatment of Stage I NSCLC with the delivery of medium BED compared with low, medium to high BED or high BED. The medium BED (range, 100–112.3Gy) for SBRT may currently be more beneficial and reasonable in Stage I NSCLC.

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      O10.02 - Radiation Therapy Oncology Group (RTOG) protocol 0915: A randomized phase II study comparing 2 Stereotactic Body Radiation Therapy (SBRT) schedules for medically inoperable patients (pts) with stage I peripheral Non-Small Cell Lung Cancer. (ID 68)

      16:15 - 17:45  |  Author(s): G. Videtic, C. Hu, A. Singh, J. Chang, W. Parker, K. Olivier, S. Schild, R. Komaki, J. Urbanic, H. Choy

      • Abstract
      • Presentation
      • Slides

      Background
      To select the most favorable treatment regimen based on the rate of grade 3 or higher protocol-specified adverse events (psAEs) at 1 year.

      Methods
      Pts with documented baseline medical conditions precluding lobectomy and biopsy-proven peripheral (greater than 2 cm from the central bronchial tree) T1/T2, N0 (clinically node negative by PET), M0 tumors were eligible. Patients (pts) were randomized to receive either 34 Gy in one fraction (arm 1) or 48 Gy in 4 consecutive once-daily fractions (arm 2). Rigorous central accreditation and quality assurance assessments were used to assure pts were treated according to protocol guidelines. The study was designed to detect whether psAEs rate>17% at a 10% significance level (1-sided) and 90% power. Secondary endpoints included primary tumor control (PC) rate, 1-year overall survival (OS), progression-free survival (PFS). The regimen selection criteria were based on pre-specified rules of psAEs and PC for each arm. Formal comparisons were not performed.

      Results
      The study opened in September 2009 and closed in March 2011 after accruing a total of 94 pts. Median follow up was 20.6 months. Of 86 evaluable pts, 41 were in arm 1 and 45 in arm 2. Baseline pt and tumor characteristics were balanced between both arms. 4 (9.8%) pts on arm 1 (95% CI: 2.7-23.1%; p=0.151) and 6 (13.3%) pts on arm 2 (95% CI: 5.1-26.8%; p=0.337) experienced psAEs. 39 (95.1%) pts on arm 1 and 45 (100%) pts on arm 2 received planned SBRT treatment. Contouring compliance indicated 100% and 95.6% of targets and 89.5% and 82.2% of normal tissue structures were outlined per protocol/minor deviations, for arms 1 and 2, respectively. OS at 1 year was 85.4% (95% CI: 70.3-93.1%) for arm 1 pts and 91.1% (95% CI: 78.0-96.6%) for arm 2. PFS at 1 year was 78.0% (95% CI: 62.1-87.9%) for arm 1 and 84.4% (95% CI: 70.1-92.3%) for arm 2. The PC rates at 1 year were 97.1% (95% CI: 85.1-99.9%) for arm 1 and 97.6% (95% CI: 87.1-99.9%) for arm 2.

      Conclusion
      At one year, 34 Gy in one fraction met pre-specified criteria with respect to adverse events and primary control, and therefore is selected as the experimental arm for a planned phase III trial. Supported by RTOG U10 CA21661 and CCOP U10 CA37422 grants from NCI.

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      O10.03 - Safety of Endobronchial Implantation of Electromagnetic Fiducials for Real-time Tracking of Lung Tumors during Radiotherapy (ID 2040)

      16:15 - 17:45  |  Author(s): D.A. Nader

      • Abstract
      • Presentation
      • Slides

      Background
      Lung tumor control has improved with advances in radiotherapy delivery (RT). Respiratory motion inders improvements. An Anchored Beacon® transponder (Varian Medical Systems, Palo Alto, CA) can track lung tumors in real time during RT. This study evaluates the safety of these bronchoscopically implanted transponders in 50 lung tumor patients undergoing RT

      Methods
      Each patient underwent implantation of 3 anchored transponders in the lung. A delivery catheter was inserted into the bronchoscope and using fluoroscopic guidance +/- radial endobronchial ultrsound (EBUS) and/or electromagnetic guidance (superDimension): the catheter was positioned in a 2-2.5 mm diameter airway, within 3 cm of the tumor. The transponder was deployed by depressing a plunger within the delivery catheter. The catheter was then withdrawn. CT's were acquired before RT and every 1-2 weeks during treatment. Transponder positions were measured.

