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Kevin L Stephans



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    MA01 - Early Stage Lung Cancer: Questions and Controversies (ID 894)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 3
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 202 BD
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      MA01.03 - An Externally Validated Nomogram for Predicting Distant Metastasis After SBRT for Early Stage Non-Small Cell Lung Cancer (ID 11182)

      10:40 - 10:45  |  Author(s): Kevin L Stephans

      • Abstract
      • Presentation
      • Slides

      Background

      SBRT is a standard option for patients with early stage NSCLC who are medically inoperable. While SBRT is associated with excellent local control, distant metastases (DM) represent the primary pattern of failure. Adjuvant systemic therapy has not traditionally been used in this patient population due to medical comorbidities. With the advent of immunotherapy that may be better tolerated, there has been a renewed interest in identifying patients that may derive benefit. We developed and internally validated a nomogram to predict the likelihood of DM after SBRT for early stage NSCLC which was then externally validated.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Our lung SBRT registry was queried for patients with early stage NSCLC treated with definitive intent from 2003-2017 and 1002 patients were identified for analysis to develop the model. A dataset from an external institution was used to similarly identify patients and 737 were used for the validation cohort. Random Survival Forest was used to assess importance, interactivity, and overall predictive ability with respect to DM for 14 variables. A Fine-Gray competing-risks regression model was formulated where apparent interactions were examined with likelihood-ratio tests. Backward variable selection was implemented to reduce to a parsimonious model. The concordance probability (C-index) of the model was internally validated with 10-fold cross validation.

      4c3880bb027f159e801041b1021e88e8 Result

      The median overall survival was 1.71 years internally and 1.92 years externally. Median follow-up was 18.3 months and 21.1 months. 1-year incidence of DM was 16% and 12.1% in the internal and external cohorts, respectively. Random Forest analysis suggested that tumor size and PET SUV are the most important predictors of distant failure. The 1-year cumulative incidence (CI) of DM was 18.5% for PET SUV ≥4.1 vs 8.4% for <4.1. 1-year CI for tumor size >3 cm was 26% vs 12.6% for ≤3 cm. The median time to DM was 0.86 years internally and 1.1 years externally. The final nomogram included tumor size, histology, PET SUV, age, KPS, and active smoking status, and had a cross-validated C-index of 0.62. The nomogram provides predictive value for probability of DM at 1-year between 10 and 70%.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This novel nomogram with external validation can be used to predict the 1-yr DM risk after SBRT for patients with early-stage NSCLC, accounting for the competing risk of death. This nomogram may help define patient subsets for stratification in future clinical trials to help identify who may benefit from adjuvant systemic therapy after SBRT to reduce the incidence of DM and disease-related death.

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      MA01.07 - Validation of RTOG 0813 Normal Tissue Constraints for Pulmonary Toxicity in SBRT for Central Non-Small Cell Lung Cancer (ID 11318)

      11:10 - 11:15  |  Author(s): Kevin L Stephans

      • Abstract
      • Presentation
      • Slides

      Background

      Stereotactic body radiation therapy (SBRT) yields excellent local control rates for medically inoperable early stage "central" non-small cell lung cancer. Normal tissue constraints provided in RTOG 0813, which tested safety and efficacy of lung SBRT for central tumors, were largely based on expert estimates, and clinical validation of constraints is limited. We sought to identify the sensitivity and specificity of the current RTOG constraints for predicting pulmonary toxicity in a large institutional data set.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We identified 136 lesions within 2 cm of the proximal bronchial tree (PBT), treated from 2005 to 2014 from a prospective registry of 1,462 patients. Dose was 50 or 60 Gy given in 5 fractions. Pulmonary toxicity was categorized as pneumonitis or non-pneumonitis (fistula, bronchial stenosis or necrosis, atelectasis, hemoptysis, or clinically significant pleural effusion). A series of dose endpoints for the PBT was generated based on dose volume histograms, where dose levels ranged from 0 Gy to 80 Gy in increments of 0.1 Gy, and volumes ranged from 0.03 cc to 50 cc in increments of 0.03cc. A total of 1,333,600 dosimetric endpoints were analyzed. The sensitivity and specificity of these endpoints in predicting pulmonary toxicity was calculated. The optimal dosimetric endpoint was chosen by identifying the highest F-score.

