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Andreas Rimner



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    MA 17 - Locally Advanced NSCLC (ID 671)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Locally Advanced NSCLC
    • Presentations: 1
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      MA 17.13 - Impact of Histologic Subtype of Locally Advanced Lung Adenocarcinoma on Outcomes After Definitive Chemoradiation (ID 10382)

      17:05 - 17:10  |  Author(s): Andreas Rimner

      • Abstract
      • Presentation
      • Slides

      Background:
      Micropapillary and solid subtypes of lung adenocarcinoma have significantly worse outcomes and survival after surgical resection for early-stage disease. These subtypes have recently been shown to have higher locoregional and metastatic progression after definitive stereotactic radiation therapy (SBRT) as well. However, the potential impact of histologic subtype on locally advanced disease treated with definitive concurrent or sequential chemoradiation (CRT) has not been previously explored. We sought to identify high-risk subtype patients treated with CRT, and compare their outcomes with those not known to have high-risk histologic subtypes.

      Method:
      We identified 249 consecutive patients with stage IIIA-B lung adenocarcinoma who had undergone CRT at our institution from 2008 to 2015. All patients had pathology reviewed by pathologists at our institution with subspecialty expertise in thoracic pathology. Twenty-five patients had elements of micropapillary and/or solid subtype on core biopsy, according to the 2015 World Health Organization classification. The remaining 224 patients were considered non-high-risk (8 patients had core biopsy with no high-risk subtypes identified; 216 patients either did not undergo core biopsy or did not have subtyping performed). Local, nodal, regional, and distant failure were estimated using cumulative incidence (CI) curves and compared using the log-rank test. Time to each event was measured from the date of diagnosis until the event of interest or the last follow-up visit.

      Result:
      With median followup of 19.7 months, there was a trend towards greater 2-year CI of local failure in the high-risk vs. non-high-risk group (40.7% vs. 26.7% p=0.060). The 2-year CI of nodal, regional, and distant failure in high-risk versus non-high-risk groups was 30.9% vs. 32.6% (p=0.576), 24.7% vs. 20.1% (p=0.468), and 63.9% vs. 59.8% (p=0.272), respectively, though statistical power was limited due to the small number of known high-risk patients.

      Conclusion:
      Though only a limited proportion of patients had demonstrated high-risk subtypes in this cohort, there was a trend towards earlier local failure in locally advanced adenocarcinoma patients treated with definitive concurrent or sequential chemoradiation, similar to what has been observed for early-stage tumors treated with SBRT. Hence, high-risk histologic subtype may be a prognostic factor for early treatment failure in locally advanced adenocarcinoma patients treated with CRT. We suggest that core biopsies, which are required for histologic subtyping, should be obtained more often in these patients, to allow for further study of the hypothesis that histologic subtype predicts outcomes after definitive chemoradiation.

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    MS 06 - Combined Modality Treatment for Thymic and Pleural Malignancy (ID 528)

    • Event: WCLC 2017
    • Type: Mini Symposium
    • Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      MS 06.05 - The Use of Adjuvant IMRT after Pleurectomy/Decortication (ID 7667)