      Results
      50 patients (28 female/ 22 male) with median age 64 had transponders inplanted. Follow-up ranged from 0- 15.5 months (median 9.2). Positional stability of the Anchored transponders over the course of RT was confirmed. Inter-transponder distance from serial CT scans have been evaluated in 47 of 49 patients who underwent RT. Inter-transponder distances were stable over the course of radiation therapy for 140/141 (99%) of Anchored transponders. 2 Anchored transponders migrated, one after completion of RT. Safety: 2 patients (4%) sustained pneumothorax with insertion. Each resolved within one day with chest tube placement and withdrwal. One patient sustained a cardiac arrest prior to bronchoscopy for implantation. 2/147 (1%) sustained migration. Patient A coughed one transponder. which was placed in too large and proximal airway. Patient B was found the have the transponder migrating to the pleural space associated with a suppurative lung infection 3 months post-treatment.

      Conclusion
      Bronchoscopic implantation of Anchored transponders can be performed with few complications. Anchored transponders are positonally stable in the lung with a 99% retention rate. There are multiple advantages to real-time localization and tracking of lung tumors. The Anchored transponder demonstrated a high safety profile and significantly low migration.

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      O10.04 - DISCUSSANT (ID 3929)

      16:15 - 17:45  |  Author(s): U. Ricardi

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      O10.05 - Blinded assessment of radiological changes after stereotactic ablative radiotherapy for early-stage lung cancer: local recurrences versus fibrosis. (ID 1416)

      16:15 - 17:45  |  Author(s): S. Senthi, K. Huang, D. Palma, A. Warner, B. Slotman, S. Senan

      • Abstract
      • Presentation
      • Slides

      Background
      Stereotactic ablative radiotherapy (SABR) is now a guideline-recommended treatment for early-stage lung cancer (ES-NSCLC), achieving 5-year local control rates of approximately 10%. The timely detection of local recurrence (LR) and early salvage following SABR is impaired by fibrotic changes, which occur commonly. Seven high-risk CT features (HRFs) that suggest LR include; enlarging opacity, cranio-caudal growth, sequential enlarging opacity, enlarging opacity after 12 months, bulging margin, loss of linear margin and loss of air bronchograms. We validated these, performing blinded clinician assessment in patients with and without LR.

      Methods
      ES-NSCLC patients treated with SABR, who developed pathology-proven LR (n=12), were matched 1:2 to patients without clinical LR (n=24), based on tumor location, SABR fractionation, PTV size and follow-up duration. Three radiation oncologists assessed serial follow-up CT images for HRFs, while blinded to outcomes. The sensitivity and specificity of HRFs and combinations of these were determined.

      Results
      The median follow-up was 24 months (range 6-67) and both cohorts were well matched. All HRFs were significantly associated with LR (p≤0.002), Table 1. The best individual predictor of LR was opacity enlargement after 12 months (100% sensitivity, 83% specificity), however this was detected slowest, at a median 22 months. The earliest HRF detected was cranio-caudal growth detected at a median 13 months. The HRFs enlarging opacity and cranio-caudal growth were each detected at least 3 months prior to the actual diagnosis of LR 42% of the time. The odds of LR increased 4-fold for each additional HRF detected (p<0.001). The sensitivity and specificity of detecting multiple HRFs is shown in Table 2, with ≥3 HRFs being the best predictor of LR (sensitivity 92%, specificity 92%). Figure 1 Figure 2

      Conclusion
      LR following SABR can be accurately predicted by the presence of HRFs on surveillance CT scans. This approach may reduce unnecessary confirmatory procedures, and facilitate earlier salvage treatment.