      4c3880bb027f159e801041b1021e88e8 Result

      We observed nine Grade 2 pneumonitis and 10 Grade ≥ 2 non-pneumonitis toxicities, of which three were Grade 5 (broncho-pleural fistula, left mainstem bronchus necrosis, and bronchial stenosis). The optimal dosimetric endpoint to avoid Grade 2-5 non-pneumonitis toxicity was D0.03cc<50 Gy to the PBT, with 90% sensitivity and 77% specificity. The optimal point dose to avoid Grade 3-5 non-pneumonitis toxicity was D0.3cc<46.5 Gy, with 100% sensitivity and 85% specificity. Applying PBT RTOG constraints to our dataset achieved 18% sensitivity and 91% specificity for D4cc<18 Gy and 29% sensitivity and 93% specificity for D0.03cc<52.5 Gy.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Clinical results from this large institutional data set validate current RTOG constraints for PBT as predictive for pulmonary toxicity. The results also suggest that RTOG constraints D4cc<18 Gy and D0.03cc<52.5 Gy to PBT have moderate sensitivity but excellent specificity for pulmonary toxicity. We identified D0.03cc <50 Gy to PBT as having the largest sensitivity and specificity for toxicity prediction, and this value parallels current RTOG constraint of D0.03cc <52.5 Gy. This analysis suggests that an additional volume/dosimetric constraint of D0.3cc<46.5 Gy may be considered for avoidance of Grade 3-5 non-pneumonitis pulmonary toxicity.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA01.11 - Salvage SBRT for Local Recurrence After Primary Surgical Resection of Early Stage Non-Small Cell Lung Cancer (ID 11284)

      11:40 - 11:45  |  Author(s): Kevin L Stephans

      • Abstract
      • Presentation
      • Slides

      Background

      To report on the patient, tumor and treatment characteristics of patients treated with salvage lung SBRT (sSBRT) for non-metastatic NSCLC that has relapsed after previous surgical resection, and the resulting clinical outcomes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We surveyed our IRB-approved prospective lung SBRT registry for patients who received sSBRT for local recurrence after previous resection of an early stage NSCLC. Following sSBRT, outcomes of interest included local control (LC), overall survival (OS), and treatment-related toxicity graded per CTCAE version 4.0.

      4c3880bb027f159e801041b1021e88e8 Result

      For the interval 2004-2017, 50 (3.4%) pts, of a total of 1,461 lung SBRT cases, met criteria for analysis. Pre-sSBRT surgical approaches were: 23 (46%) wedge resection, 2 (4%) segmentectomy, 20 (40%) lobectomy, 2 (4%) bilobectomy, 1 (2%) pneumonectomy and 1 (2%) with unspecified surgery. At the time of resection, disease stage was: 34 (68%) stage I, 4 (8%) stage II, 5 (10%) stage III and for 3 (6%) pts, pre-operative stage was unknown. Median time to local recurrence after surgery was 27.45 months. At sSBRT, 38 (76%) pts had biopsy-proven recurrence while 12 (24%) had recurrence diagnosed only by radiographic findings. Forty seven (94%) pts could not have surgical salvage due to pulmonary (60%), cardiac (2%), technical unresectability (4%), poor KPS (2%), or multifactorial reasons (26%), with 3 (6%) refusing re-resection. Median age and KPS at salvage treatment was 74 years (range 50-89) and 80 (range 60-100) respectively. The most common sSBRT schedule was 50Gy in 5 fractions (68%), with all schedules having a BED of at least 100 Gy10. Median follow up after sSBRT was 22.2 months (3.8-108.8 months). Eight pts subsequently experienced local or lobar failure (16%), and 9 patients had nodal failure (18%). Median time to local failure after sSBRT was 12.5 months (2-66.1 months). At analysis, 11 (22%) pts remain alive and free from disease progression. At 24 months, LC and OS were 83.6% (95% CI 71.1-96) and 66.7% (95% CI 53.3-80.1). Median OS after sSBRT was 29.3 months. Twenty one (42%) pts failed distantly at a median time of 11.4 months and 12 (24%) pts received systemic therapy following distant failure. 74% of pts experienced no toxicity after sSBRT and three patients (6%) developed grade III toxicity (cough, atelectasis or soft tissue necrosis).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Similar to SBRT for primary early stage NSCLC, sSBRT for local relapse following initial surgical resection of NSCLC offers high rates of LC with limited toxicity. Distant failure remains the primary pattern of failure.

