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Andreas Rimner
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IBS26 - Treatment Techniques for Localized Therapy in Malignant Pleural Mesothelioma (Ticketed Session) (ID 57)
- Event: WCLC 2019
- Type: Interactive Breakfast Session
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/10/2019, 07:00 - 08:00, Colorado Springs (1994)
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IBS26.01 - Treatment Planning for Pleural Imrt (Imprint) (Now Available) (ID 3395)
07:00 - 08:00 | Presenting Author(s): Andreas Rimner
- Abstract
- Presentation
Abstract
We have developed an Intensity-modulated pleural radiation therapy (IMPRINT) technique targeting the entire hemithoracic pleural space including the diaphragm that simultaneously spares the ipsilateral lung, heart, liver, kidneys and abdominal contents was developed.1 It provides an opportunity for safer, less toxic treatments and increased efficacy by enabling higher radiation doses to the tumor target due to a much higher level of dosimetric control and certainty leading to better target coverage than conventional radiation techniques.2 IMPRINT became technically necessary to deliver adjuvant radiation due to the increased use of lung-sparing surgical techniques such as pleurectomy/decortication (P/D) for malignant pleural mesothelioma. Here we describe the contouring and treatment planning aspects for IMPRINT and potential pitfalls.
Since developing this technique the clinical delivery of IMPRINT has been shown to be safe and feasible. Our first report in 36 MPM patients with 2 intact lungs showed that hemithoracic adjuvant IMPRINT (50.4 Gy in 28 fractions) could be delivered with a 20% (n=7) ≥ grade 3 pneumonitis risk; 1 patient had grade 5 pneumonitis.1 The median survival in resectable patients was 26 months. A tomotherapy technique was published with similar toxicity outcomes (20% ≥ grade 2 pneumonitis, one fatal case of pneumonitis).3 These encouraging results have led to a 2-institution phase II trial of trimodality therapy using induction chemotherapy with cisplatin and pemetrexed, lung-sparing P/D, and adjuvant hemithoracic IMPRINT.4 Twenty-seven patients were treated and 29.6% developed radiation pneumonitis (6 grade 2; 2 grade 3). Median progression-free and overall survival was 12.4 and 23.7 months, respectively. In resectable MPM patients who received chemotherapy and IMPRINT, 2-year OS was very promising at 59%. A review of the outcomes of trimodality therapy including IMPRINT demonstrated a median OS of 20 months from the start of RT.5
Based on these findings a multi-institutional phase II study is ongoing to demonstrate the safety and exportability of IMPRINT to 5 institutions (clinicaltrials.gov: NCT00715611). All patients’ treatment contours and plans are centrally reviewed and revised for uniformity. This will be followed by NRG LU-006, a randomized phase III study of P/D, chemotherapy +/- adjuvant IMPRINT which is planned to open in the fall of 2019.
Target delineation of the entire pleural space is a challenging task. The higher precision of IMRT delivery requires detailed knowledge of the intrathoracic anatomy, incorporation of all diagnostic imaging tools available, pathologic findings at the time of surgery, assessment of the respiratory tumor motion using a 4D scan, and image-guided treatment delivery. A systematic review of failure patterns in 67 patients identified areas at significant risk for local failures emphasizing the need for optimization of radiation targeting and experience with this complex radiation technique.6 Increasing experience over time led to fewer marginal failures and decreased toxicity, suggesting the improvement in target delineation and RT planning. Emergence of multiple pleural nodules and pleural thickening were identified as the most common features of local recurrences.7 We have developed a contouring atlas for target delineation for IMPRINT that will be presented.
Treatment planning is similarly complex and requires significant experience. Typically fixed-beam angle IMRT is delivered with six to nine coplanar 6 MV beams equispaced over 200-240 degrees around the ipsilateral hemithorax were used. More recently, rotational techniques such as volumetric arc therapy or tomotherapy have been shown to allow for even more effective sparing of organs at risk.3,8 Strict normal tissue constraints need to be applied to avoid serious toxicities, foremost radiation pneumonitis. Most recently we identified an association of radiation dose to the heart and overall survival that has led to incorporation of new dosimetric planning constraints.9 Details about dosimetric constraints will be presented.