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      O10.06 - Inter-Rater Reliability of the Categorization of Late Radiographic Changes after Lung Stereotactic Body Radiation Therapy (SBRT) (ID 1901)

      16:15 - 17:45  |  Author(s): S. Faruqi, M. Giuliani, H. Raziee, M.L. Yap, H. Roberts, L. Le, A. Brade, B.C.J. Cho, A. Sun, A. Bezjak, A. Hope

      • Abstract
      • Presentation
      • Slides

      Background
      Radiographic changes following lung SBRT have been previously categorized into 4 groups: modified conventional pattern (A), mass-like fibrosis (B), scar-like fibrosis (C) and no evidence of increased density (D) (Dahele et al.).The purpose of this study was to assess the inter-rater reliability of this categorization in patients with early stage non-small cell lung cancer.

      Methods
      79 patients treated with SBRT for early stage NSCLC at a single institution who had a minimum follow-up of 6 months were included in this study. Serial post-treatment CT images were presented to expert clinicians (up to 6) familiar with post-SBRT radiographic changes and were scored by each individual in a blinded fashion according to the published categorization of A, B, C or D. The proportion of patients categorized as A, B, C or D at each interval was determined. Krippendorff's alpha (KA) was used to establish inter-rater reliability at each time point. A leave-one-out analysis was performed at each time point on each rater to determine the sensitivity of the KA score to an individual rater. To explore if a training effect existed the KA of the first and last 20 patients scored by the raters was determined.

      Results
      There were 351 ratings on 67 patients at 12mo, 250 ratings on 49 patients at 24mo, 169ratings on 31 patients at 36mo and 80 ratings on 14 patients at 48mo. The proportion of patients scored in each category of A,B,C &D is reported in Table 1. Table 1: Scale Category by Time-Point

      A (Modified-Conventional) B (Mass-like Fibrosis) C (Scar-like Fibrosis) D (No Evidence of Increased Density)
      6 months 43% 9% 6% 42%
      12 months 50% 16% 11% 23%
      18 months 46% 18% 16% 20%
      24 months 46% 22% 17% 15%
      36 months 40% 24% 21% 15%
      48 months 29% 24% 31% 16%
      Category A was the most common at all time points except 48 months when category C was the most common. KA was 0.28, 0.27, 0.18 and 0.27 at 12, 24, 36 and 48 months respectively. The range of KA in the leave-one-out analysis was 0.25-0.31, 0.24-0.27, 0.15-0.22 and 0.24-0.31 at 12, 24, 36 and 48 months respectively. The KA of the first 20 patients vs the last 20 patients was 0.34 vs 0.47 at 12 months.

      Conclusion
      The predominant pattern of post SBRT radiographic changes evolves over time. In this study categorization of late post-SBRT radiographic changes has moderate inter-rater agreement. There is a suggestion of a training effect with more experience. However, categorization of late radiographic changes following SBRT is challenging and may require specific training.

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      O10.07 - Dose-response analysis of radiation induced rib fractures after SBRT for NSCLC (ID 2690)

      16:15 - 17:45  |  Author(s): B. Stam, A. Scheenstra, J. Belderbos, H. Peulen, J. Nijkamp, J.J. Sonke

      • Abstract
      • Presentation
      • Slides

      Background
      Symptomatic rib fractures occur in approximately 5% of patients treated with SBRT for early stage NSCLC. Only in small patient cohorts has the dose-effect relation of radiation induced rib fractures been determined. Recent developments in automatic rib segmentation allow determining the dose-effect relation in a large patient cohort, which is the aim of this study.