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    OA06 - Early Stage Lung Cancer: Outcomes and Interventions (ID 902)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 202 BD
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      OA06.05 - Do SBRT Planning and Delivery Factors Influence Local Control for Early Stage Non-Small Cell Lung Cancer (e-NSCLC)?  (ID 12730)

      14:15 - 14:25  |  Author(s): Kevin L Stephans

      • Abstract
      • Presentation
      • Slides

      Background

      Stereotactic Body Radiation (SBRT) utilizes a variety of techniques to deliver very high-dose radiation to moving targets in the lung. We investigated the impact of dose-delivery factors on local failure (LF) by surveying our 12 year experience with e-NSCLC from our prospective database.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Curative SBRT was administered to 1,085 patients (pts) between 2005 and 2016 and planned with either pencil beam (PB) or collapsed cone convolution (CCC) dose calculation algorithms (DCA), using open (dynamic arcs) or modulated beams (IMRT or VMAT), immobilized by abdominal compression or automatic breathing control (ABC), and treated with/without available CBCT (aligned to external fiducials and KV x-rays to bone if no CBCT, PTV margins were not altered based on availability of CBCT). We limited our analysis to standard fractionation regimens, [60 Gy/3, 48 Gy/4, 50 Gy/5, & 30-34 Gy/1) chosen per the treating physician in a risk-adapted approach relative to tumor size and location. The intreaction of technical variables with known patient and tumor factors on LF was analyzed using Fine and Gray univariate regression, with significant predictors selected for a forward step-wise multivariate regression model.

      4c3880bb027f159e801041b1021e88e8 Result

      At mean follow-up time of 25.6 months the cumulative incidence of LF at 1, 2, & 5 years was 3.0, 8.3, and 9.8% respectively. Overall survival (1, 2, 5 years) was 83, 62, & 28%. Univariate correlates with LF were PB TPS (HR 2.87, p=0.0004), modulated beam (HR 2.3, p=0.005), lack of CBCT (HR 2.69, p=0.0004), SBRT dose relative to 60 Gy/3 (HR 5.2, p=0.0001 for 4-5 fx; HR 2.7, p=0.051 for 1 fx), tumor size (HR 1.2 per cm, p=0.0009), PET SUV (HR 1.04 per SUV, p=0.0039), and squamous histology (HR 1.8, p=0.0051). Immobilization with ABC (n=96) versus abdominal compression (n=989) did not correlate with LF (p=0.99). On multivariate analysis PET SUV, modulated beam, and use of CBCT were no longer significant correlates with LF, while TPS (HR 2.62, p=0.0019), SBRT dose (HR 4.1, p=0.0009 for 4-5 fx relative to 60 Gy/3) & HR 2.9, p=0.039 for 1 fx versus 60 Gy/3), tumor size (HR 1.2 per cm, p=0.042) and squamous histology (HR 1.7, p=0.027) remained statistically significant.

      8eea62084ca7e541d918e823422bd82e Conclusion

      While the use of PB versus CCC DCA was associated with higher rates of LF after SBRT, the use of abdominal compression vs ABC (univariate), open vs modulated beam, and CBCT vs bony alignment (multivariate) were not correlated with higher rates of LF after SBRT in e-NSCLC.

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    P1.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 948)

    • 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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      P1.16-24 - Impact of Tumor Location &amp; Dosimetric Predictors for Chest Wall Toxicity in Single Fraction SBRT for Stage I Non-Small Cell Lung Cancer (ID 11317)

      16:45 - 18:00  |  Author(s): Kevin L Stephans

      • Abstract
      • Slides

      Background

      Single fraction stereotactic body radiation therapy (SF-SBRT) is an acceptable regimen for treatment of peripheral Stage I Non-Small Cell Lung Cancer (NSCLC). Rates of chest wall toxicity (CWT) are not stratified by distance of tumor to chest wall (CW) and dosimetric parameters are not well defined. We sought to determine the relationship of tumor location and dosimetric parameters with CWT in SF-SBRT.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      An IRB-approved prospective SBRT registry of 1,462 patients (pts) was used to identify pts treated with 30 Gy or 34 Gy in one fraction. Tumors were ≤ 5 cm, node-negative, and ≥ 2 cm from the proximal tracheo-bronchial tree. The CW was retrospectively contoured (3 cm soft-tissue structure). Gross tumor volume was measured as abutting, ≤ 1 cm, 1-2 cm or > 2 cm from the CW. CWT was graded according to CTCAE 3.0 criteria. Rates of CWT were compared using unpaired t-test. Logistic regression analysis was used to identify tumor and dosimetric parameters associated with CWT.