1. Rosenzweig KE, Zauderer MG, Laser B, et al: Pleural intensity-modulated radiotherapy for malignant pleural mesothelioma. International Journal of Radiation Oncology Biology Physics 83:1278-1283, 2012
2. Krayenbuehl J, Dimmerling P, Ciernik IF, et al: Clinical outcome of postoperative highly conformal versus 3D conformal radiotherapy in patients with malignant pleural mesothelioma. Radiat Oncol 9:32, 2014
3. Minatel E, Trovo M, Bearz A, et al: Radical Radiation Therapy After Lung-Sparing Surgery for Malignant Pleural Mesothelioma: Survival, Pattern of Failure, and Prognostic Factors. Int J Radiat Oncol Biol Phys 93:606-13, 2015
4. Rimner A, Zauderer MG, Gomez DR, et al: Phase II Study of Hemithoracic Intensity-Modulated Pleural Radiation Therapy (IMPRINT) As Part of Lung-Sparing Multimodality Therapy in Patients With Malignant Pleural Mesothelioma. J Clin Oncol 34:2761-8, 2016
5. Shaikh F, Zauderer MG, von Reibnitz D, et al: Improved Outcomes with Modern Lung-Sparing Trimodality Therapy in Patients with Malignant Pleural Mesothelioma. J Thorac Oncol 12:993-1000, 2017
6. Rimner A, Spratt DE, Zauderer MG, et al: Failure patterns after hemithoracic pleural intensity modulated radiation therapy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 90:394-401, 2014
7. Halpenny D, Raj M, Rimner A, et al: Computed tomography features of local pleural recurrence in patients with malignant pleural mesothelioma treated with intensity-modulated pleural radiation therapy. Eur Radiol, 2019
8. Dumane V, Rimner A, Yorke ED, et al: Volumetric-modulated arc therapy for malignant pleural mesothelioma after pleurectomy/decortication. Applied Radiation Oncology 5:24-33, 2016
9. Yorke ED, Jackson A, Kuo LC, et al: Heart Dosimetry is Correlated with Risk of Radiation Pneumonitis after Lung-Sparing Hemithoracic Pleural IMRT for Malignant Pleural Mesothelioma. Int J Radiat Oncol Biol Phys, 2017
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MA02 - Miscellaneous Topics in the Management of Early Stage Lung Cancer (ID 116)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Now Available
- Moderators:Mireia Serra-Mitjans, Thomas A. D'Amico
- Coordinates: 9/08/2019, 10:30 - 12:00, Interlaken (1988)
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MA02.06 - Dose-Volume Factors Predicting Airway Stenosis After SBRT for Ultra-Central Lung Tumors (Now Available) (ID 1454)
10:30 - 12:00 | Author(s): Andreas Rimner
- Abstract
- Presentation
Background
The safety of SBRT is uncertain for ultra-central tumors (near the proximal airways or esophagus). One potential toxic effect of ultra-central SBRT is stenosis of the proximal airways, which can lead to airway obstruction and lung collapse. Predictors of such toxicity in this population are urgently needed. We therefore studied dose-volume correlates of airway stenosis after ultra-central SBRT.
Method
88 patients with tumors abutting the proximal bronchial tree (PBT) or PTVs overlapping esophagus (n = 76 and 23; 11 met both criteria) were included. 53 (60%) had primary/locally recurrent lung cancer, and 35 had lung metastases. All had 5, 8 or 15 fractions of image-guided radiotherapy with BED ≥84Gy (α/β=10). The lobar bronchi (LB) were contoured from the takeoff from the main bronchus to the bifurcation into segmental bronchi. The primary endpoint was grade 2 or higher lobar bronchial stenosis (LBS), defined as radiographic evidence of narrowing or complete obstruction of at least one lobar bronchus (CTCAE v4). Dose-volume histograms (DVHs) using linear-quadratic equivalent doses in 2 Gy fractions were calculated for the LB with α/β = 3 Gy. Mean equivalent doses (MEDs) to the LB were tested for correlation with LBS using a Cox proportional hazards model, and the log rank test with patient data split at the median value of the MEDs to the LB. Statistical significance was defined as p < 0.05.
Result
Median follow up was 14.3 months. There were 24 cases of LBS (27%). Median time to onset of LBS2+ was 8.6 months after end of treatment (range 2-19 months). LBS was significantly correlated with MED to the LB (p = 0.02). Incidence of LBS was significantly different in patients with MED to the LB < or > the median value of 35.4 Gy (p = 0.004 log-rank test), with actuarial rates of 19% and 55% respectively at 14 months, and 19% and 70% respectively at 24 months; and with raw rates of 15.9% and 38.6% respectively.
Conclusion
We observed a high rate of lobar stenosis after ultra-central SBRT. Incidence of lobar stenosis was significantly correlated with dose to the lobar bronchi. In particular, mean equivalent dose to the lobar bronchi was significantly correlated with LBS. Our analysis suggests that limiting the mean equivalent dose to the lobar bronchi to < 35.4 Gy results in a two year actuarial incidence of LBS of <19%, and a raw incidence <16%.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-122 - A Clinical Utility Study of Plasma DNA Next Generation Sequencing Guided Treatment of Uncommon Drivers in Advanced Non-Small-Cell Lung Cancers (ID 2997)
09:45 - 18:00 | Author(s): Andreas Rimner
- Abstract
Background
Although EGFR and ALK testing in non-small-cell lung cancers (NSCLC) is now considered standard practice, next generation sequencing (NGS) for extended molecular testing of uncommon drivers is often difficult to perform in the community due to factors surrounding tissue adequacy, availability and turnaround time. We set out to prospectively determine the clinical utility of plasma ctDNA NGS in detecting uncommon actionable drivers and their plasma guided treatment response.