      16:45 - 17:00  |  Presenting Author(s): Andreas Rimner

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Intensity-modulated radiation therapy (IMRT) is a highly conformal radiation technique that allows more effective sparing of normal tissues, providing an opportunity for safer, less toxic treatments and increased efficacy by enabling higher radiation doses to the tumor target. It comes with a much higher level of dosimetric control and certainty leading to better target coverage than conventional OR 3D conformal radiation techniques.[1] The higher precision of IMRT delivery when used in the adjuvant setting requires detailed knowledge of the intrathoracic anatomy, incorporation of all diagnostic imaging tools available, incorporation of the pathologic findings at the time of surgery, assessment of the respiratory tumor motion using a 4D scan, and image-guided treatment delivery. IMRT with integration of a boost to areas of gross disease is technically feasible but has not yet been tested in a larger series. The use of 18-fluorodeoxyglucose positron emission tomography (PET) for RT planning purposes may reduce the likelihood of geographic misses and detect radiographically occult lymph node involvement. Small series have suggested that PET may guide the delineation of an integrated boost volume or improve local control.[2] The recent decline in extrapleural pneumonectomies (EPP) in the surgical management of malignant pleural mesothelioma (MPM) due to reports suggesting a lack of survival benefit compared with lung-sparing pleurectomy/decortication (P/D) has posed a particular challenge for adjuvant radiation treatments: how to safely treat the pleural space for microscopic residual disease without exceeding the radiation tolerance of the underlying sensitive normal lung tissue. Older radiation techniques result in unacceptable toxicity and insufficient local control.[3] Thus, an IMRT technique targeting the hemithoracic pleural space including the diaphragm that simultaneously spared the ipsilateral lung, heart, liver, kidneys and abdominal contents was developed (Figure 1).[4] Typically these patients are treated 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.[5,6] The first report in 36 MPM patients with 2 intact lungs showed that hemithoracic adjuvant pleural IMRT (50.4 Gy in 28 fractions) could be delivered with a 20% (n=7) ≥ grade 3 pneumonitis risk; 1 patient had grade 5 pneumonitis.[4] 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).[6] The radiation dose delivered was slightly higher with 50 Gy delivered in 25 fractions including a simultaneous boost to 60 Gy for areas of concern for residual disease based on FDG-PET. A matched analysis of P/D, chemotherapy, and IMRT vs. EPP, chemotherapy and IMRT found favorable median overall (28.4 vs. 14.2 months) and progression-free survival (16.4 vs. 8.2 months) with trimodality therapy involving P/D compared with EPP.[7] Local failure rates vary significantly among studies, ranging from 40 to 68% at 2 years. A systematic review of 67 patients still found a significant risk of local failures in the radiation field, mostly in unresectable patients and sites of gross residual disease, emphasizing the importance of a macroscopic complete resection, need for optimization of radiation targeting and experience with this complex radiation technique.[8] Increasing experience over time led to fewer marginal failures and decreased toxicity, suggesting the improvement in target delineation and RT planning. Most recently an association of radiation dose to the heart and overall survival was reported,[9] similar to observations in locally-advanced non-small cell lung cancer. These encouraging results have led to a 2-institution phase II trial of trimodality therapy using induction chemotherapy with cisplatin and pemetrexed, P/D, and adjuvant hemithoracic intensity-modulated pleural radiation therapy (IMPRINT).[10] 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 59%. Based on these findings a multi-institutional phase II study was initiated to demonstrate the safety and exportability of this complex IMPRINT technique in a multicenter setting involving institutions without prior experience of IMPRINT (clinicaltrials.gov: NCT00715611). All patients’ treatment contours and plans are centrally reviewed and revised for uniformity. The goal is to accrue 36 patients from 5 institutions. Given the promising outcomes this study may be succeeded by a randomized trial testing the effect of adjuvant IMPRINT vs no additional treatment after lung-sparing P/D and chemotherapy. Figure 1: Figure 1 1. 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 2. Fodor A, Fiorino C, Dell'Oca I, et al: PET-guided dose escalation tomotherapy in malignant pleural mesothelioma. Strahlentherapie und Onkologie 187:736-743, 2011 3. Gupta V, Mychalczak B, Krug L, et al: Hemithoracic radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma. International Journal of Radiation Oncology Biology Physics 63:1045-1052, 2005 4. 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 5. 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 6. 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 7. Chance WW, Rice DC, Allen PK, et al: Hemithoracic intensity modulated radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma: toxicity, patterns of failure, and a matched survival analysis. Int J Radiat Oncol Biol Phys 91:149-56, 2015 8. 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 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 10. 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



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    OA 10 - Liquid Biopsy for Genomic Alterations (ID 678)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA 10.03 - Liquid Biopsy in the Lung Cancer Clinic: A Prospective Study of Plasma DNA next Generation Sequencing to Guide Matched Therapy (ID 8218)

      11:20 - 11:30  |  Author(s): Andreas Rimner

      • Abstract
      • Presentation
      • Slides

      Background:
      Liquid biopsy for plasma circulating tumor DNA (ctDNA) next generation sequencing (NGS) is now commercially available and increasingly adopted in clinical practice with a paucity of evidence based guidance. We set out to prospectively determine the utility of plasma ctDNA NGS in the lung cancer clinic.

      Method:
      Patients (pts) with advanced NSCLC who were driver unknown or resistance mechanism unknown were eligible. Pts were enrolled prospectively at Memorial Sloan Kettering (NY, USA) and Northern Cancer Institute (Sydney, Australia). Peripheral blood was collected in Streck tubes (10-20mL) and sent to Resolution Bioscience (Bellevue, WA) for targeted NGS of extracted DNA using a bias corrected hybrid capture 21 gene assay in a CLIA laboratory with unique reads at 3000x and sensitive detection at variant allele frequency above 0.1%. Clinical endpoints included detection of oncogenic drivers, turnaround time, comparison to tissue NGS when available, and ability to match pts to targeted therapy along with their treatment outcomes.