      Methods
      From 2006-2012 453 patients with early stage NSCLC were treated with SBRT (3x18 Gy). Follow-up (FU) consisted of a physical examination and a CT scan 4 months after treatment and every 6 months up to two years and yearly thereafter. For the first 101 patients with FU>6 months, all ribs were automatically segmented using 15 atlases of manually delineated ribcages. A non-rigid registration followed by a multi-level label fusion produced for each patient a set of ribs. The physical dose distributions were NTD (Normalized Total Dose) corrected with α/β=3 Gy. Cox proportional hazard regression analysis, which takes into account the time to event with patient as random intercept, was used to find the optimal dose parameter. Evaluated were the dose received by x% of the rib D~x~ (x ranged 1-30%) and equivalent uniform dose (EUD) (volume effect 1/n ranged 0.1-60). The Lyman-Kutcher-Burman (LKB) model based on this optimal dose parameter was used to model the dose-effect relationship. Using maximum-likelihood estimation, parameters were median toxic dose (TD~50~), steepness parameter m and 1/n were optimized.

      Results
      In 354 patients with FU>6 months (median 22 months), 38 patients(11%) were diagnosed with a total of 49 rib fractures, symptomatic (grade 2) for 9 patients(2.5%). Included in the dosimetric analysis were 2410 ribs (14 ribs outside field-of-view). 26 ribs in 15 patients(15%) were fractured, symptomatic for 4 patients(4%). In the univariate analysis, all dose parameters significantly correlate with rib fracture (p-values<0.001). Hazard ratios (95%CI) for the parameters with highest log likelihood: D~1~=1.022 (1.017-1.027) and EUD~0.033~=1.021 (1.016-1.026). Multivariate analysis identified EUD as the predictor with the highest log-likelihood and was used in the LKB model. The optimal LKB parameters to predict rib fracture in this dataset were (95% CI): TD~50~=395.5 Gy (244.3-555.1), m=0.348 (0.311-0.384) and 1/n=32.3 (4.82-inf). The risk of rib fracture was <5% in case the NTD-corrected EUD<170 Gy.Figure 1

      Conclusion
      In this subgroup of NSCLC patients treated with 3x18Gy, the risk of rib fracture was significantly correlated to the dose, and was <5% in case the biological dose is kept under 170 Gy.

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      O10.08 - DISCUSSANT (ID 3930)

      16:15 - 17:45  |  Author(s): S. Senan

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    MS23 - Treatment of the Small Malignant Nodule (ID 40)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Pulmonology + Endoscopy/Pulmonary
    • Presentations: 1
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      MS23.3 - SABR for Early Stage Lung Cancer and Pulmonary Oligometastases (ID 569)