Method
Patients with advanced NSCLC who were driver unknown after routine EGFR and ALK testing were eligible. Patients were enrolled prospectively at Memorial Sloan Kettering Cancer Center (NY, USA) and Northern Cancer Institute (Sydney, Australia). Peripheral blood (10-20mL) was collected and sent to Resolution Bioscience (Kirkland, WA) for targeted ctDNA NGS using a bias-corrected hybrid-capture 21 gene assay in a CLIA laboratory achieving a mean unique read of at least 3000x and sensitivity above 0.1%. Clinical endpoints included detection of uncommon oncogenic drivers defined as actionable alterations in ROS1, RET, BRAF, MET, HER2, turnaround time, concordance with tissue NGS when available, and plasma guided treatment outcome.
Result
614 patients were prospectively accrued. Plasma NGS detected an uncommon oncogenic driver in 7% (45/614) of patients including ROS1, RET fusions, BRAF, MET exon 14 and HER2 exon 20 mutations, of whom 3% (20/614) were matched to targeted therapy producing 12 partial responses. Mean turnaround time for plasma NGS was significantly shorter than tissue NGS (10 vs 25 days, P <0.0001). 399 patients had concurrent tissue NGS results available for concordance analysis; Overall concordance, defined as the proportion of patients for whom an uncommon driver was uniformly detected or absent in both plasma and tissue NGS, was 94.7% (378/399, 95% confidence interval [CI] 92.1 – 96.7%). Among patients who tested plasma NGS positive for uncommon drivers, 87.5% (28/32, 95% CI 71.0-96.5%) were concordant on tissue NGS, and among patients tested tissue NGS positive for uncommon driver, 62.2% (28/45, 95% CI 46.5-76.2%) were concordant on plasma NGS.
Conclusion
Plasma NGS uncovered uncommon oncogenic drivers with faster turnaround time than tissue NGS, directly matched patients to targeted therapy and produced clinical responses independent of tissue results. A positive finding of an oncogenic driver in plasma is highly specific and can immediately guide treatment, but a negative finding may still require tissue biopsy. Our findings provide prospective evidence to support a “blood first” approach in molecular diagnostics for the care of patients with NSCLC.
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P2.17 - Treatment of Early Stage/Localized Disease (ID 189)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.17-32 - Using Next-Generation Sequencing to Identify Genetic Predictors of Local Failure After Lung Stereotactic Body Radiation Therapy (Now Available) (ID 2708)
10:15 - 18:15 | Author(s): Andreas Rimner
- Abstract
Background
Lung stereotactic body radiation therapy (SBRT) is a well-established therapy for primary lung tumors or metastatic lung lesions from other primary sites. However, local failure after SBRT still occurs. We hypothesized that next-generation tumor sequencing may identify genetic characteristics that predict local failure.
Method
We conducted a retrospective analysis of all patients at our institution who received SBRT to the lung for either primary or metastatic tumors, and who underwent next-generation tumor sequencing utilizing an FDA-approved targeted panel of at least 341 genes. Patient and tumor characteristics, local failure, radiation dose, and all genetic alterations identified by the panel were collected. Univariate Cox proportional hazards analysis was performed. Because of the large number of genes in the panel, we limited analysis to genes with at least a 5% incidence of alteration in this cohort. To correct for multiple testing, we used a p-value of ≤ 0.001 as the significance threshold for genetic alterations.
Result
Between 2013 and 2018, 140 patients with 160 lung lesions (76 primary lung, 84 non-lung primary) were treated with SBRT to a median radiation biologically effective dose of 100 Gy (range 48-151 Gy). Median follow-up for local failure was 13.8 months. There were 39 local failures (24.4%) during the study period. On univariate analysis, colorectal histology (HR 2.2, p=0.037), BED<100 Gy (HR 2.1, p=0.019), and larger lesion size (HR 1.2, p=0.023) were associated with higher risk of local failure. 45 mutations occurred with greater than 5% frequency (≥8 times) in our cohort. Univariate analysis identified three genes for which alterations were significantly associated with local failure: APC (mutated 17 times, HR 3.5, p<0.001), ARID2 (n=8, HR 5.5, p<0.0005), and MGA (n=8, HR 5.2, p<0.001)
Conclusion
Next-generation tumor sequencing was able to identify genetic alterations associated with higher risk of local failure after lung SBRT. This hypothesis-generating study yielded three candidate genes significantly correlated with local failure. Further study is needed to validate the predictive value of these gene mutations, and their potential for selecting patients at higher risk for treatment failure after lung SBRT.