      Result:
      Seventy-six pts were prospectively accrued. Plasma NGS detected an oncogenic driver in 36% (27/76) of pts, of whom 14% (11/76) were matched to targeted therapy; including pts matched to clinical trials for HER2 exon 20 insYVMA, BRAF L597Q and MET exon14. Of the 10 evaluable pts, 10 partial responses were observed. Mean turnaround time for plasma was 6 days (3-12) vs 21 days (16-30) for tissue (P <0.0001). Plasma ctDNA was detected in 60% (46/76) of pts; detection rate was 46% (16/35) if blood was drawn on active therapy and 73% (30/41) if drawn off therapy, either at diagnosis or progression (Odds ratio 0.31, 95% CI 0.12 – 0.81; P=0.02). Of the 25 concurrent tissue NGS performed to date, there was a 96% plasma concordance with tissue and a 60% tissue concordance with plasma for driver mutations.

      Conclusion:
      In pts who were driver or resistance mechanism unknown, plasma NGS identified a variety of oncogenic drivers with significantly shorter turnaround time compared to tissue NGS, and matched patients onto targeted therapy with clinical benefit. Plasma ctDNA is best detected at diagnosis of metastatic disease or at progression. 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 evidence to support the incorporation of plasma NGS into practice guidelines.

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    P3.15 - SCLC/Neuroendocrine Tumors (ID 731)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      P3.15-011 - Contemporary Treatment and Prognosis of Non-Metastatic Atypical Bronchopulmonary Carcinoid Tumors (ID 10424)

      09:30 - 09:30  |  Author(s): Andreas Rimner

      • Abstract

      Background:
      Despite rising incidence, there remains limited data guiding the prognostication and treatment of patients with bronchopulmonary carcinoid tumors, particularly atypical carcinoids. We report outcomes of a large, modern, single-institutional series of patients treated for localized or locally advanced atypical carcinoid of the lung.

      Method:
      We retrospectively analyzed the demographic, histologic and treatment histories of 69 patients (74% female) with median age of 65 at diagnosis (range 31-83) who were treated between 2004-2016. The Kaplan-Meier method was used for overall survival (OS) estimates and compared by log-rank. Cox proportional hazards models were used for univariate (UVA) and multivariate analyses (MVA).

      Result:
      Median follow-up time was 33.6 months. The majority (96%) of patients underwent surgical resection (86% R0, 9% R1, 3% R2) with common approaches being lobectomy (59%), wedge resection (13%) and pneumonectomy (9%). Three patients (4%) received definitive radiotherapy as their local treatment. Nearly half (49%) of patients had nodal involvement with a stage distribution of 39% stage I, 25% stage II and 36% stage III. Twenty-one patients received chemotherapy as part of their initial treatment, 81% of whom had stage III disease. Sixteen patients received radiotherapy (median 50.4 Gy, range 18-66 Gy) as part of their initial treatment, most of whom received postoperative radiation for N2 disease (63%). Five patients (31%) received postoperative radiotherapy due to concern of incompletely resected disease. Higher stage was significantly associated with poorer OS (p=0.04). 3-year OS for Stage I, II and III disease was 96%, 88% and 72%, respectively. Stage I disease also had a significantly lower risk of distant metastasis compared to Stage II/III disease (17% vs. 31% at 3 years p=0.04). On UVA, Stage III disease was significantly associated with poorer OS (HR 4.7, p=0.021) and risk of distant failure (HR 2.8, p=0.039). Multivariate modeling showed that older age (HR 1.05, p=0.03) and stage III status (HR 6.6, p=0.009) were predictive of poorer OS. For stage III patients treated surgically, receipt of adjuvant therapy (chemotherapy and/or radiotherapy) was not significantly associated with OS (p=0.36) or distant failure (p=0.69).

      Conclusion:
      This is one of the largest reported series of atypical pulmonary carcinoid patients treated with curative intent. We observed generally favorable prognosis in this cohort that was primarily treated with surgery. We did not observe a significant impact of adjuvant therapy on outcomes, but small patient numbers limit our ability to quantify their potential effect.