      14:00 - 15:30  |  Author(s): H. Onishi

      • Abstract
      • Presentation
      • Slides

      Abstract
      With the recent popularization of computed tomography (CT) screening, small malignant nodules are increasingly detected. In Japanese cases of lung cancer surgery, tumors in more than 60% of lung cancer patients were under 3cm in diameter. Stereotactic ablative radiotherapy (SABR) is a new treatment modality where narrow beams from several directions focus on the target while sparing the adjacent normal tissues with high accuracy. By SABR, the biological effect of radiation on tumors was increased and the overall treatment time was shortened. SABR has emerged as one of the radical treatment options for stage I non-small cell lung cancer (NSCLC), mainly in medically inoperable patients. First of all, Uematsu et al reported in 2001, that 3-year local control and overall survival rates of SABR (50-60Gy in 10 fractions) were 94% and 66%, respectively. Then Nagata et al reported in 2005, that 3-year overall survival rate of SABR (48Gy in 4 fractions) was 83% in stage IA and 72% in stage IB. In Japanese multi-centers large database of more than 2000 patients treated with SABR for stage I NSCLC, overall survival rate at three year (OS-3y) and disease-specific survival rate at three year of total patients was 72% and 85%, respectively. Locally progression free rate at three year of T1 and T2 tumors were 87% and 72%, respectively. In USA, Timmerman et al reported in 2010, that 3-year overall survival rate of SABR (54Gy in 3 fractions) was 55.8%. In Europe, Bauman et al reported in 2009, that 3-year overall survival rate of SABR (45Gy in 3 fractions) was 60%. According to a lot of previous studies demonstrating better results of SABR compared with conventional radiotherapy, a consensus that SABR is a standard radical treatment for inoperable patients with stage I NSCLC has been generally accepted. The overall survival rate for subgroup of medically operable patients who rejected surgery in retrospective and prospective studies was almost comparative to that of surgical series considering the same age range though its evidence level is not high. Onishi et al reported five-year overall survival of 87 patients with stage I NSCLC was 69% according to the multicenter retrospective study,. In the phase II trial of SABR with 48Gy in 4 fractions for stage IA (JCOG0403), Nagata et al reported three-year overall of 65 operable patients was 76%. For patients with stage I NSCLC, resection of full lobe and systemic lymph nodes represents standard treatment but can be associated with significant morbidity and even mortality, particularly because patients suffering from lung cancer are often elderly with high comorbidity rates. For such high-risk operable patients, SABR is considered as an alternative option of radical treatment. According to American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, SABR and surgical wedge resection are suggested over no therapy for patients with clinical stage I NSCLC who cannot tolerate a lobectomy or segmentectomy (Grade 2C), but surgical resection has the potential benefit of definitive histologic analysis and pathologic nodal information. In compromised patients for whom such information would not change management and also in patients for whom an adequate margin in unlikely with a surgical wedge resection, SABR is a preferred option. According to good results of these retrospective or prospective studies, some phase III prospective trials comparing SABR versus surgery (lobar resection) have been started, but the patient accrual seems to be difficult. Patient accrual of a trial exploring the efficacy and safety of sublobar resection for patients with smaller tumors has been completed by surgeon recently. SABR is a just local therapy, therefore it essentially should be compared with sublobar resection in high-risk operable patients for lobar resection with such small peripheral tumors. In the meantime, SABR represents a recent trend in radiation oncology also for oligometastases. Local aggressive therapy for oligometastases may improve outcomes, including survival in some cases. SABR has emerged as one option for local therapy against oligometastases in various body sites, most commonly in the lungs and liver. According to published papers of SABR for lung metastases, local control with SABR distributed from 70 to 90% with very low rates of serious toxicities. Although further investigation should be undertaken to clarify the benefits of SABR for the treatment of oligometastases, SABR may be worthwhile for patients who hope for treatment to acquire better local control and possible longer survival. Concerning toxicities, SABR for peripheral tumors is an almost safe and comfortable treatment. Rib fracture is a common adverse effect after SABR but the symptom is generally mild. But severe radiation-related pneumonitis occurs occasionally in the patients having pulmonary fibrosis. As the clear dose-constraint for mediastinal organs has not been demonstrated, the safety of SABR for cases with a central lesion has not been assured. When the tumor recurred only locally after SABR in operable patients, salvage radical surgery was mostly operated safely. Primary radiation therapy remains the primary curative intent approach generally for patients who refuse surgical resection or are determined by a multidisciplinary team to be inoperable or high-risk operable. However, good tumor control, less toxicity, and fewer treatment courses of SABR decrease the indirect costs of cancer care, including lost time and economic productivity secondary to treatment-related and cancer-related illness and death. On the other hand of promising results and advantages of SABR, it is imperative to assess its cost-effectiveness as well as its efficacy because SABR is becoming used in more clinical situations. SABR employing image guidance, high-precision dose delivery, more accurate target definition with better anatomical and biological imaging, and the possibility of dose verification during treatment via dose-adaptive radiation therapy permits a higher probability of tumor control. Such major technological progress certainly comes at a higher cost, and there are many concerns regarding the value of that progress. In the symposium, we will discuss what the benefits and disadvantages of SABR compared to surgical treatment in high or low risk surgical patients with early-stage NSCLC or pulmonary oligometastases are, and how we can decide best to proceed with treatment.

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