      4c3880bb027f159e801041b1021e88e8 Result

      This study included 146 lesions treated with SF-SBRT. Median follow-up was 23.8 months. There were 80 pts (55%) treated with 30 Gy and 66 pts (45%) treated with 34 Gy. The rate of CWT was 30.6% for lesions abutting CW, 8.2% for ≤ 1 cm from CW, 3.8% for 1-2 cm from CW, and 5.7% for > 2 cm from CW. Grade ≥ 3 CWT was modest (1.4%). Tumor abutment (OR 6.5; p=0.0005), BMI (OR 1.1; p= 0.02), rib D1cc (OR 1.01 per Gy; p= 0.03), CW D1cc (OR= 1.08 per Gy; p=0.03), and CW D5cc (OR 1.10 per Gy; p= 0.01) were significant predictors for CWT on univariate analysis. Tumor abutment was the only significant predictor for CWT (OR 7.5; p= 0.007) on multivariate analysis. CWT occurred in only 1 out of 40 pts with CW D5cc < 18 Gy, while our model suggested a 15% risk of CWT with D5cc of 27.2 Gy to CW.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The rate of CWT is significantly associated with distance from the CW. When considering lesions adjacent to the CW, the rate of CWT in this series (30.6%) does not appear to exceed rates in the published fractionated SBRT literature (20-33%). Location adjacent to CW should not be a contraindication to SF-SBRT. CW D1cc and D5cc may be used as predictors of CWT rates. As most CWT is low-grade and self-limited, these dosimetric parameters should be utilized as a guideline, rather than an absolute constraint.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.16-27 - Using Rates of Clinical Brachial Plexopathy after Lung SBRT to Better Characterize the Tolerance of the Brachial Plexus (ID 12741)

      16:45 - 18:00  |  Author(s): Kevin L Stephans

      • Abstract
      • Slides

      Background

      Treatment of apical lung tumors with stereotactic body radiation therapy (SBRT) can be challenging due to proximity to the brachial plexus (BP). We retrospectively investigated outcomes after treatment of apical lung tumors to compare the rate of brachial plexopathy (BPX) with what would be estimated based on published protocol-derived BP constraints.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Apical lung tumors were defined in this analysis as those whose lung SBRT target had a planning-derived PTV edge <1cm from the anatomic BP. We surveyed an IRB-approved prospective registry of 1,462 patients treated with SBRT for the interval 2003-2017 and included all patients who received definitive or salvage SBRT using dose/fractionation schedules of 50 Gy/5 fx, 60 Gy/5 fx, or 48 Gy/4 fx. Salvage SBRT included patients with local recurrence after conventional fractionation radiotherapy. Per RTOG protocols, the subclavian vein (SCV) ipsilateral to target was contoured as the BP surrogate. In this study, the ipsilateral subclavian artery (SCA), and BP were also contoured to characterize dosimetric differences between structures. Statistical analysis involved repeated measures ANOVA.

      4c3880bb027f159e801041b1021e88e8 Result

      Sixty-four patients, which includes six patients (9.4%) receiving salvage SBRT, met inclusion criteria (median follow up of 21 months). No significant differences (p=0.77) were observed between maximum point doses to BP, SCV, and SCA. Within one year post-SBRT, two patients (3%) developed BPX (grade 2); both patients had exceeded 32 Gy to the BP and were treated with salvage SBRT. No patient treated with definitive SBRT (91%) developed BP, despite 17 of these exceeding recommended maximum doses.

      8eea62084ca7e541d918e823422bd82e Conclusion

      No BPX was observed for patients that exceeded a maximum dose of 32 Gy to the BP, unless they were treated as salvage SBRT. This suggests higher doses to the BP may be considered when clinically required for definitive SBRT. However, salvage SBRT may require more conservative BP constraints than used in the definitive setting.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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